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The European Commission has approved nivolumab plus fluoropyrimidine- and platinum-based chemotherapy for the frontline treatment of adult patients with HER2-negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors have a PD-L1 combined positive score of 5 or higher.
The European Commission has approved nivolumab (Opdivo) plus fluoropyrimidine- and platinum-based chemotherapy for the frontline treatment of adult patients with HER2-negative advanced or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma whose tumors have a PD-L1 combined positive score (CPS) of 5 or higher.1
The regulatory decision is based on data from the phase 3 CheckMate-649 trial (NCT02872116), in which the addition of nivolumab to chemotherapy resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) over chemotherapy alone in this patient population.
At a minimum follow-up of 19.4 months, nivolumab plus chemotherapy resulted in a median OS of 14.4 months (95% CI, 13.1-16.3) in those with a PD-L1 CPS of 5 or higher vs 11.1 months (95% CI, 10.0-12.1) with chemotherapy alone (HR, 0.69; 95% CI, 0.60-0.81). The median PFS in the investigative arm was 8.31 months (95% CI, 7.03-9.26) vs 6.05 months (95% CI, 5.55-6.90) in the control arm (HR, 0.68; 95% CI, 0.59-0.79).
“The approval marks a great achievement for many patients with gastric, gastroesophageal junction, and esophageal adenocarcinomas, who now have a new treatment option that has demonstrated superior overall survival compared with the longer-standing standard of care,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “With limited advances for HER2-negative gastric cancers made in the past 10 years, we are especially pleased to move forward and introduce this [nivolumab]-based combination for patients in the European Union.”
The multicenter, open-label, phase 3 CheckMate-649 trial enrolled patients with previously untreated, unresectable, advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma without known HER2-positive status. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1.
A total of 1581 participants were randomized 1:1:1 to receive nivolumab at 360 mg plus capecitabine and oxaliplatin (CapeOx) every 3 weeks; nivolumab at 240 mg plus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or nivolumab at 1 mg/kg plus ipilimumab (Yervoy) at 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab at 240 mg every 2 weeks (n = 789); or FOLFOX or CapeOx every 2 or 3 weeks (n = 792). Of the patients enrolled, 60% (n = 955) had a PD-L1 CPS of 5 or higher.
Treatment was administered for 2 years or until progressive disease, intolerable toxicity, or withdrawn consent.
Stratification factors included PD-L1 tumor cell expression (1% or higher vs less than 1%), region (Asia vs United States/Canada vs rest of the world), performance status (0 vs 1), and chemotherapy received (CapeOx vs FOLFOX).
The dual primary end points of the trial were OS and PFS in the subset of patients with a PD-L1 CPS of 5 or higher. Secondary end points included OS in patients with a PD-L1 CPS of 1 or higher or all randomized patients; OS in those with a PD-L1 CPS or 10 or higher; PFS in those with a PD-L1 CPS of 10 or higher, 1 or higher, or all randomized patients; and objective response rate (ORR). Exploratory end points included safety and quality of life.
The median age of patients with a PD-L1 CPS of 5 or higher was 62.5 years, 71% were male, 75.5% were not Asian, and 58.8% had a performance status of 1.2 Additionally, 69.5% of patients had gastric cancer, 18% had GEJ cancer, and 12.5% had esophageal adenocarcinoma. Most patients (96%) had metastatic disease. Moreover, 42.5% had liver metastases, 14.5% had signet ring cell carcinoma, and 88.5% had microsatellite stable status. Regarding chemotherapy received, 51.5% received FOLFOX and 48.5% were given CapeOx.
At a data cutoff of May 27, 2020, and a minimum follow-up of 12.1 months, nivolumab plus chemotherapy (n = 378) resulted in an ORR of 60% (95% CI, 55%-65%) in the subset of patients with a PD-L1 CPS of 5 or higher vs 45% (95% CI, 40%-50%) with chemotherapy alone (n = 391; P < .0001).
The median time to treatment response in the investigative and control arms was 1.5 months (range, 0.8-10.2) and 1.5 months (range, 1.0-7.1), respectively. The duration of response with the nivolumab-based combination (n = 226) in this subset was 9.5 months (95% CI, 8.0-11.4) vs 7.0 months (95% CI, 5.7-7.9) with chemotherapy alone (n = 177).
Regarding safety, the most common adverse effects reported were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), musculoskeletal pain (20%), pyrexia (19%), rash (18%), stomatitis (17%), palmar-plantar erythrodysesthesia syndrome (13%), cough (13%), oedema (12%), headache (11%), and upper respiratory tract infection (10%).
Previously, in April 2021, the FDA approved nivolumab plus select types of chemotherapy for the first-line treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma based on earlier data from CheckMate-649.3