Nivolumab/Chemo Approaches EU Approval for Select HER2– Advanced or Metastatic Gastric, GEJ, or Esophageal Adenocarcinoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of nivolumab (Opdivo) plus fluoropyrimidine and platinum-containing chemotherapy as frontline treatment for adult patients with HER2-negative advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma with a PD-L1 combined positive score (CPS) of 5 or higher.¹

The positive opinion is based on data from the phase 3 CheckMate-649 trial (NCT02872116), which showed that the addition of nivolumab resulted in superior overall survival (OS) over chemotherapy alone, with a clinically meaningful progression-free survival (PFS) benefit and durable responses in treatment-naïve patients with gastric cancer, GEJ cancer, and esophageal adenocarcinoma.²

In patients with a PD-L1 CPS of 5 or higher, the median OS with nivolumab/chemotherapy (n = 378) was 14.4 months (95% CI, 13.1-16.2) vs 11.1 months (95% CI, 10.1-12.1) with chemotherapy alone (n = 391; HR, 0.71; 95% CI, 0.59-0.86; P < .0001). In this subset, the median PFS was 7.7 months (95% CI, 7.0-9.2) in the investigative arm vs 6.0 months (95% CI, 5.6-6.9) in the control arm (HR, 0.68; 95% CI, 0.56-0.81; P < .0001).

Nivolumab/chemotherapy elicited an objective response rate (ORR) of 60% (95% CI, 55%-65%) in this subset vs 45% (95% CI, 40%-50%) with chemotherapy (P < .0001). The median duration of response in the investigative (n = 226) and control arms (n = 177) was 9.5 months (95% CI, 8.0-11.4) and 7.0 months (95% CI, 5.7-7.9).

“Gastric and GEJ cancers, along with esophageal adenocarcinomas, are among the deadliest in the world, and there has been no major advancement for [patients with] HER2-negative [disease] in many years,” Ian M. Waxman, MD, development lead, gastrointestinal cancers, at Bristol Myers Squibb, stated in a press release. “With the results of the CheckMate-649 trial, [nivolumab] plus chemotherapy is the first regimen to deliver superior OS vs chemotherapy alone in this patient population. We look forward to the European Commission’s decision and to potentially bringing this new treatment to address the remaining high unmet need.”

The global, open-label phase 3 trial enrolled patients with previously untreated, unresectable, advanced or metastatic gastric/GEJ/esophageal adenocarcinoma without known HER2-positive status. Patients had to have an ECOG performance status of 0 or 1.

Study participants were randomized 1:1:1 to receive nivolumab at 1 mg/kg plus ipilimumab (Yervoy) at 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab at a dose of 240 mg every 2 weeks; nivolumab at 360 mg plus capecitabine and oxaliplatin (CapeOx) every 3 weeks or nivolumab at 240 mg plus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks (n = 789); or CapeOx every 3 weeks or FOLFOX every 2 weeks (n = 792).

Patients were stratified based on PD-L1 tumor cell expression (≥1% vs <1%), region (Asia vs United States/Canada vs rest of world), ECOG performance status (0 vs 1), and chemotherapy (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. Key secondary end points were OS in the patients with a PD-L1 CPS of 1 or higher and the all-randomized population; OS in a subset of patients with a PD-L1 CPS of 10 or higher; PFS in the subset with a PD-L1 CPS of 10 or higher, in the subset with a PD-L1 CPS of 1 or higher, and in the all-randomized population; and ORR.

Important exploratory end points included safety and quality of life.

The median age in the subset of patients with a PD-L1 CPS of 5 or higher was 62.5 years, 71% were male, 75.5% were Non-Asian, and 58.8% had an ECOG performance status of 1. Moreover, 69.5% of patients had gastric cancer, 18% had GEJ cancer, and 12.5% had esophageal adenocarcinoma. Ninety-six percent of patients had metastatic disease, 42.5% had liver metastases, 14.5% had signet ring cell carcinoma, and 88.5% had microsatellite stable status. Additionally, 51.5% of patients received FOLFOX and 48.5% received CapeOx.

In the subset of patients who had a PD-L1 CPS of 1 or higher, the median OS with nivolumab/chemotherapy (n = 641) was 14.0 months (95% CI, 12.6-15.0) vs 11.3 months (95% CI, 10.6-12.3) with chemotherapy alone (n = 655; HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001). Within this subset, the median PFS in the investigative and control arms was 7.5 months (95% CI, 7.0-8.4) and 6.9 months (95% CI, 6.1-7.0), respectively (HR, 0.74; 95% CI, 0.65-0.85).

Additional data presented during the 2021 ASCO Annual Meeting showed that in the all-randomized population, the median OS with nivolumab/chemotherapy was 13.8 months (95% CI, 12.6-14.6) vs 11.6 months (95% CI, 10.9-12.5) with chemotherapy (HR, 0.80; 95% CI, 0.68-0.94; P = .0002).3 The median PFS in the investigative and control arms was 7.7 months (95% CI, 7.1-8.5) and 6.9 months (95% CI, 6.6-7.1), respectively (HR, 0.77; 95% CI, 0.68-0.87).

The addition of nivolumab to chemotherapy resulted in an ORR of 58% (95% CI, 54%-62%) vs 46% (95% CI, 42%-50%) with chemotherapy alone. The median DOR in the nivolumab/chemotherapy arm was 8.5 months (95% CI, 7.2-9.9%) vs 6.9 months (95% CI, 5.8-7.2) in the chemotherapy-alone arm.

In the all-randomized patients, the time to symptom deterioration had not yet been reached (95% CI, 22.6–not evaluable [NE]) with nivolumab plus chemotherapy vs 21.0 months (95% CI, 12.5–NE) with chemotherapy alone (HR, 0.77; 95% CI, 0.63-0.95; P = .0129).

No new safety signals were identified with nivolumab plus chemotherapy.

References

1. Bristol Myers Squibb receives positive CHMP opinion for Opdivo (nivolumab) + chemotherapy for patients with HER2-negative advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma whose tumors express PD-L1 with CPS ≥ 5. News release. Bristol Myers Squibb. September 17, 2021. Accessed September 17, 2021. https://bit.ly/3kgAjM4
2. Moehler M, Shitara K, Garrido M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: first results of the CheckMate 649 study. Ann Oncol. 2020;31(suppl 4):S1191. doi:10.1016/j.annonc.2020.08.2296
3. Moehler MH, Shitara K, Garrido M, et al. First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in advanced gastric cancer/gastroesphageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): expanded efficacy and safety data from CheckMate 649. J Clin Oncol. 2021;39(suppl 15):4002. doi:10.1200/JCO.2021.39.15_suppl.4002