On February 3, 2023 Sanofi reported its quarterly 2022 report (Press release, Sanofi, FEB 3, 2023, View Source [SID1234626830]).

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Q4 2022 sales growth of 2.6% at CER and business EPS(1) growth of 17.4% at CER
•Specialty Care grew 18.1% driven by Dupixent (€2,402 million, +42.1%) and new product launches
•Vaccines sales (-16.3%) reflecting influenza and PPH sales phasing (Q3 influenza sales: up 32.4%) as well as ramp up of non-consolidated Vaxelis sales
•General Medicines core assets up 8.0% while GBU sales were lower (-3.7%) mainly due to Lantus and spin-off of EUROAPI
•CHC sales increased 6.6% driven by double-digit growth of Digestive Wellness, Cough & Cold and Allergy categories
Full-year 2022 delivered 7.0% sales growth and 17.1% business EPS growth at CER
•Sales grew to €42,997 million driven by Dupixent (€8,293 million, +43.8%), adding €3 billion of incremental sales, Vaccines up 6.3% in line with the mid-term growth objective as well as CHC strategy execution (+8.6%)
•Mid-term BOI margin target of 30% and cost savings objective of €2.5 billion achieved
•Business EPS(1) of €8.26 up 25.9% on a reported basis and 17.1% at CER
•IFRS EPS of €5.37 (up 8.0%)
•Board held on February 2, proposes annual dividend of €3.56, an increase of 6.9%
Progress on Corporate Social Responsibility strategy in Q4
•Positive phase 2/3 results of acoziborole with the potential to further transform the treatment of sleeping sickness
•Accelerating our ambition towards net zero emissions by 5 years, now targeting 2045
Key R&D milestones and regulatory achievements in Q4
•Dupixent approved in Europe for prurigo nodularis and CHMP positive opinion for eosinophilic esophagitis
•Beyfortus (nirsevimab) approved in Europe for the prevention of RSV disease in all infants
•VidPrevtyn Beta approved in Europe as a booster for the prevention of COVID-19 in adults
•Enjaymo approved in Europe in adult patients with cold agglutinin disease (CAD)
Full-year 2023 business EPS guidance
•Sanofi expects 2023 business EPS(1) to grow low single digit(2) at CER, barring unforeseen major adverse events. Applying average January 2023 exchange rates, the currency impact on 2023 business EPS is estimated between -3.5% to -4.5%
Sanofi Chief Executive Officer, Paul Hudson, commented:
"We closed 2022, marking the successful execution of the first chapter of our 6-year ‘Play to Win’ strategy. Specialty Care delivered the highest sales among our businesses. Dupixent and Vaccines continue to be our leading growth drivers. We are particularly proud of the progress we made in R&D transformation with multiple approvals of transformative medicines and new product launches across Specialty Care. At the same time, we keep delivering strong proof points of our improved financial performance underpinned by the achievement of the 30% BOI margin. Moving to the next chapter of our strategy, we are looking forward to the planned launches of Altuviiio and Beyfortus as well as key pivotal readouts, including the COPD indication for Dupixent. With the view on the expected entrants of generic competition for Aubagio in the coming months, we remain confident in our outstanding commercial capabilities, including the ambition to reach sales of 10 billion euros for Dupixent in 2023, enabling us to guide to low single-digit EPS growth for the year."
Q4 2022 Change Change
at CER 2022 Change Change
at CER
IFRS net sales reported €10,725m +7.3% +2.6% €42,997m +13.9% +7.0%
IFRS net income reported €1,460m +29.1% _ €6,720m +8.0% —
IFRS EPS reported €1.16 +28.9% _ €5.37 +8.0% —
Free cash flow(3)
€2,546m +0.2% _ €8,483m +4.8% —
Business operating income €2,724m +20.7% +15.0% €13,040m +21.7% +13.3%
Business net income(1)
€2,141m +23.8% +17.6% €10,341m +25.9% +17.0%
Business EPS(1)
€1.71 +23.9% +17.4% €8.26 +25.9% +17.1%

Changes in net sales are expressed at constant exchange rates (CER) unless otherwise indicated (definition in Appendix 9). (1) In order to facilitate an understanding of operational performance, Sanofi comments on the business net income statement. Business net income is a non-GAAP financial measure (definition in Appendix 9). The consolidated income statement for Q4 2022 is provided in Appendix 3 and a reconciliation of reported IFRS net income to business net income is set forth in Appendix 4; (2) 2022 business EPS was €8.26; (3) Free cash flow is a non-GAAP financial measure (definition in Appendix 9).

2022 fourth-quarter and full-year Sanofi sales
—————————-
Unless otherwise indicated, all percentage changes in sales in this press release are stated at CER1
———————
In the fourth quarter of 2022, Sanofi sales were €10,725 million, up 7.3% on a reported basis. Exchange rate movements had a positive effect of 4.7 percentage points, mainly due to the U.S. dollar. At CER, company sales were up 2.6%.
In 2022, Sanofi sales reached €42,997 million, up 13.9% on a reported basis. Exchange rate movements had a positive effect of 6.9 percentage points. At CER, company sales were up 7.0%.

Global Business Units
Fourth-quarter 2022 net sales by Global Business Unit (variation at CER; € million; % of total sales)
chart-8f98b6910d09426f888.jpg
Fourth-quarter 2022 net sales by geographic region (variation at CER; € million; % of total sales)
chart-77caa408d3724fb9a48.jpg
Fourth-quarter 2022 operating income
Fourth-quarter business operating income (BOI) increased 20.7% to €2,724 million. At CER, BOI increased 15.0%. The ratio of BOI to net sales increased 2.8 percentage point to 25.4% (25.3% at CER). In 2022, BOI increased 21.7% to €13,040 million. At CER, BOI increased 13.3%. The ratio of business operating income to net sales increased 1.9 percentage point to 30.3% (30.0% at CER).
1 See Appendix 9 for definitions of financial indicators.

Pharmaceuticals
Fourth-quarter Pharmaceutical sales increased 7.3% to €7,793 million, mainly driven by the Specialty Care portfolio (up 18.1%) with continued strong performance of Dupixent while sales in General Medicines decreased 3.7%. In 2022, Pharmaceuticals sales increased 6.9% to €30,688 million reflecting the strong performance of Specialty Care and General Medicines core assets.
Specialty Care
Dupixent
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Total Dupixent
2,402 +42.1 % 8,293 +43.8 %

In the fourth quarter, Dupixent (collaboration with Regeneron) sales increased 42.1% to €2,402 million. In the U.S., Dupixent sales of €1,890 million (up 43.8%) were driven by continued strong demand in the approved indications, atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP) and the strong launches of AD in children as young as 6 months as well as eosinophilic esophagitis and prurigo nodularis. Dupixent total prescriptions (TRx) increased 34% (year-over-year) and new-to-brand prescriptions (NBRx) grew 48%. In Europe, fourth-quarter Dupixent sales grew 33.2% to €249 million reflecting continued growth in AD, asthma and CRSwNP. In the Rest of the World region, fourth-quarter sales reached €263 million, up 40.1%, driven mainly by sales in Japan and China. Full-year 2022 Dupixent sales reached €8,293 million, up 43.8%.
Neurology and Immunology
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Aubagio
493 -4.6 % 2,031 -4.3 %
Lemtrada
17 -15.8 % 80 -8.5 %
Kevzara
79 -17.6 % 339 +11.8 %
Total Neurology and Immunology
589 -7.0 % 2,450 -2.5 %

Fourth-quarter and full-year 2022 Neurology and Immunology sales decreased 7.0% (to €589 million) and 2.5%, respectively, mainly due to lower Aubagio sales.
Aubagio sales decreased 4.6% in the fourth quarter to €493 million mainly due to lower sales in the Rest of the World region as a result of generic competition in Canada. In the U.S., generics of teriflunomide could enter the market on March 12, 2023, as settled with generic makers in 2017. In Europe, teriflunomide generic competition is expected in the fourth quarter of 2023.
Fourth-quarter Kevzara (collaboration with Regeneron) sales decreased 17.6% to €79 million due to lower sales in Europe and the Rest of the World region. This is due to a high base in the fourth quarter of 2021 which benefitted from a temporary increased global demand for IL-6 receptor blockers.
Rare Disease
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Myozyme / Lumizyme
216 -17.7 % 958 -8.8 %
Fabrazyme
240 +3.6 % 938 +5.2 %
Cerezyme
159 -8.3 % 707 +2.6 %
Cerdelga
71 +1.5 % 288 +6.7 %
Aldurazyme
65 +1.6 % 267 +6.6 %
Nexviazyme/Nexviadyme
65 +306.7 % 196
–
Others Rare Disease 34 +126.7 % 91 +11.0 %
Total Rare Disease 850 +1.8 % 3,445 +5.7 %

In the fourth quarter, Rare Disease sales increased 1.8% to €850 million driven by the launch of XenpozymeTM. Full-year 2022 Rare Disease sales increased 5.7% reflecting growth across all three geographic regions and across all franchises.
Fourth-quarter sales of the Pompe franchise increased 0.4% to €281 million driven by the ramp up of Nexviazyme/Nexviadyme in the U.S., Europe and Japan. Sales of Nexviazyme/Nexviadyme were

€65 million in the fourth quarter (of which €49 million in the U.S.). Myozyme/Lumizyme sales decreased 17.7% to €216 million as a result of the conversion to Nexviazyme in the eligible Pompe population (late-onset disease).
Sales of the Gaucher franchise decreased 5.6% (to €230 million) in the fourth quarter. Cerezyme sales were down 8.3% to €159 million, mainly reflecting lower sales in the Rest of the World region due to unfavorable shipping patterns. Cerdelga sales were up 1.5% driven by new patients and Cerezyme switch.
Fourth-quarter Fabrazyme sales increased 3.6% to €240 million, reflecting growth in the U.S. and the Rest of the World region.
XenpozymeTM (olipudase alfa) was launched in the U.S., some European countries and Japan in 2022 as the first and only enzyme replacement therapy for the treatment of non-Central Nervous System (CNS) manifestations of Acid Sphingomyelinase. Fourth-quarter and full-year 2022 sales were €17 million and €21 million, respectively.
Oncology
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Jevtana
87 -24.5 % 391 -20.0 %
Sarclisa
86 +55.6 % 294 +60.2 %
Fasturtec
47 +7.3 % 177 +8.6 %
Libtayo
— -100.0 % 88 -34.1 %
Total Oncology 221 -11.7 % 952 -1.5 %

Fourth-quarter Oncology sales decreased 11.7% (to €221 million) reflecting the end of consolidation of Libatyo sales from the beginning of July. Excluding Libtayo, Oncology sales were up 3.4% with Sarclisa being the main driver. Full-year 2022 Oncology sales decreased 1.5% and increased 3.8% when excluding Libtayo sales in both years.
Sanofi stopped consolidating Libtayo non-U.S. sales from the third quarter of 2022 following the restructuring of its immuno-oncology collaboration with Regeneron Pharmaceuticals, Inc. Under the amended and restated license and collaboration agreement, Regeneron has obtained worldwide exclusive license rights to Libtayo. Prior, the companies had split equally Libtayo’s worldwide operating profits and co-commercialized Libtayo in the U.S., with Sanofi solely responsible for commercialization in the rest of the world.
Fourth-quarter Sarclisa sales were €86 million, up 55.6% primarily driven by performance in the U.S. Europe and Japan.
Fourth-quarter Jevtana sales decreased 24.5% to €87 million due to the entry of generic competition in Europe at the end of March 2021 and lower sales in the U.S., reflecting increased competition. In the U.S., Jevtana is currently covered by four Orange Book listed patents US 7,241,907, US 8,927,592, US 10,583,110 and US 10,716,777. Sanofi filed patent infringement suits under Hatch-Waxman against generic filers asserting the ‘110 patent, the ‘777 patent and the ‘592 patent in the US District Court for the District of Delaware. Sanofi has reached settlement agreements with most of the defendants and the suit against the only remaining defendant Sandoz is ongoing. In August 2022, the district court dismissed Sanofi’s infringement claim related to the ‘592 patent. A 3-day trial took place on January 11-13 2023 and Sandoz has agreed not to launch any generic cabazitaxel product until the earlier of a district court decision in favor of Sandoz or four months after the completion of the post-trial briefing.

Rare Blood Disorders
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Eloctate
138 -9.2 % 580 -5.9 %
Alprolix
141 +14.2 % 504 +10.4 %
Cablivi
62 +52.6 % 211 +20.7 %
EnjaymoTM
11
–
22
–
Total Rare Blood Disorders 352 +11.3 % 1,317 +5.6 %

Fourth quarter and full-year 2022 Rare Blood Disorders franchise sales increased 11.3% (to €352 million) and 5.6% respectively, driven by Alprolix, Cablivi and the launch of Enjaymo, more than offsetting lower Eloctate sales.

Eloctate sales were €138 million in the fourth quarter, down 9.2% reflecting lower sales in the U.S. due to competitive pressure.
Fourth-quarter Alprolix sales were up 14.2% to €141 million driven by the Rest of the World region which includes sales to Sobi.
Cablivi sales increased by 52.6% to €62 million in the fourth quarter supported by the performance in the U.S.
Fourth-quarter and full-year sales of Enjaymo, the first approved treatment for patients with cold agglutinin disease were €11 million and €22 million, respectively (launched in the U.S. and Japan in 2022 and approved in Europe in November 2022).
General Medicines
Fourth-quarter General Medicines sales decreased 3.7% to €3,379 million. The deconsolidation of EUROAPI2 third party sales had a negative impact of -3.6 percentage point (ppt) and divestments of non-core assets -0.7 ppt. Fourth-quarter Industrial sales were €177 million, down 22.7% and reflected deconsolidation of EUROAPI third party sales from May 10.
Full-year 2022 General Medicines sales decreased 4.2% to €14,231 million. The deconsolidation of EUROAPI third party sales had a negative impact of -2.4ppt and divestments of non-core assets -0.8ppt in 2022. In 2022, Industrial sales were €620 million, down 26.2% and reflected deconsolidation of EUROAPI third party sales. In 2022, core assets3 sales accounted for 47% of General Medicines sales compared with 43% in 2021 (excluding Industrial sales).
Core assets
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Lovenox*
289 -13.1 % 1,310 -13.8 %
Toujeo
272 +13.9 % 1,117 +9.8 %
Plavix
245 +11.7 % 983 +2.5 %
Praluent
96 +70.9 % 376 +65.1 %
Thymoglobulin
118 +26.4 % 446 +16.9 %
Multaq
104 -6.1 % 383 +4.3 %
Mozobil
69 +3.2 % 261 +4.3 %
Soliqua
55 -5.6 % 215 +1.5 %
Rezurock
63 +180.0 % 207
–
Others 287 +3.4 % 1,091 -0.2 %
Total core assets 1,598 +8.0 % 6,389 +5.2 %

*Excluding Auto generics
In the fourth quarter and full-year 2022, core assets3 sales increased 8.0% (to €1,598 million) and 5.2%, respectively, mainly driven by growth of Praluent, Toujeo, Thymoglobulin and as well as the strong performance of Rezurock, partially offset by lower sales of Lovenox.
Fourth-quarter Lovenox sales decreased 13.1% to €289 million, reflecting lower COVID-19 related demand compared to 2021, leading to a decrease of the Low Weight Molecular Heparins market. At the same time biosimilar competition increased.
Fourth-quarter Toujeo sales increased 13.9% to €272 million, due to strong growth in the Rest of the World region primarily driven by China reflecting increasing demand and a favorable basis for comparison. In Q4 2021, sales in China were impacted by price and inventory adjustment in anticipation of the Volume Based Procurement (VBP) for insulins. Sales in the U.S. were down 7.5% reflecting lower average price in the fourth quarter which more than offset volume growth.
Plavix sales were up 11.7% in the fourth quarter at €245 million, reflecting consistent volume growth in China (sales up 21.6% to €108 million) which largely offset lower sales in Europe and also Japan where the product was impacted by a mandatory price cut at the beginning of April.
Praluent fourth-quarter sales were €96 million, up 70.9%, driven by performance in Europe and an accelerated ramp-up in China due to the inclusion in the National Reimbursement Drug List (NRDL) effective January 2022.
2 EUROAPI third party sales were deconsolidated from May 10
3 Sanofi has prioritized core assets in its General Medicines portfolio with differentiated and/or established profiles that have significant opportunity for growth in key markets.

Multaq fourth-quarter sales decreased 6.1% to €104 million, reflecting a negative price effect in the U.S. despite higher volume.
Fourth-quarter Soliqua sales were €55 million, down 5.6% due to lower sales in the U.S. which more than offset growth in the Rest of the World region. Soliqua was approved in January in China and Sanofi will work with Chinese authorities to get access to patients through inclusion into the NRDL.
Sales of Rezurock were €63 million in the fourth quarter. Since launch more than 1400 patients have been treated with Rezurock (representing more than 30% of current addressable patient population) with strong persistency rates.
Non-core assets
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Lantus*
429 -27.6 % 2,259 -14.4 %
Aprovel/Avapro
104 -9.8 % 478 +7.6 %
Other non-core assets 1,071 -1.8 % 4,485 -7.7 %
Total non-core assets 1,604 -10.8 % 7,222 -9.0 %

In the fourth quarter, non-core assets sales decreased 10.8% to €1,604 million reflecting divestments (-1.9 ppt), and lower sales of Lantus in the U.S. In 2022, non-core assets sales decreased 9.0% (and 7.4% excluding divestments), reflecting VBP impact in China on Lantus, Eloxatin and Taxotere sales as well as lower Lantus sales in the U.S.
Lantus sales were €429 million, down 27.6% in the fourth quarter. In the U.S., sales decreased 56.7%, impacted by prior formulary losses as well as by erosion of the basal insulin market. In Rest of the World region, sales were down 7.7% reflecting the insulin VBP in China starting in May this year.
In China, Sanofi participated in the VBP tender for basal insulin analogues in November 2021 and was among the bidding winners in Group A with Toujeo and Lantus. In China, fourth-quarter Toujeo and Lantus sales were €51 million (up 18.6%), mainly reflecting higher Toujeo sales which benefited from growing demand and a favorable base of comparison due to price and inventory adjustment in the fourth quarter of 2021 in anticipation of the VBP. In 2022, Toujeo and Lantus sales were €447 million (down 10.7%), mainly reflecting lower Lantus sales which benefitted from higher volumes at significantly lower prices.
Fourth-quarter Aprovel/Avapro sales were down 9.8% to €104 million mainly due to lower sales in the Rest of the World region.
Pharmaceuticals business operating income
In the fourth quarter, business operating income (BOI) of Pharmaceuticals increased 19.1% to €2,490 million (up 15.1% at CER). The ratio of BOI to net sales increased by 1.8 percentage point to 32.0% (32.4% at CER), reflecting an improvement of the gross margin ratio, moderate growth of SG&A expenses despite continued increase in R&D expenses. In 2022, business operating income of Pharmaceuticals increased 17.4% to €11,043 million (up 10.5% at CER). The ratio of BOI to net sales increased by 1.1 percentage point to 36.0% (36.0% at CER).

Vaccines
Net sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
Influenza vaccines
(incl. Fluzone HD/ Efluelda, Fluzone, Flublok, Vaxigrip)
802 -32.0 % 2,977 +2.4 %
Polio/Pertussis/Hib vaccines
(incl. Hexaxim / Hexyon, Pentacel, Pentaxim and Imovax)
443 -16.9 % 2,285 +2.5 %
Meningitis vaccines
(incl. Menactra, MenQuadfi)
110 +14.3 % 703 -3.6 %
Booster vaccines (incl. Adacel )
148 +12.1 % 587 +11.3 %
Travel and endemic vaccines 121 +28.6 % 510 +57.8 %
Other vaccines 92 +309.1% 167 +86.9%
Total Vaccines 1,716 -16.3 % 7,229 +6.3 %

Fourth-quarter Vaccines sales decreased 16.3% (to €1,716 million) mainly reflecting accelerated supply phasing of influenza vaccines between the third and the fourth quarter 2022. In 2022, Vaccines sales were up 6.3%, reflecting progressive recovery of Travel and Booster vaccines.
Influenza vaccines sales decreased 32.0% to €802 million in the fourth quarter and accounted for 30% of northern hemisphere sales in the second half of 2022 compared to 45% in the fourth quarter of 2021.
New manufacturing capacity in the U.S. allowing for a new record year for influenza vaccines sales. This was again driven by continuous conversion to differentiated premium priced vaccines such as Fluzone HD in the U.S. and Efluelda in Europe that have demonstrated improved efficacy against a standard dose vaccine in randomized controlled trials. Full-year 2022 influenza sales reached €2,977 million.
In the fourth quarter, Polio/Pertussis/Hib (PPH) vaccines sales decreased -16.9% to €443 million reflecting lower sales in the Rest of the World region due to unfavorable purchasing pattern. In addition, Pentaxim sales in China decreased due to the COVID disruption. In the U.S. Vaxelis continues to capture market share progressively replacing pentavalent vaccines in the primary series of infant immunization. As a reminder, Vaxelis in-market sales are not consolidated and the profits are shared equally between Sanofi and Merck & co. Full-year 2022 PPH sales reached €2,285 million.
Fourth-quarter Meningitis sales increased 14.3% to €110 million, reflecting significant growth in the Rest of the World region. In the U.S., Meningitis sales benefited from favorable purchasing pattern.
Booster vaccines sales increased 12.1% in the fourth quarter to €148 million, driven by the Rest of the World region.
Fourth-quarter Travel and endemic vaccines sales increased 28.6% to €121 million, reflecting growth across all geographies in a post pandemic environment.
Sales of Other Vaccines were €92 million (up +309.1%) in the fourth quarter and included also sales of the recently approved monovalent recombinant-protein COVID-19 booster vaccine VidPrevtyn Beta.

Vaccines business operating income
In the fourth quarter, business operating income (BOI) decreased 8.3% (down 13.6% at CER) to €599 million compared to the same period of last year, reflecting earlier time to market of flu vaccines sales, higher R&D expenses related to the mRNA center of excellence which were partially offset by the capital gain generated by the sale of the Japanese encephalitis vaccine, a non-core vaccine. BOI to net sales ratio was 34.9% (34.3% at CER) versus 33.2% in the fourth quarter of 2021.
In 2022, BOI of Vaccines increased 21.4% (up 9.8% at CER) to €3,168 million reflecting strong sales growth, gross margin improvement, moderate SG&A evolution despite higher R&D costs. The ratio of BOI to net sales was 43.8% (42.6% at CER) versus 41.3% in 2021.

Consumer Healthcare
Net sales (€ million) Q4 2022
Change
at CER
2022
Change
at CER
Allergy 156 +15.0 % 734 +10.5 %
Cough & Cold 132 +11.2 % 478 +46.3 %
Pain Care 303 +8.7 % 1,213 +7.9 %
Digestive Wellness 306 +12.0 % 1,318 +12.4 %
Physical and Mental Wellness 124 -8.5 % 562 +0.7%
Personal Care 157 +8.3 % 586 +2.3 %
Non-Core / Others 38 -29.1 % 189 -27.4 %
Total Consumer Healthcare 1,216 +6.6 % 5,080 +8.6 %

In the fourth quarter, Consumer Healthcare (CHC) sales increased 6.6% to €1,216 million driven by growth in all regions. This global performance includes a positive price effect of 4.7 percentage points (ppt). The divestments of non-core products had a negative impact of 0.9 ppt in the fourth quarter mainly impacting the Non-core/others category. (The CHC organic sales growth was 7.5% in the fourth quarter excluding divestments impact). In 2022, CHC sales increased 8.6% supported by double-digit growth in Europe and the Rest of the World region. In 2022, the divestments of non-core products had a negative impact of 1.0 ppt. (The CHC organic sales growth was 9.6% in 2022 excluding divestments impact).
In the U.S., fourth-quarter CHC sales increased 3.9% to €326 million driven by Digestive Wellness and Personal Care categories.
In Europe, fourth-quarter CHC sales increased 8.7% to €371 million mainly reflecting double-digit growth of Cough & Cold season and Digestive Wellness categories.
In Rest of World, fourth-quarter CHC sales increased 6.6% to €519 million, supported by double-digit growth of Pain Care and Allergy categories.

CHC business operating income
In the fourth quarter, business operating income (BOI) of CHC increased 27.9% (up 25.5% at CER) to €381 million, driven by solid sales performance, moderate SG&A growth as well as higher capital gains related to divestments of non-strategic assets. The ratio of BOI to net sales increased 4.5 percentage points to 31.3% (31.6% at CER) versus the fourth quarter of 2021. In 2022, BOI of CHC increased 21.2% (up 15.8% at CER) to €1,810 million mainly driven by sales growth and higher capital gains related to divestments of non-strategic assets. The ratio of BOI to net sales increased 2.2 percentage points to 35.6% (35.6% at CER).
Company sales by geographic region
Sanofi sales (€ million) Q4 2022 Change
at CER 2022 Change
at CER
United States 4,671 +8.7 % 18,275 +12.2 %
Europe 2,636 -5.6 % 9,999 +2.4 %
Rest of the World 3,418 +2.4 % 14,723 +4.8 %
of which China 578 +2.3 % 3,123 +6.2%
of which Japan 406 +10.9 % 1,613 +3.1 %
of which Brazil 204 +4.9 % 927 -2.0 %
of which Russia
172 -0.7 % 674 +0.7%
Total Sanofi sales 10,725 +2.6 % 42,997 +7.0 %

In the U.S., fourth-quarter sales increased 8.7% (to €4,671 million), supported by the strong performance of Specialty Care driven by Dupixent.
In Europe, fourth-quarter sales decreased 5.6% (to €2,636 million) reflecting lower flu vaccines sales and deconsolidation of Libtayo sales, partially offset by Dupixent and CHC performance.
In the Rest of World region, fourth-quarter sales increased 2.4% (to €3,418 million), reflecting the performance of Specialty Care driven by Dupixent, growth of General Medicines core assets and CHC which largely offset lower Vaccines sales. Sales in China increased 2.3% to €578 million, driven by Dupixent, Praluent, Plavix and Toujeo which more than offset the VBP impact on Lantus and lower Vaccines sales. In Japan, fourth-quarter sales increased 10.9% to €406 million mainly driven by the

growth of Dupixent, Sarclisa and CHC. In Brazil, fourth-quarter sales were up 4.9% driven by General Medicines core-assets. Full-year 2022 sales in Brazil were down 2.0% reflecting lower Vaccines and Lovenox sales. In Russia, fourth-quarter sales decreased 0.7% to 172 million. In March 2022, Sanofi has stopped any new spending not related to the supply of its essential and life-changing medicines and vaccines in Russia. This includes all advertising and promotional spending.

R&D update at the end of the fourth quarter 2022

Regulatory update
•The European Commission (EC) approved Beyfortus (nirsevimab) for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants during their first RSV season. RSV is a common and highly contagious seasonal virus, infecting nearly all children by the age of two. Beyfortus is the first and only single-dose RSV protective option for the broad infant population, including those born healthy, at term or preterm, or with specific health conditions. Beyfortus was also granted approval in the United Kingdom.
•The U.S. Food and Drug Administration (FDA) accepted the Biologics License Application (BLA) for Beyfortus for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants entering or during their first RSV season and for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.
•The EC expanded the marketing authorization for Dupixent (dupilumab) in the European Union to treat adults with moderate-to-severe prurigo nodularis (PN) who are candidates for systemic therapy. With this approval, Dupixent is the first and only targeted medicine specifically indicated to treat PN in Europe and the U.S.
•The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for Dupixent, recommending the approval in Europe, to treat adults and adolescents with eosinophilic esophagitis (EoE).
•VidPrevtyn Beta was approved by the EC, as a booster for the prevention of COVID-19 in adults who have previously received an mRNA or adenoviral COVID-19 vaccine. Designed to provide broad protection against multiple variants, the protein-based COVID-19 booster vaccine is based on the Beta variant antigen and includes GSK’s pandemic adjuvant.
•The EC granted marketing authorization for Enjaymo (sutimlimab) for the treatment of adult patients with cold agglutinin disease (CAD), a rare, serious, and chronic autoimmune hemolytic anemia.
•Regeneron announced that the FDA approved Libtayo (cemiplimab-rwlc) in combination with platinum-based chemotherapy for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with no EGFR, ALK or ROS1 aberrations.This approval triggered Sanofi receiving a $100 million regulatory milestone payment

Portfolio update
Phase 3:
•The Dupixent Phase 3 results in adults and adolescents with eosinophilic esophagitis (EoE) were published in the New England Journal of Medicine. Dupixent is the first and only targeted medicine indicated in the U.S. to treat EoE patients aged 12 and older, weighing at least 40 kg.
•The tolebrutinib Phase 3 trial in nrSPMS (non-relapsing secondary progressive multiple sclerosis, HERCULES) was fully recruited in December 2022. Non-relapsing SPMS is an area of highest unmet need in MS as no approved treatments are currently available. Sanofi continues to recruit in PERSEUS, the trial for PPMS (primary progressive MS), outside of the U.S.
•The URSA study, a randomized, double blind, placebo-controlled trial evaluating the efficacy and safety of tolebrutinib in patients with moderate-to-severe myasthenia gravis (MG) was discontinued after careful evaluation of the emerging competitive treatment landscape in MG.

Phase 2:
•The study evaluating eclitasertib (RIPK1 inhibitor) in patients with ulcerative colitis (UC) enrolled its first participants.
•Sanofi decided to terminate its collaboration program with Revolution Medicines for the development of SAR442720 (SHP2 inhibitor) for the treatment of solid tumors, following a pipeline review and reprioritization of projects.

Phase 1:
•The development program for SAR444419 (anti-TNFa/IL-6 Nanobody VHH) in inflammatory indication was initiated.
•The study evaluating SAR444559, an anti-CD38 mAb of next generation in inflammatory indication enrolled its first participants.
•The study of the anti PD1/IL-15 fusion protein, SAR445877 (formerly known as KD050, entering our pipeline through Kadmon acquisition) in patients with solid tumors enrolled its first participants.

•The study evaluating the safety and tolerability of intravenous SAR446159 (also known as ABL301), an anti-alpha-synuclein/IGF1R mAb in Parkinson’s Disease, was initiated in collaboration with ABL Bio.
•The randomized, double-blind study evaluating the safety, tolerability, and activity of SAR439459 (anti-TGFb mAb), for the treatment of Osteogenesis Imperfecta, was initiated.
•Three Phase 1/2 studies with different LNP formulations evaluating the safety and immunogenicity of Quadrivalent Influenza mRNA vaccine in adults, enrolled their first participants.
•The Phase 1/2 study evaluating the safety and immunogenicity of the RSV mRNA vaccine in older adults, formulated with 2 different LNPs, enrolled its first participants.

Acquisitions and major collaborations
•Sanofi and Innate Pharma announced an expansion of their collaboration, with Sanofi licensing a natural killer (NK) cell engager program targeting B7H3 from Innate’s ANKETTM (Antibody-based NK Cell Engager Therapeutics) platform. Sanofi will also have the option to add up to two additional ANKETTM targets. Upon candidate selection, Sanofi will be responsible for all development, manufacturing and commercialization.

An update of the R&D pipeline at as of Dec 31, 2022, is available on our website: View Source

Corporate Social Responsibility update at the end of the fourth quarter 2022

Access to medicines
Positive Phase 2/3 results of acoziborole with the potential to further transform the treatment of sleeping sickness
Sanofi has collaborated with the World Health Organization (WHO) since 2001, with the objective to contribute to eliminate sleeping sickness, or Human African Trypanosomiasis (HAT), by 2030.
Sleeping sickness is a neglected tropical disease, which affects mostly poor populations living in remote rural areas of sub-Saharan Africa. If left untreated, the parasitic disease is usually fatal. Since the start of Sanofi’s collaboration with the WHO, the number of cases of sleeping sickness has fallen by 97%, from 26,950 in 2001 to 805 in 2021, dropping below 1,000 for the fourth consecutive year. Through Sanofi’s partnership with the World Health Organization (WHO), the company supports disease management, including screening of populations, disease awareness campaign, capacity building, as well as drug donation.
In September 2020, Sanofi and the Drugs for Neglected Diseases initiative (DNDi) signed an agreement to develop and roll out acoziborole, a single dose treatment administered at the point of diagnosis making it a potential game-changer to support the sustainable elimination of the disease once approved. This new chemical entity has been tested in Phase 2/3 clinical studies in Democratic Republic of Congo and Guinea. The results, which were published in the Lancet Infectious Diseases medical journal in November 2022, showed that the 18-month treatment success rate for acoziborole was 95% in late-stage g-HAT patients. The study shows that acoziborole has a favorable safety profile, with no significant drug-related safety signals being reported.
Upon approval, acoziborole could replace fexinidazole, also developed by Sanofi and DNDi and first approved in 2018. Fexinidazole is a ten-day once-a-day treatment that is effective in both the first and the second stages of the disease in adults and children aged six years and older.

Environment
Accelerating our ambition towards net zero emissions by 5 years, now targeting 2045
Sanofi is accelerating its efforts to address climate change and now build the road to net zero emissions across all operations (scope 1 & 2) and the entire value chain (scope 3) by 2045. This is an acceleration of 5 years compared to Sanofi’s previous commitment towards net zero emissions by 2050.
This new commitment will be building on years of work to reduce the environmental footprint of its products and activities. The progress of Sanofi’s environmental strategy is disclosed in appendix 10: CSR dashboards.

ESG ratings
Sanofi has been recognized again on the 2022 CDP’s Climate Change A List for its commitment and transparency in the fight against climate change. In addition, Sanofi has also achieved the leadership score (A-) for its actions to protect water resources.
Sanofi has also been awarded the 2022 Terra Carta Seal. The Seal is being awarded to companies from around the world who are driving innovation and leadership in their industry and tackling climate change. All recipients must have credible transition roadmaps underpinned by globally recognised, scientific metrics for achieving net zero by 2050 or earlier and have ambitions aligned with those of the Terra Carta, a recovery plan for Nature, People and Planet.

Additionally, in recognition of Sanofi’ continued CSR strategy implementation, a few of Sanofi’s ESG rankings have been positively updated:

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Fourth-quarter and full-year 2022 financial results
Business Net Income4
In the fourth quarter of 2022, Sanofi generated net sales of €10,725 million, an increase of 7.3% (up 2.6% at CER). Full-year 2022 net sales were €42,997 million up 13.9% (up 7.0% at CER).
Fourth-quarter other revenues increased 73.6% (up 58.2% at CER) to €731 million, including increased VaxServe sales of non-Sanofi products of €413 million (up 27.4% at CER). In 2022, other revenues increased 69.2% (up 51.9% at CER) to €2,392 million, including VaxServe sales of non-Sanofi products of €1,567 million (up 28.5% at CER).
Fourth-quarter Gross Profit increased 11.2% (up 5.4% at CER) to €7,722 million. The gross margin ratio increased 2.5 percentage point to 72.0% versus the same period of 2021, reflecting positive currency effect, improvement of the Pharmaceuticals gross margin ratio (which increased from 75.4% to 77.1%) driven by favorable product mix and efficiency gains and Vaccines gross margin ratio (58.9% from 56.0%), benefitting from a favorable comparison basis. CHC gross margin ratio increased 0.2 percentage point to 62.7%. In 2022, the gross margin ratio increased 2.4 percentage points to 73.7% (73.1% at CER) driven by Pharmaceuticals and Vaccines.
Research and Development (R&D) expenses were up 15.0% (up 10,1% at CER) to €1,823 million in the fourth quarter, reflecting increased expenses in pharmaceuticals priority assets and early-stage projects as well as in Vaccines. In 2022, R&D expenses increased 17.8% to €6,706 million (up 12.3% at CER).
Fourth-quarter selling general and administrative expenses (SG&A) increased 5.0% to €2,895 million. At CER, SG&A expenses were stable, reflecting efficiency measures which more than offset increased commercial investments in Specialty Care growth drivers. In the fourth quarter, the ratio of SG&A to sales decreased 0.6 percentage point to 27.0% compared to the prior year. In 2022, SG&A expenses increased 9.8% to €10,492 million (up 3.3% at CER) and the ratio of SG&A to sales was 0.9 percentage point lower at 24.4% compared to 2021.
Fourth-quarter and full-year 2022 operating expenses were €4,718 million, (up 8.6% and 3.7% at CER) and €17,198 million (up 12.8% and 6.6% at CER).
Fourth-quarter other current operating income net of expenses was €-276 million versus €-356 million in the fourth quarter of 2021. Other current operating income net of expenses included an expense of €659 million (versus an expense of €444 million in the fourth quarter of 2021) corresponding to the share of profit to Regeneron of the monoclonal antibodies Alliance, additional share of profit paid by Regeneron towards development costs (which increased from 10% to 20% from April 1st) and the reimbursement of commercialization-related expenses incurred by Regeneron. In the fourth quarter, this line also included €227 million of net capital gains related to portfolio streamlining compared to €61 million in the same period of 2021.
In 2022, other current operating income net of expenses was €-1,514 million versus €-946 million in 2021 and included €615 million of net capital gains related to portfolio streamlining compared to €318 million in 2021. In 2022 expense associated with the monoclonal antibodies Alliance with Regeneron was €2,367 million, which compared with an expense of €1,429 million in 2021 (see appendix 7 for further details).
The fourth-quarter and full-year share of profit from associates was €6 million and €88 million versus €18 million and €39 million in the same periods of 2021, respectively, and included the share of U.S. profit related to Vaxelis.
Fourth-quarter business operating income4 (BOI) increased 20.7% to €2,724 million. At CER, BOI increased 15.0%. The ratio of BOI to net sales increased 2.8 percentage points to 25.4%. In 2022, BOI was €13,040 million, up 21.7% (up 13.3% at CER). In 2022, the ratio of business operating income to net sales increased 1.9 percentage point to 30.3% (30.0% at CER).
Net financial expenses were €-28 million and €-234 million in the fourth quarter and full-year 2022, respectively, versus €-83 million and €-328 million in the same periods of 2021.
Fourth-quarter effective tax rate was 20,6% versus 20.5% in the same periods of 2021. Full-year 2022 effective tax rate was 19.3% versus 20.9% in 2021. Sanofi expects its effective tax rate to be around 19% in 2023.
Fourth-quarter business net income4 increased 23.8% to €2,141 million and increased 17.6% at CER. The ratio of business net income to net sales increased 2.7 percentage points to 20.0% versus the fourth quarter of 2021. In 2022, business net income increased 25.9% to €10,341 million and increased 17.0%
4See Appendix 3 for 2022 fourth-quarter consolidated income statement; see Appendix 9 for definitions of financial indicators, and Appendix 4 for reconciliation of IFRS net income reported to business net income.

at CER. The ratio of business net income to net sales increased 2.4 percentage points to 24.1% versus 2021.
In the fourth quarter of 2022, business earnings per share4 (EPS) was €1.71, up 23.9% on a reported basis (up 17,4% at CER). The average number of shares outstanding was 1,254.0 million versus 1,254.9 million in the fourth quarter of 2021. In 2022, business earnings per share8 was €8.26, up 25.9% on a reported basis and up 17.1% at CER. The average number of shares outstanding was 1,251.9 million versus 1,252.5 million in 2021.

Reconciliation of IFRS net income reported to business net income (see Appendix 4)
In 2022, the IFRS net income was €6,720 million. The main items excluded from the business net income were:
•An amortization charge of €2,053 million related to fair value remeasurement on intangible assets of acquired companies (primarily Genzyme: €535 million, Bioverativ: €377 million, Boehringer Ingelheim CHC business: €188 million, Ablynx: €168 million and Kadmon €159 million) and to acquired intangible assets (licenses/products: €334 million). These items have no cash impact on the Company.
•An impairment of intangible assets of €1,700 million of which €1,586 million are related to SAR444245 recorded in the third quarter.
•An upfront payment of $900 million (€856 million) and a regulatory milestone payment of $100 million (€96 million) received by Sanofi from Regeneron following the restructuring of the Immuno-Oncology agreement and collaboration. These items are included in Consolidated income statements line Other Operating Income (see Appendix 7).
•Restructuring costs and similar items of €1,336 million related to streamlining initiatives.
•Other gains and losses, and litigation charge of €370 million, mainly including costs related to major litigations (including the estimated future defense costs relating to the Zantac litigation).
•A €962 million tax effect arising from the items listed above, mainly comprising €771 million of deferred taxes generated by amortization and impairments of intangible assets and €231 million associated with restructuring costs and similar items (see Appendix 4).

Capital Allocation
In 2022, free cash flow before restructuring, acquisitions and disposals decreased by 10.8% to €8,902 million, after net changes in working capital (€-477 million) and capital expenditures (€-1,594 million). After acquisitions5 (€-824 million), proceeds from disposals5 (€1,531 million) and payments related to restructuring and similar items (-€1,126 million), free cash flow6 increased 4.8% to €8,483 million. After the acquisition of Amunix (-€875 million), the dividend paid by Sanofi (-€4,168 million), net debt decreased from €9,983 million at December 31, 2021 to €6,437 million at December 31, 2022 (amount net of €12,736 million cash and cash equivalents).

On February 3, 2023 Oncocyte Corporation, a California corporation ("Oncocyte" or the "Company"), entered into a Stock Purchase Agreement (the "Agreement") with Dragon Scientific, LLC, a Delaware limited liability company ("Buyer"), and Razor Genomics Inc., a Delaware corporation and wholly-owned subsidiary of Oncocyte ("Razor") (Filing, 8-K, Oncocyte, FEB 3, 2023, View Source [SID1234626829]). Pursuant to the Agreement, Oncocyte agreed to sell, and Buyer agreed to purchase, 3,188,181 shares of common stock of Razor, which constitutes approximately 70% of the issued and outstanding equity interests of Razor on a fully-diluted basis. Following the closing of the transaction (the "Closing"), Oncocyte will own 1,366,364 shares of common stock of Razor, which will constitute approximately 30% of the issued and outstanding equity interests of Razor on a fully-diluted basis. Pursuant to the terms of the Agreement, the Agreement may be terminated under certain circumstances, including, among other things, if the Closing has not occurred by February 1, 2023 (the "Outside Date").

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On January 30, 2023, the Company, Buyer and Razor entered into a First Amendment to Stock Purchase Agreement whereby the parties agreed to the extend the Outside Date, as set forth in Section 3.1(e) of the Agreement, to February 15, 2023 ("First Amendment"). No other provisions of the Agreement were otherwise amended or waived by the First Amendment, and the Agreement remains in full force and effect.

The foregoing description of the First Amendment does not purport to be complete and is qualified in its entirety by reference to the complete text of the First Amendment, which is filed as Exhibit 10.1 to this Current Report on Form 8-K and incorporated herein by reference.

On February 3, 2023 Moleculin Biotech, Inc. ("Company") delivered written notice to Oppenheimer & Co. Inc. (the "Agent") that it was terminating its At Market Issuance Sales Agreement, dated June 25, 2021 (the "ATM Agreement"), pursuant to Section 13(b) of the ATM Agreement, effective on February 13, 2023 (Filing, 8-K, Moleculin, FEB 3, 2023, View Source [SID1234626828]). Pursuant to the ATM Agreement, the Company could offer and sell, from time to time, through the Agent, shares of the Company’s common stock having an aggregate offering price of up to $50,000,000. During the term of the ATM Agreement, the Company did not sell any shares of its common stock thereunder. The ATM Agreement was terminable at will by the Company with no penalty.

A copy of the ATM Agreement was filed as Exhibit 1.1 to the Company’s Current Report on Form 8-K filed with the Securities and Exchange Commission on June 25, 2021 (the "Prior Form 8-K"). The description of the ATM Agreement contained herein does not purport to be complete and is qualified in its entirety by reference to the copy of the Sales Agreement filed as Exhibit 1.1 to the Prior Form 8-K.

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On February 3, 2023 Mersana Therapeutics, Inc. (NASDAQ:MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported that on February 1, 2023, an authorized sub-committee of the Board of Directors of Mersana granted inducement awards, consisting of stock options to purchase an aggregate of 42,000 shares of its common stock and restricted stock unit awards (RSUs) to acquire an aggregate of 97,665 shares of its common stock, to 10 new employees whose employment commenced in January 2023 (Press release, Mersana Therapeutics, FEB 3, 2023, View Source [SID1234626827]). The awards were granted pursuant to terms and conditions fixed by the Compensation Committee and as an inducement material to each new employee entering employment with Mersana in accordance with Nasdaq Listing Rule 5635(c)(4).

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The option awards have an exercise price of $6.72 per share, which is equal to the closing price of Mersana’s common stock on February 1, 2023. Each option has a 10-year term and will vest over a period of four years, with 25% of the shares vesting on the one-year anniversary of the commencement of the employee’s employment and the remainder vesting in equal quarterly installments over the following three years, subject to the applicable employee’s continued service with Mersana on each such vesting date. The options are subject to the terms and conditions of Mersana’s 2022 Inducement Stock Incentive Plan and the terms and conditions of a stock option agreement covering each grant.

The RSUs will vest in four equal annual installments following February 15, 2023, subject to the applicable employee’s continued service with Mersana on each such vesting date. The RSUs are subject to the terms and conditions of Mersana’s 2022 Inducement Stock Incentive Plan and the terms and conditions of an RSU agreement covering each grant.

On February 3, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that the Phase 3 NRG-GY018 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with standard of care chemotherapy (carboplatin and paclitaxel) met its primary endpoint of progression-free survival (PFS) for the treatment of patients with stage III-IV or recurrent endometrial carcinoma regardless of mismatch repair status (Press release, Merck & Co, FEB 3, 2023, View Source [SID1234626826]). At a pre-specified interim analysis review conducted by an independent Data Monitoring Committee, KEYTRUDA in combination with chemotherapy then continued as single agent every six weeks for up to 14 cycles demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in these patients whose endometrial carcinoma was either mismatch repair proficient (pMMR) or mismatch repair deficient (dMMR).

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The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies; no new safety signals were identified. Results will be presented at an upcoming medical meeting and discussed with regulatory authorities.

"Patients with advanced stage or recurrent endometrial cancer, the most common type of gynecologic cancer in the U.S., face a poor prognosis with limited treatment options. This is particularly notable in patients who progress after prior platinum-based adjuvant therapy with disease not amenable to curative surgery or radiation," said Dr. Ramez Eskander, principal investigator and gynecologic oncologist, University of California, San Diego. "In this study, pembrolizumab in combination with carboplatin and paclitaxel resulted in a statistically significant and clinically meaningful improvement in progression-free survival in both the dMMR and pMMR study populations. We look forward to presenting these exciting findings at an upcoming scientific congress."

"In certain patients with advanced endometrial cancer who have progressed following prior systemic therapy and are not candidates for surgery or radiation, KEYTRUDA has become an important treatment option, both as monotherapy and in combination," said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. "These latest results in the first-line setting are very encouraging and show the potential of KEYTRUDA plus chemotherapy for patients with stage III to IV or recurrent disease regardless of mismatch repair status. We thank our collaborators for their partnership on this study, and we are grateful to the patients and investigators for their participation."

This trial was sponsored by the U.S. National Cancer Institute (NCI), part of the National Institutes of Health. NRG Oncology designed and led the trial with funding from the NCI and participation from all the National Clinical Trials Network (NCTN) Groups. Merck provided funding and support through a Cooperative Research and Development Agreement (CRADA) between Merck and NCI.

Merck has a comprehensive clinical development program in endometrial cancer. In the U.S., KEYTRUDA has two approved indications in endometrial cancer: in combination with LENVIMA (lenvatinib), in collaboration with Eisai, for the treatment of patients with advanced endometrial carcinoma that is pMMR, as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation; and as a single agent, for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Additionally, Merck is evaluating KEYTRUDA in first-line advanced endometrial cancer both as monotherapy (KEYNOTE-C93/ENGOT-en15/GOG-3064) and in combination with LENVIMA (LEAP-001/ENGOT-en9), as well as in the adjuvant setting (KEYNOTE-B21/ENGOT-en11/GOG-3053).

About NRG-GY018

NRG-GY018 is a randomized, blinded, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03914612) evaluating KEYTRUDA in combination with standard of care chemotherapy (paclitaxel and carboplatin) versus placebo plus standard of care chemotherapy alone for the treatment of measurable stage III, IVA, IVB or recurrent endometrial cancer in pMMR and dMMR cohorts. The primary endpoint is PFS, and secondary endpoints include overall survival, objective response rate, duration of response and safety. The trial enrolled 819 patients who were randomized to receive KEYTRUDA plus chemotherapy every three weeks for approximately six cycles followed by KEYTRUDA as a single agent every six weeks for up to 14 cycles, or placebo plus chemotherapy. Enrolled patients were required to have MMR testing prior to randomization; approximately 70% of patients were pMMR, and approximately 30% were dMMR.

About endometrial carcinoma

Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. This disease remains the only gynecologic malignancy with a rising incidence and mortality. In the U.S., it is estimated there will be approximately 66,000 new cases of uterine body cancer and approximately 13,000 deaths from the disease in 2023. Globally, endometrial cancer is the sixth most common cancer in women and 15th most common cancer overall.

About KEYTRUDA (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

In KEYNOTE-581, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced renal carcinoma (n=352), fatal adverse reactions occurred in 4.3% of patients. Serious adverse reactions occurred in 51% of patients; the most common (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension, myocardial infarction, pneumonitis, and vomiting (3% each), acute kidney injury, adrenal insufficiency, dyspnea, and pneumonia (2% each).

Permanent discontinuation of KEYTRUDA, LENVIMA, or both due to an adverse reaction occurred in 37% of patients; 29% KEYTRUDA only, 26% LENVIMA only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, LENVIMA, or the combination were pneumonitis, myocardial infarction, hepatotoxicity, acute kidney injury, rash (3% each), and diarrhea (2%).

The most common adverse reactions (≥20%) observed with KEYTRUDA in combination with LENVIMA were fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain and hemorrhagic events (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%).

In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

In KEYNOTE-775, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced endometrial carcinoma that was pMMR or not MSI-H (n=342), fatal adverse reactions occurred in 4.7% of patients. Serious adverse reactions occurred in 50% of these patients; the most common (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%).

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).

The most common adverse reactions for KEYTRUDA in combination with LENVIMA (reported in ≥20% patients) were hypothyroidism and hypertension (67% each), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain and weight loss (34% each), urinary tract infections (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar- plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%).

Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use

In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Additional Selected KEYTRUDA Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

who are not eligible for any platinum-containing chemotherapy, or
who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at View Source and Medication Guide for KEYTRUDA at View Source .

About LENVIMA (lenvatinib); available as 10 mg and 4 mg capsules

LENVIMA, discovered and developed by Eisai, is a multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, the combination of lenvatinib with an anti-PD-1 monoclonal antibody decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity compared to either treatment alone.

LENVIMA (lenvatinib) Indications in the U.S.

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with pembrolizumab, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC)
In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Selected Safety Information for LENVIMA

Warnings and Precautions

Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

Withhold LENVIMA if ONJ develops and restart based on clinical judgment of adequate resolution.

Embryo‐Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions

In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). The most common serious adverse reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

In EC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab-treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar‐plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).

Use in Specific Populations

Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

Please see Prescribing Information for LENVIMA (lenvatinib) at View Source .

Merck’s focus on cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.