Category: Healthcare

KEYTRUDA Is First Checkpoint Inhibitor Approved in Europe to Treat MSI-H or dMMR Colorectal Cancer

European Approval Based on Results From KEYNOTE-177 Trial Demonstrating KEYTRUDA Significantly Reduced Risk of Disease Progression or Death by 40% Compared With Chemotherapy

KENILWORTH, N.J. — (BUSINESS WIRE) — $MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the European Commission has approved KEYTRUDA, Merck’s anti-PD-1 therapy, as a monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. This approval is based on results from the pivotal Phase 3 KEYNOTE-177 trial, in which KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.45-0.80]; p=0.0002) compared with chemotherapy (investigator’s choice: mFOLFOX6 [oxaliplatin, leucovorin and fluorouracil (FU)] with or without bevacizumab or cetuximab; or FOLFIRI [irinotecan, leucovorin and FU] with or without bevacizumab or cetuximab). In the trial, treatment with KEYTRUDA also more than doubled median progression-free survival (PFS) compared with chemotherapy (16.5 months [95% CI, 5.4-32.4] versus 8.2 months [95% CI, 6.1-10.2]). There was a lower incidence of Grade ≥3 treatment-related adverse events (TRAEs) with KEYTRUDA compared with chemotherapy (22% versus 66%), and no new toxicities were observed. This approval marks the first gastrointestinal indication for KEYTRUDA in Europe and makes KEYTRUDA the first anti-PD-1/L1 therapy approved in Europe for these patients.

“Before the KEYNOTE-177 trial, conventional chemotherapy with targeted therapy was the standard of care for patients with metastatic colorectal cancer who have tumors that are MSI-H/dMMR,” said Dr. Thierry Andre, professor of medical oncology at Sorbonne University and head of the medical oncology department at St. Antoine Hospital, Assistance Publique Hôpitaux de Paris. “With this approval, patients with metastatic colorectal cancer that is MSI-H or dMMR status will gain a monotherapy treatment option that has shown superior progression-free survival compared to standard of care chemotherapy.”

“This decision by the European Commission, which was based on the important findings from KEYNOTE-177, exemplifies our commitment to using biomarkers such as MSI/MMR to help identify patients who are most likely to respond to KEYTRUDA,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “Our efforts in biomarker-driven research across tumor types – including colorectal cancer, the most common type of gastrointestinal cancer – will continue to help us bring new options to patients across the globe.”

This approval allows marketing of KEYTRUDA monotherapy in all 27 European Union (EU) member states plus Iceland, Lichtenstein, Norway and Northern Ireland. Following Brexit, in line with the reliance route, this approval is also valid in Great Britain.

Data Supporting the European Approval

The approval was based on data from KEYNOTE-177, a multi-center, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated metastatic MSI-H or dMMR colorectal cancer. Microsatellite instability (MSI) or mismatch repair (MMR) tumor status was determined locally using polymerase chain reaction or immunohistochemistry, respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients were randomized 1:1 to receive KEYTRUDA (200 mg intravenously) every three weeks or investigator’s choice of the following chemotherapy regimens given intravenously every two weeks:

• mFOLFOX6 (oxaliplatin, leucovorin and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: oxaliplatin 85 mg/m², leucovorin 400 mg/m² (or levoleucovorin 200 mg/m²), and FU 400 mg/m² bolus on Day 1, then FU 2,400 mg/m² over 46-48 hours; plus bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m² on first infusion, then 250 mg/m² weekly
• FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: irinotecan 180 mg/m², leucovorin 400 mg/m² (or levoleucovorin 200 mg/m²), and FU 400 mg/m² bolus on Day 1, then FU 2,400 mg/m² over 46-48 hours; plus bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m² on first infusion, then 250 mg/m² weekly

Treatment with KEYTRUDA or chemotherapy continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every nine weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measure was PFS as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, and overall survival (OS). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR).

In this trial, KEYTRUDA monotherapy significantly reduced the risk of disease progression or death from any cause by 40% (HR=0.60 [95% CI, 0.45-0.80]; p=0.0002) and showed a median PFS of 16.5 months (95% CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2) for patients treated with chemotherapy. For PFS, in the KEYTRUDA arm, there were 82 patients (54%) with an event versus 113 patients (73%) in the chemotherapy arm. Overall survival analysis is ongoing. For patients treated with KEYTRUDA, the ORR was 44% (95% CI, 35.8-52.0), with a complete response rate of 11% and a partial response rate of 33%. For patients treated with chemotherapy, the ORR was 33% (95% CI, 25.8-41.1), with a complete response rate of 4% and a partial response rate of 29%. Median DOR was not reached (range, 2.3+ to 41.4+) with KEYTRUDA versus 10.6 months (range, 2.8 to 37.5+) with chemotherapy. Based on 67 patients with a response in the KEYTRUDA arm and 51 patients with a response in the chemotherapy arm, 85% in the KEYTRUDA arm had a duration of response greater than or equal to 12 months versus 44% in the chemotherapy arm.

Among the 153 patients with MSI-H or dMMR colorectal cancer treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range, 1 day to 30.6 months). Adverse reactions occurring in patients with MSI-H or dMMR colorectal cancer were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with KEYTRUDA as a single agent.

About Microsatellite Instability-High

Microsatellite instability (or MSI) is defined by the National Cancer Institute as a change that occurs in the DNA of certain cells, such as tumor cells, in which the number of microsatellite repeats (short, repeated sequences of DNA) is different from the number of repeats that was in the DNA when it was inherited. The cause of MSI may be a defect in the ability to repair mistakes made when DNA is copied in the cell. This defect is also referred to as mismatch repair deficiency (dMMR).

About Colorectal Cancer in Europe

Colorectal cancer starts in the colon or the rectum, and these cancers are referred to as colon cancer or rectal cancer depending on where the cancer starts. Colorectal cancer often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. Worldwide, it is estimated there were more than 1,930,000 new cases of colorectal cancer in 2020. In Europe, it is estimated there were nearly 520,000 new cases of colorectal cancer. It is estimated approximately 4-20% of colorectal cancer patients (inclusive of all stages of disease) have tumors that score as either MSI-H or dMMR when testing is performed.

About KEYTRUDA^® (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. 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 confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

• solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
• colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. 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.

Hepatocellular Carcinoma

KEYTRUDA 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.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. 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.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment.

Contacts

Media Contacts:

Patrick Ryan

(201) 452-2409

Ayn Wisler

(908) 740-5590

Investor Contacts:

Peter Dannenbaum

(908) 740-1037

Courtney Ronaldo

(908) 740-6132

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Expands Focus on Sulfur Nutrition for Wide Variety of Crops Including Soybeans

Robust Operational Performance Supports Improved Granular Conversion

Acquires Certain Assets of Commonwealth Industrial Services (CIS), Adding Packaging, Warehousing and Logistics Capabilities

PARSIPPANY, N.J. & HOPEWELL, Va. — (BUSINESS WIRE) — AdvanSix (NYSE: ASIX) said today it continues to build on the company’s longstanding leadership and expertise in ammonium sulfate and sulfur nutrition while creating further opportunities for growth and efficiencies across the value chain. The company shared details of recent activities, including investment in soybean application research, marketing and grower education, operational improvements and the acquisition of certain assets of Commonwealth Industrial Services, Inc. (CIS), an ammonium sulfate packaging, warehousing and logistics services business based in Hopewell, Va.

“AdvanSix is a leader in plant nutrients, producing top-quality ammonium sulfate at our Hopewell facility – which is the largest single-site producer in the world – for nearly 70 years,” said Erin Kane, president and CEO of AdvanSix. “We continue to see increased demand for sulfur nutrition, and ammonium sulfate is proven to deliver pound-for-pound the most readily available sulfur and nitrogen to a wide variety of crops, including wheat, cotton, corn and soybeans. We remain committed to our growth in this area and to advancing grower education and research that validates the return on investment and effectiveness of ammonium sulfate to support the success of our customers.”

Value of Ammonium Sulfate on Soybeans

Today’s modern soybean varieties require better management of essential nutrients, like nitrogen and sulfur, throughout the planting season to maximize and enhance their yield potential.

Ammonium sulfate is an efficient, versatile and proven source of critical nutrients that substantially improve crop production, according to lab and field trials conducted by prominent university researchers. The company is now working to educate growers and retailers about these results, especially the benefits of ammonium sulfate, which adds sulfur and supplemental nitrogen to their soybean crop management plans. With soybean prices currently at a seven-year high and season ending stocks projected to be down over 70% from the previous year, farmers have a great opportunity by boosting production through new nutrient management strategies.

Research has shown yield increases as much as 10 or more bushels per acre. These findings also demonstrate the importance of sulfur in improving plant health throughout the growing season, especially as clean air regulations have led to less sulfur in the air that is available to crops.

For more information on the value of Ammonium Sulfate for soybeans, visit soybeans.advansix.com.

Increase in Granular Grade Ammonium Sulfate

Operational excellence continues to be a key focus and priority for AdvanSix with initiatives underway targeting improvements in rate, cost, quality and yield. As a result of these efforts and recent enhancements in crystallizer technology and operations, the company is now producing more high-quality granular grade ammonium sulfate to meet the growing demand of our customers.

The company is now targeting conversion of approximately 65% of the ammonium sulfate produced in higher-value granular form, an increase of approximately 5%.

Packaged Ammonium Sulfate

The recent acquisition of certain assets of CIS enables AdvanSix to expand its offering to directly supply packaged ammonium sulfate to customers, primarily in North and South America. It diversifies and optimizes our offerings to include spray-grade adjuvant to support crop protection, as well as other specialty fertilizers and products for industrial use. The company also expects the addition of packaging and warehousing capabilities to bolster logistics and operational efficiency in the Richmond, Va.-area plants.

“AdvanSix has been both a supplier to and customer of CIS for many years, and we understand the business well. This acquisition extends our industry-leading value chain for ammonium sulfate and creates further opportunities for us to quickly diversify and optimize our offerings to serve existing and new customers,” said Mike Hamilton, vice president, Plant Nutrients at AdvanSix.

About AdvanSix

AdvanSix is a leading manufacturer of Nylon 6, a polymer resin which is a synthetic material used by our customers to produce fibers, filaments, engineered plastics and films that, in turn, are used in such end-products as carpets, automotive and electronic components, sports apparel, food packaging and other industrial applications. As a result of our backward integration and the configuration of our manufacturing facilities, we also sell caprolactam, ammonium sulfate fertilizer, acetone and other intermediate chemicals, all of which are produced within unit operations across our integrated manufacturing value chain. More information on AdvanSix can be found at http://www.advansix.com.

Forward Looking Statements

This release contains certain statements that may be deemed “forward-looking statements” within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements, other than statements of historical fact, that address activities, events or developments that our management intends, expects, projects, believes or anticipates will or may occur in the future are forward-looking statements. Forward-looking statements may be identified by words such as “expect,” “anticipate,” “estimate,” “outlook,” “project,” “strategy,” “intend,” “plan,” “target,” “goal,” “may,” “will,” “should” and “believe” and other variations or similar terminology and expressions. Although we believe forward-looking statements are based upon reasonable assumptions, such statements involve known and unknown risks, uncertainties and other factors, many of which are beyond our control and difficult to predict, which may cause the actual results or performance of the Company to be materially different from any future results or performance expressed or implied by such forward-looking statements. Such risks and uncertainties include, but are not limited to: general economic and financial conditions in the U.S. and globally, including the impact of the coronavirus (COVID-19) pandemic and any resurgences; the scope and duration of the pandemic and pace of recovery; the timing of the development and distribution of an effective vaccine or treatment for COVID-19; governmental, business and individuals’ actions in response to the pandemic, including our business continuity and cash optimization plans that have been, and may in the future be, implemented; the impact of social and economic restrictions and other containment measures taken to combat virus transmission; the effect on our customers’ demand for our products and our suppliers’ ability to manufacture and deliver our raw materials, including implications of reduced refinery utilization in the U.S.; our ability to sell and provide our goods and services, including as a result of travel and other COVID-19-related restrictions; the ability of our customers to pay for our products; and any closures of our and our customers’ offices and facilities; risks associated with increased phishing, compromised business emails and other cybersecurity attacks and disruptions to our technology infrastructure; risks associated with employees working remotely or operating with a reduced workforce; risks associated with our indebtedness including compliance with financial and restrictive covenants, and our ability to access capital on reasonable terms, at a reasonable cost or at all due to economic conditions resulting from COVID-19 or otherwise; the impact of scheduled turnarounds and significant unplanned downtime and interruptions of production or logistics operations as a result of mechanical issues or other unanticipated events such as fires, severe weather conditions, natural disasters and pandemics including the COVID-19 pandemic; price fluctuations, cost increases and supply of raw materials; our operations and growth projects requiring substantial capital; growth rates and cyclicality of the industries we serve including global changes in supply and demand; failure to develop and commercialize new products or technologies; loss of significant customer relationships; adverse trade and tax policies; extensive environmental, health and safety laws that apply to our operations; hazards associated with chemical manufacturing, storage and transportation; litigation associated with chemical manufacturing and our business operations generally; inability to acquire and integrate businesses, assets, products or technologies; protection of our intellectual property and proprietary information; prolonged work stoppages as a result of labor difficulties or otherwise; cybersecurity, data privacy incidents and disruptions to our technology infrastructure; failure to maintain effective internal controls; disruptions in transportation and logistics; our inability to achieve some or all of the anticipated benefits of our spin-off including uncertainty regarding qualification for expected tax treatment; fluctuations in our stock price; and changes in laws or regulations applicable to our business. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. Such forward-looking statements are not guarantees of future performance, and actual results, developments and business decisions may differ from those envisaged by such forward-looking statements. We identify the principal risks and uncertainties that affect our performance in our filings with the Securities and Exchange Commission (SEC), including the risk factors in Part 1, Item 1A of our Annual Report on Form 10-K for the year ended December 31, 2019, as updated in subsequent reports filed with the SEC.

Contacts

Media
Debra Lewis

(973) 526-1767

debra.lewis@advansix.com

Investors
Adam Kressel

(973) 526-1700

adam.kressel@advansix.com

In CheckMate -9ER, OPDIVO in combination with CABOMETYX doubled median progression-free survival and objective response rate and showed superior overall survival vs. sunitinib¹

Approved across all International Metastatic Renal Cell Carcinoma Database Consortium risk categories^1,2

Approval expands Company’s presence in first-line advanced renal cell carcinoma, which includes OPDIVO + YERVOY as a standard of care for intermediate- or poor-risk patients³

 

PRINCETON, N.J. — (BUSINESS WIRE) — $BMY #BMS—Bristol Myers Squibb (NYSE: BMY) today announced that OPDIVO^® (nivolumab) 240 mg (injection for intravenous use) every two weeks or 480 mg every four weeks in combination with CABOMETYX^® (cabozantinib) 40 mg once daily tablets was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of patients with advanced renal cell carcinoma (RCC).¹ The approval is based on the Phase 3 CheckMate -9ER trial, which compared OPDIVO in combination with CABOMETYX (n=323) versus sunitinib (n=328) in patients with advanced RCC.¹ This application was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible. ⁴ Please see below for additional CheckMate -9ER data context.

“At Bristol Myers Squibb, we are focused on developing transformative medicines that may improve survival for people living with cancer. The role of OPDIVO + YERVOY is well established for intermediate/poor-risk patients with advanced RCC, and today’s achievement extends the potential of an OPDIVO-based combination to even more patients,” says Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb.¹ “OPDIVO in combination with CABOMETYX brings together the strong heritage of both medicines to now provide physicians a new combination in advanced RCC that may offer improved outcomes to patients for whom an immunotherapy plus tyrosine kinase inhibitor regimen is appropriate.”¹

OPDIVO and YERVOY are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.¹ Please see the Important Safety Information section below.

“This combination of cabozantinib and nivolumab significantly improved key efficacy measures compared to sunitinib – progression-free survival, overall survival and objective response rate – while showing a low rate of treatment discontinuations due to side effects. The therapeutic benefit demonstrated in CheckMate -9ER and quality of life measures explored emphasize the role of this combination for patients with advanced kidney cancer,” said Toni Choueiri, M.D., director, Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School.^1,2 “With this important FDA approval, the combination is poised to become a standard in newly diagnosed metastatic kidney cancer.”

In the CheckMate -9ER trial, the primary endpoint was progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR), and the secondary endpoints included overall survival (OS) and BICR-assessed objective response rate (ORR).¹ In the trial, patients treated with OPDIVO in combination with CABOMETYX lived twice as long without their tumors progressing as patients who were treated with sunitinib (median PFS was 16.6 months [95% Confidence Interval [CI]: 12.5-24.9] versus median PFS of 8.3 months [95% CI: 7.0-9.7]; [Hazard Ratio [HR]: 0.51 [95% CI: 0.41–0.64], P<0.0001; median follow-up of 18.1 months]; range: 10.6-30.6 months).^1,2 OPDIVO in combination with CABOMETYX also reduced the risk of death by 40% compared to sunitinib (HR: 0.60 [98.89% CI 0.40–0.89]; P=0.0010; median OS was not reached for OPDIVO in combination with CABOMETYX and not available for sunitinib [range: 22.6-NR months]).¹

Additionally, more patients responded to OPDIVO in combination with CABOMETYX than sunitinib, with an ORR of 55.7% (n=180/323) (95% CI: 50.1 to 61.2) versus 27.1% (n=89/328) (95% CI: 22.4 to 32.3); P<0.0001, respectively.¹ In the combination arm, 8.0% (n=26/323) of patients experienced a complete response and 47.7% (n=154/323) experienced a partial response versus 4.6% (n=15/328) and 22.6% (n=74/328) of those treated with sunitinib.^1,2 Among patients who responded, the median duration of response was 20.2 months for OPDIVO in combination with CABOMETYX (95% CI: 17.3 to NA) and 11.5 months for sunitinib (95% CI: 8.3 to 18.4).¹ Consistent results for PFS were observed across pre-specified subgroups of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk categories and PD-L1 tumor expression status.¹

Adverse reactions greater than Grade 3 in the trial were similar with OPDIVO in combination with CABOMETYX versus sunitinib (75% versus 71%).² All-cause adverse reactions leading to discontinuation of either OPDIVO or CABOMETYX occurred in 19.7% of patients; 6.6% of OPDIVO only, 7.5% of CABOMETYX only and 5.6% of the combination due to same adverse reaction at the same time.^1,5

“While significant progress has been made in the treatment landscape for advanced kidney cancer over the last several years, patients still need more therapeutic options to treat this disease as we search for a possible cure,” said Bryan Lewis, president and co-founder of KidneyCAN.^6,7 “As patients are living longer with advanced kidney cancer, focusing on the safety and effectiveness of new treatments has become even more important. The findings for the combination of OPDIVO and CABOMETYX in the CheckMate -9ER trial make the FDA approval of this combination a notable development for the patient community.”¹

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, Phase 3 trial evaluating patients with previously untreated advanced renal cell carcinoma (RCC).¹ A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk) were randomized to OPDIVO in combination with CABOMETYX (n=323) versus sunitinib (n=328).¹ Patients were randomized to receive 240 mg of OPDIVO every two weeks intravenously and 40 mg of CABOMETYX orally daily or sunitinib 50 mg orally daily for the first four weeks of a six-week cycle.¹ Treatment with OPDIVO continued until disease progression per Response Evaluation version 1.1 (RECIST v1.1) or unacceptable toxicity.¹ The recommended dosing for OPDIVO and CABOMETYX is 240 mg of OPDIVO every two weeks or 480 mg every four weeks in combination with 40 mg of CABOMETYX once daily administered orally without food.¹ The recommended treatment for OPDIVO is until disease progression, unacceptable toxicity or up to two years.¹ Treatment with CABOMETYX is until disease progression or unacceptable toxicity.¹ The primary endpoint was progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR), using RECIST v1.1.¹ Secondary endpoints included overall survival (OS) and objective response rate (ORR), the latter of which was assessed by BICR using RECIST v1.1.¹ The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

Select Safety Profile from CheckMate -9ER Study

Adverse reactions leading to discontinuation of either OPDIVO or CABOMETYX occurred in 19.7% of patients: 6.6% OPDIVO only, 7.5% CABOMETYX only and 5.6% both drugs due to the same adverse reaction at the same time.^1,5 Adverse reactions leading to dose interruption or reduction of either OPDIVO or CABOMETYX occurred in 83% of patients: 3% OPDIVO only, 46% CABOMETYX only, 21% both drugs due to same adverse reaction at the same time and 6% both drugs, sequentially.¹ Serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with CABOMETYX (n=320).¹ The most frequent (≥2%) serious adverse reactions in those patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection and hyponatremia.¹ Fatal intestinal perforations occurred in 3 (0.9%) patients.¹ The most common (≥20%) adverse reactions of any grade in patients receiving OPDIVO and CABOMETYX were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%).¹

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for approximately 15,000 deaths in the United States each year.^8,9 RCC is approximately twice as common in men as in women.¹⁰ In the United States, the five-year survival rate, based on data from 2010 to 2016, for those diagnosed with metastatic (or advanced) kidney and renal pelvis cancer is 13%.⁹

INDICATIONS

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

OPDIVO^® (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%), and Grade 2 (4.5%).

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. 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 YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In RCC 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 Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Common Adverse Reactions

In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%).

Contacts

Bristol Myers Squibb

Media Inquiries:
Media@BMS.com

Investors:
Tim Power

609-252-7509

Timothy.Power@BMS.com

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