On February 8, 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 that the first patient has been successfully enrolled and dosed in the randomized, open-label, phase III, multicenter clinical study (NCT04720716) evaluating its IBI310 (anti CTLA-4 monoclonal antibody) in combination with TYVYT (sintilimab injection) for the first-line treatment of patient with advanced hepatocellular carcinoma (HCC) (Press release, Innovent Biologics, FEB 8, 2021, View Source [SID1234574757]).

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In recent years, immune checkpoint inhibitors have brought new hope to HCC patient population with acceptable safety and encouraging efficacy. NCT04720716 is a randomized, open-label, controlled, multicenter phase III study evaluating the efficacy and safety of IBI310 in combination with TYVYT (sintilimab injection) for advanced HCC patients. Primary endpoints include overall survival and objective response rate. The study was led by Professor Fan Jia from Zhongshan Hospital of Fudan University, and Professor Qin Shukui from Affiliated Jinling Hospital, Medical School of Nanjing University. This study involves more than 50 clinical centers.

Dr. Hui Zhou, Vice President and Head of Medical Sciences and Oncology Strategy of Innovent, stated: "CTLA-4 is an important immunosuppressive receptor. IBI310 in combination with TYVYT (sintilimab injection) has shown promising preliminary good safety and anti-tumor activity, suggesting the potential anti-tumor value for this combination. We will evaluate the efficacy of IBI310 combined with TYVYT (sintilimab injection) in this study and we hope to provide more effective treatment to benefit patients and their families."

About IBI310

IBI310 is a recombinant fully-human monoclonal antibody against cytotoxic T lymphocytic associated antigen 4 (CTLA-4). IBI310 can interfere with the binding of CTLA-4 and CD80/CD86 on antigen presenting cells, thereby blocking the inhibitory effect on T cell activation. IBI310 can promote the activation and amplification of T cells, and enhance the anti-tumor ability of the immune system.

CTLA-4 provides a new approach for immunotherapy in many diseases, including tumors. Innovent has announced the preliminary results of the Phase 1 clinical study about anti-CTLA-4 monoclonal antibody (NCT03545971) at the 56th Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Online Publication, Abstract No. 302489). Phase II/III clinical studies of IBI310 combined with TYVYT (sintilimab injection) for multiple tumors are ongoing.

About TYVYT (Sintilimab Injection)

TYVYT (sintilimab injection) is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Eli Lilly and Company. In December 2018, TYVYT (sintilimab injection) was first approved by the China NMPA for the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy. In February 2021, TYVYT (sintilimab injection) was approved by the China NMPA in combination with pemetrexed and platinum chemotherapy as first-line therapy for the treatment of nonsquamous non-small cell lung cancer. TYVYT (sintilimab injection) was included in the 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.

Currently TYVYT (sintilimab injection) has three supplemental New Drug Applications ("sNDA") under review by the NMPA. In August 2020, the NMPA accepted sNDA for TYVYT (sintilimab injection) in combination with GEMZAR (gemcitabine for injection) and platinum chemotherapy as first-line therapy in squamous NSCLC. In January 2021, the NMPA accepted the sNDA for TYVYT (sintilimab injection) in combination with BYVASDA (bevacizumab injection) as first-line therapy in Hepatocellular Carcinoma (HCC) and the sNDA for TYVYT (sintilimab injection) as second-line therapy in squamous NSCLC. Besides, in May 2020, TYVYT (sintilimab injection) monotherapy met the primary endpoint of overall survival in the Phase 2 ORIENT-2 study as second-line therapy in patients with advanced or metastatic esophageal squamous cell carcinoma.

TYVYT (sintilimab injection), is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, block the PD-1 / PD-Ligand 1 (PD-L1) pathway and reactivate T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies with TYVYT (sintilimab injection) to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical studies. Meanwhile, Innovent is conducting clinical research studies on TYVYT (sintilimab injection) worldwide.

On February 8, 2021 Yingli Pharma reported that it reached strategic collaboration with Hengrui Medicine (600276.SH), a partnership which will significantly accelerate the expansion of Yingli Pharma’s oncology business in China, the second largest pharmaceutical market in the world (Press release, Yingli Pharmaceutical, FEB 8, 2021, View Source [SID1234574756]). As an innovation-driven enterprise, Yingli Pharma demonstrates commitment to continuous investment in R&D and is committed to the research, development and commercialization of new drugs for hematological tumors, solid tumors and kidney-related metabolic diseases.

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As part of the cooperation:

Hengrui Medicine will invest USD 20 million in Yingli Pharma as an equity investment.
Yingli Pharma will grant Hengrui Medicine joint development rights and exclusive commercialization rights of PI3kδ inhibitor YY-20394 in Greater China.
"The collaboration with Hengrui Medicine is a significant milestone that will enable Yingli Pharma to further promote the commercialization of developed innovative drugs. It also demonstrates the confidence mature industrial investors have in our product pipeline and innovative drug R&D, and fully recognizes the strategic vision of Yingli Pharma to build a leading international biopharmaceutical company," said Dr. Xu Zusheng, Co-founder of Yingli Pharma.

"Hengrui Medicine has extensive commercial operation and clinical development capabilities in China which are implemented in accordance with international quality standards. It is an ideal strategic partner in the commercialization process of Yingli Pharma. We will work together to bring benefits to more patients in China and around the world," he added.

Dr. Zhang Lianshan, Senior Deputy General Manager and President of Global R&D of Hengrui Medicine, said, "There are about 4 million newly diagnosed cancer patients in China every year, and there is an urgent need for innovative drugs and regimens for cancer treatment. The oncology market has become one of the fastest-growing fields in the whole pharmaceutical market. It is believed that the cooperation between Hengrui Medicine and Yingli Pharma will bring meaningful changes to the lives of millions of cancer patients in China and even around the world. This collaboration will further enrich the layout of Hengrui Medicine in the field of hematological tumor and oncology and supplement the existing product line."

On February 8, 2021 Bayer reported that new NUBEQA (darolutamide) and Xofigo (radium Ra 223 dichloride) data will be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium, taking place from February 11-13, 2021 (Press release, Bayer, FEB 8, 2021, businesswire.com/news/home/20210208005889/en/Bayer-to-Present-Data-that-Reinforce-Established-Prostate-Cancer-Portfolio-at-2021-ASCO-GU-Cancers-Symposium [SID1234574754]). Among featured presentations are additional Phase III ARAMIS trial analyses evaluating the crossover effect from placebo to NUBEQA and safety follow-up in men with non-metastatic castration-resistant prostate cancer (nmCRPC).

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Prostate cancer is the second most commonly diagnosed cancer in men and a key area of focus for Bayer.1 The data that will be showcased at ASCO (Free ASCO Whitepaper) GU 2021 further build on the company’s ongoing research in areas of unmet need in this patient population. An oncology leader, Bayer’s prostate cancer portfolio is pivotal to the company’s wider commitment to exploring key areas of innovation, such as cell and gene therapy and targeted alpha therapies, with the ultimate goal to help people living with cancer.

"Our priority at Bayer is to advance the treatment of men with prostate cancer across the disease continuum. The focus of our data at ASCO (Free ASCO Whitepaper) GU 2021 is reflective of our patient-centric approach to prostate cancer research," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceutical Division. "We look forward to presenting our newest research, which is encouraging for the prostate cancer community."

Notable data that will be presented at the meeting is listed below. More details on meeting registration can be found here.

Darolutamide

Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial
Abstract 240; February 11, 8:00am EST and 4:30pm EST
Safety of darolutamide (DARO) for nonmetastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial
Abstract 239; February 11, 8:00am EST
Frequency, management, and resource use of adverse events (AEs) in nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients receiving apalutamide or enzalutamide: A real-world study
Abstract 217; February 11, 8:00am EST
DASL-HiCaP: Darolutamide and standard therapy for localized very high-risk cancer of the prostate (ANZUP1801)—A randomized phase III double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation – Investigator-Initiated Research (IIR)
Abstract TPS266; February 11, 8:00am EST
Radium Ra 223 dichloride

Synergistic antitumor effect of radium-223 and enzalutamide in the intratibial LNCaP prostate cancer xenograft model
Abstract 105; February 11, 8:00am EST
Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Final efficacy and safety results – Investigator-Initiated Research (IIR)
Abstract 135; February 11, 8:00am EST and 4:30pm EST
A phase I/II study of combination olaparib and radium-223 in men with metastatic castration-resistant prostate cancer with bone metastases (COMRADE): A trial in progress – Investigator-Initiated Research (IIR)
Abstract TPS182; February 11, 8:00am EST
Real-world clinical outcomes study of sequential novel antihormonal therapy (NAH) or radium-223 (Ra-223) treatment of metastatic castration-resistant prostate cancer (mCRPC) that progressed after first-line NAH
Abstract 48; February 11, 8:00am EST
Randomized phase II study evaluating the addition of pembrolizumab to radium-223 in metastatic castration-resistant prostate cancer – Investigator-Initiated Research (IIR)
Abstract 98; February 11, 8:00am EST
Fractionated docetaxel and radium-223 (Ra223) in metastatic castration-resistant prostate cancer (CRPC): A phase I trial – Investigator-Initiated Research (IIR)
Abstract TPS175; February 11, 8:00am EST
Clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving radium-223 (Ra-223) early versus late in the treatment sequence
Abstract 136; February 11, 8:00am EST
About NUBEQA (darolutamide)2

NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.2 A Phase III study in metastatic hormone-sensitive prostate cancer (ARASENS) is ongoing. Information about this trial can be found at www.clinicaltrials.gov.

On July 30th, 2019, the FDA approved NUBEQA (darolutamide) based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with nmCRPC who were receiving a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. In the clinical study, 1,509 patients were randomized in a 2:1 ratio to receive 600 mg of NUBEQA orally twice daily or androgen deprivation therapy (ADT) alone. The primary efficacy endpoint was metastasis-free survival (MFS) and secondary endpoints include overall survival (OS), time to pain progression and time to initiation of cytotoxic chemotherapy.

Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of men with nmCRPC.2 The approvals of NUBEQA in the U.S., European Union (EU), and other global markets have been based on the pivotal Phase III ARAMIS trial data evaluating the efficacy and safety of NUBEQA plus ADT compared to ADT alone.2 Filings in other regions are underway or planned.

INDICATION FOR NUBEQA (darolutamide)

NUBEQA (darolutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.

IMPORTANT SAFETY INFORMATION FOR NUBEQA (darolutamide)

Embryo-Fetal Toxicity: Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1 % of patients who received NUBEQA were urinary retention, pneumonia, and hematuria. Overall, 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for NUBEQA.

Adverse reactions occurring more frequently in the NUBEQA arm (≥2% over placebo) were fatigue (16% vs 11%), pain in extremity (6% vs 3%) and rash (3% vs 1%).

Clinically significant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease (4.0% vs 3.4% on placebo) and heart failure (2.1% vs 0.9% on placebo).

Drug Interactions

Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.

Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.

Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.

NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.

Review the prescribing information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.

For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information.

About Xofigo (radium Ra 223 dichloride) Injection3

Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Important Safety Information for Xofigo (radium Ra 223 dichloride) Injection

Warnings and Precautions:

Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure
Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care
Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued
Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established
Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo
Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia

Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo

Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial

Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy

Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride).

About Prostate Cancer

Prostate cancer is the second most commonly diagnosed malignancy in men worldwide.1 In 2020, about 192,000 men in the U.S. were diagnosed with prostate cancer and an estimated 33,000 have died from the disease.4 Prostate cancer is the fifth leading cause of death from cancer in men.1 Prostate cancer results from the abnormal proliferation of cells within the prostate gland, which is part of a man’s reproductive system.5 It mainly affects men over the age of 50, and the risk increases with age.6

Treatment options range from surgery to radiation treatment to therapy using hormone-receptor antagonists, i.e., substances that stop the formation of testosterone or prevent its effect at the target location.7 However, in nearly all cases, the cancer eventually becomes resistant to conventional hormone therapy.8

Castration-resistant prostate cancer (CRPC) is an advanced form of the disease where the cancer keeps progressing even when the amount of testosterone is reduced to very low levels in the body. The field of treatment options for castration-resistant patients is evolving rapidly for CRPC patients who have prostate cancer that has not spread to other parts of the body with rising prostate-specific antigen (PSA) levels despite a castrate testosterone level, which is called non-metastatic castration-resistant prostate cancer, or nmCRPC.9,10 About one-third of men with nmCRPC go on to develop metastases within two years.11 In men with progressive nmCRPC, a short PSA doubling time is correlated with shortened time to first metastasis and death.10

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On February 8, 2021 Ipsen (Euronext: IPN; ADR: IPSEY) reported the first presentation of new analyses from the pivotal Phase III CheckMate -9ER trial demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of Cabometyx (cabozantinib) and Opdivo (nivolumab) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC) (Press release, Ipsen, FEB 8, 2021, View Source;9ER-trial-of-Cabometyx%C2%AE-in-Combination-with-Opdivo%C2%AE-Showed-Significantly-Improved-QoL-Benefits-and-Sustained-Superior-Efficacy-Versus-sunitinib-in-Patients-Living-with-aRCC [SID1234574753]).1 These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Genitourinary Cancers Symposium (ASCO GU) from 11 – 13 February 2021 and featured in the Poster Highlights Session on 13 February 2021 from 9:00 a.m. – 9:45 a.m. EDT.4

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In a new analysis from the CheckMate -9ER trial (Abstract #308) with a median follow-up of two years (23.5 months), Cabometyx in combination with Opdivo continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation.1 No new safety signals were identified with extended follow-up. Across the full study population, the combination doubled median PFS (17.0 months vs. 8.3 months, respectively; HR 0.52; 95% CI: 0.43 to 0.64), the trial’s primary endpoint, compared to sunitinib. The ORR indicated that nearly twice as many patients responded to Cabometyx in combination with Opdivo vs. sunitinib (54.8% vs. 28.4) and the combination maintained improvements in OS, demonstrating a 34% reduction in the risk of death compared to sunitinib (HR: 0.66; 95% CI: 0.50 to 0.87). In an exploratory analysis, the combination was associated with a disease control rate (including complete response, partial response and stable disease) of 88.2% vs. 69.9% with sunitinib and a complete response rate of 9.3% compared to 4.3% with sunitinib. Among patients treated with Cabometyx in combination with Opdivo, 6.6% discontinued both agents due to TRAEs, 9.7% discontinued Opdivo only and 7.2% discontinued Cabometyx only.1

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of Cabometyx with Opdivo showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).1

"There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma," said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. "In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also, of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease"

In a second analysis from the CheckMate -9ER trial (Abstract #285) conducted with 18.1 months of median follow-up, patients treated with the combination of Cabometyx and Opdivo reported statistically significant health-related quality of life (HRQoL) benefits.2 Treatment with Cabometyx in combination with Opdivo was associated with a lower treatment burden, decreased the risk of confirmed deterioration in HRQoL and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.2

"As the advances in treatments for kidney cancer transform outcomes for patients, the goals of therapy have expanded from increasing survival to improving quality of life," said Dr. Cristina Suárez, Medical Oncologist at the Vall d´Hebron University Hospital, Barcelona, Spain and a lead investigator on the Phase III CheckMate -9ER trial. "The additional analyses presented at ASCO (Free ASCO Whitepaper) GU mean that physicians treating people living with advanced renal cell carcinoma can consider this combination at diagnosis as a first-line option to improve patient outcomes and significantly reduce the risk of deterioration in health-related quality of life scores for their patients. This, in addition to the extended follow-up outcomes data including patients with sarcomatoid features, point to this combination becoming an important treatment approach."

Cabometyx in combination with Opdivo is under review with health authorities globally following the combination’s approval for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021.

"We’re pleased to share these positive results at ASCO (Free ASCO Whitepaper) GU, building on the growing body of data for the use of Cabometyx in first- and second-line settings. These data further support the importance of research investigating outcomes which really matter to patients," said Prof. Dr. Steven Hildemann, Executive Vice President, Chief Medical Officer, Head of Global Medical Affairs and Patient Safety, Ipsen. "The validations of the type II variation applications to the European Medicines Agency (EMA) for Cabometyx in combination with Opdivo last year brought this new combination regimen one step closer to the previously untreated kidney cancer patient population. Despite recent advances, these patients remain in need of more therapeutic options that extend survival and improve quality of life."

A further notable presentation at ASCO (Free ASCO Whitepaper) GU evaluated the use of Cabometyx versus other TKIs after CPI treatment in the real-world management of patients with metastatic renal cell carcinoma (mRCC) (Abstract #293).3

A retrospective observational cohort study evaluating outcomes associated with Cabometyx or other TKIs (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib) in patients with mRCC following CPI treatment3

Cabometyx (n = 187)

Other TKI (n=60)

p value

6-month response rate (RR6months, primary)

50.8%

33.3%

<0.001

Overall response rate (ORR)

53.5%

38.3%

0.041

Overall survival (OS) (95% CI)

6 months

81.9 (75.5, 86.8)

75.1 (61.5, 84)

0.765

12 months

61.5 (53.5, 68.4)

59.6 (44.7, 71.8)

18 months

51.7 (43.1, 59.6)

45.9 (29.6, 60.7)

Time to treatment discontinuation (TTD, median months)

6.2

3.1

0.015

Dose reductions

47.1%

41.7%

0.466

Discontinuation due to adverse events (AEs)

31.3%

40.4%

Findings from the study suggest that Cabometyx is an effective and well tolerated option, associated with a significantly higher response rate and a lower discontinuation rate versus other TKIs included in the study, after treatment with CPIs.3

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About renal cell carcinoma
There are over 400,000 new cases of kidney cancer diagnosed worldwide each year.5 Of these, renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 90% of cases.6,7 It is twice as common in men, and male patients account for over two thirds of deaths.5 If detected in the early stages, the five-year survival rate is high, but for patients with advanced or late-stage metastatic RCC the survival rate is much lower, around 12%, with no identified cure for this disease.8,9

About the CheckMate -9ER trial
CheckMate -9ER is an open-label, randomized, multi-national Phase III trial evaluating patients 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 (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination versus sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Cabometyx (cabozantinib)
Cabometyx is currently approved in 54 countries, including in the European Union, the U.S., the U.K., Norway, Iceland, Australia, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong-Kong, Singapore, Macau, Jordan, Lebanon, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile, Panama and New Zealand for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, the U.K., Norway, Iceland, Canada, Australia, Brazil, Taiwan, Hong Kong, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, Saudi Arabia, Israel, Mexico, Chile, Panama and New Zealand for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, the U.S., the U.K., Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel, Taiwan, Hong Kong, South Korea, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, Ukraine, Lebanon and Panama for HCC in adults who have previously been treated with sorafenib.

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

Cabometyx is marketed by Exelixis, Inc. in the United States and by Takeda Pharmaceutical Company Limited in Japan. Ipsen has exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. Cabometyx is a registered trademark of Exelixis, Inc.

On February 8, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported results from a retrospective analysis evaluating CABOMETYX (cabozantinib) activity in brain metastases in patients with renal cell carcinoma (RCC) (Press release, Exelixis, FEB 8, 2021, View Source [SID1234574752]). The findings will be presented as part of the Poster Session: Renal Cell Cancer at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary Cancers Symposium (ASCO GU), which is being held virtually, February 11-13, 2021. All posters will be available on demand beginning at 5:00 a.m. PT on Thursday, February 11.

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In this retrospective analysis of medical records from patients with metastatic RCC with brain metastases, an intracranial response rate of 61% (95% CI: 39%-80%), including a complete response rate of 13%, was seen for patients with progressing intracranial metastases at baseline (Cohort 1; n=25) who were treated with CABOMETYX. Patients without progressing intracranial metastases (Cohort 2; n=44) had an intracranial response rate of 57% (95% CI: 41%-72%). The rate of brain disease progression at six months was 16% for patients with progressive brain disease at baseline and 9% for those without. Median overall survival was 14.7 months for Cohort 1 and 14.1. months for Cohort 2. The reported safety data are consistent with the known safety profile for CABOMETYX.

"With these exciting results, oral systemic cabozantinib is showing intriguing activity on brain metastases in renal cell carcinoma," said Dr. Toni Choueiri, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. "The high intracranial response rates seen in this retrospective analysis suggest cabozantinib has the potential for helping patients with difficult-to-treat brain lesions from kidney cancer. We look forward to building on these encouraging findings through the ongoing phase 2 CABRAMET trial (NCT03967522) led by our French colleagues, which is prospectively evaluating cabozantinib in patients with brain metastases from renal cell carcinoma."

"Brain metastases resulting from renal cell carcinoma are especially difficult to treat, as the blood-brain barrier poses a challenge for therapies to reach their targets," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "These encouraging results including a high intracranial response rate, suggest CABOMETYX may reduce the size of brain metastases, without neurological toxicity, and thereby may be of interest to physicians treating kidney cancer patients with brain metastases."

About the Study

For this retrospective study, sponsored by the Dana-Farber Cancer Institute, consecutive medical records from patients with metastatic RCC with brain metastases who had been treated with cabozantinib monotherapy across 15 institutions in the United States (ten centers), Belgium (three centers), Spain (one center) and France (one center) were reviewed.

Patients were divided into two cohorts based on the presence (n=25) or absence (n=44) of progressing intracranial metastases at start of CABOMETYX therapy. Most patients (87%) were International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk, and 75% had been previously treated. Prior brain-directed therapy was received by 65% of patients with progressing brain metatstases and by 93% of those without. All patients were treated with CABOMETYX. Four patients were not included in the intracranial analysis due to brain lesion size under 5 mm.

About RCC

The American Cancer Society’s 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common form of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as "clear cell" carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. 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 United States 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 United States.

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 and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. 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 36% (17% 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. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% 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.

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 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 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. 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.

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 is observed. 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.

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, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

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.

Please see accompanying full Prescribing Information View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.