FDA Grants Priority Review to 1L Nivolumab Combination in Gastric/GEJ/Esophageal Cancers

The FDA has granted a Priority Review to the combination of nivolumab (Opdivo) with fluoropyrimidine- and platinum-containing chemotherapy, which is a potential treatment option for patients with advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma, announced Bristol Myers Squibb, in a press release.¹

The FDA has set a Prescription Drug User Fee Act action date of May 25, 2021, for this potential approval.

“Today’s filing acceptance by the FDA marks important progress for the gastrointestinal cancer community and builds on our momentum of advancing immunotherapies to help improve the lives of those with advanced gastric and esophageal tumors,” said Ian M. Waxman, MD, development lead, gastrointestinal cancers, Bristol Myers Squibb, in a statement.

The supplement Biologic License Application (sBLA) for frontline nivolumab plus chemotherapy in advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma is supported by findings from the phase 3 CheckMate 649 clinical trial (NCT02872116). Findings from the study showed statistically significant improvements in overall survival (OS) and progression-free survival (PFS) with nivolumab and fluoropyrimidine- and platinum-containing chemotherapy in the subset of patients with tumors expressing PD-L1 with a combined positive score (CPS) ≥5, compared with chemotherapy alone. In addition, the overall population has a statistically significant improvement in OS.

CheckMate 649 is the largest randomized, global phase 3 study to date evaluating an immune checkpoint inhibitor regimen as treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.

Data for the randomized, multicenter, open-label study were presented at the European Society of Medical Oncology Congress 2020.² A total of 1581 patients were randomized to receive either nivolumab plus chemotherapy (n = 473) or chemotherapy alone (n = 482) as frontline treatment. Patients in the nivolumab arm received 240 mg of the immunotherapy with leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) every 2 weeks, or patients received a 360-mg dose of nivolumab with capecitabine and oxaliplatin (CAPEOX), every 3 weeks for 4 cycles followed by nivolumab monotherapy at 240 mg every 2 weeks. Treatment continued for up to 2 years or until disease progression, unacceptable toxicity, or withdrawal of consent.

The coprimary end points explored in the study were OS in PD-L1–positive patients with a CPS ≥5, and PFS, which were assessed by Blinded Independent Central Review. The secondary end points of the study were OS in the CPS ≥1 population, as well as in all randomized patients. The study also assessed the secondary end point of time to symptom deterioration.

The median OS observed in patients with CPS ≥5 was 14.4 months (95% CI, 13.1-16.2) in the nivolumab-combination arm versus 11.1 months (95% CI, 10.0-12.1) in the chemotherapy-alone arm (HR, 0.71; 98.4% CI, 0.59-0.86; P <.0001). The median PFS in the study was 7.7 months (95% CI, 7.0-9.2) with the addition of frontline nivolumab to chemotherapy compared with 6.1 months (95% CI, 5.6-6.9) with chemotherapy alone (HR, 0.68; 98.0% CI, 0.56-0.81; P <.0001).

In the population of patients with CPS ≥1, which included 641 patients in the nivolumab-combination arm and 655 in the chemotherapy-alone arm, the median OS was 14.0 months (95% CI. 12.6-15.0) versus 11.3 months (95% CI, 10.6-12.3), respectively (HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001). In all randomized patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma, the median OS was 13.8 months (955 CI, 12.6-14.6) among the nivolumab/chemotherapy arm of 789 patients versus 11.6 months (95% CI, 10.9-12.5) in the chemotherapy arm of 792 patients (HR, 0.80; 99.3% CI, 0.68-0.94; P = .0002).

The safety of the nivolumab combination was shown to be consistent with the safety profile known for each treatment alone.1 Safety data were available for patients with a PD-L1 CPS ≥5, which including 468 patients in the nivolumab arm and 465 patients in the chemotherapy arm. Treatment-related adverse events (TRAEs) of any grade were observed in 95% of patients who received nivolumab plus chemotherapy compared with 88% of patients who received chemotherapy alone, and grade 3/4 TRAEs were seen in 59% and 49%, respectively. TRAEs led to treatment discontinuation for 38% of patients treated with nivolumab plus chemotherapy compared with 25% of those treated with chemotherapy alone. Eight patients died as a result of a safety event in the nivolumab/chemotherapy group versus only 4 in the chemotherapy-alone arm.

“The positive results of the CheckMate 649 trial are potentially practice-changing, and we look forward to working with the FDA to possibly bring the first immunotherapy-based treatment option to front-line patients, for whom no novel therapies have been made available in the last decade,” said Waxman, in a statement.

_References:

_{1. U.S. Food and Drug Administration accepts for Priority Review application for Opdivo® (nivolumab) combined with chemotherapy as first-line treatment in metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma. News release. January 20, 2021. Accessed January 20, 2020. https://bit.ly/3quBVSG}

_{2. Moehler M, Shitara K, Garrido M, et al. LBA6_PR Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol. 2020;31(4):S1191. doi:10.1016/j.annonc.2020.08.2296}