On June 4, 2021 Precision BioSciences Inc. (Nasdaq: DTIL), a clinical stage biotechnology company developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS genome editing platform, reported encouraging progress on two strategies designed to optimize the durability of allogeneic CAR T therapy in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) (Press release, Precision Biosciences, JUN 4, 2021, View Source [SID1234583521]). The Company reported updated interim results from its Phase 1/2a study of PBCAR0191, the Company’s investigational, off-the-shelf, allogeneic CAR T cell therapy targeting CD19. As of May 21, 2021, 12 patients with R/R NHL were enrolled and evaluated for response to PBCAR0191 with enhanced lymphodepletion (eLD). The Company also reported preclinical data demonstrating the potential mechanism by which its investigational immune evading stealth cell, PBCAR19B, may avoid rejection by T cells and natural killer (NK) cells.

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"These interim results in heavily pretreated R/R NHL patients illustrate the potential for PBCAR0191 to recognize and target CD19 positive cancer cells and suggest that enhanced lymphodepletion may be a strategy to help suppress host immune rejection. We’re encouraged by the high initial response rates and look forward to monitoring the responses for evidence of long-term durability," said Alan List, MD, Chief Medical Officer of Precision BioSciences. "In addition, our PBCAR19B Phase 1 study is open for enrollment, and we believe this candidate has the potential to build on the encouraging clinical responses we’ve seen with PBCAR0191 to date and reduce the need for prolonged immunosuppression."

As of May 21, 2021, 18 subjects in the Phase 1/2a study of PBCAR0191 with R/R NHL completed Day 28 evaluation and received either eLD1 (n=12) or standard lymphodepletion2 (sLD; n=6) with Dose Level 33 of PBCAR0191.

Efficacy

Use of eLD mitigated PBCAR0191 rejection and markedly increased peak cell expansion (~72x) and area under the curve (AUC) (~59x), each as compared to sLD.
A single dose of PBCAR0191 cells following eLD yielded clinical responses in the majority of patients, with overall response rates (ORR) and complete response (CR) rates of 75% and 50%, respectively at Day ≥ 28.
Five of nine responding patients (56%) who received PBCAR0191 cells following eLD remained progression-free, including 4/9 evaluable subjects with responses lasting > 4 months. Assessment of duration of response is on-going.
Median interval from confirmation of eligibility to start of LD was 1 day, reinforcing the potential feasibility for rapid delivery of off-the-shelf, allogeneic, cellular therapy for high-risk patients.
Day ≥ 28 Evaluation

* Three of four responding patients had prior auto-SCT and auto CD19 CAR treatment.

Safety and Tolerability

As of May 21, 2021, PBCAR0191 with eLD continued to show acceptable tolerability without evidence of graft versus host disease (GvHD) and with a similar frequency of immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) compared to patients who received sLD. Infections occurred more frequently when PBCAR0191 was dosed following eLD.

Adverse Event Max Grade

(Graft versus host disease)

Three treatment emergent deaths without disease progression occurred, including two cases of infection and one case of cardiac arrest after a choking incident. Two of these patients were in ongoing complete responses at time of death. Only one death, as previously reported on December 4, 2020 was assessed by the investigator as possibly related to study treatment.

Demographics for Enrolled R/R NHL Patients (PBCAR0191 with eLD)

Over 80% of subjects had advanced and aggressive lymphomas.
75% had stage III/IV disease.
Subjects had received a median of seven lines of therapy prior to study enrollment.
33% of subjects had prior CD19-directed CAR therapy.
PBCAR19B Immune Evading Stealth Cell

PBCAR19B is designed to extend persistence of allogeneic CAR T cells by evading rejection by the immune system of the patient. In preclinical studies, the anti-CD19 PBCAR19B stealth cell exhibited substantial resistance to rejection mediated by both allo-reactive T cell and NK cells, suggesting the potential utility of this approach.

In January 2021, Precision announced that the U.S. Food and Drug Administration accepted its investigational new drug application to evaluate the safety and clinical activity of PBCAR19B in patients with R/R NHL. Initial clinical trial sites have been selected for the Phase 1 study that is now open for enrollment. PBCAR19B will be evaluated at increasing flat dose levels beginning at 2.7 x 108 cells using sLD with the ability to dose up to 8.1 x 108 cells. Of note, the first dose level is approximately equivalent to Dose Level 3 in the PBCAR0191 trial.

Company-Hosted Conference Call and Web Cast Information

Precision will host a conference call and webcast today, Friday, June 4, 2021 at 8:00 a.m. ET to discuss the most recent interim clinical data for PBCAR0191 and preclinical data for PBCAR19B. The dial-in conference call numbers for domestic and international callers are (866) 996-7202 and (270) 215-9609, respectively. The conference ID number for the call is 5647916. Participants may access the live webcast and the accompanying presentation materials on Precision’s website www.precisionbiosciences.com in the Investors and Media section under Events and Presentations. An archived replay of the webcast will be available on Precision’s website.

About PBCAR0191 and Study Design (Clinical Trials Study Identifier: NCT03666000)

PBCAR0191 is an investigational allogeneic chimeric antigen receptor T cell therapy (CAR T) in a Phase 1/2a trial for the treatment of patients with R/R NHL and R/R B-ALL. PBCAR0191 was designed using Precision BioSciences novel and proprietary ARCUS genome editing platform. It has been granted Fast Track Designation by the FDA for B-ALL. Precision also holds Orphan Drug Designation from the FDA for this program in mantle cell lymphoma, an aggressive subtype of NHL.

About PBCAR19B (Clinical Trials Study Identifier: NCT04649112)

PBCAR19B is a next-generation, stealth cell candidate for patients with CD19-positive malignancies such as R/R NHL. PBCAR19B is designed to improve the persistence of allogeneic CAR T cells following infusion by reducing rejection by T cells and NK cells. In addition to the CAR gene, the PBCAR19B stealth cell vector carries a short hairpin RNA that suppresses expression of beta-2 microglobulin, a component of Major Histocompatibility Complex (MHC) Class I molecules found on the cell surface. Reducing or knocking-down Class I MHC expression on allogeneic CAR T cells has been shown to reduce CAR T cell killing by cytotoxic allo-reactive T cells. Additionally, in an effort to attenuate NK cell-mediated elimination due to MHC class I knockdown, the PBCAR19B vector also carries an HLA-E gene designed to inactivate NK cells.

On June 4, 2021 AstraZeneca reported that Updated results from the positive PACIFIC Phase III trial showed its Imfinzi (durvalumab) demonstrated a sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit at five years in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT) (Press release, AstraZeneca, JUN 4, 2021, View Source [SID1234583519]).

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Lung cancer is the leading cause of cancer death accounting for about one-fifth of all cancer deaths, and 80-85% of patients with lung cancer have NSCLC.1-3 One in four patients with NSCLC are diagnosed at Stage III, where the majority of tumours are unresectable (cannot be removed with surgery).4,5 The approval of Imfinzi in this setting based on the results of this trial was the first new treatment to be available to these patients in decades.2,6,7

Results from the updated post-hoc analyses showed an estimated five-year OS rate of 42.9% for patients treated with Imfinzi versus 33.4% for those on placebo after CRT. Median OS was 47.5 months for Imfinzi versus 29.1 for placebo. Following a maximum treatment course of one year, an estimated 33.1% of patients treated with Imfinzi had not progressed five years after enrolment versus 19% for placebo. These results build on the primary PFS and OS analyses published in The New England Journal of Medicine in 2017 and 2018, which demonstrated a sustained, significant benefit with Imfinzi for these primary endpoints.8,9

David Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute, and investigator in the PACIFIC trial, said: "This trial has once again set a new precedent in the treatment of patients with unresectable, Stage III non-small cell lung cancer. Historically, only 15-30% of these patients survived five years but these results show that with up to one year of treatment with Imfinzi, an estimated 43% of patients are still alive at five years. Moreover, three quarters of these patients had also not progressed in that time. This is a momentous achievement at the five-year landmark in this curative-intent setting."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "Five-year survival is a clinically significant and emotionally meaningful milestone for people with cancer and their families, and it’s incredible to see the majority of patients surviving that long have not progressed four years after completing treatment. These results – the first of their kind in Stage III unresectable lung cancer – reinforce the long-term benefit of Imfinzi as the established standard of care in this curative-intent setting. With trials like PACIFIC and our comprehensive development programme in early-stage disease across cancer settings, our strategy is to improve cancer outcomes by treating patients as early as possible, aiming to deliver life-changing treatments that increase the potential for cure."

In the primary OS analysis of the PACIFIC Phase III trial, the most common adverse events (AEs) (greater than or equal to 20%) among patients treated with Imfinzi versus placebo were cough (35.2% versus 25.2%), fatigue (24.0% versus 20.5%), dyspnoea (22.3% versus 23.9%) and radiation pneumonitis (20.2% versus 15.8%). A grade 3 or 4 AE was experienced by 30.5% of patients treated with Imfinzi versus 26.1% for placebo, and 15.4% of patients discontinued treatment due to AEs with Imfinzi versus 9.8% for placebo.9

These results were presented on 4 June during the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after CRT in the US, Japan, China, across the EU and in many other countries. Since the first approval in February 2018, more than 80,000 patients in this setting have been treated with Imfinzi.

AstraZeneca has several ongoing registrational trials focused on testing Imfinzi in earlier stages of lung cancer, including in potentially curative settings (PACIFIC-2, 4 and 5, MERMAID-1 and 2, AEGEAN, ADJUVANT BR.31, and ADRIATIC Phase III trials). The Company is also testing novel combinations with Imfinzi in two Phase II platform trials in the Stage III unresectable setting (COAST) and neoadjuvant early-stage setting (NeoCOAST).

Stage III NSCLC
In 2020, an estimated 2.2 million people were diagnosed with lung cancer worldwide.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.2,3,5 Stage III NSCLC represents approximately one quarter of NSCLC incidence.4

Stage III (locally advanced) NSCLC is divided into three subcategories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally. In contrast to Stage IV, when cancer has spread (metastasised), the majority of Stage III patients are currently treated with curative intent.5,10

PACIFIC
The PACIFIC trial was a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in ‘all-comer’ patients (regardless of PD-L1 status) with unresectable, Stage III NSCLC whose disease had not progressed following concurrent platinum-based CRT.

The trial was conducted at 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate and duration of response.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to approvals in the unresectable, Stage III NSCLC setting, Imfinzi is approved for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial in the EU, US, Japan and many other countries around the world. Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with NSCLC, SCLC, bladder cancer, hepatocellular carcinoma, biliary tract cancer (a form of liver cancer), oesophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer and other solid tumours.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; and savolitinib in collaboration with HUTCHMED; as well as a pipeline of new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer including and beyond treatment.

AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored in immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small, targeted molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On June 4, 2021 Y-mAbs Therapeutics, Inc. (the "Company" or "Y-mAbs") (Nasdaq: YMAB) a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported that Dr. Jaume Mora, M.D., Ph.D. from SJD Barcelona Children’s Hospital will present frontline data for DANYELZA and GM-CSF for consolidation of high-risk neuroblastoma ("HR-NB") patients in complete remission at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Virtual Annual Meeting on June 4, 2021 (Press release, Y-mAbs Therapeutics, JUN 4, 2021, View Source [SID1234583517])

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Patients received five cycles of DANYELZA and GM-CSF in a compassionate use setting for consolidation of HR-NB in first or subsequent complete remission ("CR"). DANYELZA was administered in an outpatient setting on days 1, 3 and 5 at 9.0 mg/kg/cycle in combination with GM-CSF, and treatment cycles were repeated every four weeks. From June 2017 to November 2020, a total of 73 patients were treated: 55 patients (75%) in first CR and 18 patients (25%) in second or more CR. The three-year event free survival ("EFS") for patients in first CR was 74% and 19% for second or later CR. The three-year overall survival ("OS") for the patients in first CR was 92% and 66% for second or later CR patients. Dr. Mora reported two-year EFS and OR at the Company’s R&D Day in December 2020 and those data have been maintained for the three-year follow up.

"We are very pleased to report such encouraging three-year follow-up data in frontline high-risk neuroblastoma for DANYELZA in patients that are in full remission after the induction regiment," stated Thomas Gad, founder, Chairman and President.

Dr. Claus Moller, Chief Executive Officer, continued, "We are excited to see the three-year data holding up so well for the frontline patients and, if approved, we believe this could potentially significantly differentiate DANYELZA from other existing therapies."

Researchers at MSK developed DANYELZA, which is exclusively licensed by MSK to Y-mAbs. As a result of this licensing arrangement, MSK has institutional financial interests in the product.

About DANYELZA (naxitamab-gqgk)

DANYELZA (naxitamab-gqgk) is indicated, in combination with granulocyte-macrophage colony-stimulating factor ("GM-CSF"), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. This indication was approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefits in a confirmatory trial. DANYELZA includes a Boxed Warning for serious infusion-related reactions, such as cardiac arrest and anaphylaxis, and neurotoxicity, such as severe neuropathic pain and transverse myelitis. See full Prescribing Information for complete Boxed Warning and other important safety information.

On June 4, 2021 Cellectar Biosciences, Inc. (NASDAQ: CLRB), a late-stage clinical biopharmaceutical company focused on the discovery and development of drugs for the treatment of cancer, reported a poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting (Press release, Cellectar Biosciences, JUN 4, 2021, View Source [SID1234583516]). In conjunction with the poster presentation, management will host a KOL call with the lead investigator for the company’s Phase 2 CLOVER-1 study of CLR 131 in patients with relapsed/refractory B-cell hematologic cancers, Dr. Sikander Ailawadhi, M.D. of the Mayo Clinic.

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The poster presentation entitled: Treatment Free Remission (TFR) and Overall Response Rate (ORR) Results in Patients with Relapsed/Refractory Waldenstrom’s Macroglobulinemia (WM) Treated with CLR 131 is an in-depth update of six patients from the company’s Phase 2a study of CLR 131 in Waldenstrom’s macroglobulinemia. To date, data have shown:

100% (6/6) overall response rate, 83.3% (5/6) major response rate and a 16.7% (1/6) complete response rate
Median time to initial response was 22 days after first infusion
Median time to major response, as defined as at least a 50% reduction in IgM, was 44 days after first infusion
Mean treatment free remission, as defined as the time from the last CLR 131 infusion to progression of disease, is 1.1 years and remains ongoing
Duration of response has not been reached, with 100% of the MYD88 wild type and high risk patients exceeding 8.5 months
Progression free survival (PFS) for both MYD88 wild type patients as well as the high-risk subgroup has not been reached after 18 months; PFS for multidrug refractory patients was 11 months
The most frequently reported treatment emergent adverse events were cytopenias
"CLR 131 is a differentiated targeted radiotherapy that has the potential to address patients with any mutational status, risk profile or multi-drug refractoriness in WM. Our pivotal study strategy will leverage these properties to address the treatment needs of patients, including the potential to provide durable response rates and meaningful treatment-free remission," said Dr. John Friend, chief medical officer at Cellectar. "CLR 131 has demonstrated impressive results including, to our knowledge, the only monotherapy to result in a complete response in this challenging WM patient set."

James Caruso, president and CEO of Cellectar added, "The data presented today from our ongoing Phase 2 CLOVER-1 study of CLR 131 in Waldenstrom’s further validates our clinical development program and gives us confidence in our goal of providing a new and better treatment with the potential to prolong and improve the quality of life for patients suffering from this devastating disease."

Management will host a conference call and webcast today, June 4, at 10:00 am ET featuring key opinion leader Dr. Sikander Ailawadhi. Dr. Ailawadhi is a Professor of Medicine, Lead, International Cancer Center, Division of Hematology/Oncology, Departments of Medicine and Cancer Biology at Mayo Clinic Florida. He was awarded the 2013 NCI Cancer Clinical Investigator Team Leadership Award as an Assistant Professor of Medicine at the USC Norris Comprehensive Cancer Center. Subsequently, he joined the Division of Hematology and Oncology at Mayo Clinic in Florida as a Senior Consultant in order pursue his career goal of clinical, translational and outcomes-based research in B-cell malignancies.

A replay of the call will be available on the Events page of company website following the live event.

About the Pivotal Trial of CLR 131 in Waldenstrom’s macroglobulinemia (WM)
The pivotal trial is designed as a global, non-comparator, single arm, expansion cohort of the currently ongoing Phase 2 CLOVER-1 study of CLR 131. The study will enroll 50 WM patients. Patients in the trial will receive up to four doses of CLR 131 over two cycles (cycle one days 1, 15, and cycle two days 57, 71). The primary endpoint of the trial is response rate as defined as a partial response (a minimum of a 50% reduction in the biological marker IgM) or better in patients that receive a minimum total body dose of 60 mCi with secondary endpoints of treatment free survival, duration of response and progression free survival. An independent data monitoring committee (iDMC) will perform an interim safety and futility evaluation on the first 10 patients enrolled. The assessment will occur patient by patient and will conclude after the tenth patient is evaluated; there is no planned study stoppage.

About Waldenstrom’s macroglobulinemia
Waldenstrom’s macroglobulinemia (WM) is a rare and incurable disease defined by specific genotypic subtypes that defines patient responses and long-term outcomes. The annual incidence is 6,500 with prevalence of approximately 60,000 patients globally. WM is a lymphoma, or cancer of the lymphatic system. The disease occurs in a type of white blood cell called a B-lymphocyte or B-cell, which normally matures into a plasma cell whose job is to manufacture immunoglobulins (antibodies) to help the body fight infection. In WM, there is a malignant change to the B-cell in the late stages of maturing, and it continues to proliferate into a clone of identical cells, primarily in the bone marrow but also in the lymph nodes and other tissues and organs of the lymphatic system. These clonal cells over-produce an antibody of a specific class called IgM.

WM cells have characteristics of both cancerous B-lymphocytes (NHL) and plasma cells (multiple myeloma), and they are called lymphoplasmacytic cells. For that reason, WM is classified as a type of non-Hodgkin’s lymphoma called lymphoplasmacytic lymphoma (LPL). About 95% of LPL cases are WM; the remaining 5% do not secrete IgM and consequently are not classified as WM.

There is no standard treatment for WM. Several drugs have demonstrated activity either alone or in combinations, but only a single drug has received regulatory approval. Treatment is mainly focused on the control of symptoms and the prevention of organ damage. Front-line treatments for WM include rituximab alone or in combination with other agents. In the salvage therapy (second line or later) setting, ibrutinib, combinations of proteosome inhibitors and immunomodulatory drugs and stem cell transplantation are considered. Ibrutinib is the only drug to receive regulatory approval (2015) as a salvage therapy; in late 2019, it was approved for front-line treatment in combination with rituximab. Factors such as long-term cytopenias, age, hyper viscosity, the need for quick disease control, lymphadenopathy, co-morbidities, and IgM-related end-organ damage are key consideration in the choice of treatment.

On June 4, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported results from a post-hoc analysis of the phase 3 CheckMate -9ER trial demonstrating that CABOMETYX (cabozantinib) in combination with Bristol Myers Squibb’s OPDIVO (nivolumab) resulted in a statistically significant and clinically meaningful increase in quality-adjusted survival compared with sunitinib for patients with previously untreated advanced renal cell carcinoma (RCC) (Press release, Exelixis, JUN 4, 2021, View Source [SID1234583515]). The quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) data will be presented as part of the Poster Session: Health Services Research and Quality Improvement at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held virtually, June 4-8, 2021. All posters will be available on demand beginning at 6:00 a.m. PT on Friday, June 4.

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"Physicians must balance efficacy, safety and quality-of-life considerations when recommending treatment for patients with advanced kidney cancer; longer survival alone is not enough if the quality of life during that time is poor," said David Cella, Ph.D., the Ralph Seal Paffenbarger Professor and chair of the Department of Medical Social Sciences at the Northwestern University Feinberg School of Medicine and presenting author. "This analysis shows that the overall survival benefit demonstrated in the phase 3 CheckMate -9ER trial results in clinically important gains in quality-adjusted survival. For this community, time with relatively good health can be an important factor in treatment decisions, and these results offer both patients and physicians a fuller picture of the clinical benefits of the combination of cabozantinib and nivolumab."

The Q-TWiST metric combines the quantity and quality of time patients spend in each of the following three states: time without symptoms of disease or toxicity before progression (TWiST), time with any grade 3 or 4 adverse events after randomization and before progression or censoring and time after disease progression until death. In the intent-to-treat population (n = 651) in this post-hoc analysis, patients treated with CABOMETYX in combination with OPDIVO had a Q-TWiST gain of 4.0 months (95% confidence interval [CI]: 2.4-5.7) compared with patients treated with sunitinib. The resulting relative gain of 16.9% is considered "clearly clinically important" (defined as a gain of at least 15% based on published minimally important difference norms).

Most gains were driven by added time in relatively good health (TWiST) (4.7 months; 95% CI: 2.9-6.7) for CABOMETYX in combination with OPDIVO compared with sunitinib. Time with any grade 3/4 adverse events was 0.5 months longer (95% CI: 0.1-0.9) with CABOMETYX in combination with OPDIVO than with sunitinib. Time after disease progression until death was 2.0 months longer (95% CI: 0.1-4.1) with sunitinib than with CABOMETYX in combination with OPDIVO.

"There is a need for additional first-line advanced kidney cancer treatments that demonstrate quality-of-life improvements as well as efficacy benefits, and this analysis along with the patient-reported outcomes from CheckMate -9ER presented earlier this year add to the clinical evidence supporting the use of CABOMETYX in combination with OPDIVO," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "These are important findings that reinforce our efforts to bring treatment options to patients that may offer an improved quality of life while on therapy."

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized (1:1), multi-national phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component. A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to CABOMETYX at a dose of 40 mg QD and OPDIVO (n = 323) versus sunitinib (n = 328). The primary endpoint is PFS. Secondary endpoints include OS and ORR. The primary efficacy analysis compares the doublet combination regimen of CABOMETYX and OPDIVO 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 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 hepatocellular carcinoma who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. 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.