FDA Approves Nivolumab, First Immunotherapy for First-line Gastric Cancer

By Michael Vlessides, /alert Contributor

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For the first time ever, the US Food and Drug Administration (FDA) has approved an immunotherapeutic agent for first-line treatment of gastric cancer.

On April 16, the agency approved nivolumab (Opdivo; Bristol Myers Squibb) – in combination with certain types of chemotherapy – for the initial treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. 

The FDA’s approval of the monoclonal antibody is based on results from the randomized, multicenter, open-label phase-III CheckMate-649 trial, which compared combination therapy with nivolumab plus mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or nivolumab plus CapeOX (capecitabine and oxaliplatin) with chemotherapy alone (mFOLFOX6 or CapeOX).

That investigation comprised 1,581 adult patients with previously untreated, unresectable advanced, or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma, regardless of PD-L1 expression. Participants received either 360 mg nivolumab every three weeks plus chemotherapy or 240 mg nivolumab every two weeks plus chemotherapy, nivolumab plus ipilimumab (Yervoy; Bristol Myers Squibb), or chemotherapy alone. 

The trial found that nivolumab plus chemotherapy was superior to chemotherapy alone with respect to overall survival, both in all randomized patients (hazard ratio 0.80; p=0.0002), as well as in patients with a PD-L1 combined positive score ≥5 (HR 0.71; p<0.0001).

On average, the 789 patients who received nivolumab plus chemotherapy also lived longer than the 792 patients who received chemotherapy alone. Indeed, median survival was 13.8 months for combination therapy patients, compared with 11.6 months for those receiving chemotherapy alone.

An exploratory analysis of all patients further revealed that 55% of patients in the combination nivolumab-chemotherapy group were alive at one year, compared with 48% of their counterparts who underwent chemotherapy alone.

Combination therapy was also found to significantly reduce the risk of disease progression or death compared to chemotherapy alone. Indeed, the hazard ratio for progression-free survival among patients with a PD-L1 combined positive score ≥5 was 0.68 (p<0.0001).

“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research said in a statement

“The FDA is committed to bringing new safe and effective treatment options like Opdivo to patients with advanced cancer,” he added. 

The most common adverse reactions in CheckMate-649 (reported in ≥20% of patients receiving nivolumab-chemotherapy) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Serious adverse reactions were observed in 52% of patients treated with combination nivolumab-chemotherapy. Of these, the most common – reported in at least 2% of these patients – included vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 patients (2.0%) treated with nivolumab and chemotherapy. 

Results of the CheckMate-649 trial were met with enthusiasm by the study’s principal investigator, Yelena Y. Janjigian, MD, of the Memorial Sloan Kettering Cancer Center in New York, NY. “These findings are important,” she said in a statement, “reinforcing the potential of this [nivolumab]-based combination as a standard of care for this population of patients in high need of treatment options that may extend their lives.”

The FDA-approved dosing for nivolumab intravenous injection is 360 mg every three weeks (30-minute IV infusion) with fluoropyrimidine- and platinum-containing chemotherapy every three weeks, or 240 mg every two weeks (30-minute IV infusion) with fluoropyrimidine- and platinum-containing chemotherapy every two weeks until disease progression, unacceptable toxicity, or up to two years.

The FDA’s review was conducted under the agency’s Project Orbis initiative, which enables concurrent review by health authorities in Canada, Australia, Switzerland, and Brazil. Those reviews are still ongoing.

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