On June 4, 2018 CytomX Therapeutics, Inc. (Nasdaq:CTMX) a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, reported that preliminary clinical results from two arms of the PROCLAIM (PRObody CLinical Assessment In Man) module, PROCLAIM-072 (Press release, CytomX Therapeutics, JUN 4, 2018, View Source [SID1234527137]). PROCLAIM-072 is an ongoing Phase 1/2 trial evaluating CX-072, a Probody therapeutic targeting PD-L1, as monotherapy and in combination with Yervoy (ipilimumab) or Zelboraf (vemurafenib) in patients with advanced, unresectable solid tumors. Data from the CX-072 monotherapy arm and ipilimumab combination arm were presented today in two posters as part of the Developmental Therapeutics—Immunotherapy Session at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois.

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"These first clinical results mark a major milestone for CytomX as we advance our Probody platform and introduce a fundamentally new approach to antibody therapeutic drug development," said Sean McCarthy D.Phil., president and chief executive officer of CytomX Therapeutics. "The findings presented today show that our lead wholly-owned program, the PD-L1 targeting Probody therapeutic, CX-072, has the potential to become a new centerpiece of combination cancer therapy. These preliminary results suggest that CX-072 as monotherapy and in combination with ipilimumab has a favorable safety profile and encouraging antitumor efficacy in late-stage, heavily pretreated cancer patients. Moreover, these clinical data check important boxes for the development of our core platform technology by showing that CX-072 remains stable in circulation over extended periods of dosing and elicits anti-tumor effects within the tumor microenvironment. Based on these initial results, we have initiated multiple monotherapy expansion cohorts to further explore the safety and efficacy of this potentially differentiated PD-L1 inhibitor."

Preliminary Results of the First-In-Human, Dose-Finding PROCLAIM-072 Trial of the PD-L1 Probody Therapeutic CX-072 as Monotherapy in Patients with Advanced Solid Tumors

Session: Developmental Therapeutics—Immunotherapy (Poster #285)
Presenter: Karen A. Autio, M.D., MSc., Memorial Sloan Kettering Cancer Center

The primary objectives of this first-in-human, dose-escalation, monotherapy arm are to assess safety and tolerability, including determination of the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of CX-072 as monotherapy. At the completion of escalation, the arm had enrolled 22 patients, with an average of four prior anti-cancer treatments in a variety of tumor types for which no anti-PD-1 or anti-PD-L1 agents are available for their disease. Patients received escalating doses of CX-072 from 0.03 mg/kg to 30 mg/kg. Enrollment is complete and patient follow-up is ongoing.

Monotherapy Well Tolerated

The maximum tolerated dose (MTD) was not reached. As of an April 20, 2018 data cutoff, results showed that the administration of monotherapy CX-072 was well tolerated with the majority of treatment-related adverse events (TRAEs) as Grade 1/2. Grade 3/4 TRAEs were reported in two patients: neutropenia and thrombocytopenia in a patient with thymic cancer (3 mg/kg) and transaminase elevation in a patient with breast cancer (30 mg/kg). Both events were successfully managed with therapeutic intervention including steroids and discontinuation of CX-072.

Evidence of Activity

As of an April 20, 2018 data cutoff, results showed that among 20 evaluable patients who received CX-072, objective responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a commonly used guideline for evaluating tumors, were observed in 3 (15%) patients: thymoma (unconfirmed PR (uPR); 3 mg/kg), PD-L1 negative TNBC (confirmed PR; 10 mg/kg) and cervical cancer (uPR; 10 mg/kg) (all partial responses (PR)). Stable disease was observed in 8 patients (40%) for a disease control rate of 55%. Decreased target lesions were observed in 42% (8/19) of all evaluable patients with measurable disease at baseline and in 60% (6/10) of the subset of patients who received > 3 mg/kg of CX-072. Two of the responders were still on treatment (8 months each) at the time of the data cutoff.

Evidence of Probody Platform Performance

Results from a preliminary single-dose pharmacokinetic analysis of single-agent CX-072 suggest that, as designed, CX-072 circulates predominantly as the intact masked prodrug across all dose levels. Further, CX-072 is only minimally influenced by target mediated drug disposition at low doses, suggesting that masking is effective in blocking interaction with PD-L1 in the periphery.

Based on these preliminary safety, efficacy and translational data, further evaluation of CX-072 monotherapy (10 mg/kg every two weeks) is now underway in 8 expansion cohorts in a variety of cancer types.

Preliminary Interim Results of the First-In-Human, Dose-Finding PROCLAIM-072 Trial of the PD-L1 Probody Therapeutic CX-072 in Combination with Ipilimumab in Patients with Advanced Solid Tumors

Session: Developmental Therapeutics—Immunotherapy (Poster #286)
Presenter: Rachel E. Sanborn, M.D., Earle A. Chiles Research Institute, Providence Cancer Center

The primary objectives of this ongoing arm of the study are to assess safety and tolerability, and to determine the MTD and DLT of CX-072 when administered in a concomitant combination schedule with ipilimumab. At the April 20, 2018 data cutoff, the study had enrolled 16 immunotherapy naïve patients who had received an average of four prior anti-cancer treatments in a variety of tumor types for which no anti-PD-1 or PD-L1 agents were available for their disease. Patients received the combination ipilimumab (3 mg/kg) and CX-072 (escalating doses of 0.3 mg/kg to 10 mg/kg) every three weeks for four cycles followed by monotherapy CX-072 every two weeks.

Combination with Ipilimumab Well Tolerated

As of the April 20, 2018 data cutoff date, the MTD had not yet been reached and no new safety signals were observed beyond those expected for each component of the ipilimumab plus CX-072 combination. The majority of TRAEs were Grade 1/2. Of the 16 treated patients, 5 (31%) reported a Grade 3/4 TRAE, a rate similar to that reported previously for 3 mg/kg ipilimumab monotherapy1. These events included: Grade 3 colitis (n=1), Grade 3 dyspnea/pneumonitis (n=1), Grade 3 headache/Grade 3 hyponatremia (n=1), and Grade 3 amylase/Grade 4 lipase (n=1)2. A dose limiting toxicity of Grade 3 dyspnea was reported in one patient. The study is still ongoing with enrollment and dose escalation continuing.

Evidence of Activity

As of an April 20, 2018 data cutoff, results also showed that among 12 evaluable patients who received ipilimumab (3 mg/kg) combined with CX-072 (0.3 to 10 mg/kg), 3 (25%) achieved objective responses by RECIST v1.1, including patients with: anal cancer (confirmed complete response (CR); 0.3 mg/kg CX-072), testicular cancer (uPR; 1 mg/kg CX-072) and cancer of unknown primary (uPR; 3 mg/kg CX-072). Stable disease was observed in 8% of patients for a disease control rate of 33%. All 3 of the responders remained on treatment (10, 6 and 5 months, respectively) at the data cutoff.

Preliminary Single-Dose Clinical Pharmacokinetics of an anti-PD-L1 Probody Therapeutic in Cancer Patients
ASCO Supplement of the Journal of Clinical Oncology [J Clin Oncol 36, 2018 (suppl; abst 214558)]. (Abstract #e14558)

Preliminary pharmacokinetic clinical data showed that single-agent, single-dose CX-072 behaved as designed and circulated predominantly as the intact antibody prodrug and is only minimally affected by target-mediated drug disposition, consistent with being effectively masked in circulation.

Conference Call and Webcast

CytomX will host a conference call and live webcast with slides today, Monday, June 4, 2018, beginning at 5:00 p.m. CT/ 6:00 p.m. ET to discuss these data presentations. This event can be accessed in three ways:

From the CytomX website: View Source Please access the website 15 minutes prior to the start of the call to download and install any necessary audio software.

By telephone: Participants can access the call by dialing 1-877-809-6037 (United States) or 1-615-247-0221 (International) referencing Conference ID 4294667.

By replay: A replay of the webcast will be located under the Investor Relations section of CytomX’s website approximately two hours after the conclusion of the live call and will be available for 30 days following the call.
About PROCLAIM

PROCLAIM (Probody Clinical Assessment In Man) is an international umbrella program designed to evaluate CytomX’s Probody therapeutics. The first module is the PROCLAIM-CX-072 clinical program, an open-label, dose-finding Phase 1/2 trial evaluating CX-072 as monotherapy and in combination with Yervoy (ipilimumab) or Zelboraf(vemurafenib) in patients with metastatic or locally advanced unresectable solid tumors or lymphomas. CytomX aims to achieve three goals as part of the PROCLAIM-072 clinical trial:

Tolerability: Demonstrate that CX-072 is well tolerated in patients and potentially improves safety, particularly in the combination setting.
Anti-cancer activity: Demonstrate initial evidence of CX-072’s anti-cancer activity as monotherapy and in combination.
Translational program and Probody platform proof-of-concept: Explore mechanistic aspects of Probody activity in patients as observed in preclinical models.

On June 4, 2018 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi reported that pivotal data from two trials evaluating cemiplimab in advanced cutaneous squamous cell carcinoma (CSCC) were published today in the New England Journal of Medicine (NEJM) and presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Regeneron, JUN 4, 2018, View Source [SID1234527153]). Advanced CSCC, the deadliest nonmelanoma skin cancer, encompasses both patients with metastatic CSCC and those with locally advanced CSCC who are not candidates for surgery; there is currently no approved treatment for these patients. Cemiplimab is an investigational human monoclonal antibody targeting the immune checkpoint PD-1 (programmed cell death protein 1).

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"The strong results seen with cemiplimab are noteworthy given that advanced CSCC is a very serious condition that currently has no approved treatments once surgery is no longer an option," said Michael R. Migden, M.D., co-lead author and Associate Professor in the Departments of Dermatology and Head and Neck Surgery at The University of Texas MD Anderson Cancer Center. "Advanced CSCC tumors were shown to be responsive to cemiplimab in both metastatic and locally advanced patients, with the results being clinically meaningful and consistent between the Phase 1 and Phase 2 trials."

Data published in NEJM and/or presented at ASCO (Free ASCO Whitepaper), and confirmed by independent central review, include:

Phase 2 EMPOWER-CSCC-1 trial:
Cemiplimab-treated patients had a 47.5 percent response rate (28 of 59 patients, including 4 complete responses and 24 partial responses [PRs]) with a median observed time to response of 2 months as of the data cut-off date. The durable disease control rate (DCR) was 61 percent (36 of 59 patients) and was defined as the proportion of patients without progressive disease for at least 105 days.
The median duration of response (DOR), median progression free survival, and median overall survival have not been reached as of the data cut-off date (median follow-up for all patients: 8 months). Of the responding patients, 82 percent remained in response and continued on cemiplimab. The estimated progression-free probability at 12 months was 52.5 percent, and the estimated probability of survival at 12 months was 81 percent.
The most common treatment-emergent adverse events were diarrhea (27 percent), fatigue (24 percent), nausea (17 percent), constipation and rash (each 15 percent). Grade 3 or higher adverse events regardless of attribution were reported in 25 patients (42 percent), of whom seven (12 percent) were considered related to treatment. Three patients (5 percent) had adverse events with the outcome of death; however, none were considered related to treatment.
Data are from 59 metastatic CSCC patients who received cemiplimab (3 mg/kg every 2 weeks) for up to 96 weeks.
CSCC expansion cohorts of Phase 1 trial:
Cemiplimab-treated patients had a response rate of 50 percent (13 of 26 patients, all of which were PRs) with a median observed time to response of 2 months as of the data cut-off date. The durable DCR was 65 percent (17 of 26 patients). The median DOR has not been reached as of the data cut-off date (median follow-up for all patients: 11 months).
The most common treatment-emergent adverse events of any grade were fatigue (27 percent), constipation, decreased appetite, diarrhea, hypercalcemia, hypophosphatemia, nausea and urinary tract infection (each 15 percent). Grade 3 or higher adverse events regardless of attribution were reported in 12 patients (46 percent), of which five (19 percent) were considered related to treatment. Two patients (8 percent) had adverse events related to treatment that led to treatment discontinuation.
Data are from 26 advanced CSCC patients who participated in two Phase 1 expansion cohorts and received cemiplimab (3 mg/kg every 2 weeks) for up 48 weeks. Patients either had metastatic CSCC or locally advanced CSCC who were not candidates for surgery.
These findings formed part of the data set used for regulatory applications for cemiplimab as a potential treatment for advanced CSCC. These applications were accepted earlier this year for priority review by the U.S. Food and Drug Administration (FDA) and review by the European Medicines Agency (EMA). The FDA target action date is October 28, 2018, and the EMA review process is expected to be complete by the first half of 2019. Regulatory applications in additional countries are also being considered for submission later in 2018. There are currently no FDA- or EMA-approved treatments for patients with metastatic CSCC or patients with locally advanced CSCC who are not candidates for surgery.

Cemiplimab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement, and was invented by Regeneron using the company’s proprietary VelocImmune technology that yields optimized fully-human antibodies. In addition to CSCC, cemiplimab is also being investigated in potentially pivotal/pivotal trials in non-small cell lung cancer, basal cell carcinoma and cervical cancer alongside exploratory trials in squamous cell carcinoma of the head and neck, melanoma, colorectal cancer, prostate cancer, multiple myeloma, Hodgkin lymphoma and non-Hodgkin lymphoma.

Cemiplimab is currently under clinical development, and its safety and efficacy have not been evaluated by any regulatory authority.

About CSCC
CSCC is the second most common type of skin cancer in the U.S., accounting for approximately 20 percent of all skin cancers and with the number of newly diagnosed cases expected to rise annually. Although CSCC has a good prognosis when caught early, the cancer can prove especially difficult to treat effectively when it is advanced, and patients can experience reduced quality of life due to the impact of the disease as it progresses. Advanced CSCC is the deadliest non-melanoma skin cancer. While estimates vary, sources suggest that between 4,000 to 8,000 people in the U.S. die annually of advanced CSCC.

About Regeneron Pharmaceuticals, Inc.
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to six FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye disease, heart disease, allergic and inflammatory diseases, pain, cancer, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite technologies, such as VelocImmune which produces optimized fully-human antibodies, and ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

On June 4, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported results from a part of the Phase 3 CheckMate -227 trial that evaluated Opdivo (nivolumab) plus low-dose Yervoy (ipilimumab) and Opdivo plus chemotherapy versus chemotherapy in patients with first-line advanced non-small cell lung cancer (NSCLC) with PD-L1 expression <1%, across squamous and non-squamous tumor histologies (Part 1b) (Press release, Bristol-Myers Squibb, JUN 4, 2018, View Source [SID1234527122]).

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Data show that Opdivo plus chemotherapy (n=177) extended progression-free survival (PFS) versus chemotherapy (n=186) in patients with PD-L1 expression <1% (HR 0.74; 95% CI: 0.58 to 0.94). PFS is a secondary endpoint for Opdivo plus chemotherapy in Part 1b of the study, and results are based on a descriptive analysis.

In an exploratory analysis of patients with high tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb) and PD-L1 expression <1%, the one-year PFS rates were 45% with Opdivo plus low-dose Yervoy (n=38), 27% with Opdivo plus chemotherapy (n=43) and 8% with chemotherapy (n=48). In patients with low TMB (<10 mut/Mb) and PD-L1 <1%, the one-year PFS rate was 18% with both Opdivo plus low-dose Yervoy (n=52) and Opdivo plus chemotherapy (n=54) and was 16% with chemotherapy (n=59).

Hossein Borghaei, D.O., study investigator and chief of thoracic medical oncology at Fox Chase Cancer Center in Philadelphia, said, "For the first time, CheckMate -227 allows the oncology community to look at I-O/I-O and I-O/chemotherapy in one data set. Results show Opdivo plus chemotherapy improved progression-free survival versus chemotherapy in first-line lung cancer patients whose tumors do not express PD-L1. Taken together with the totality of CheckMate -227 data presented to date, the results reinforce that TMB status provides clinically relevant information for Opdivo-based combinations and that Opdivo plus low-dose Yervoy provided durable efficacy in patients with high TMB."

Results from Part 1b of CheckMate -227 will be presented today from 3:12-3:24 PM CDT during the Lung Cancer—Non-Small Cell Metastatic oral abstract session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Abstract #9001).

Sabine Maier, M.D., development lead, thoracic cancers, Bristol-Myers Squibb, commented, "In today’s evolving NSCLC treatment landscape, the Opdivo-based combination data from CheckMate -227 continue to advance the science of I-O, driving a more precise understanding of predictive biomarkers, such as TMB, to determine who may benefit from I-O combinations."

In this report, Grade 3-4 treatment-related adverse events (TRAEs) were observed in 25% of patients who received Opdivo plus low-dose Yervoy, 52% with Opdivo plus chemotherapy and 35% with chemotherapy. The most common select Grade 3-4 TRAEs with Opdivo plus low-dose Yervoy were hepatic (8%), gastrointestinal (3%), endocrine (3%), skin (3%), diarrhea (2%), anemia (2%), fatigue (1%), asthenia (1%) and nausea (1%). The most common Grade 3-4 TRAEs with Opdivo plus chemotherapy were anemia (17%), neutropenia (12%), decreased neutrophil count (10%), fatigue (5%), hepatic (3%), decreased appetite (2%), nausea (2%), gastrointestinal (2%), diarrhea (1%), skin (1%) and endocrine (0.6%).

About CheckMate -227

CheckMate -227 is an open-label Phase 3 trial evaluating Opdivo-based regimens versus platinum-doublet chemotherapy in patients with first-line advanced non-small cell lung cancer (NSCLC) across non-squamous and squamous tumor histologies. This program is comprised of three parts:

Part 1a: Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1
Part 1b: Opdivo plus low-dose Yervoy or Opdivo plus chemotherapy versus chemotherapy in patients whose tumors do not express PD-L1
Part 2: Opdivo plus chemotherapy versus chemotherapy, regardless of PD-L1 or tumor mutational burden (TMB) status
There are two co-primary endpoints in Part 1 for the Opdivo plus low-dose Yervoy combination versus chemotherapy: overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a); and progression-free survival (PFS) in patients with high TMB ≥10 mut/Mb across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b).

Data for the co-primary endpoint of PFS were previously presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 and published in The New England Journal of Medicine.

In Part 1b of this study, patients were randomized 1:1:1 to Opdivo 3 mg/kg every two weeks plus low-dose Yervoy 1 mg/kg every six weeks (n=187); Opdivo 360 mg every three weeks plus histology-based platinum-doublet chemotherapy, followed by Opdivo monotherapy (n=177); and histology-based platinum-doublet chemotherapy every three weeks for up to four cycles (n=186). TMB status was assessed using the validated assay, FoundationOne CDx.

The primary endpoint in Part 2 is OS.

About Tumor Mutational Burden (TMB)

Over time, cancer cells accumulate mutations that are not seen in normal cells of the body. Tumor mutational burden, or TMB, is a quantitative biomarker that reflects the total number of mutations carried by tumor cells. Tumor cells with high TMB have higher levels of neoantigens, which are thought to help the immune system recognize tumors and incite an increase in cancer-fighting T cells and an anti-tumor response. TMB is one type of biomarker that may help predict the likelihood a patient responds to immunotherapies.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational medicines, including Immuno-Oncology (I-O) therapeutic approaches, for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the integrated scientific understanding of both tumor cell and immune system pathways, through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 24 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance the I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of transformational medicines like I-O therapies a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology, and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor-risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is 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 benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous use.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), and decreased appetite (21% vs 29%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain.

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Checkmate Trials and Patient Populations

Checkmate 067–advanced melanoma alone or in combination with YERVOY (ipilimumab); Checkmate 037 and 066–advanced melanoma; Checkmate 017–squamous non-small cell lung cancer (NSCLC); Checkmate 057–non-squamous NSCLC; Checkmate 025–renal cell carcinoma; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 141–squamous cell carcinoma of the head and neck; Checkmate 214–renal cell carcinoma; Checkmate 275–urothelial carcinoma; Checkmate 040–hepatocellular carcinoma, Checkmate 238–adjuvant treatment of melanoma.

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

On June 4, 2018 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that the independent safety review committee has recommended dose escalation in the MAGE-A4 basket study, based on an acceptable safety profile in three patients dosed with 100 million cells (Press release, Adaptimmune, JUN 4, 2018, View Source;p=irol-newsArticle&ID=2352953 [SID1234527138]). The company will start treating patients with the target dose of one billion transduced MAGE-A4 SPEAR T-cells in the ongoing basket study.

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In addition, after confirming expression levels for MAGE-A4 from synovial sarcoma and myxoid/round cell liposarcoma (MRCLS) tumor samples, Adaptimmune has amended the study to add these two indications to the ongoing basket study, which already includes bladder, melanoma, head & neck, esophageal, gastric, ovarian, and non-small cell lung (NSCLC) cancers. Screening of patients with synovial sarcoma and MRCLS is ongoing.

"Today’s announcement that we are dosing patients with one billion cells, which we believe is a potentially therapeutic dose based on data from NY-ESO, means that we are on target to get response data in our MAGE-A4 study, to which we have added two solid tumor indications, in 2018," said James Noble, Adaptimmune’s Chief Executive Officer. "This follows the earlier announcement that pilot studies in our other program, MAGE-A10, have also moved to the one billion cells dose."

Target validation, investigating antigen expression in tumor samples, has been a key focus for Adaptimmune to understand the breadth of patients that have the potential to benefit from SPEAR T-cell treatment. Data from monitoring target antigen expression levels across literature, databases, and tumor samples indicate that MAGE‑A4 is expressed in both synovial sarcoma and MRCLS. Evaluation of expression of target antigens, including MAGE-A4, in other cancers will continue.

The MAGE-A4 basket study is a Phase 1, open-label, pilot study to evaluate the safety and efficacy of Adaptimmune’s SPEAR T-cells targeting MAGE-A4 in cancers in which MAGE-A4 is expressed.

Conference Call Information
The Company will host a live teleconference to answer questions about the updated safety data today, June 4, 2018, at 8:00 a.m. EDT (1:00 p.m. BST). The live webcast of the conference call will be available via the events page of Adaptimmune’s corporate website at https://bit.ly/2shwniM. An archive will be available after the call at the same address. To participate in the live conference call, if preferred, please dial please dial +1-(833) 652-5917 (U.S.) or +1-(430) 775-1624 (International). After placing the call, please ask to be joined into the Adaptimmune conference call and provide the confirmation code (9199456).

On June 4, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that highlighted data from the phase 3 ECHELON-1 clinical trial evaluating ADCETRIS (brentuximab vedotin) in combination with chemotherapy in newly diagnosed stage III or IV classical Hodgkin lymphoma (HL) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 1-5 in Chicago, Illinois (Press release, Seattle Genetics, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2353005 [SID1234527154]). In March 2018, the U.S. Food and Drug Administration (FDA) approved ADCETRIS in combination with chemotherapy for the treatment of adult patients with previously untreated stage III or IV classical HL based on the positive results of the phase 3 ECHELON-1 clinical trial. ADCETRIS is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials, including trials led by Seattle Genetics and its development and commercialization partner, Takeda, as well as by independent investigators.

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"For over 40 years, the standard of care for the treatment of frontline HL in North America has been combination chemotherapy with ABVD. Unfortunately, approximately 30 percent of advanced stage HL patients will not respond or relapse to this therapy," said Radhakrishnan Ramchandren, M.D., Barbara Ann Karmanos Cancer Center. "The ECHELON-1 phase 3 clinical trial is the first trial to demonstrate superior clinical activity utilizing a novel therapeutic agent, ADCETRIS, in combination with AVD in comparison to ABVD. At ASCO (Free ASCO Whitepaper) 2018, we presented outcomes specifically evaluating the North American population, which demonstrated a two-year modified progression-free survival benefit of approximately 11 percent over ABVD. Importantly, an analysis of traditional progression-free survival at two years also demonstrated a benefit for ADCETRIS plus AVD versus ABVD with a difference of 11.7 percent, a Hazard Ratio of 0.500 and a p-value of 0.002. These findings represent a significant and meaningful difference in outcomes for these patients."

"Our goal is to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas, including HL, and the data presented at ASCO (Free ASCO Whitepaper) continue to support this goal," said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Affairs at Seattle Genetics. "Multiple posters featuring additional analyses from the ECHELON-1 trial for ADCETRIS combination use in the treatment of patients with stage III or IV classical HL demonstrate superior efficacy benefit when compared with ABVD. In addition, data from an ongoing phase 2 study evaluating frontline use of ADCETRIS in older HL patients demonstrate a durable efficacy benefit with both monotherapy and combination therapy. Our data at ASCO (Free ASCO Whitepaper) highlight the substantial potential for ADCETRIS to address the needs of patients with lymphoma."

Three poster presentations highlight analyses from the ECHELON-1 phase 3 clinical trial evaluating ADCETRIS in combination with AVD (Adriamycin, vinblastine and dacarbazine) compared to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) in stage III or IV frontline classical HL patients. The ECHELON-1 poster presentations include the results of the North American patient population, optimizing therapy with the use of primary prophylactic growth factors (G-CSF) and improvement of modified progression-free survival (PFS) outcomes in patients who received ADCETRIS plus AVD regardless of cycle 2 PET (PET2) status. In addition, long-term follow-up from an ongoing phase 2 clinical trial in newly diagnosed older HL patients was reported.

Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: North American Results (Abstract #7541, poster presentation on Monday, June 4, 2018)

Of the 1,334 advanced stage classical HL patients who participated in the ECHELON-1 clinical trial, 497 patients were treated in North America, with 250 patients in the ADCETRIS plus AVD arm and 247 patients in the ABVD control arm. The North American results presented by Dr. Radhakrishnan Ramchandren, Barbara Ann Karmanos Cancer Center, are included below and a video summary of the poster presentation can be found here:

Per Independent Review Facility (IRF) assessment, the two-year modified PFS rate for patients in the ADCETRIS plus AVD arm was 84.3 percent compared to 73.7 percent in the control arm (HR 0.596; p-value=0.012), which corresponds to a difference of 10.6 percent.
Per investigator assessment, the two-year modified PFS rate for patients in the ADCETRIS plus AVD arm was 86.4 percent compared to 73.6 percent in the control arm (HR 0.516; p-value=0.002), which corresponds to a difference of 12.8 percent.
Per investigator assessment, the two-year PFS rate for patients in the ADCETRIS plus AVD arm was 88.1 percent compared to 76.4 percent in the control arm (HR 0.500; p-value=0.002), which corresponds to a difference of 11.7 percent.
Consistent improvement in modified PFS per IRF was observed among patients treated with ADCETRIS plus AVD compared with ABVD across all pre-specified subgroups, including age, disease stage, International Prognostic Score and baseline ECOG score.
On the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 80 percent of patients compared to 56 percent on the ABVD arm. In the ADCETRIS plus AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2 (41 percent and 21 percent, respectively). Grade 3 events were reported in 17 percent of patients. In the ABVD arm, Grade 3 events were reported in less than one percent of patients. There were no Grade 4 events on either arm. Across both arms of the study, approximately 75 percent of the patients with peripheral neuropathy reported resolution or improvement at last follow-up.
Febrile neutropenia during treatment was reported in 20 percent of patients in the ADCETRIS plus AVD arm compared with nine percent in the ABVD arm. In the ADCETRIS plus AVD arm, 35 patients received primary prophylactic G-CSF within five days of starting treatment and nine percent (three patients) reported febrile neutropenia.
Pulmonary toxicity was reported in three percent of patients in the ADCETRIS plus AVD arm versus ten percent of patients in the ABVD arm. Grade ≥3 events were reported in two percent versus six percent of patients, in the ADCETRIS plus AVD and ABVD arms, respectively.
Improving Outcomes with Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma (Abstract #7534, poster presentation on Monday, June 4, 2018)

During the ECHELON-1 clinical trial, an independent monitoring committee (IDMC) recommended the use of primary prophylactic G-CSF for patients in the ADCETRIS plus AVD arm of the study due to an increased risk of febrile neutropenia. In the ADCETRIS plus AVD arm, 83 patients received G-CSF primary prophylaxis (defined as receipt of G-CSF by day five of the first treatment cycle) and 579 patients did not. An analysis of these two patient populations in the ECHELON-1 study presented by Dr. David Straus, Memorial Sloan Kettering Cancer Center, included:

The two-year modified PFS rate for patients in the ADCETRIS plus AVD arm who received G-CSF primary prophylaxis was 84.6 percent compared to 81.7 percent for those who did not (HR 0.737; 95% CI, 0.396 to 1.372) and compared to 77.2 percent in the ABVD control arm (HR 0.586; 95% CI, 0.317 to 1.081).
Use of G-CSF primary prophylaxis in the ADCETRIS plus AVD arm was associated with a decrease in neutropenia (35 percent versus 73 percent), overall febrile neutropenia (11 percent versus 21 percent) and febrile neutropenia in the first treatment cycle (one percent versus 11 percent). Seven of the nine deaths that occurred in the ADCETRIS plus AVD arm were associated with neutropenia, none of whom had received primary prophylaxis with G-CSF before the onset of neutropenia.
There was no evidence of an association between use of G-CSF primary prophylaxis and pulmonary toxicity.
In the ADCETRIS plus AVD arm, incidence of peripheral neuropathy was 57 percent in patients with G-CSF primary prophylaxis versus 68 percent without.
Lastly, use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS dose delays and dose reductions compared to those without.
Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin Lymphoma: Impact of Cycle 2 PET Result on Modified Progression-Free Survival (Abstract #7539, poster presentation on Monday, June 4, 2018)

A post-hoc analysis of the ECHELON-1 clinical trial was conducted to evaluate modified PFS outcomes and clinical characteristics by PET2 status per IRF. In the ADCETRIS plus AVD arm of the study, 588 patients were PET2-negative (Deauville score ≤3) and 47 were PET2-positive (Deauville score ≥4). In the ABVD arm of the study, 577 patients were PET2-negative and 58 were PET2-positive. The analysis presented by Dr. Robert Chen, City of Hope National Medical Center, included:

ADCETRIS plus AVD improved modified PFS outcomes in patients regardless of PET2 status. The modified PFS in PET2-negative patients in the ADCETRIS plus AVD arm was 85.2 percent compared to 80.9 percent in the ABVD arm (HR 0.774; 95% CI, 0.586 to 1.022). The modified PFS in PET2-positive patients in the ADCETRIS plus AVD arm was 57.5 percent compared to 42.0 percent in the ABVD arm (HR 0.609; 95% CI, 0.341 to 1.088). PET2-positive patients in the ADCETRIS plus AVD arm had superior results compared to historical controls.
The safety profile of ADCETRIS plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. There were no notable differences in the safety profile between PET2-positive or PET2-negative subgroups in either arm of the study.
Long-Term Follow-Up of Brentuximab Vedotin +/- Dacarbazine as First-Line Therapy in Elderly Patients with Hodgkin Lymphoma (Abstract #7542, poster presentation on Monday, June 4, 2018)

Long-term follow-up results were presented from an ongoing phase 2 clinical trial evaluating ADCETRIS alone or in combination with dacarbazine as frontline therapy for HL patients age 60 years or older. Data were reported from 27 patients treated with ADCETRIS monotherapy and 22 patients treated with ADCETRIS in combination with dacarbazine. The median age of patients was 78 years in the ADCETRIS monotherapy arm and 69 years in the dacarbazine combination arm. Over 60 percent of patients in each arm had stage III/IV disease at the time of diagnosis and the majority were frail with multiple comorbidities. Long-term data highlighted by Dr. Jonathan Friedberg, University of Rochester, included:

In the ADCETRIS monotherapy arm, the median observation time from first dose was 42.6 months. Estimated three-year PFS and overall survival rates were 34 percent and 71 percent, respectively, with no deaths occurring within 30 days of last treatment. Median PFS was 10.48 months and median overall survival had not yet been reached.
In the dacarbazine combination arm, the median observation time from first dose was 37.8 months. Estimated three-year PFS and overall survival rates were 52 percent and 90 percent, respectively, with no deaths occurring within 30 days of last treatment. Both median PFS and overall survival had not yet been reached.
Treatment-emergent peripheral neuropathy of any grade was observed in 24 patients (89 percent) in the ADCETRIS arm and 19 patients (86 percent) in the dacarbazine combination arm, with most Grade 1 or 2 and sensory in nature. The majority of patients with treatment-emergent peripheral neuropathy had either complete resolution or some resolution or improvement.
Adverse events leading to treatment discontinuation in the ADCETRIS monotherapy arm were peripheral sensory neuropathy (30 percent), peripheral motor neuropathy (seven percent) and orthostatic hypotension (four percent). Adverse events leading to treatment discontinuation in the dacarbazine combination arm were peripheral sensory neuropathy (36 percent); asthenia, systemic lupus erythematosus, hypotension and non-cardiac chest pain (five percent each).
ADCETRIS in combination with dacarbazine is not approved for use in frontline HL.

About ECHELON-1

ECHELON-1 is a randomized, open-label, two-arm, multi-center phase 3 study designed to compare ADCETRIS plus (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) as frontline therapy in patients with previously untreated advanced classical HL. The primary endpoint is modified progression-free survival (PFS) per Independent Review Facility (IRF). Modified PFS is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy per IRF followed by subsequent anticancer therapy. The study enrolled 1,334 patients who had histologically-confirmed diagnosis of Stage III or IV Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.

About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including two ongoing phase 3 studies: the ECHELON-2 trial in frontline mature T-cell lymphomas (also known as peripheral T-cell lymphoma) and the CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA regular approval for five indications in adult patients with: (1) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, (2) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (3) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (4) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (5) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 71 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.