On September 19, 2021 Ipsen (Euronext: IPN; ADR: IPSEY) reported presentation of new analyses at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 across different forms of cancer for people treated with Cabometyx (cabozantinib) (Press release, Ipsen, SEP 19, 2021, View Source [SID1234587933]). Of note, the final analysis of the pivotal Phase III COSMIC-311 trial (Abstract LBA67) will be presented, with Cabometyx demonstrating a clinically meaningful, sustained efficacy benefit versus placebo in people living with previously treated radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC).

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With a median follow-up of 10.1 months, Cabometyx continued to demonstrate superior median progression-free survival (mPFS) with a reduction in the risk of disease progression or death of 78% versus placebo (hazard ratio [HR]: 0.22, 96% confidence interval [CI]: 0.15-0.32; p<0.0001).1 This final analysis is consistent with data from the interim analysis, presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2021 and published in The Lancet Oncology, (HR: 0.22; 96% CI: 0.13-0.36; p<0.0001).5,6 Further data from the final analysis also confirmed that superior efficacy with Cabometyx was maintained irrespective of previous vascular endothelial growth factor receptor (VEGFR)-targeted therapy.

Efficacy and safety data from the COSMIC-311 interim analysis formed the basis of a type II variation submission to the European Medicines Agency (EMA) for an extension of indication for Cabometyx in RAI-R DTC. On 14 August 2021, the EMA validated the type II variation, confirming the submission is complete and beginning its centralized review process.

The safety profile identified in the COSMIC-311 trial was consistent with that previously observed for cabozantinib and adverse events (AEs) were managed with dose modifications. The discontinuation rate due to treatment-emergent AEs (TEAEs) was 8.8% for Cabometyx vs. 0% for placebo. Grade 3/4 TEAEs occurred in 62% of patients who received Cabometyx vs. 28% for placebo, with no treatment-related grade 5 events.

Steven Hildemann, M.D., Executive Vice President, Chief Medical Officer, Head of Global Medical Affairs and Global Patient Safety, Ipsen said, "The therapeutic potential of Cabometyx as a key treatment option in our arsenal against a broad range of tumors is continuing to be realized. These final data from the COSMIC-311 trial are a strong example of how Cabometyx can make a tangible difference to the lives of people living with cancer and we look forward to receiving a decision from the EMA next year. We are committed to further evaluating the role Cabometyx may continue to play against difficult-to-treat cancers as we also look towards the results of the ongoing Phase III trials in non-small cell lung cancer (CONTACT-01) and metastatic castration-resistant prostate cancer (CONTACT-02)."

Additional data to be presented at ESMO (Free ESMO Whitepaper) featuring Cabometyx include new results from cohort 6 of the COSMIC-021 Phase Ib trial evaluating the combination of Cabometyx and atezolizumab in people living with previously treated metastatic castration-resistant prostate cancer (mCRPC) (Abstract LBA24).2 These additional analyses build on the interim data presented at ASCO (Free ASCO Whitepaper) 2020,7 with an expanded cohort 6 of 132 patients evaluated.2 With a median follow-up of 15.2 months, the primary endpoint of objective response rate (ORR) assessed by investigator per RECIST 1.1 (response evaluation criteria in solid tumours) was 23%, with three patients demonstrating a complete response (CR).2

Prof. Dr. Gunhild von Amsberg, University Medical Center Hamburg-Eppendorf (UKE) and investigator in the CONTACT-02 trial, said, "As a uro-oncologist, I am encouraged by the results presented at this year’s ESMO (Free ESMO Whitepaper) congress. For people living with advanced metastatic castration-resistant prostate cancer, the prognosis is often poor and the potential of new innovative therapies is critically important. Based on these clinically meaningful results of Cabometyx plus atezolizumab from cohort 6 of the COSMIC-021 trial, we now look forward to the results of the ongoing Phase III CONTACT-02."

Further analyses from the landmark Phase III CheckMate -9ER trial investigating the combination of Cabometyx and nivolumab were are also being presented at ESMO (Free ESMO Whitepaper), providing additional evidence to inform clinical decision-making in advanced renal cell carcinoma (RCC). New data demonstrated improved efficacy for Cabometyx and nivolumab regardless of prior nephrectomy status, when measured by PFS, ORR, CR and response durability outcomes, versus sunitinib (Abstract 663P).3 Additionally, a matching-adjusted indirect comparison analysis is being presented, demonstrating superior, statistically significant differences in health-related quality of life across all outcomes analysed in favour of Cabometyx and nivolumab versus the combination of axitinib and pembrolizumab (Abstract 668P).4

More information on these data can be found during the presentation sessions outlined below:

Title

Date and time

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC): results of expanded cohort 6 of the COSMIC-021 Study

Saturday 18 September
13:30-13:40 CEST

Cabozantinib Versus Placebo in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer (DTC) Who Have Progressed After Prior VEGFR-Targeted Therapy: Updated Results From the Phase 3 COSMIC-311 Trial

Monday 20 September
17:30-17:35 CEST

First-line nivolumab + cabozantinib (NIVO+CABO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in subgroups based on prior nephrectomy in the CheckMate 9ER trial

Poster presentation – Available on-demand beginning September 16 at 8:30 am CEST

Matching-adjusted indirect comparison (MAIC) of health-related quality of life (HRQoL) of nivolumab plus cabozantinib (N+C) vs pembrolizumab plus axitinib (P+A) in previously untreated advanced renal cell carcinoma (aRCC)

Poster presentation – Available on-demand beginning September 16 at 8:30 am CEST

About radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC)
In 2020, over 580,000 new cases of thyroid cancer were diagnosed worldwide.8 Thyroid cancer is the ninth most commonly occurring cancer globally and incidence is three times higher in women than in men, with the disease representing one in every 20 cancers diagnosed among women.7 While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90 to 95% of cases.9,10 These include papillary, follicular and Hürthle cell cancer.7,8 DTC is typically treated with surgery, followed by ablation of the remaining thyroid tissue with radioactive iodine (RAI), but approximately 5 to 15% of cases are resistant to RAI treatment.11 Patients who develop RAI-R DTC have a poor prognosis with an average estimated survival of three to five years.12

About the COSMIC-311 trial
COSMIC-311 is a multicenter, randomized, double-blind, placebo-controlled Phase III trial that enrolled 258 patients at 164 sites globally.6 Patients were randomized in a 2:1 ratio to receive either Cabometyx 60 mg or placebo once-daily.6 The primary endpoints were progression-free survival and objective response rate, evaluated by a blinded independent radiology committee. Additional endpoints include safety, overall survival and quality of life.2 More information about this trial is available at ClinicalTrials.gov.

About metastatic castration-resistant prostate cancer (mCRPC)
In 2020, over 1.4 million new cases of prostate cancer were diagnosed worldwide,13 making it the fourth most commonly occurring cancer globally.13 Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies which reduce the levels of testosterone, a common treatment for prostate cancer, is known as mCRPC.14 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years.15

About the COSMIC-021 trial
COSMIC-021 is a multicenter, Phase Ib, open-label trial that is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced renal cell carcinoma (RCC) with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent urothelial carcinoma (UC), (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy. Ultimately, all 12 patients who enrolled in this stage of the trial were patients with advanced RCC. The dose-escalation phase of the study determined the optimal dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every 3 weeks).

In the expansion phase, the trial is enrolling 24 cohorts in 12 tumor types: RCC, urothelial carcinoma, non-small cell lung cancer, CRPC, hepatocellular carcinoma, triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and DTC.

Four of the cohorts are exploratory single agent cohorts. In UC, NSCLC, CRPC with cabozantinib as a single-agent, and in CRPC with single-agent atezolizumab.

Exelixis is the study sponsor of COSMIC-021. Both Ipsen Pharma SAS (Ipsen) and Takeda Pharmaceutical Company Limited (Takeda) have opted in to participate in the trial and are contributing to the funding for this study under the terms of the companies’ respective collaboration agreements with Exelixis. Roche is providing atezolizumab for the trial.

About renal cell carcinoma (RCC)
There are over 400,000 new cases of kidney cancer diagnosed worldwide each year.16 Of these, RCC is the most common type of kidney cancer, accounting for approximately 90% of cases.17,18 It is twice as common in men, and male patients account for over two thirds of deaths.16 If detected in the early stages, the five-year survival rate is high, but for patients living with advanced or late-stage metastatic RCC the survival rate is much lower, around 12%, with no identified cure for this disease.19,20

About the CheckMate -9ER trial
CheckMate -9ER was an open-label, randomized, multi-national Phase III trial evaluating people living with previously untreated advanced or metastatic RCC. A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to Cabometyx plus Opdivo (n = 323) versus sunitinib (n = 328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival and objective response rate. The primary efficacy analysis compared the doublet combination versus sunitinib in all randomized patients. The trial was sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Cabometyx (cabozantinib)
In the U.S., Cabometyx tablets are approved for the treatment of patients living with advanced RCC; for the treatment of patients living with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; and for patients living with advanced RCC as a first-line treatment in combination with nivolumab. Outside the U.S., Cabometyx is currently approved in 59 countries, including in the European Union, Great Britain, Norway, Iceland, Australia, New Zealand, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong Kong, Singapore, Macau, Jordan, Lebanon, the Russian Federation, Ukraine, Turkey, United Arabic Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile, Peru, Panama, Guatemala, Dominican Republic, Ecuador, Thailand, Malaysia and Egypt for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, Great Britain, Norway, Iceland, Canada, Australia, New Zealand, Brazil, Taiwan, Hong Kong, Singapore, Lebanon, Jordan, the Russian Federation, Ukraine, Turkey, the United Arab Emirates (U.A.E.)., Saudi Arabia, Israel, Mexico, Chile, Peru, Panama, Guatemala, the Dominican Republic, Ecuador, Thailand, Egypt and Malaysia for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, Great Britain Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel, Taiwan, Hong Kong, South Korea, Singapore, Jordan, the Russian Federation, Ukraine, Turkey, Lebanon, the U.A.E., Peru, Panama, Guatemala, Chile, the Dominican Republic, Ecuador, Thailand, Brazil, New Zealand and Malaysia for HCC in adults who have previously been treated with sorafenib. Cabometyx is also approved in combination with nivolumab as first line treatment for people living with advanced RCC, in the European Union, Great Britain, Norway, Iceland, Switzerland, Taiwan, the Russian Federation.

The detailed recommendations for the use of Cabometyx are described in the Summary of Product Characteristics (EU SmPC) and in the U.S. Prescribing Information (USPI).

Ipsen has exclusive rights for the commercialization of Cabometyx outside the U.S. and Japan. Cabometyx is marketed by Exelixis in the U.S. and by Takeda Pharmaceutical Company Limited in Japan. Cabometyx is a registered trademark of Exelixis.

On September 19, 2021 Verastem Oncology (Nasdaq:VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported a mini oral presentation highlighting updated data from the ongoing investigator-sponsored Phase 1/2 FRAME study (Press release, Verastem, SEP 19, 2021, View Source [SID1234587932]). The FRAME study, led by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, is investigating VS-6766, Verastem’s RAF/MEK inhibitor, in combination with defactinib, its FAK inhibitor, in patients with low grade serous ovarian cancer (LGSOC). The findings will be presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021, taking place September 16-21, 2021.

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"Low-grade serous ovarian cancer is a rare, slow-growing cancer that does not respond well to chemotherapy or hormone therapy, and disproportionately affects younger women. The results presented at ESMO (Free ESMO Whitepaper) this year show that VS-6766 combined with defactinib continues to demonstrate encouraging response rates in patients with LGSOC, including a 46% partial response rate across the overall patient population and a 64% partial response rate in patients with KRAS-mutated LGSOC, with manageable rates of side-effects," said Dr Susana Banerjee, MBBS, MA, PhD, FRCP, lead author of the presentation, Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Consultant Medical Oncologist and Research Lead for The Royal Marsden NHS Foundation Trust Gynaecology Unit.

"It’s particularly promising that the combination was also effective in patients who had previously received a MEK inhibitor. I am delighted that this drug combination has shown such encouraging results in a group of patients who urgently need new treatments."

"The investigator-sponsored FRAME study, the initial results of which led the U.S. Food and Drug Administration (FDA) to grant Breakthrough Therapy designation for the VS-6766 and defactinib combination in LGSOC, continues to be instrumental in providing the foundational data for safety, efficacy and durability in this novel combination for RAS pathway tumors," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "These data indicate that combining VS-6766 with defactinib results in promising response rates and median progression-free survival in patients who have already received MEK inhibitors. Verastem’s company-sponsored, registration-directed Phase 2 RAMP 201 study evaluating VS-6766 both alone and in combination with defactinib in patients with recurrent LGSOC is ongoing and we look forward to reporting top-line results from the selection portion of the study during the first half of 2022."

Updated Phase 1/2 FRAME Study Results in Patients with LGSOC

Among the evaluable patients with LGSOC (n=24), the overall response rate (ORR) was 46% (11 of 24). Among the patients with KRAS mutant LGSOC (n=11), the ORR was 64% (7 of 11). Among the patients with KRAS wild type LGSOC (n=9), the ORR was 44% (4 of 9). Of the evaluable patients, 10 (42%) received previous MEK inhibitor therapy.

The mPFS across all patients was 23.0 months (95% CI: 10.6- not reached). As of the April 2021 data cutoff date, 13 of 24 patients (54%) remained on study.

For context, for other therapies studied in recurrent LGSOC, response rates have been between 6% and 26% and mPFS was between 7.2 and 13.0 months.1,2

In the FRAME study, the most common Grade 3/4 treatment-related adverse events (AEs) were creatine kinase elevation (12%), rash (8%), diarrhea (4%), mouth ulcer/mucositis/glossitis (4%) and hyperbilirubinemia (4%), with only one discontinuation due to AEs as of the data cutoff.

These updated data suggest that the novel, intermittent dosing schedule used in the FRAME study continues to show encouraging clinical activity in patients with recurrent LGSOC, including in patients previously treated with a MEK inhibitor. Expansion cohorts are also ongoing in pancreatic cancer, KRAS/BRAF mutant endometrioid cancer and KRAS-G12V NSCLC.

Details for the ESMO (Free ESMO Whitepaper) 2021 mini oral presentation are as follows:

Title: Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer

Speaker: Dr Susana Banerjee, Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Consultant Medical Oncologist and Research Lead for The Royal Marsden NHS Foundation Trust Gynaecology Unit

Presentation #: 725MO
Session: Mini oral – Gynaecological cancers
Date and Time: Sunday, September 19, 2021; 17:50-17:55 CEST

About the Phase 1/2 FRAME Study

The FRAME study is an open-label, investigator-initiated study that is designed to assess safety, dose response and preliminary efficacy of the VS-6766/defactinib combination in patients with KRAS mutant solid tumors, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The FRAME study is being led by Professor Udai Banerji, MBBS, MD, DNB, PhD, FRCP, Deputy Director of the Drug Development Unit at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and is being conducted in the United Kingdom. In this study, VS-6766 was administered using a twice-weekly dose escalation schedule and is administered 3 out of every 4 weeks. Defactinib is administered using a twice-daily dose escalation schedule, also 3 out of every 4 weeks. Dose levels are assessed in 3 cohorts: cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg, defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib 400mg). The recommended Phase 2 dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).

About RAMP 201

Verastem Oncology has initiated a Phase 2 registration-directed trial evaluating VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC as part of RAMP (Raf And Mek Program). RAMP 201 (ENGOTov60/GOG3052) is an adaptive, two-part multicenter, parallel cohort, randomized, open-label trial to evaluate the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC.3 The first part of the study will determine the optimal regimen of either VS-6766 monotherapy or in combination with defactinib in patients with recurrent LGSOC randomized 1:1 in each treatment arm. The determination of which regimen to take forward into the expansion phase of the trial will be made based on objective response rate data. The expansion phase of the study will examine efficacy and safety parameters of the regimen selected.

For more information, please visit www.RAMP201Study.com.

About the VS-6766/Defactinib Combination

The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors. In an ongoing investigator-initiated Phase 1/2 FRAME study, the combination of VS-6766 and defactinib is being evaluated in patients with LGSOC, KRAS mutant NSCLC and colorectal cancer (CRC). The FRAME study was expanded to include new cohorts in pancreatic cancer, KRAS mutant endometrioid cancer and KRAS-G12V NSCLC. Verastem Oncology is also supporting an investigator-initiated Phase 2 trial evaluating VS-6766 with defactinib in patients with metastatic uveal melanoma. Verastem Oncology has initiated Phase 2 registration-directed trials of VS-6766 with defactinib in patients with recurrent LGSOC and in patients with recurrent KRAS-G12V mutant NSCLC as part of its RAMP (Raf And Mek Program).

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK inhibitor VS-6766, with defactinib, its FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

On September 19, 2021 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results from a cohort of the Phase 1/2 KRYSTAL–1 study evaluating adagrasib at the 600mg BID dose as both monotherapy and in combination with cetuximab in patients with heavily pretreated colorectal cancer harboring a KRASG12C mutation (Press release, Mirati, SEP 19, 2021, View Source [SID1234587931]). Results showed that adagrasib alone and with cetuximab demonstrated significant clinical activity and broad disease control in these patients. The findings (Abstract # LBA6) will be presented today at 9:47 a.m. ET as a late-breaking oral presentation during the Presidential Symposium II session at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) 2021.

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"Patients living with KRAS-mutated colorectal cancer face a significant medical need for new treatment options," said Dr. Jared Weiss M.D., lead study investigator and associate professor of medicine, division of oncology at University of North Carolina-Chapel Hill. "The positive results presented today show that adagrasib alone or in combination with cetuximab may improve clinical outcomes in patients with colorectal cancer harboring a KRASG12C mutation."

Summary of Clinical Results

As of May 25, 2021, 80% of patients enrolled in the adagrasib monotherapy arm (n=46) received at least two prior lines of systemic anticancer therapies, and had a median follow up of 8.9 months. Of the evaluable patients (n=45), results showed an investigator assessed response rate (RR) of 22%, including one unconfirmed partial response (PR), and a disease control rate (DCR) of 87%; the median duration of response (DOR) was 4.2 months. In all enrolled patients, the median progression free survival (PFS) was 5.6 months (95% Confidence Interval, CI: 4.1,8.3).
As of July 9, 2021, 90% patients enrolled in the adagrasib plus cetuximab arm (n=32) received at least two prior lines of systemic anticancer therapies, and had a median follow up of 7 months. Of the evaluable patients (n=28), results showed an investigator assessed RR of 43%, including two unconfirmed PRs and a DCR rate of 100%. After the data cutoff date, of the two unconfirmed PRs, follow up scans showed one patient had a confirmed PR, and the second patient progressed. At the time of the analysis, 63% (20/32) of enrolled patients remained on treatment.
Adagrasib monotherapy and in combination with cetuximab was well-tolerated in this study, with a manageable safety profile. Grade 3/4 treatment related adverse events (TRAEs) were observed in 30% of patients treated with adagrasib alone, and in 16% of patients treated with the combination. Treatment related adverse events led to treatment discontinuation in 6% of patients who received combination therapy and in none (0%) of those who received adagrasib monotherapy. No Grade 5 TRAEs were observed in either treatment arm.
"Adagrasib represents Mirati’s scientific commitment to the discovery and development of novel targets that may lead to new treatment options for people with cancer," said Charles M. Baum, M.D., Ph.D., president and chief executive officer, Mirati Therapeutics, Inc. "The results presented at ESMO (Free ESMO Whitepaper) support further study of adagrasib in KRAS-mutated colon cancer, including with our ongoing, global registrational Phase 3 trial, KRYSTAL–10, comparing adagrasib plus cetuximab to standard of care chemotherapy in second-line KRASG12C-mutated colorectal cancer."

Virtual Investor Event

Mirati Therapeutics will host a virtual Investor Event on Monday, September 20, 2021 at 8:30 a.m. ET / 5:30 a.m. PT.

Company executives will discuss:

A top-line update from the Phase 2 registrational cohort of the KRYSTAL-1 study evaluating adagrasib in previously-treated patients with KRASG12C-mutated non-small cell lung cancer (NSCLC)
Findings from the CRC cohort of the Phase 1/2 KRYSTAL-1 study evaluating adagrasib as monotherapy and in combination with cetuximab in patients with heavily pretreated CRC harboring the KRASG12C mutation, as presented at the 2021 ESMO (Free ESMO Whitepaper) Congress
Results from the Phase 2 MRTX-500 study evaluating sitravatinib combined with nivolumab in patients with non-squamous NSCLC who progressed on or after prior checkpoint inhibitor therapy, to be presented at the 2021 ESMO (Free ESMO Whitepaper) Congress
Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

About the KRYSTAL-1 Study

KRYSTAL–1 is an open-label Phase 1/2 multiple expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anticancer therapies in patients with advanced solid tumors harboring a KRASG12C mutation.

About Adagrasib (MRTX849)

Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24−48 hours. Adagrasib is a being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including non-small cell lung cancer (NSCLC), colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.

On September 19, 2021 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi announced positive Phase 3 results for a Libtayo (cemiplimab) combination treatment were presented today during a late-breaking session at the European Society for Medical Oncology Virtual Congress 2021. The trial, which met its primary overall survival (OS) endpoint and all key secondary endpoints, assessed the investigational use of PD-1 inhibitor Libtayo in combination with a physician’s choice of platinum-doublet chemotherapy (Libtayo combination) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) irrespective of histology and across all PD-L1 expression levels, compared to chemotherapy alone. These results were also achieved in a patient population with varied baseline characteristics and will form the basis of regulatory submissions, including in the U.S. and European Union (EU).

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"Libtayo added to chemotherapy significantly improved patient outcomes, extending median overall survival to 22 months and median progression-free survival to 8 months," said Miranda Gogishvili, M.D., an oncologist at the High Technology Medical Center University Clinic, in Tbilisi, Georgia and a trial investigator. "Exploratory analyses showed that survival improvements were seen across squamous and non-squamous histologies and in patients with reduced daily functioning, with 43% of patients having squamous disease and 84% having an ECOG 1 performance status. Furthermore, in another exploratory analysis, the Libtayo combination helped delay deterioration in patient-reported quality of life and pain symptoms."

In the overall population, patients treated with the Libtayo combination (n=312) experienced significant improvements compared to those receiving chemotherapy alone (n=154), including a:

22-month median OS compared to 13 months for chemotherapy, representing a 29% relative reduction in the risk of death (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.53 to 0.93; p=0.014). The 12-month probability of survival was 66% for the Libtayo combination and 56% for chemotherapy.
8-month median progression-free survival (PFS) compared to 5 months for chemotherapy, representing a 46% relative reduction in the risk of disease progression (HR: 0.56; 95% CI: 0.44 to 0.70; p<0.0001). The 12-month probability of PFS was 38% for the Libtayo combination and 16% for chemotherapy.
43% objective response rate (ORR) compared to 23% for chemotherapy.
16-month median duration of response (DOR) compared to 7 months for chemotherapy.
Favorable patient-reported outcomes were also observed. Specifically, the Libtayo combination delayed deterioration in pain symptoms (HR: 0.39; 95% CI: 0.26 to 0.60; nominal p<0.0001) and showed a trend towards delayed deterioration in global health status/quality of life (HR: 0.78; 95% CI: 0.51 to 1.19; nominal p=0.248), compared to chemotherapy. The Libtayo combination also improved pain symptoms, compared to chemotherapy (-4.98 difference in baseline changes between treatment groups; 95% CI: -8.36 to -1.60; nominal p=0.004).

No new Libtayo safety signals were identified. The median duration of exposure was 38 weeks for the Libtayo combination (n=312) and 21 weeks for chemotherapy (n=153). Adverse events (AEs) of any grade occurred in 96% of patients receiving the Libtayo combination and 94% of patients receiving chemotherapy alone, with 19% and 0% being immune-mediated, respectively. For the Libtayo combination and chemotherapy groups, the most common AEs were anemia (44%, 40%), alopecia (37%, 43%) and nausea (25%, 16%); grade ≥3 AEs occurring in ≥5% of patients were anemia (10%, 7%) and neutropenia (both 6%). Treatment discontinuation due to AEs occurred in 5% of patients receiving the Libtayo combination and 3% receiving chemotherapy.

"This Phase 3 trial was stopped early because Libtayo significantly improved overall survival compared to chemotherapy, a milestone also achieved by our Phase 3 trial for Libtayo monotherapy as a first-line treatment for advanced non-small cell lung cancer with high PD-L1 expression," said Israel Lowy, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Oncology at Regeneron. "Both trials were designed to reflect everyday clinical practice by allowing for the enrollment of patients with difficult-to-treat disease characteristics. And this is the second Libtayo trial to demonstrate significant improvement in its primary and key secondary endpoints for these patient populations, compared to chemotherapy."

Lung cancer is the leading cause of cancer death worldwide. In 2020, an estimated 2.2 million and 225,000 new cases were diagnosed globally and in the U.S., respectively. Approximately 84% of all lung cancers are NSCLC, with 75% of these cases diagnosed in advanced stages. While PD-1 inhibitor monotherapy has primarily advanced the treatment of NSCLC with ≥50% PD-L1 expression, approximately 70% of all NSCLC cases will have <50% PD-L1 expression, making it the most common treatment setting.

"These data add to the growing body of evidence supporting the use of Libtayo in patients with advanced non-small cell lung cancer," said Peter C. Adamson, M.D., Global Development Head, Oncology and Pediatric Innovation at Sanofi. "With additional trials underway investigating Libtayo as the backbone in combinations with conventional and novel therapeutic approaches, we are encouraged by the potential to further improve outcomes for patients with difficult-to-treat cancers."

The use of Libtayo in combination with chemotherapy for advanced NSCLC is investigational, and its safety and efficacy have not been fully evaluated by any regulatory authority.

Investor Webcast Information
Regeneron will host a conference call and simultaneous webcast to share updates on Regeneron’s oncology portfolio on Monday, September 20 at 8:30 a.m. ET. To access this call, dial 888 660 6127 (U.S.) or +1 973 890 8355 (International). A link to the webcast may be accessed from the "Investors and Media" page of Regeneron’s website at www.regeneron.com. A replay of the conference call and webcast will be archived on the Company’s website and will be available for at least 30 days.

About the Phase 3 Trial
The randomized, multicenter Phase 3 trial, called EMPOWER-Lung 3, investigated a first-line combination treatment of Libtayo and platinum-doublet chemotherapy, compared to platinum-doublet chemotherapy alone. The trial enrolled 466 patients with locally advanced or metastatic NSCLC, as well as squamous or non-squamous histologies across all PD-L1 expression levels and with no ALK, EGFR and ROS1 aberrations.

Patients were randomized 2:1 to receive either Libtayo 350 mg (n=312) or placebo (n=154) administered intravenously every 3 weeks for 108 weeks, plus platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The primary endpoint was OS, and key secondary endpoints were PFS and ORR. The probability of survival and PFS at 12 months were calculated according to Kaplan-Meier estimates.

Notably, patients in the trial had a variety of baseline characteristics commonly considered difficult-to-treat. Among those enrolled, 43% had tumors with squamous histology, 67% had tumors with <50% PD-L1 expression, 15% had inoperable locally advanced disease not eligible for definitive chemoradiation, and 7% had pretreated and clinically stable brain metastases. Additionally, 84% of patients had an ECOG 1 performance status. ECOG performance status assesses patient ability to conduct daily living activities and prognosis on a scale of increasing severity ranging from 0 (no symptoms) to 5 (death).

About Libtayo
Libtayo is a fully human monoclonal antibody targeting the PD-1 immune checkpoint receptor on T-cells. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation.

The generic name for Libtayo in its approved U.S. indications is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. FDA. Libtayo is being jointly developed by Regeneron and Sanofi under a global collaboration agreement.

The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. Libtayo is currently being investigated in advanced cervical cancer, as well as in trials combining Libtayo with either conventional or novel therapeutic approaches for other solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.

About Regeneron’s VelocImmune Technology
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately a quarter of all original, FDA-approved and authorized fully human monoclonal antibodies currently available. This includes REGEN–COV (casirivimab with imdevimab), Dupixent (dupilumab), Libtayo (cemiplimab-rwlc), Praluent (alirocumab), Kevzara (sarilumab), Evkeeza (evinacumab-dgnb) and Inmazeb (atoltivimab, maftivimab and odesivimab-ebgn).

IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS

What is Libtayo?
Libtayo is a prescription medicine used to treat people with a type of skin cancer called cutaneous squamous cell carcinoma (CSCC) that has spread or cannot be cured by surgery or radiation.

Libtayo is a prescription medicine used to treat people with a type of skin cancer called basal cell carcinoma that cannot be removed by surgery (locally advanced BCC) and have received treatment with a hedgehog inhibitor (HHI), or cannot receive treatment with an HHI.

Libtayo is a prescription medicine used to treat people with a type of skin cancer called basal cell carcinoma that has spread (metastatic BCC) and have received treatment with an HHI, or cannot receive treatment with an HHI. This use is approved based on how many patients responded to treatment and how long they responded. Studies are ongoing to provide additional information about clinical benefit.

Libtayo is a prescription medicine used to treat people with a type of lung cancer called non-small cell lung cancer (NSCLC). Libtayo may be used as your first treatment when your lung cancer has not spread outside your chest (locally advanced lung cancer) and you cannot have surgery or chemotherapy with radiation, or your lung cancer has spread to other areas of your body (metastatic lung cancer), and your tumor tests positive for high "PD-L1" and your tumor does not have an abnormal "EGFR"," ALK "or "ROS1" gene.

It is not known if Libtayo is safe and effective in children.

What is the most important information I should know about Libtayo?
Libtayo is a medicine that may treat certain cancers by working with your immune system. Libtayo can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:

Lung problems: cough, shortness of breath, or chest pain
Intestinal problems: diarrhea (loose stools) or more frequent bowel movements than usual, stools that are black, tarry, sticky or have blood or mucus, or severe stomach area (abdomen) pain or tenderness
Liver problems: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach area (abdomen), dark urine (tea colored), or bleeding or bruising more easily than normal
Hormone gland problems: headache that will not go away or unusual headaches, eye sensitivity to light, eye problems, rapid heartbeat, increased sweating, extreme tiredness, weight gain or weight loss, feeling more hungry or thirsty than usual, urinating more often than usual, hair loss, feeling cold, constipation, your voice gets deeper, dizziness or fainting, or changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Kidney problems: decrease in your amount of urine, blood in your urine, swelling of your ankles, or loss of appetite
Skin problems: rash, itching, skin blistering or peeling, painful sores or ulcers in mouth or nose, throat, or genital area, fever or flu-like symptoms, or swollen lymph nodes
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with Libtayo. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: chest pain, irregular heartbeat, shortness of breath or swelling of ankles, confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs, double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight, persistent or severe muscle pain or weakness, muscle cramps, low red blood cells, or bruising
Infusion reactions that can sometimes be severe. Signs and symptoms of infusion reactions may include: nausea, chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, feel like passing out, fever, back or neck pain, or facial swelling.
Rejection of a transplanted organ. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.
Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with Libtayo. Your healthcare provider will monitor you for these complications.
Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during your treatment with Libtayo. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with Libtayo if you have severe side effects.

Before you receive Libtayo, tell your healthcare provider about all your medical conditions, including if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome are pregnant or plan to become pregnant. Libtayo can harm your unborn baby
Females who are able to become pregnant:

Your healthcare provider will give you a pregnancy test before you start treatment.
You should use an effective method of birth control during your treatment and for at least 4 months after your last dose of Libtayo. Talk with your healthcare provider about birth control methods that you can use during this time.
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Libtayo.
are breastfeeding or plan to breastfeed. It is not known if Libtayo passes into your breast milk. Do not breastfeed during treatment and for at least 4 months after the last dose of Libtayo.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Libtayo include muscle or bone pain, tiredness, rash, and diarrhea. These are not all the possible side effects of Libtayo. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Regeneron Pharmaceuticals and Sanofi at
1-877-542-8296.

On September 19, 2021 Novartis reported results of the final overall survival (OS) analysis of the Phase III MONALEESA-2 study, which evaluated Kisqali (ribociclib) in combination with letrozole compared to placebo plus letrozole in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer with no prior systemic treatment for advanced disease (Press release, Novartis, SEP 19, 2021, View Source [SID1234587928]). These data will be presented as a late-breaker oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 on September 19 (#LBA17).

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Kisqali in combination with letrozole met its key secondary endpoint of OS, demonstrating a statistically significant and clinically meaningful improvement in survival (median 63.9 vs. 51.4 months; HR=0.76; 95% CI: 0.63-0.93; p=0.004)2. The analysis found that after a median follow-up of over six and a half years, the longest for any CDK4/6 inhibitor trial to date, the improvement in the median OS was over one year2. MONALEESA-2 showed that after five years, patients treated with Kisqali in combination with letrozole had more than a 50% chance of survival (52.3% vs. 43.9%; 95% CI: 46.5-57.7 vs. 38.3-49.4)2.

"These remarkable ribociclib overall survival data are highly encouraging and represent the longest reported median survival from a randomized trial in HR+/HER2- advanced breast cancer. This extension of life is great news for our patients and the building block for further progress," said Gabriel N. Hortobagyi, MD, FACP, professor of medicine with The University of Texas MD Anderson Cancer Center. "I have spent the last 45 years researching and increasing our scientific understanding of breast cancer, so it is incredibly rewarding to see just how far we’ve come."

In MONALEESA-2, a 12-month delay in time to chemotherapy was observed with Kisqali (median 50.6 vs. 38.9 months; HR=0.74; 95% CI: 0.61-0.91) compared to those taking letrozole alone2. With this longer follow-up, no new safety signals were observed; adverse events were consistent with previously reported Phase III trial results for Kisqali.

"As we reimagine medicine and strive for cures, our MONALEESA program continues to push boundaries by demonstrating that Kisqali is unique in its ability to give people living with advanced breast cancer more time," said Susanne Schaffert, PhD, President, Novartis Oncology. "Our mission is to improve and extend the lives of those with cancer. For people with HR+/HER2- advanced breast cancer, these data are not just numbers and may mean more life milestones — yet, we will not rest as we continue to investigate the full potential that Kisqali can bring to patients."

In MONALEESA-2, the primary endpoint progression-free survival (PFS) was met at the initial analysis [median PFS; 95% CI (19.3 months – not reached) vs. 14.7 months (13.0 – 16.5 months); HR=0.556; p=0.00000329]5. These new OS results mark the third statistically significant and clinically meaningful survival benefit achieved by Kisqali in the MONALEESA program. Novartis will submit the data to global health authorities to support label updates.

"When treatment offers long overall survival—and in this case, the longest ever reported in HR+/HER2- advanced breast cancer—patients have more time to be with family and loved ones and to pursue whatever makes them happy. These data offer new hope for people with advanced or metastatic breast cancer, which remains the leading cause of cancer death in women worldwide," said Shirley A. Mertz, President, Metastatic Breast Cancer Network (MBCN).

Visit View Source for the latest information from Novartis, including our commitment to the Oncology community, and access to our ESMO (Free ESMO Whitepaper)2021 Virtual Scientific Program data presentations (for registered participants).

About Kisqali (ribociclib)
Kisqali is the CDK4/6 inhibitor with the largest body of clinical trial evidence demonstrating consistent and superior overall survival benefit compared to endocrine therapy alone. Overall survival results from MONALEESA-7 and MONALEESA-3 were presented at ASCO (Free ASCO Whitepaper) 2019 and ESMO (Free ESMO Whitepaper) 2019 respectively, as well as published in the New England Journal of Medicine, with updated exploratory analyses presented at SABCS 2020 and ASCO (Free ASCO Whitepaper) 2021, demonstrating Kisqali plus endocrine therapy significantly extends life in pre/perimenopausal or postmenopausal women with HR+/HER2- advanced breast cancer3,4,6,7.

Kisqali is approved by the US Food and Drug Administration (FDA) and by the European Commission (EC) as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor. Kisqali in combination with an aromatase inhibitor is approved for the treatment of pre-, peri- or postmenopausal women as initial endocrine-based therapy, and also indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women by the FDA and by the EC9. Kisqali is approved in over 95 countries1.

Novartis is continuing to reimagine cancer with additional trials of Kisqali. NATALEE is a large confirmatory clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- early breast cancer being conducted in collaboration with Translational Research In Oncology (TRIO)10. Novartis is also collaborating with SOLTI, who is leading the Phase III HARMONIA clinical trial evaluating Kisqali compared to palbociclib in patients with HR+/HER2- advanced breast cancer with aggressive tumor biology, defined as HER2-enriched1.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About Novartis in Advanced Breast Cancer
Novartis tackles breast cancer with superior science, collaboration and a passion for transforming patient care. We’ve taken a bold approach to our research by including patient populations often neglected in clinical trials, identifying new pathways or mutations that may play a role in disease progression and developing therapies that not only maintain, but also improve, quality of life for patients. Our priority over the past 30 years and today is to deliver treatments proven to improve and extend lives for those diagnosed with advanced breast cancer.

Important Safety Information from the Kisqali EU SmPC
Kisqali (ribociclib) is a prescription medicine approved in combination with an aromatase inhibitor as initial endocrine – based therapy in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer or fulvestrant as initial endocrine – based therapy or following disease progression on endocrine therapy in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if Kisqali is safe and effective in children or adolescents. Kisqali can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Kisqali is not indicated for concomitant use with tamoxifen due to an increased risk of QT prolongation. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their health care provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use highly effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) include infections, white blood cell count decreases, headache, cough, nausea, tiredness, diarrhea, vomiting, constipation, hair loss and rash. The most common Grade 3/4 side effects (incidence >5%) were infections, low neutrophils, low leukocytes, low red blood cells, abnormal liver function tests, low lymphocytes, low phosphate levels and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Please see full Prescribing Information for Kisqali, available at www.Kisqali.com.