On November 21, 2021 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, metabolic, autoimmune and other major diseases, reported first interim analysis results of the randomized, double-blinded, multi-center Phase 3 ORIENT-31 study conducted in China evaluating sintilimab and anti-VEGF antibody combination therapy (i.e., sintilimab plus BYVASDA [bevacizumab biosimilar injection] combined with chemotherapy [pemetrexed and cisplatin]) in patients with EGFR-mutated non-squamous non-small cell lung-cancer (nsqNSCLC) who progressed after EGFR-TKI therapy in an oral presentation at the ESMO (Free ESMO Whitepaper) (European Society for Medical Oncology) Virtual Plenary: November 2021 (Abstract #300) (Press release, Innovent Biologics, NOV 21, 2021, View Source [SID1234595868]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

In the first interim analysis reviewed by the Independent Data Monitoring Committee (IDMC), in the intent-to-treat (ITT) population, based on assessment by the Independent Radiographic Review Committee (IRRC), Arm A (sintilimab plus BYVASDA[bevacizumab biosimilar injection] in combination with chemotherapy group) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with Arm C (chemotherapy group), with a HR of 0.464 (95%CI: 0.337, 0.639; p<0.0001). The median progression-free survival (PFS) (95%CI) was 6.9 months (6.0, 9.3) in Arm A, and 4.3 months (4.1, 5.4) in Arm C. The prespecified PFS futility analysis that compares Arm A to Arm B (sintilimab and chemotherapy group) did not cross futility stopping boundary (HR=0.726, 95%CI: 0.528, 0.998). A numerical benefit of adding BYVASDA (bevacizumab biosimilar injection) to sintilimab and chemotherapy combination was observed (based on IRRC assessment). Additionally, the key secondary endpoints of objective response rate (ORR) and duration of response (DOR) were improved in Arm A compared with Arm C, and the results of PFS, ORR and DOR assessed by the investigator were consistent with the results assessed by IRRC. The PFS data of Arm B vs Arm C was immature yet, with a numerical benefit observed as well. The safety profile of this study was consistent with that observed in previously reported studies of sintilimab and BYVASDA (bevacizumab biosimilar injection), without new unexpected safety signals. Innovent plans to review these results and file the supplemental New Drug Application (sNDA) to the National Medical Products Administration (NMPA) in China in the near future.

The principal investigator of the ORIENT-31, Prof. Shun Lu from the Oncology Department of Shanghai Chest Hospital, stated, "Despite initial clinical response to EGFR-TKI, virtually all advanced EGFR-mutated NSCLC inevitably acquire resistance mechanisms and progress after treatment with an EGFR-TKI. For those patients with EGFR-mutated advanced nsqNSCLC who have progressed following EGFR-TKI treatment, platinum-based chemotherapy is the current standard of care, but with limited benefit. New treatment options are imperative for this unmet medical need. Globally, ORIENT-31 is the first prospective, double-blind Phase 3 study to demonstrate significant PFS benefit of combination therapy of PD-1 and VEGF inhibitors with chemotherapy compared to standard care of therapy in this patient population. The study has shown the clinical value of adding sintilimab plus BYVASDA (bevacizumab biosimilar injection) to platinum-based chemotherapy. I am honored to have this opportunity to share the results of this study as an oral presentation at this year’s ESMO (Free ESMO Whitepaper) Virtual Plenary. This modified regimen brings forth a new and more effective treatment option and provides clinically meaningful benefits to patients with EGFR-mutated nsqNSCLC following treatment with an EGFR TKI."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "Lung cancer is one of the most prevalent cancers and remains the leading cause of cancer-related mortality both in China and worldwide. EGFR-mutated NSCLC is the most prevalent molecular subtype in Chinese lung cancer patients, accounting for 40% to 50% of nsqNSCLC. While immunotherapy has greatly changed the treatment paradigm for many malignancies, it has not yet conquered driver genes mutated cancers. Drug resistance is unavoidable for patients with EGFR-mutated advanced NSCLC after first, second and third generation EGFR-TKIs treatments, with limited treatment options, representing a large unmet medical need. The ORIENT-31 data at this year’s ESMO (Free ESMO Whitepaper) indicates the potential of combination therapy to prolong lives of these patients. We are grateful for all the contributions made by the investigators and patients in the ORIENT-31 study – together we accomplished this meaningful milestone."

About Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death worldwide, and the second most commonly diagnosed tumor type. Non-small cell lung cancer (NSCLC) accounts for about 80% to 85% of all lung cancer, in which about 70% of NSCLC patients present with locally advanced or metastatic disease that is not suitable for surgical resection at diagnosis. In China, nsqNSCLC accounts for 70% of NSCLC, in which about 40% to 50% of nsqNSCLC patients have an EGFR mutation. The standard first-line treatment for patients with advanced EGFR-mutated NSCLC is a third generation EGFR TKI, or first or second generation EGFR TKI. For patients who have progressed following EGFR-TKI treatment, platinum-based chemotherapy is still the standard therapy with limited benefit, representing a large unmet medical need.

About the ORIENT-31 Study

ORIENT-31 is a randomized, double-blind, multi-center Phase 3 clinical study conducted in China evaluating sintilimab, with or without BYVASDA (bevacizumab biosimilar injection), combined with chemotherapy (pemetrexed and cisplatin) in patients with EGFR-mutated locally advanced or metastatic nsqNSCLC who have progressed following EGFR TKI treatment (ClinicalTrials.gov, NCT003802240). The primary endpoint is PFS as assessed by BIRRC based on RECIST v1.1. The secondary endpoints include overall survival (OS), PFS as assessed by investigators, ORR and safety.

Eligible patients included: patients with disease progression following first or second generation EGFR TKI and confirmed as T790M negative, or T790M positive but further progressed on third generation EGFR-TKI treatment, or patients with disease progression following third generation EGFR TKI as first line treatment.

Patients were randomized in a 1:1:1 ratio to receive sintilimab plus BYVASDA (bevacizumab biosimilar injection) combined with pemetrexed and cisplatin (Arm A), sintilimab plus placebo 2 combined with pemetrexed and cisplatin (Arm B), or placebo 1 plus placebo 2 combined with pemetrexed and cisplatin (Arm C). After 4 cycles of combination treatment, patients will receive maintenance treatment of sintilimab plus BYVASDA and pemetrexed, sintilimab plus placebo 2 and pemetrexed, placebo 1 plus placebo 2 and pemetrexed, until radiographic disease progression, unacceptable toxicity or any other conditions that required treatment discontinuation. Target accrual is 480 patients. By the data cutoff date of the first interim analysis, 444 patients were enrolled.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Eli Lilly and Company. Sintilimab is an immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab worldwide, to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for four indications, including:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of nonsquamous non-small cell lung cancer
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of hepatocellular carcinoma
Additionally, Innovent currently has two regulatory submissions accepted for review in China for sintilimab monotherapy for the first-line treatment of esophageal squamous cell carcinoma, and for sintilimab in combination with chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma.

Additionally, three clinical studies of sintilimab have met their primary endpoints:

Phase 2 study as second-line treatment of esophageal squamous cell carcinoma
Phase 3 study as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy
Phase 3 study in combination with BYVASDA (bevacizumab biosimilar injection) and chemotherapy (pemetrexed and cisplatin) for EGFR-mutated nonsquamous NSCLC following EGFR-TKI treatment.
In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

Sintilimab was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

About BYVASDA (bevacizumab biosimilar injection)

BYVASDA, also known as IBI305, is a bevacizumab biosimilar and a recombinant humanized anti-VEGF monoclonal antibody drug. Vascular endothelial growth factor (VEGF) is an important factor in angiogenesis that is highly expressed by the endothelial cells in most human tumors. An anti-VEGF antibody binds VEGF-A selectively with high affinity and blocks its binding to VEGF-2 receptors on the surface of vascular endothelial cells, thereby inhibiting signaling pathways such as PI3K-Akt/PKB and Ras-Raf-MEK-ERK. BYVASDA produces anti-tumor effects by inhibiting the growth, proliferation and migration of vascular endothelial cells, blocking angiogenesis, reducing vascular permeability, blocking blood supply to tumor tissues, inhibiting the proliferation and metastasis of tumor cells and inducing apoptosis in tumor cells. Since its launch, bevacizumab has been approved for the treatment of patients with multiple malignant tumors globally, including non-small cell lung cancer, metastatic colorectal cancer, glioblastoma, renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer. The efficacy and safety of bevacizumab in these tumor types have been well recognized worldwide.

In China, BYVASDA (bevacizumab biosimilar injection) is approved for indications including advanced non-small cell lung cancer, metastatic colorectal cancer, adult recurrent glioblastoma, and advanced or unresectable hepatocellular carcinoma.

On November 21, 2021 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies and cytokines for the treatment of cancer and autoimmune diseases, and Zenas BioPharma ("Zenas"), a global biopharmaceutical company based in the USA and China committed to the development and delivery of immune-based therapies, reported that Zenas has acquired from Xencor exclusive worldwide rights to develop, manufacture and commercialize the investigational antibody obexelimab (Press release, Xencor, NOV 21, 2021, View Source [SID1234595866]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Obexelimab is a potential first-in-class bifunctional antibody that targets CD19 with its variable domain and uses Xencor’s XmAb Immune Inhibitor Fc Domain to target FcγRIIb, a receptor that inhibits the function of B-cells, which are important components in the immune system. Xencor demonstrated through early-stage clinical studies that obexelimab effectively inhibits B-cell function without depleting the cells and generates an encouraging treatment effect in patients with multiple autoimmune diseases.

"Zenas is advancing a broad pipeline of differentiated drug candidates that are intended to bring best-in-class innovation to patients with underserved medical needs," said Hua Mu, Ph.D., MD, president and chief executive officer at Zenas. "Today, we are pleased to add obexelimab to our portfolio, and based on its clinical profile, we believe it is positioned as a first-in-class candidate with the potential to treat numerous autoimmune diseases."

"Obexelimab’s highly potent and broad blockade of B-cell activation—without depleting B cells—differentiates it from other B-cell targeting therapies, and it has demonstrated disease-modifying activity in settings where B-cell inhibition is a proven strategy," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "In Zenas BioPharma, we have found a partner committed to broadly and aggressively developing therapeutics like obexelimab for patients with autoimmune diseases, enabling Xencor’s continued focus on the growing opportunities provided by our XmAb bispecific antibody and cytokine pipeline."

Under the terms of the new agreement, Zenas will issue to Xencor a warrant giving Xencor the right to acquire additional Zenas equity, such that Xencor’s total equity in Zenas would be 15% of its fully diluted capitalization following the closing of Zenas’ next round of equity financing, subject to certain requirements. Xencor previously received equity in Zenas under a separate license agreement. Xencor is also eligible to receive up to $480 million based on the achievement of certain clinical development, regulatory and commercialization milestones and is eligible to receive tiered, mid-single digit to mid-teen percent royalties upon commercialization of obexelimab, dependent on geography. Zenas will have sole responsibility for advancing the research, development, regulatory and commercial activities of obexelimab worldwide.

On November 20, 2021 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that investigators presented results from the neratinib arm of the Phase II Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT Trial) at the 2021 Society for Neuro-Oncology Annual Meeting (Press release, Puma Biotechnology, NOV 20, 2021, View Source [SID1234595867]). The presentation, entitled "Preliminary results of the neratinib arm in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): a phase II platform trial using Bayesian adaptive randomization," was presented as an oral presentation in the Abstract Session: Clinical Trials II Session. A copy of the presentation is available on the Puma Biotechnology website.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

The INSIGhT trial is a multisite investigator-initiated Phase II screening adaptive platform trial where patients with newly diagnosed unmethylated glioblastoma who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. All patients receive radiation therapy and temozolomide and then patients are randomized to receive either adjuvant temozolomide or adjuvant treatment with an experimental agent (neratinib). At the initiation of INSIGhT, three experimental arms, each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms were allowed to drop because of low probability of treatment impact on overall survival. The primary endpoint of INSIGhT is overall survival (OS). Progression-free survival (PFS) analysis is used to influence randomization. For the neratinib arm of the trial, patients received 240 mg of neratinib daily as a single agent with mandatory loperamide prophylaxis.

For the neratinib arm of the trial, there were 149 patients in the intent-to-treat population, including 81 patients treated with neratinib and 68 patients in the control arm. For the intent-to-treat population, PFS was not significantly longer (HR 0.75; p=0.12, log rank test) with neratinib (median 6.0 months) versus the control arm (median 4.7 months) and there was no significant improvement in OS (HR 1.01; p=0.75) between neratinib (median 13.8 months) vs. the control arm (median 14.7 months). For patients with activation of the EGFR pathway, defined as patients with either EGFR amplification or mutation, PFS was significantly longer (HR 0.58; p=0.04, log rank test) with neratinib (median 6.3 months) vs. the control arm (median 4.6 months); however, there was no significant improvement in overall survival (HR 0.97; p= 0.94) between neratinib (median 14.4 months) vs. the control arm (median 15.3 months).

Neratinib was generally well tolerated in the trial and toxicities for neratinib were similar to that previously described. For the 81 patients treated with neratinib, there were 6 cases (7.4%) of grade 3 diarrhea and no cases of grade 4 diarrhea. No new toxicity signals were identified in the trial.

Isabel Arrillaga-Romany, MD, PhD, Director of Neuro-Oncology Clinical Trials at Mass General Cancer Center, an investigator on the trial who presented the data at SNO, said, "Although preliminary results did not achieve the primary endpoint, subgroup analyses demonstrated improved PFS in patients with EGFR activation and a non-significant trend toward improved overall survival in patients with EGFRVIII mutations, which could warrant further investigation. Additionally, we are very pleased that this trial reinforced feasibility of randomized Bayesian adaptive platform trials for newly diagnosed glioblastoma."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "We would like to thank the INSIGHT trial investigators and the patients for their participation in the trial. This is the first data demonstrating an effect of neratinib in EGFR amplified or mutated glioblastoma. While we are not looking to pursue further clinical investigations of neratinib in this indication, we are evaluating the potential to develop a backup compound HKI-357, which has preclinically demonstrated better EGFR activity, in this indication."

On November 20, 2021 Exelixis, Inc. (Nasdaq: EXEL) reported detailed results from the first planned analysis of COSMIC-312, the ongoing phase 3 pivotal trial evaluating cabozantinib (CABOMETYX) in combination with atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma (HCC) (Press release, Exelixis, NOV 20, 2021, View Source [SID1234595865]). The data are being presented at 7:00 p.m. SGT (6:00 a.m. EST, 3:00 a.m. PST) on Saturday, November 20 in the Virtual Plenary Session during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Virtual Oncology Week 2021.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

As announced in June and presented today, at a median follow-up of 15.8 months, the primary analysis showed the primary endpoint of progression-free survival (PFS) per RECIST 1.1 by blinded independent review committee (BIRC) was met; in the PFS intent-to-treat (PITT) population, cabozantinib in combination with atezolizumab significantly reduced the risk of disease progression or death by 37% compared with sorafenib (hazard ratio [HR]: 0.63; 99% confidence interval [CI]: 0.44-0.91; P=0.0012; pre-specified critical p-value of 0.01). Median PFS was 6.8 months for cabozantinib in combination with atezolizumab (n=250) versus 4.2 months for sorafenib (n=122).

New results presented during the 2021 ESMO (Free ESMO Whitepaper) Virtual Plenary include detailed data for a prespecified interim analysis for the primary endpoint of overall survival (OS) in the intent-to-treat (ITT) population, which was conducted at the same time as the primary analysis for PFS in the PITT population. At a median follow-up of 13.6 months, the interim OS analysis in the ITT population showed a trend that favored cabozantinib in combination with atezolizumab but did not reach statistical significance (HR: 0.90; 96% CI: 0.69-1.18; P=0.438). Median OS was 15.4 months for cabozantinib in combination with atezolizumab (n=432) versus 15.5 months for sorafenib (n=217). The trial is continuing as planned to the final analysis of OS, anticipated in early 2022.

"We are encouraged by the significant improvement in progression-free survival observed in COSMIC-312, suggesting cabozantinib in combination with atezolizumab holds potential as a treatment to reduce the risk of disease progression or death for patients with advanced liver cancer," said R. Kate Kelley, M.D., Professor of Clinical Medicine, Division of Hematology/Oncology, University of California, San Francisco, and lead investigator on COSMIC-312. "Patients with this aggressive form of cancer, who may also have other comorbid conditions due to liver disease, face a poor prognosis and are in need of additional approaches to treatment."

Subgroup analyses of PFS in the PITT population and preliminary interim OS results in the ITT population were performed by disease etiology:

Median PFS in hepatitis B virus patients (n=109): 6.7 months for patients treated with cabozantinib in combination with atezolizumab compared with 2.7 months for sorafenib (HR: 0.46; 95% CI: 0.29–0.73).
Median OS in hepatitis B virus patients (n=191): 18.2 months for patients treated with cabozantinib in combination with atezolizumab compared with 14.9 months for sorafenib (HR: 0.53; 95% CI: 0.33–0.87).
Median PFS in hepatitis C virus patients (n=105): 7.9 months for patients treated with cabozantinib in combination with atezolizumab compared with 5.6 months for sorafenib (HR: 0.64; 95% CI: 0.38–1.09).
Median OS in hepatitis C virus patients (n=203): 13.6 months for patients treated with cabozantinib in combination with atezolizumab compared with 14.0 months for sorafenib (HR: 1.10; 95% CI: 0.72–1.68).
Median PFS in non-viral patients (n=158): 5.8 months for patients treated with cabozantinib in combination with atezolizumab compared with 7.0 months for sorafenib (HR: 0.92; 95% CI: 0.60–1.41).
Median OS in non-viral patients (n=255): 15.2 months for patients treated with cabozantinib in combination with atezolizumab, and not reached for sorafenib (HR: 1.18; 95% CI: 0.78–1.79).
In an interim analysis of the secondary endpoint of PFS per RECIST 1.1 by BIRC performed to determine the contribution of cabozantinib to the combination with atezolizumab, cabozantinib monotherapy reduced the risk of disease progression or death in the ITT population by 29% versus sorafenib (HR: 0.71; 99% CI: 0.51-1.01; P=0.0107; pre-specified critical p-value of 0.00451). Median PFS was 5.8 months for cabozantinib (n=188) versus 4.3 months for sorafenib (n=217).

Objective response rates per RECIST 1.1 by BIRC in the ITT population were 11% for cabozantinib in combination with atezolizumab, 3.7% for sorafenib and 6.4% for cabozantinib monotherapy. Disease control rates (complete response + partial response + stable disease) were 78%, 65% and 84%, respectively.

"Exelixis has a longstanding commitment to patients with liver cancer, and we are pleased to present more detailed efficacy and safety data during this ESMO (Free ESMO Whitepaper) Virtual Plenary Session reinforcing the potential of cabozantinib in combination with atezolizumab for patients with this disease who are in need of additional first-line treatment options," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. "We look forward to the final COSMIC-312 overall survival analysis in early 2022 and to submitting an sNDA to the FDA at that time."

The safety profile for cabozantinib in combination with atezolizumab was consistent with those previously observed for each single agent, and no new safety signals were identified. The most common grade 3 or higher adverse events (AEs) for cabozantinib in combination with atezolizumab were palmar-plantar erythrodysesthesia (7.9% versus 8.2% for sorafenib and 8.5% for cabozantinib monotherapy), hypertension (7.0%, 6.3% and 11.0%, respectively), aspartate aminotransferase increased (6.5%, 2.4% and 5.3%) and alanine aminotransferase increased (6.3%, 1.9% and 5.9%).

Rates of grade 3/4 treatment-related AEs were 51% for cabozantinib and atezolizumab, 30% for sorafenib and 52% for cabozantinib monotherapy. Rates of grade 5 treatment-related AEs were 1.9% for cabozantinib and atezolizumab, 0.5% for sorafenib and 0.5% for cabozantinib monotherapy. Treatment discontinuations due to treatment-related AEs in the combination arm were 6.1% for the combination of cabozantinib and atezolizumab and 14.0% for either cabozantinib and/or atezolizumab. The treatment-related discontinuation rate for sorafenib was 7.7% and for cabozantinib monotherapy was 8.5%.

About COSMIC-312

COSMIC-312 is a global, multicenter, randomized, controlled phase 3 pivotal trial that enrolled 837 patients at 281 study centers globally. Nine enrolled patients were from Mainland China, 232 were from elsewhere in Asia, and 596 were from outside Asia. An extension phase in China is ongoing and is not included in this current analysis. Patients were randomized approximately 2:1:1 to one of three arms: cabozantinib (40 mg) in combination with atezolizumab (n=432), sorafenib (n=217) or cabozantinib (60 mg; n=188). Exelixis is sponsoring COSMIC-312, and Ipsen is co-funding the trial. Genentech, a member of the Roche Group, is providing atezolizumab for use in this trial. More information about COSMIC-312 is available at ClinicalTrials.gov.

About HCC

More than 900,000 new cases of liver cancer, 90% of which are HCC, are diagnosed worldwide each year.1,2 HCC is a leading cause of cancer-related death, expected to cause 1 million global deaths annually by 2030.3 In the U.S., HCC is the fastest-rising cause of cancer-related death.4 Median survival for patients with symptomatic advanced HCC who are treated with systemic therapies is just 1 to 1.5 years.2 Research has shown that gastrointestinal varices – which are associated with a higher risk of death from bleeding – occur in about 60-75% of patients with advanced HCC, the presence of which can impact the therapies available to these patients.5,6

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with HCC 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 differentiated thyroid cancer (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.

CABOMETYX is not indicated as a treatment for previously untreated advanced HCC.

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.

On November 19, 2022 Betta Pharmaceutical Co., Ltd. reported that the company received the "Drug Registration Certificate" approved and issued by the National Medical Products Administration (NMPA) (Press release, Betta Pharmaceuticals, NOV 19, 2021, View Source [SID1234610680]). Ensatinib Hydrochloride Capsules (trade name: Bemena ) was officially approved for marketing , becoming the first domestic class 1 new drug for the treatment of ALK-mutated advanced non-small cell lung cancer in China.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Lung cancer is the malignant tumor with the highest mortality and morbidity in China, of which non-small cell lung cancer (NSCLC) accounts for about 80%-85% of lung cancers. Anaplastic lymphoma kinase (ALK) is one of the important oncogenic drivers of NSCLC, and ALK mutations are found in 5%-7% of NSCLC patients . Because this mutation is more common in young, non-smoking or light-smoking lung adenocarcinoma patients, it is easier to achieve 5-year survival after using targeted drugs than other gene mutations. ALK fusion mutation is also known as "diamond mutation".

△Mechanism of action of Ensatinib

Ensatinib hydrochloride is a new-generation, potent and highly selective new-generation ALK inhibitor. It is a brand-new innovative drug with completely independent intellectual property rights jointly developed by Betta Pharmaceuticals and its holding subsidiary Xcovery. In December 2018 , the drug registration application of ensatinib for patients with ALK -positive locally advanced or metastatic non-small cell lung cancer who had progressed after receiving crizotinib treatment or who were intolerant to crizotinib received national approval. Accepted by the Food and Drug Administration. In February 2019 , ensatinib was included in the priority review list by the Center for Drug Evaluation (CDE) of the State Food and Drug Administration. Since then, the clinical verification and registration on-site inspection organized by the Center for Food and Drug Inspection and Inspection ( CFDI ) of the State Food and Drug Administration have been completed successively .

The domestic phase II registration clinical study of ensatinib hydrochloride was led by Professor Zhang Zhang from Sun Yat-sen University Cancer Center, and a total of 27 domestic medical centers participated. The results of the study were published in full in the internationally renowned medical academic journal "The Lancet Respiratory Medicine" in October 2019 . Subsequent updated data showed that the overall ORR of crizotinib-resistant patients treated with ensatinib was 52.6% , the disease control rate was 87.8% , the median PFS was 11.2 months, the intracranial ORR was 71.4% , and the intracranial disease was 71.4%. The control rate was 95.2% . Studies have shown that ensatinib has more advantages compared with similar imported drugs in efficacy, especially in patients with intracranial metastasis, it has a higher response rate and has a good and controllable safety.

36BD9EA4-860C-4D7A-BF10-EC1D3BDFF35A.jpeg

△The full text of the ensatinib clinical study was published in The Lancet Respiratory Medicine

International oncology authoritative expert – Professor Ross Camidge from the University of Colorado in the United States commented in the editor’s note of The Lancet Respiratory Medicine that ensatinib is effective and safe, and is the second-line treatment for patients with ALK-mutated advanced non-small cell lung cancer The new option , and as the first-line treatment research progresses, may become the first-line treatment drug. Professor Zhang Li said when ensatinib was awarded the "Top Ten Original Researches in China’s Oncology Field in 2019" for its registered clinical study : " Ensatinib has outstanding efficacy and safety, and it can be said to be the ‘J-20’ in China’s ALK field . We hope to continue to work with Betta to create more new drugs to better meet the needs of patients and contribute to China’s pharmaceutical innovation. "

As the second targeted new drug approved by Betta Pharmaceuticals after icotinib, ensatinib, like icotinib , fills the domestic blank of similar drugs. Promoting international multi-center head-to-head, first-line Phase III clinical research ( eXalt3 ) overseas. In August 2020 , Dr. Leora Horn of Vanderbilt University in the United States released the interim analysis results of the eXalt3 study to the world at the World Conference on Lung Cancer ( WCLC ) Bureau Symposium . Results showed that patients with ALK -positive non-small cell lung cancer ( NSCLC ) treated with ensatinib had significantly longer median progression-free survival ( mPFS ) than patients treated with crizotinib.

Professor Mao Li, Senior Vice President and Chief Medical Officer of Betta Pharmaceuticals and CEO of Xcovery in the United States, said: "I am very pleased to see ensatinib emerge as a dark horse in the field of ALK-TKI . The R&D process is the first step for Betta Pharmaceuticals to "base itself in China and go global". The company is also actively preparing for the listing application for first-line indications in China and the United States. It is believed that after successful listing in the future, it will launch a full-scale attack in the whole process of ALK-positive NSCLC patients. In the management, the patient’s life is fully protected."

Dr. Ding Lieming, Chairman and Chief Executive Officer of Betta Pharmaceuticals, said: " I am delighted that ensatinib has been approved for marketing, providing patients with a new treatment option. Ensatinib is confident that it will be the second icotinib, continued The next story of icotinib , and it is expected to become the first targeted new drug for lung cancer to be simultaneously marketed globally by a Chinese company, benefiting not only Chinese patients, but also patients in other countries in the world. Betta will focus on ‘ becoming a The vision of a multinational pharmaceutical company headquartered in China is to strive to develop more affordable Best-in-class and First-in-class new drugs and good drugs, so that people can live a better life. "