On September 7, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported longer term survival and safety data from CheckMate -017 and -063, two pivotal trials evaluating Opdivo in previously treated squamous (SQ) non-small cell lung cancer (NSCLC), showing sustained survival benefit across these studies (Press release, Bristol-Myers Squibb, SEP 7, 2015, View Source [SID:1234507403]). In both trials, Opdivo showed an estimated 18 month overall survival (OS) rate of 27% (CheckMate -063) to 28% (CheckMate -017); survival benefit was independent of PD-L1 expression.

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The safety profile of Opdivo is consistent with previously-reported trials, and in CheckMate -017, is also favorable compared to docetaxel. These data will be presented today at the 16th World Conference on Lung Cancer (Abstract #736, CheckMate -017 and #828, CheckMate -063).

"Immuno-Oncology agents like Opdivo provide a novel approach to treating cancer. The improvement in survival observed in advanced squamous non-small cell lung cancer represents an important step forward for our patients," said Suresh S. Ramalingam, M.D., director, Division of Medical Oncology, Winship Cancer Institute of Emory University. "These updated results demonstrate the ability to achieve longer term survival outcomes in this patient population. In fact, the Kaplan-Meier curve from this study suggests a prolonged survival benefit for a subset of patients."

Previously-reported one year results from CheckMate -017 showed a significantly superior OS rate of 42% versus 24% for docetaxel. In CheckMate -063, the estimated one-year survival rate was 39%.

"Our approach to Immuno-Oncology research is intended to show meaningful improvement over the traditional standard of care on the benchmark endpoint of overall survival," said Michael Giordano, senior vice president, head of Development, Oncology. "We have taken a comprehensive research approach in lung cancer, one focused on a commitment to providing the first major advancement in squamous non-small cell lung cancer in more than a decade – Opdivo – that offers the potential to replace chemotherapy. With the data presented today, we remain confident in our Immuno-Oncology strategy, including fulfilling our goal in showing the survival benefit for Opdivo, not only in non-small cell lung cancer, but similar to the data already observed in advanced melanoma and other tumor types."

About CheckMate -017 & CheckMate -063

CheckMate -017 and CheckMate -063 demonstrated the efficacy and safety of Opdivo in patients with advanced or metastatic SQ NSCLC who had progressed following previous chemotherapy treatment. Together, the trials investigated Opdivo monotherapy at a dose of 3 mg/kg every two weeks, which has been well-established across the Phase 3 Opdivo clinical development programs for various tumors. These trials also formed the basis for Opdivo’s approvals in the U.S. and European Union, and helped to establish the agent as standard of care for previously treated SQ NSCLC.

CheckMate -017 is a landmark Phase 3, open-label, randomized clinical trial that evaluated Opdivo (n=135) 3mg/kg intravenously over 60 minutes every two weeks versus standard of care, docetaxel (n=137) 75 mg/m2 intravenously administered every three weeks in patients with advanced SQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The study’s primary endpoint was OS and secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). The trial included patients regardless of their PD-L1 expression status.

CheckMate -017 showed a doubling in 18 month OS benefit with an estimated 28% of patients alive at 18 months for Opdivo versus 13% for docetaxel. The median OS for the Opdivo arm was 9.2 months and 6.0 months for docetaxel (hazard ratio: 0.62 [95% CI, 0.48, 0.81; P = 0.0004]). In addition, Opdivo showed a statistically significant improvement in PFS and ORR. The PFS rate at 18 months was 17% for the Opdivo arm versus 2.7% for docetaxel. Median PFS was 3.5 months for patients administered Opdivo versus 2.8 months for docetaxel (hazard ratio: 0.63; [95% CI, 0.48, 0.83; P = 0.0008]). The ORR was 20% for the Opdivo arm versus 9% for docetaxel for an estimated odds ratio of 2.6 (95% CI, 1.3, 5.5; P = 0.0083), with an ongoing response seen in 63% of patients treated with Opdivo. In the trial, 28 patients were treated with Opdivo beyond initial progression, and nine demonstrated a non-conventional pattern of benefit (7%). The safety profile of Opdivo continued to be favorable versus docetaxel and treatment-related AEs occurred less frequently with Opdivo (n=131; any grade, 59%; grade 3–5, 8%; no grade 5 events) than docetaxel (n=129; any grade, 87%; grade 3–5, 58%), including both hematologic and non-hematologic toxicities. The majority of treatment-related select AEs in patients receiving Opdivo occurred within the first three months of treatment.

CheckMate -063 is a Phase 2, single-arm, open-label trial that included patients with metastatic SQ NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen (n=117). In this trial, Opdivo showed an estimated 18-month OS rate of 27%. At 18 months, confirmed objective response rate, the study’s primary endpoint, was 15% (95% CI: 9, 22). Median OS was 8.1 months (95% CI: 6.1, 10.9). Most treatment-related AEs were of low grade (any grade, 75%; grade 3-4, 17%) and managed using established treatment algorithms.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Lung cancer results in more deaths worldwide than colorectal, breast and prostate cancers combined. Non-small cell lung cancer (NSCLC) is one of the most common types of the disease and accounts for approximately 85% of cases. Squamous cell NSCLC accounts for approximately 25% to 30% of all lung cancer cases. Five year survival rates vary globally depending on the stage and type of lung cancer.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as a monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the FDA as a monotherapy in two cancer indications. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous (SQ) non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy.

INDICATION

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO 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 OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. 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 Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).