Opdivo demonstrated superior overall survival benefit compared to docetaxel or paclitaxel1

First approved immunotherapy in this patient population regardless of tumor PD-L1 expression level

PRINCETON, N.J.--(BUSINESS WIRE)--

Bristol Myers Squibb (NYSE: BMY) today announced that Opdivo® (nivolumab) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.1 This application was granted Priority Review Designation by the FDA, and the approval is based on the Phase 3 ATTRACTION-3 trial in which Opdivo (n=210) demonstrated superior overall survival (OS) versus taxane chemotherapy (n=209) (investigator’s choice of docetaxel or paclitaxel) (hazard ratio [HR] 0.77; 95% confidence interval [CI]: 0.62 to 0.96; p=0.0189).1,2 The median OS was 10.9 months (95% CI: 9.2 to 13.3) for Opdivo compared to 8.4 months (95% CI: 7.2 to 9.9) for docetaxel or paclitaxel.1 Opdivo is the first approved immunotherapy in this setting regardless of tumor PD-L1 expression level.

Opdivo is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion-related reactions; 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.

“Many cases of esophageal cancer are diagnosed at the advanced stage, when the disease could have a significant impact on a patient’s health.3 Treatment options can be limited once patients with advanced esophageal squamous cell carcinoma progress,”2,4 said Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb. “The approval of Opdivo as a new treatment option for previously treated patients with advanced esophageal squamous cell carcinoma, regardless of PD-L1 expression, highlights our commitment to providing new options to address the unmet needs of patients and brings us another step closer to understanding the full potential of immunotherapy for gastrointestinal cancers.”1,2,5,6,7

About ATTRACTION-3

ATTRACTION-3 (NCT02569242) is a Phase 3, multicenter, randomized, active-controlled, open-label global study evaluating Opdivo versus taxane chemotherapy (investigator’s choice of docetaxel or paclitaxel) in patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma, refractory or intolerant to at least one prior fluoropyrimidine- and platinum-based regimen. 1,2 The trial included patients regardless of tumor PD-L1 status, but tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory.1

The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants or had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract.1 Patients were randomized to receive Opdivo 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=210) or investigator’s choice of taxane chemotherapy (n=209) of either docetaxel 75 mg/m2 intravenously every 3 weeks (n=65), or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off (n=144).1,2 Patient enrollment occurred predominantly in Asia, with the United States and Europe accounting for the remainder.2 Patients were treated until disease progression, assessed by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or unacceptable toxicity.1

The major efficacy outcome measure was OS.1 Additional efficacy outcome measures included overall response rate (ORR) and progression-free survival (PFS) as assessed by the investigator using RECIST v1.1 and duration of response (DOR).1 There was no statistically significant difference between the two arms for ORR (19.3% [33/171, 95% CI: 13.7 to 26.0] versus 21.5% [34/158, 95% CI: 15.4 to 28.8] for Opdivo (0.6% complete response [CR] and 18.7% partial response [PR]) and investigator’s choice chemotherapy (1.3% CR and 20.3% PR), respectively; p=0.6323).1 The median PFS was 1.7 months (95% CI: 1.5 to 2.7) for Opdivo versus 3.4 months (95% CI: 3.0 to 4.2) for investigator’s choice chemotherapy (HR 1.1; 95% CI: 0.9 to 1.3), however it was not tested due to the pre-specified hierarchical testing strategy.1 This trial was sponsored by Ono Pharmaceutical Co. Ltd. of Japan, Bristol Myers Squibb’s development partner for Opdivo.8

Select Safety Profile from ATTRACTION-3

The safety of Opdivo was evaluated in ATTRACTION-3 in 209 patients.1 Serious adverse reactions occurred in 38% of patients receiving Opdivo.1 Serious adverse reactions reported in ≥2% of patients who received Opdivo were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received Opdivo: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).1 Opdivo was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.1 The most common adverse reactions occurring in ≥20% of Opdivo-treated patients were rash (22%) and decreased appetite (21%).1

About Esophageal Cancer

In the United States, it is estimated that approximately 18,440 new cases of esophageal cancer will be diagnosed and approximately 16,170 deaths will result from the disease this year alone.9 Esophageal cancer is a type of gastrointestinal cancer that starts in the inner layer of the esophagus (the mucosa) and grows.10 The mucosa is normally lined with squamous cells, and cancer starting in these cells is called squamous cell carcinoma, and accounts for less than 30% of esophageal cancers in the United States.10 For about 25% of patients, the disease is diagnosed in the advanced stage, which is typically harder to treat.3,7

Indication

OPDIVO® (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

The recommended dosage of OPDIVO for this indication is 240 mg IV infusion over 30 minutes every 2 weeks or 480 mg IV infusion over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity.1

OPDIVO (10 mg/mL) is an injection for intravenous (IV) use.1

IMPORTANT SAFETY INFORMATION

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.

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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.

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. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

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. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients.

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 monotherapy, adrenal insufficiency occurred in 1% (20/1994) 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 monotherapy, diabetes occurred in 0.9% (17/1994) of patients.

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.

Immune-Mediated Skin Adverse Reactions

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.

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.

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, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in