On September 17, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported interim data from the randomised phase II coopERA Breast Cancer trial evaluating neoadjuvant treatment with giredestrant (formerly known as GDC-9545), an investigational next generation oral selective oestrogen receptor degrader (SERD), in post-menopausal women with ER-positive, HER2-negative early breast cancer (Press release, Hoffmann-La Roche, SEP 17, 2021, View Source [SID1234587865]). In the window of opportunity phase, after 14 days of treatment, giredestrant showed a reduction in Ki67, a prognostic marker that measures tumour proliferation, compared to anastrozole (80% versus 67% respectively, p=0.0222). The safety profile of giredestrant remained consistent with previous trials and fewer patients experienced side effects assessed as related to giredestrant versus anastrozole.1 Interim analysis results from the coopERA Breast Cancer study will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 and the primary analysis data will be presented at an upcoming medical meeting.

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"We are pleased to share the first randomised phase II data for giredestrant, which shows encouraging activity and safety in early HR-positive, HER2-negative breast cancer," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Our ongoing comprehensive programme in HR-positive breast cancer aims to address significant unmet needs for people who still experience a profound impact on their quality of life, including the risk of treatment resistance and disease recurrence."

The interim analysis data from 83/202 patients enrolled in the coopERA Breast Cancer study demonstrated superior anti-proliferative activity of giredestrant compared with anastrozole and a favourable safety profile in HR-positive, HER2-negative breast cancer1:

During the window of opportunity phase (1-14 days) in this neoadjuvant (pre-operative) study, the pharmacodynamic effect of giredestrant was assessed using the relative Ki67 reduction as proliferation biomarker, which indicates the ability of a therapy to suppress tumour growth:
Giredestrant showed a mean Ki67 reduction of 80% (95% CI: –85%, –72%) versus 67% for anastrozole (95% CI; 95% CI: –75%, –56%) p=0.0222.
Consistent Ki67 suppression was observed in patients with baseline Ki67 ≥20% (83% reduction for giredestrant versus 71% for anastrozole) or baseline Ki67 <20% (65% vs 24% respectively).
After 14 days of treatment, 25% of tumours exhibited Complete Cell Cycle Arrest Rate (CCCA) with giredestrant versus 5% with anastrozole (Δ 20%; 95% CI: -37%, -3%).
The safety profile of giredestrant was consistent with its mechanism of action, with fewer patients experiencing side effects assessed as related to giredestrant (28%) versus anastrozole (38%) by the reporting investigators. No Grade ≥3 adverse events (AEs) or serious AEs were giredestrant-related.

Further data from the primary analysis of this study are expected to be presented at an upcoming medical meeting and will include results from the full population of the window of opportunity phase and early results from the neoadjuvant phase of the study, which evaluates giredestrant plus palbociclib versus anastrozole plus palbociclib.

Roche is currently enrolling patients into a second phase II study (acelERA Breast Cancer) evaluating giredestrant in second/third-line oestrogen receptor (ER)-positive early breast cancer, as well as two phase III studies: persevERA Breast Cancer, evaluating giredestrant plus palbociclib against letrozole plus palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer and lidERA Breast Cancer, evaluating adjuvant giredestrant versus endocrine therapy of physician’s choice in patients with medium- and high-risk ER-positive and HER2-negative early breast cancer.3,4,5 In August 2021, the first patient was enrolled in the lidERA study, the first study to evaluate an oral SERD in the adjuvant setting.6 Data was also recently published in the Journal of Medicinal Chemistry; with giredestrant shown to be a potent SERD and a full antagonist, with best in class potential due to its better anti-proliferative activity than other known SERDs. Among the various SERDs reported so far, giredestrant ‘stands out in its overall preclinical package’.2,7

Giredestrant received U.S. Food and Drug Administration (FDA) Fast Track Designation (FTD) for ER-positive, HER2-negative, second and third-line metastatic breast cancer on 15 December 2020. FTD is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.8

About giredestrant
Giredestrant is a next generation investigational SERD, designed to fully block ER signalling with robust receptor occupancy and demonstrates an exceptional preclinical profile. Oestrogen encourages HR-positive breast cancer cells to grow by attaching to the ER. Giredestrant works by blocking this receptor to prevent the action of oestrogen, and in the process causes the receptor to be degraded. This investigational medicine has also shown efficacy regardless of ESR1 mutation status (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).9.10,11,12

Orally given, giredestrant delivers an encouraging clinical efficacy and safety profile and has shown superior pre-clinical potency over other SERDs in development.2,11,13 The oral administration of giredestrant has the potential to transform the treatment experience for patients, offering greater convenience and a less painful option compared to therapies administered via intramuscular injection.

Giredestrant has a comprehensive development programme across a broad range of settings and treatment combinations for patients with HR-positive, HER2-negative breast cancer. A standardised once-daily 30 mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

About coopERA (NCT04436744)14
An open-label, two-arm, phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window of opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, ER-positive, HER2-negative early breast cancer. The primary endpoint of the study is the geometric change in Ki67 scores (a measure of how quickly cancer cells are proliferating) from baseline to week 2 during the window of opportunity phase. Secondary endpoints include overall response rate, CCCA, safety outcomes and plasma concentration of giredestrant.

About Roche in breast cancer
Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough innovations in HER2-positive and triple-negative breast cancers. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for all forms of early and advanced breast cancer, including triple-negative and hormone receptor-positive.

Our targeted medicines Herceptin (trastuzumab), Perjeta (pertuzumab), Phesgo, Kadcyla (trastuzumab emtansine) and Tecentriq (atezolizumab) are continuing to transform the treatment of early and advanced HER2-positive and triple-negative breast cancers and, through our clinical programmes, we hope to bring new treatment combinations to people with breast cancer, ultimately improving outcomes.

On September 17, 2021 ERYTECH Pharma (Nasdaq & Euronext: ERYP), a clinical-stage biopharmaceutical company developing innovative therapies by encapsulating therapeutic drug substances inside red blood cells, reported that it will host its second quarter 2021 conference call and webcast on Tuesday, September 21, 2021, at 2:30 PM CEST/8:30 AM ET to discuss operational highlights (Press release, ERYtech Pharma, SEP 17, 2021, View Source [SID1234587881]).

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On September 17, 2021 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE: CFBI), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address inflammatory, cancer and liver diseases, reported its Vice President of Business of Development Dr. Sari Fishman will participate in three upcoming conferences to conduct meetings with potential development and commercialization partners for the Company’s portfolio of drug candidates (Press release, Can-Fite BioPharma, SEP 17, 2021, View Source [SID1234587898]).

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Details are below:

BioPharm America 2021

Virtual Conference: part of Biotech Week Boston

Date: September 20 – 23, 2021

TAP Diabetes 2021

Virtual Conference: Therapeutics Area Partnership (TAP) specialized partnering event for diabetes

Date: October 5 – 7, 2021

BIO-Europe 2021

Virtual Conference: bringing global biopharma together to build partnerships that facilitate innovation

Date: October 25 – 29, 2021

Can-Fite currently has out-licensing agreements for its Namodenoson and Piclidenoson drug candidates in several territories and has received approximately $20 million in upfront and milestone payments to date with additional potential milestone payments of up to approximately $130 million, plus double-digit royalties on net sales following regulatory approval.

On September 17, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported four e-poster presentations at the ESMO (Free ESMO Whitepaper) Congress 2021 (Press release, Deciphera Pharmaceuticals, SEP 17, 2021, View Source [SID1234587866]). The presentations include updated preliminary results from the ongoing Phase 1b/2 study of rebastinib in combination with paclitaxel in patients with PROC and updated preliminary results from the ongoing Phase 1/2 study of vimseltinib in patients with TGCT. A long-term update on the Phase 3 INVICTUS study of QINLOCK (ripretinib) in patients with advanced gastrointestinal stromal tumors (GIST), and results from the expansion phase of the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma will also be presented.

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All e-poster presentations are now available on-demand via the ESMO (Free ESMO Whitepaper) website and on the Company’s website at www.deciphera.com/presentations-publications. Deciphera will also host an investor event featuring key opinion leaders to discuss the rebastinib and vimseltinib data today, September 17, 2021, at 10 AM ET. A live webcast of the event may be accessed through the "Investors" section of Deciphera’s website at www.deciphera.com. A replay of the webcast will be available following the event.

"We are excited to present strong results at this year’s ESMO (Free ESMO Whitepaper) Congress, which support both our plans to initiate a Phase 3 pivotal study for rebastinib pending regulatory feedback, and our plans to initiate a Phase 3 pivotal study for vimseltinib. The updated safety and efficacy results for rebastinib in combination with paclitaxel show highly encouraging results, including a median progression free survival of 9.1 months, in heavily pretreated patients with PROC where additional treatment is heterogeneous and single agent paclitaxel retreatment has historically shown only 3-4 months of PFS. Based on these impressive results in patients with a significant unmet medical need, we have begun planning for a pivotal Phase 3 study that we plan to initiate in 2022 following regulatory feedback," said Matthew L. Sherman, MD, Executive Vice President and Chief Medical Officer of Deciphera. "We are equally encouraged by the tolerability and efficacy data presented today from the Phase 1/2 study of vimseltinib in TGCT. The data presented today with vimseltinib in TGCT reinforce its potential to be a best-in-class treatment for this disease. We are rapidly moving forward with this program and we expect to initiate our Phase 3 study, MOTION, in the fourth quarter of this year."

Dr. Sherman continued, "In addition to rebastinib and vimseltinib, we presented positive results from the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma, and a long-term update from the Phase 3 INVICTUS study of QINLOCK, which shows further prolonged clinically meaningful median overall survival among patients receiving QINLOCK. Finally, we look forward to our Phase 3 INTRIGUE readout later this year in patients with second-line GIST."

Updated Preliminary Data from the Ongoing Phase 1b/2 Study of Rebastinib in Combination with Paclitaxel in PROC

The Phase 1b/2 study of rebastinib in combination with paclitaxel is a two-part, open-label, multicenter study assessing the safety, tolerability, anti-tumor activity, and pharmacokinetics of rebastinib in patients with advanced or metastatic solid tumors. The data presented today is from the second stage of Part 2 of the Simon two-stage design in PROC.

As of the June 22, 2021 cutoff date, 38 patients with PROC initiated treatment with rebastinib and paclitaxel and are included in the safety population and 34 patients that met the criteria for the modified intent-to-treat population (mITT) are included in the efficacy analysis.

The median progression-free survival (PFS) was 9.1 months.
There were 13 patients with objective responses (10 confirmed) for an objective response rate (ORR) of 38% (confirmed and unconfirmed) and 29% (confirmed only) with a median duration response of 5.5 months.
The clinical benefit rate at 16 weeks was 76%.
A CA-125 response occurred in 19 of 26 patients (73%).
Rebastinib in combination with paclitaxel was generally well tolerated at 50 mg BID, and most common (≥15%) treatment-emergent adverse events (TEAEs) were Grade 1 or 2.
Four patients experienced serious adverse events (SAEs) at least possibly related to rebastinib including reversible muscular weakness (n=2), constipation (n=1), fatigue (n=1), and urinary tract infection (n=1).
Based on the strength of these findings, the Company has begun planning for a pivotal study in PROC that is anticipated to start in 2022, subject to feedback from regulators.

Updated Preliminary Data from the Ongoing Phase 1/2 Study of Vimseltinib in TGCT

The Phase 1/2 study of vimseltinib is an open-label, multicenter study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of vimseltinib in patients with solid tumors and TGCT. The data today is from patients with TGCT in both the Phase 1 dose escalation portion of the study and from cohort A in the Phase 2 expansion portion of the study. Cohort A includes TGCT patients with no prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib is allowed) and cohort B includes patients with prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib are not eligible).

As of the June 7, 2021 cutoff date, 68 TGCT patients were treated with vimseltinib and included in the safety population, including 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 36 TGCT patients enrolled in cohort A in the Phase 2 portion of the study. Efficacy data presented today is from 51 TGCT patients, including all 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 19 TGCT patients enrolled in cohort A in the Phase 2 portion of the study that were evaluable for efficacy as of the cutoff date.

Dose Cohorts and Demographics:

32 patients enrolled in Phase 1 (dose escalation) and 36 patients enrolled in Phase 2 cohort A (expansion):
Phase 1 cohort 5 (n=8): 30 mg loading dose daily for five days followed by a maintenance dose of 30 mg twice a week.
Phase 1 cohort 8 (n=12): 30 mg loading dose daily for three days followed by a maintenance dose of 10 mg daily.
Phase 1 cohort 9 (n=12): 20 mg loading dose daily for three days followed by a maintenance dose of 6 mg daily.
Phase 2 cohort A (n=36): 30 mg twice weekly (no loading dose).
12 out of 32 patients (38%) in Phase 1 and 32 out of 36 patients (89%) in Phase 2 cohort A had at least one prior surgery; five patients (16%) in Phase 1 and two patients (6%) in Phase 2 cohort A had received at least one prior systematic therapy.
51 patients were evaluable for efficacy by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 at the data cutoff in Phase 1 across all dose cohorts and in Phase 2 cohort A; response data is based on independent central radiologic review with the exception of one patient who had a local assessment, and for whom no central assessment was performed.
Updated Preliminary Efficacy and Duration of Treatment:

Of the 51 efficacy-evaluable patients in Phase 1 across all dose cohorts and in the Phase 2 cohort A, 24 patients had a response resulting in an ORR of 47%.
Of the 32 patients in Phase 1, 16 patients achieved an objective response for an ORR of 50% with durable responses observed across all dose cohorts, including one complete response in cohort 5. The median duration of treatment for all patients was 10.1 months. 72% of patients remain active in the study as of the data cutoff date.
Of the 36 patients enrolled in Phase 2 cohort A, 19 patients were evaluable for efficacy, of which there were eight patients with an objective response for an ORR of 42%. Of the 19 patients, 10 had more than one follow-up imaging assessment and two responses occurred at later scans. The median duration of treatment for all patients was 1.9 months. The study is ongoing and follow-up evaluation is continuing with 83% of patients remaining active as of the data cutoff date.
Safety and Tolerability:

In both Phase 1 and Phase 2 cohort A, treatment with vimseltinib was generally well tolerated in patients with TGCT. Two patients (6%) discontinued treatment due to a TEAE in Phase 1 and one patient (3%) discontinued treatment due to an TEAE in Phase 2 cohort A.
Two patients experienced SAEs at least possibly related to vimseltinib, including metabolic encephalopathy and vaginal hemorrhage in Phase 1; no treatment-related SAEs were reported in Phase 2 cohort A.
The majority of the common (≥15%) TEAEs were Grade 2 or lower.
Observed transaminase, pancreatic, and creatine phosphokinase enzyme elevations were mostly low grade, asymptomatic, and consistent with mechanism of action of CSF1R inhibitors.
No abnormalities in bilirubin levels were reported.
Phase 3 MOTION Study

Based on the positive results of the ongoing Phase 1/2 study, the Company plans to advance vimseltinib into a pivotal Phase 3 study in patients with TGCT. The MOTION study is two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with symptomatic TGCT who are not amenable to surgery. In Part 1 of the study, eligible study participants will be assigned to receive either vimseltinib or matching placebo for 24 weeks. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib for Part 2 of the study. Part 2 is a long-term treatment phase in which all participants receive open-label vimseltinib. The primary endpoint of the study is ORR at 25 weeks as measured by RECIST v1.1 by blinded independent central review. The Company expects to initiate the MOTION study in the fourth quarter of this year.

Long-term Update from Phase 3 INVICTUS Study of QINLOCK in Patients with Advanced GIST

The INVICTUS Phase 3 clinical study is a randomized (2:1), double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of QINLOCK compared to placebo in patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The Company previously reported primary results from the randomized portion of the INVICTUS study, in which QINLOCK significantly improved PFS and showed a clinically meaningful overall survival (OS) benefit.

An exploratory evaluation of primary and secondary endpoints in the Phase 3 INVICTUS study, with a cutoff date of January 15, 2021, an additional 19 months after the primary analysis, demonstrates consistent PFS with no change since the primary data cut off, and improved median OS among patients receiving ripretinib.

Median PFS was 6.3 months with QINLOCK compared to 1.0 month with placebo.
Median OS was 18.2 months with QINLOCK compared to 6.3 months with placebo.
Median OS was 10 months in placebo patients who crossed over to QINLOCK.
Median ORR was 11.8% with QINLOCK compared to 0% with placebo.
Median duration of response with QINLOCK was 14.5 months.
Safety findings were consistent with the primary analysis results and most TEAEs were Grade 1 or 2. Increases in TEAEs and TEAEs leading to dose modifications in the additional 19 months of follow up were minimal.

These more mature results continue to support the clinically meaningful benefit in PFS and OS for QINLOCK with an acceptable safety profile in patients with advanced GIST treated with three or more prior lines of therapy.

Phase 1 Study of Ripretinib in Patients with KIT-altered Metastatic Melanoma

As part of the expansion phase of the Phase 1 study, 26 patients with KIT-altered metastatic melanoma were treated with ripretinib at the recommended Phase 2 dose of 150 mg daily in repeated 28-day cycles. Tumor progression was assessed by the investigator using computed tomography/magnetic resonance imaging according to RECIST v1.1 on day 1 of cycles 3, 5, 7, and every three cycles thereafter, and a final study visit. ORR was confirmed with follow-up imaging approximately 28 days later. Patients who had disease progression at ripretinib 150 mg daily were allowed to dose escalate to 150 mg twice daily.

Ripretinib demonstrated encouraging efficacy in patients with KIT-altered metastatic melanoma with a confirmed ORR of 23%, median duration of response of 9.1 months, and median PFS of 7.3 months. In addition, there were two unconfirmed partial responses resulting in an ORR of 31% (confirmed and unconfirmed).
Tyrosine kinase inhibitor (TKI)-naïve patients had a greater response (confirmed ORR of 29% and median PFS of 10.2 months) to ripretinib than those with prior TKI treatment (confirmed ORR of 11% and median PFS of 2.9 months).
Ripretinib had an acceptable safety profile in KIT-altered metastatic melanoma consistent with the approved indication in GIST.

On September 17, 2021 Exelixis, Inc. (Nasdaq: EXEL) reported that the U.S. Food and Drug Administration (FDA) approved CABOMETYX (cabozantinib) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible (Press release, Exelixis, SEP 17, 2021, View Source [SID1234587882]). The FDA granted Breakthrough Therapy designation and Priority Review to CABOMETYX and its approval comes more than two months ahead of the Prescription Drug User Fee Act (PDUFA) target action date of December 4, 2021. DTC is the most common type of thyroid cancer in the U.S., and patients who are resistant to radioactive iodine treatment face a poor prognosis.1,2,3,4

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"Before today, patients with radioactive iodine-refractory differentiated thyroid cancer who have progressed following prior VEGFR-targeted therapy were facing aggressive disease and no standard treatment option," said Marcia S. Brose, M.D., Ph.D., Chief, Cancer Center Operation Sidney Kimmel Cancer Center at Jefferson Torresdale Hospital, Co-Director, Community Based Clinical Trials, Sidney Kimmel Cancer Center at Thomas Jefferson University, and principal investigator of COSMIC-311. "In the COSMIC-311 pivotal phase 3 trial, CABOMETYX extended the time patients live without progression of their cancer. The FDA approval of CABOMETYX is an important advancement for these patients who are badly in need of new treatment options."

The approval is based on results from COSMIC-311, a phase 3 pivotal trial evaluating CABOMETYX versus placebo in patients with radioactive iodine-refractory DTC who progressed after up to two prior VEGFR-targeted therapies. At a planned interim analysis, CABOMETYX significantly reduced the risk of disease progression or death versus placebo (p<0.0001) in the intent-to-treat population. At a follow-up analysis with a median follow-up of 10.1 months, the median progression-free survival (PFS) as assessed by blinded independent radiology committee was 11.0 months for patients treated with CABOMETYX (n=170) compared with 1.9 months for patients treated with placebo (n=88); hazard ratio (HR): 0.22; 95% confidence interval (CI): 0.15–0.31. These results will be presented at the 2021 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress this month.

"This approval of CABOMETYX builds on our existing legacy of delivering transformational medicines for patients with difficult-to-treat forms of cancer," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. "We would like to thank the clinical trial participants, the physicians and their staff who participated in the COSMIC-311 trial and to acknowledge the team at the FDA for their collaboration during the quick review of our application."

The most common adverse events (AEs) reported in at least 25% of patients treated with CABOMETYX were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension and stomatitis. Grade 3/4 AEs that occurred in at least 5% of patients were palmar-plantar erythrodysesthesia, hypertension, fatigue, diarrhea and stomatitis. Serious AEs occurred in 34% of patients who received CABOMETYX, and the most common serious AEs reported in at least 2% of patients included diarrhea, pleural effusion, pulmonary embolism and dyspnea. Fatal AEs occurred in 1.6% of patients treated with CABOMETYX arm, including arterial hemorrhage (0.8%) and pulmonary embolism (0.8%). Dose reductions were required in 56% of patients treated with CABOMETYX, and 22% of patients required a second dose reduction. AEs leading to discontinuation of CABOMETYX occurred in 5% of patients.

"Patients with differentiated thyroid cancer who have progressed following prior therapy and are radioactive iodine-refractory often face a poor prognosis and have limited treatment options," said Gary Bloom, Executive Director of ThyCa: Thyroid Cancer Survivors’ Association. "We are excited about the latest approval of CABOMETYX, which will offer hope for patients with this type of thyroid cancer."

About COSMIC-311

COSMIC-311 was a multicenter, randomized, double-blind, placebo-controlled phase 3 pivotal trial that enrolled 258 patients at 164 sites globally. Patients were randomized in a 2:1 ratio to receive either CABOMETYX 60 mg or placebo once daily. The primary endpoints were PFS and objective response rate. Exelixis is sponsoring COSMIC-311, and Ipsen is co-funding the trial. More information about this trial is available at ClinicalTrials.gov.

About DTC

Approximately 44,000 new cases of thyroid cancer will be diagnosed in the U.S. in 2021.5 Nearly three out of four of these cases will be in women, and the disease is more commonly diagnosed at a younger age compared to most other adult cancers.1 While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90% of cases.1 These include papillary, follicular and Hürthle cell cancer.1 DTC is typically treated with surgery followed by ablation of the remaining thyroid tissue with radioiodine, but approximately 5% to 15% of cases are resistant to radioiodine treatment.1,6 For these patients, life expectancy is only three to five years from the time metastatic lesions are detected.2,3,4

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.