On July 27, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported financial results for the second quarter of 2018 (Press release, Merck & Co, JUL 27, 2018, View Source [SID1234527919]).

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"Strong commercial execution globally for KEYTRUDA, GARDASIL, BRIDION and other products led the company to deliver growth in the second quarter," said Kenneth C. Frazier, Merck Chairman and CEO. "We continue to solidify our leadership in immuno-oncology and, along with our other key pillars of growth including Animal Health, we are confident in the strength of our business."

GAAP (generally accepted accounting principles) earnings per share assuming dilution (EPS) were $0.63 for the second quarter of 2018. Non-GAAP EPS of $1.06 for the second quarter of 2018 excludes acquisition- and divestiture-related costs, restructuring costs and certain other items. Year-to-date results can be found in the attached tables.

Oncology Pipeline Highlights

Merck continued to expand its oncology program by further advancing the development programs for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy; Lynparza (olaparib), a PARP inhibitor being co-developed and co-commercialized with AstraZeneca; and Lenvima (lenvatinib mesylate), an orally available tyrosine kinase inhibitor being co-developed and co-commercialized with Eisai.

KEYTRUDA

Merck announced that the U.S. Food and Drug Administration (FDA) accepted for review a supplemental Biologics License Application (sBLA) for KEYTRUDA as a first-line treatment for metastatic squamous non-small cell lung cancer (NSCLC), regardless of PD-L1 expression. The sBLA, which is seeking accelerated approval for this new indication, is based on overall response rate (ORR) data from the pivotal Phase 3 KEYNOTE-407 trial, which were recently presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting. The FDA granted Priority Review and set a PDUFA date of Oct. 30, 2018. Additional data showing a significant improvement in overall survival (OS) were also presented, making this the fifth study in advanced NSCLC in which KEYTRUDA demonstrated an improved survival benefit.

Merck announced results from KEYNOTE-042, a pivotal Phase 3 study evaluating KEYTRUDA as monotherapy for the first-line treatment of locally advanced or metastatic nonsquamous or squamous NSCLC with PD-L1 tumor proportion score of ≥1 percent without EGFR or ALK genomic tumor aberrations. In this study, KEYTRUDA monotherapy resulted in significantly longer OS than platinum-based chemotherapy. These results were presented in the plenary session and during the press program at ASCO (Free ASCO Whitepaper) 2018.
Merck announced interim data from a cohort of the Phase 2 KEYNOTE-158 study evaluating KEYTRUDA as monotherapy in patients with previously treated advanced small cell lung cancer (SCLC). Findings showed an ORR, the primary endpoint of the study, of 18.7 percent in patients in the SCLC cohort. Additionally, in a pre-specified exploratory analysis, ORR was 35.7 percent in patients whose tumors expressed PD-L1 with a combined positive score (CPS) of ≥1. These results, as well as other findings from the KEYNOTE-158 cohort in SCLC, were presented for the first time at ASCO (Free ASCO Whitepaper) 2018.

The company announced that the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), met a primary endpoint of OS as monotherapy in patients whose tumors expressed PD-L1 (CPS≥20). KEYTRUDA is the first anti-PD-1 therapy to show an OS benefit as first-line therapy for recurrent or metastatic HNSCC. At the time of the interim analysis, the dual-primary endpoint of progression-free survival (PFS) for patients whose tumors expressed PD-L1 (CPS≥20) had not been reached. These results will be presented at an upcoming medical meeting and submitted to regulatory authorities worldwide.

Merck announced that KEYTRUDA has been approved by the China National Drug Administration for the treatment of adult patients with unresectable or metastatic melanoma following failure of one prior line of therapy. This is the first and only approval of an anti-PD-1 therapy for advanced melanoma in China.
The FDA accepted and granted Priority Review for a new sBLA seeking approval for KEYTRUDA as a treatment for previously treated patients with advanced hepatocellular carcinoma, based on data from the Phase 2 KEYNOTE-224 trial, which were presented at ASCO (Free ASCO Whitepaper) 2018. The FDA set a PDUFA date of Nov. 9, 2018.
Merck announced that the FDA accepted for standard review a new sBLA for KEYTRUDA as adjuvant therapy in the treatment of patients with resected, high-risk stage III melanoma and granted a PDUFA date of Feb. 16, 2019. This sBLA is based on a significant benefit in recurrence-free survival demonstrated by KEYTRUDA in the pivotal Phase 3 EORTC1325/ KEYNOTE-054 trial, which was conducted in collaboration with the European Organisation for Research and Treatment of Cancer.

The FDA approved KEYTRUDA for two new indications under its accelerated approval regulations based on tumor response rate and durability of response:
For the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma, or who have relapsed after two or more prior lines of therapy.
For the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 as determined by an FDA-approved test.
Lynparza

Merck and AstraZeneca announced positive results from the randomized, double-blinded, placebo-controlled, Phase 3 SOLO-1 trial of Lynparza tablets, showing women with BRCA-mutated (BRCAm) advanced ovarian cancer treated first-line with Lynparza maintenance therapy had a statistically significant and clinically meaningful improvement in PFS compared to placebo.

Merck and AstraZeneca announced that Japan’s Pharmaceuticals and Medical Devices Agency approved Lynparza tablets for use in patients with unresectable or recurrent BRCAm, human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have received prior chemotherapy.

Merck and AstraZeneca announced that the European Medicines Agency approved Lynparza tablets for use as a maintenance therapy for patients with platinum-sensitive relapsed high-grade, epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy, regardless of BRCA status.

Merck and AstraZeneca presented data from the Phase 2 Study 08 trial, which showed clinical improvement in median radiologic PFS with Lynparza in combination with abiraterone compared to abiraterone monotherapy, a current standard of care, in metastatic castration-resistant prostate cancer.
Lenvima

Merck and Eisai announced results from presentations of new data and analyses of Lenvima in combination with KEYTRUDA in four different tumor types: unresectable hepatocellular carcinoma, squamous cell carcinoma of the head and neck, advanced renal cell carcinoma and advanced endometrial carcinoma. The data were included in presentations at ASCO (Free ASCO Whitepaper) 2018.
Other Pipeline Highlights

The company also continued to advance its vaccines and HIV pipelines.

Merck announced that the FDA accepted for review a new sBLA for GARDASIL 9 (Human Papillomavirus 9-valent Vaccine, Recombinant), the company’s nine-valent HPV vaccine, for an expanded age indication for use in women and men 27 to 45 years old for the prevention of certain cancers and diseases caused by the nine human papillomavirus (HPV) types covered by the vaccine. The FDA granted Priority Review and set a PDUFA date of Oct. 6, 2018.

China’s Food and Drug Administration approved GARDASIL 9 for use in girls and women 16 to 26 years old.
Merck announced Week 96 results from the Phase 3 DRIVE-FORWARD clinical trial evaluating the efficacy and safety of doravirine (DOR), the company’s investigational non-nucleoside reverse transcriptase inhibitor, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. At Week 96, 73.1 percent of the group treated with once-daily DOR plus FTC/TDF or ABC/3TC achieved viral suppression as measured by the proportion of patients who achieved HIV-1 RNA of less than 50 copies/mL, compared to 66.0 percent of the group treated with once-daily ritonavir-boosted darunavir (DRV+r) plus FTC/TDF or ABC/3TC. These study results were presented as a late-breaking abstract at the recent 22nd International AIDS Conference.
Second-Quarter Revenue Performance

Second-quarter pharmaceutical sales increased 6 percent to $9.3 billion, including a 3 percent positive impact from foreign exchange. The increase was primarily driven by growth in oncology, vaccines and hospital acute care, partially offset by lower sales in virology and the ongoing impacts of the loss of market exclusivity for several products.

Growth in oncology was driven by a significant increase in sales of KEYTRUDA, reflecting the company’s continued launches with new indications globally and the strong momentum for the treatment of patients with NSCLC, as KEYTRUDA is the only anti-PD-1 approved in the first-line setting. Additionally, oncology sales reflect alliance revenue of $44 million related to Lynparza and $35 million related to Lenvima, which represents Merck’s share of profits from product sales, net of cost of sales and commercialization costs.

Growth in vaccines was primarily driven by higher sales of GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] and GARDASIL 9, vaccines to prevent certain cancers and other diseases caused by HPV, reflecting growth in Asia Pacific, primarily due to the ongoing commercial launch in China, and growth in Europe, partially offset by lower sales in the United States due to the continued transition to the two-dose regimen. Vaccines performance was negatively affected by a significant decrease in sales of ZOSTAVAX (zoster vaccine live), a vaccine for the prevention of herpes zoster, primarily due to the approval of a competitor product that received a preferential recommendation from the U.S. Advisory Committee on Immunization Practices in October 2017. The company anticipates that future sales of ZOSTAVAX will continue to be unfavorably affected by this competition.

Growth in hospital acute care reflects strong global demand of BRIDION (sugammadex) Injection 100 mg/mL, a medicine for the reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide in adults undergoing surgery.

Pharmaceutical sales growth in the quarter was partially offset by lower sales in virology, largely reflecting a significant decline in ZEPATIER (elbasvir and grazoprevir), a medicine for the treatment of chronic hepatitis C virus genotypes 1 or 4 infection, due to increasing competition and declining patient volumes, which the company expects to continue.

Pharmaceutical sales growth for the quarter was also partially offset by the ongoing impacts from the loss of U.S. market exclusivity for ZETIA (ezetimibe) in late 2016 and VYTORIN (ezetimibe/simvastatin) in April 2017, medicines for lowering LDL cholesterol; and biosimilar competition for REMICADE (infliximab), a treatment for inflammatory diseases, in the company’s marketing territories in Europe.

Animal Health

Animal Health sales totaled $1.1 billion for the second quarter of 2018, an increase of 14 percent compared with the second quarter of 2017, including a 2 percent positive impact from foreign exchange. Growth was driven by higher sales of companion animal products, primarily from the BRAVECTO (fluralaner) line of products that kill fleas and ticks in dogs and cats for up to 12 weeks, due in part to a delayed flea and tick season and the timing of customer purchases. Growth was also driven by livestock products, including poultry, ruminants and swine products.

Animal Health segment profits were $450 million in the second quarter of 2018, an increase of 14 percent compared with $395 million in the second quarter of 2017.3

Second-Quarter Expense, EPS and Related Information

Gross margin was 67.3 percent for the second quarter of 2018 compared to 68.6 percent for the second quarter of 2017. The decrease in gross margin for the second quarter of 2018 was primarily driven by the amortization of amounts capitalized for potential future milestone payments related to collaborations, the amortization of unfavorable manufacturing variances, in part resulting from the June 2017 cyber-attack, as well as the unfavorable effects of foreign exchange. The decrease was partially offset by a lower net impact of acquisition- and divestiture-related costs and restructuring costs, which reduced gross margin by 7.1 percentage points in the second quarter of 2018 compared with 8.7 percentage points in the second quarter of 2017.

Marketing and administrative expenses were $2.5 billion in the second quarter of 2018, comparable to the second quarter of 2017, reflecting the unfavorable effects of foreign exchange and higher administrative costs, offset by lower promotion and direct selling costs.

Research and development (R&D) expenses were $2.3 billion in the second quarter of 2018 compared with $1.8 billion in the second quarter of 2017. The increase was driven primarily by a $344 million charge for the Viralytics Limited (Viralytics) acquisition, increased clinical development spending, in particular from oncology collaborations, as well as investment in early drug development.

GAAP EPS was $0.63 for the second quarter of 2018 compared with $0.71 for the second quarter of 2017.

Non-GAAP Expense, EPS and Related Information

The non-GAAP gross margin was 74.4 percent for the second quarter of 2018 compared to 77.3 percent for the second quarter of 2017. The decrease in non-GAAP gross margin was predominantly due to the amortization of amounts capitalized for potential future milestone payments related to collaborations, the amortization of unfavorable manufacturing variances, in part resulting from the June 2017 cyber-attack, as well as the unfavorable effects of foreign exchange.

Non-GAAP marketing and administrative expenses were $2.5 billion in the second quarter of 2018, comparable to the second quarter of 2017, reflecting the unfavorable effects of foreign exchange and higher administrative costs, offset by lower promotion and direct selling costs.

Non-GAAP R&D expenses were $1.9 billion in the second quarter of 2018, a 9 percent increase compared to the second quarter of 2017. The increase primarily reflects higher clinical development spending, in particular from oncology collaborations, as well as investment in early drug development.

Non-GAAP EPS was $1.06 for the second quarter of 2018 compared with $1.01 for the second quarter of 2017.

Merck narrowed its full-year 2018 revenue range to be between $42.0 billion and $42.8 billion, including a slightly positive impact from foreign exchange at current exchange rates.

Merck narrowed and raised its full-year 2018 GAAP EPS range to be between $2.51 and $2.59. Merck narrowed and raised its full-year 2018 non-GAAP EPS range to be between $4.22 and $4.30. Both include an approximately 1 percent negative impact from foreign exchange at current exchange rates. The non-GAAP range excludes acquisition- and divestiture-related costs, costs related to restructuring programs, charges related to the formation of the Eisai collaboration and the Viralytics acquisition, and certain other items.

*The company does not have any non-GAAP adjustments to revenue.

**EPS guidance for 2018 assumes a share count (assuming dilution) of approximately 2.7 billion shares.

A reconciliation of anticipated 2018 GAAP EPS to non-GAAP EPS and the items excluded from non-GAAP EPS are provided in the table below.

The expected full-year 2018 GAAP effective tax rate of 23.0 percent to 24.0 percent reflects an unfavorable impact of approximately 4.5 percentage points from the above items.

Earnings Conference Call

Investors, journalists and the general public may access a live audio webcast of the call today at 8:00 a.m. EDT on Merck’s website at View Source Institutional investors and analysts can participate in the call by dialing (706) 758-9927 or (877) 381-5782 and using ID code number 6985606. Members of the media are invited to monitor the call by dialing (706) 758-9928 or (800) 399-7917 and using ID code number 6985606. Journalists who wish to ask questions are requested to contact a member of Merck’s Media Relations team at the conclusion of the call.

On July 27, 2018 Pierre Fabre reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) in combination for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation (Press release, Pierre Fabre, JUL 27, 2018, View Source [SID1234527945]). This opinion is based on data from the Phase 3 COLUMBUS trial.1 The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). The decision will be applicable to all 28 EU member states plus Liechtenstein, Iceland and Norway.

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"We are delighted to be one step closer to bringing BRAFTOVI and MEKTOVI to patients with advanced BRAF-mutant melanoma in Europe," said Frédéric Duchesne, President & CEO of the Pierre Fabre Pharmaceuticals Division. "If the European Commission approves BRAFTOVI and MEKTOVI, this will be a new treatment option for these patients who currently have a challenging prognosis."

The CHMP positive opinion is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination improved median progression-free survival (PFS), compared with vemurafenib alone (14.9 months versus 7.3 months, respectively: hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41–0.71; p<0.0001).1 As presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June 2018, treatment with BRAFTOVI and MEKTOVI achieved a median overall survival (OS) of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of OS in the COLUMBUS trial.2 Adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.1 The most common Grade 3–4 adverse events, seen in more than 5% of patients, were: increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (7%) and hypertension (6%).1

Important safety information and recommendations for the use of BRAFTOVI and MEKTOVI will be detailed in the summary of product characteristics (SmPC), which will be published in the European Public Assessment Report (EPAR) and made available in all official EU languages if marketing authorisation is granted by the EC.

On 27 June 2018, Pierre Fabre’s partner Array BioPharma, which has exclusive rights for these medicines in the United States (US), announced that BRAFTOVI and MEKTOVI were approved by the Food and Drug Administration (FDA) in the US for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.3,4 BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. BRAFTOVI and MEKTOVI are investigational medicines and are not currently approved in any other country outside of the US. Applications for marketing authorisation for BRAFTOVI and MEKTOVI in other countries are currently under review.

About BRAF-mutant Metastatic Melanoma

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.5,6 There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma.6–9

About BRAFTOVI (encorafenib) and MEKTOVI (binimetinib)

BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor and MEKTOVI (binimetinib) is an oral small-molecule MEK inhibitor which targets key enzymes in the MAPK signalling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma, colorectal cancer, non-small-cell lung cancer, thyroid and others.

Pierre Fabre has exclusive rights to develop and commercialise BRAFTOVI and MEKTOVI worldwide, except in the US and Canada, where Array BioPharma retains exclusive rights; Israel, where Medison has exclusive rights; and in Japan and South Korea, where Ono Pharmaceutical has exclusive rights to commercialise both products.

About COLUMBUS

The COLUMBUS trial (NCT01909453) is a two-part, international, randomised, open-label, Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared with vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation.1 All secondary efficacy analyses, including OS, are descriptive in nature. More than 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the COLUMBUS trial.

The CHMP positive opinion is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination improved median PFS, compared with vemurafenib alone (14.9 months versus 7.3 months, respectively: HR 0.54, 95% CI, 0.41–0.71; p<0.0001).1 As presented at ASCO (Free ASCO Whitepaper) in June 2018, treatment with BRAFTOVI and MEKTOVI achieved a median OS of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of OS in the COLUMBUS trial.2 Adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.1 The most common Grade 3–4 adverse events, seen in more than 5% of patients, were: increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (7%) and hypertension (6%).1

On July 26, 2018 CBT Pharmaceuticals (CBT), a U.S. and China-based innovative biopharmaceutical company committed to becoming a leader in the discovery and development of oncology combination therapies, reported the continuation of the CBT-501 (genolimzumab injection) Phase 1 clinical trial with the initiation of the Phase 1b segment of the study in patients with select advanced or relapsed/recurrent solid tumors (Press release, CBT Pharmaceuticals, JUL 26, 2018, View Source [SID1234527879]). CBT-501 is a novel IgG4 humanized monoclonal antibody against the Programmable Death-1 (PD-1) membrane receptor on immune cells.

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Following a meeting by the trial’s Safety Review Committee (SRC), the SRC determined that the safety data to date demonstrates CBT-501 is well tolerated and recommended a dose and schedule to advance the program. The Phase 1b segment will evaluate four tumor types, each expected to enroll approximately 20 patients. The ongoing clinical trial is being conducted in Australia.

"We are pleased that our PD-1 drug candidate, CBT-501, has demonstrated encouraging pharmacokinetics, pharmacodynamic engagement, a well-tolerated safety profile, and encouraging activity in advanced stage cancer patients," stated Sanjeev Redkar, PhD, President and Chief Executive Officer. "We expect the Phase 1b to further evaluate the safety profile of CBT-501 and its utility as a single agent in a number of homogenous tumor types. Results from this study may lead to a Phase 2 trial utilizing CBT-501 as a single agent or in combination with chemotherapy, radiation, targeted therapies, or other cancer immunotherapy agents."

For additional information regarding the trial, please visit clinicaltrials.gov identifier: NCT03053466.

About CBT-501 (genolimzumab Injection)

CBT-501 is a novel IgG4 humanized monoclonal antibody against the Programmable Death-1 (PD-1) membrane receptor on immune cells. It has a comparable efficacy profile in in vitro and in vivo studies to the marketed anti-PD-1 antibodies, nivolumab and pembrolizumab, and has a favorable profile with very low antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) activity. In China, CBT-501 is referred to as GB226 where it is being developed by CBT partner Genor BioPharma Co. Ltd. Visit clinicaltrials.gov for additional information on the ongoing clinical trials: NCT03053466, NCT03374007, and NCT03502629.

On July 26, 2018 Five Prime Therapeutics, Inc. (NASDAQ: FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that it will report its second quarter 2018 financial results on Wednesday, August 8, 2018, after the U.S. financial markets close (Press release, Five Prime Therapeutics, JUL 26, 2018, View Source [SID1234527901]). Five Prime will host a conference call and live audio webcast on Wednesday, August 8, 2018, at 4:30 p.m. (ET)/1:30 p.m. (PT) to discuss the company’s financial results and provide a general business update.

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The live audio webcast may be accessed through the "Events & Presentations" page in the "Investors" section of the company’s website at www.fiveprime.com. Alternatively, participants may dial (877) 878-2269 (domestic) or (253) 237-1188 (international) and refer to conference ID 4194786.

The archived conference call will be available on Five Prime’s website beginning approximately two hours after the event and will be archived and available for replay for at least 30 days after the event.

On July 26, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA, Merck’s anti-PD-1 therapy, has been approved by the China National Drug Administration (CNDA) for the treatment of adult patients with unresectable or metastatic melanoma following failure of one prior line of therapy (Press release, Merck & Co, JUL 26, 2018, View Source [SID1234527880]). This is the first and only approval of an anti-PD-1 therapy for advanced melanoma in China.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"Over the past decades, we have had limited effective options in the treatment of patients with advanced melanoma," Professor Jun Guo, M.D., Ph.D, director of the Department of Melanoma & Renal Cancer, Peking University Cancer Hospital and Institute Secretary-General of the Chinese Society of Clinical Oncology, primary investigator, KEYNOTE-151. "Advanced melanoma is one of the cancers that has been most responsive to immunotherapy, and outside of China, anti-PD-1 therapies such as pembrolizumab have become the standard therapy for this disease. With the approval of pembrolizumab in China, the treatment of advanced melanoma will now be aligned with international standards."

The approval of KEYTRUDA in China was based on overall response rate (ORR) data from the Phase 1b KEYNOTE-151 study, which evaluated KEYTRUDA monotherapy in Chinese patients with previously treated locally advanced or metastatic melanoma who received one prior line of systemic therapy. In 2018, the CNDA granted priority review status to KEYTRUDA, which accelerated the approval process by allowing for simultaneous clinical validation for the first time – creating an industry leading approval turnaround time for imported cancer medicine in China.

"Merck is committed to bringing new treatment advances, like KEYTRUDA, to cancer patients in China," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "The approval of KEYTRUDA in China, for this first indication, was made possible through extensive collaborative effort with the Chinese patients and investigators who participated in KEYNOTE-151, as well as the regulatory and government authorities who prioritized this filing. We appreciate their commitment to bringing forward the first anti-PD-1 therapy for advanced melanoma in China."

"The approval of our anti-PD-1 therapy reflects the Chinese government’s strong commitment to expedite the introduction of innovative therapies to Chinese patients," said Joseph Romanelli, president of MSD China. "The approval of KEYTRUDA in advanced melanoma marks the sixth new product approval for MSD China in 2018. We are encouraged that our scientific advancements are leading to new options for patients and their families."

About Melanoma in China

Malignant melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. Melanoma is one of the fastest growing malignant cancers in China, increasing at an annual rate of 3-5 percent, which makes it one of the deadliest diseases in the country. Research data has shown that once the disease metastasizes, the five-year survival rate for metastatic melanoma in Chinese patients is only 4.6 percent.

About KEYNOTE-151

KEYNOTE-151 is an open-label, single-arm, multi-center, Phase 1b trial evaluating KEYTRUDA monotherapy in 103 Chinese patients with previously treated locally advanced or metastatic melanoma who received one prior line of systemic therapy. Patients were enrolled to receive KEYTRUDA at a dose of 2 mg/kg every three weeks. The primary efficacy outcome measure was ORR as assessed by Blinded Independent Central Review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were duration of response (DOR) and progression-free survival (PFS; as assessed by BICR per RECIST 1.1 and irRECIST), ORR (as assessed by BICR per irRECIST) and overall survival (OS).

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-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, which currently involves more than 750 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.

KEYTRUDA (pembrolizumab) Indications and Dosing in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also 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, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. 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. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. 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. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

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. 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 confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy. In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10], or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) 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 that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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. In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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 recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA 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. 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 recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA. While immune-mediated adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, they may occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including cHL, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (one fatal case), and two developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (one fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

In clinical 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 a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to 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%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

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 (reported in at least 20% of patients) 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, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) 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, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent (25%) of patients had an adverse reaction requiring systemic corticosteroid therapy. 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 (occurring in ≥20% of patients) 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 metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

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

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).