Nivolumab and Chemotherapy as First-Line Treatment for Metastatic Gastric Cancer: Updated Analysis and the Impact of FGFR2

“Nivolumab in combination with chemotherapy is the standard first-line treatment for metastatic gastric cancer expressing PD-L1.

In a randomized phase 3 study CheckMate-649, nivolumab + chemotherapy demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit in comparison with chemotherapy in previously untreated, metastatic HER2-negative gastric cancer, leading to approvals in many countries.

At the ASCO 2024 Annual Meeting, 4-year follow-up results were presented [1].

The 4-year OS rate for patients with PD-L1 expression (CPS) 5 or more was twice as high in the immunochemotherapy group compared to the chemotherapy group, at 17% and 8%, respectively (Figure 1). Median OS was 14.4 months in the immunochemotherapy group and 11.1 months in the chemotherapy group (HR=0.7).

The 4-year PFS was also significantly better (HR=0.71) in the nivolumab group compared to chemotherapy alone, at 12% versus 7%, with median PFS of 8.3 and 6.1 months, respectively (Figure 2). The objective response rate was higher in the immunochemotherapy group, at 60% compared to 45%.

In cases of disease progression on first-line therapy, PFS2 continued to favor the nivolumab plus chemotherapy group compared to chemotherapy alone, with a median of 13.7 months versus 9.8 months (HR=0.67).

Updated analysis of quality-adjusted time without symptoms and toxicity also showed better values for the combination of nivolumab and chemotherapy [2].

Meanwhile, could the efficacy of immunotherapy be compromised in patients expressing both PD-L1 and FGFR2?

FGFR2 plays an important role in the pathogenesis of gastric cancer and could be involved in mechanisms of resistance to immunotherapy . It is a prospective alternative target for the targeted therapy of this tumor.

In the single-arm, multi-center, phase 2 study NIVOFGFR2, presented at ASCO 2024, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma with PD-L1 expression (CPS≥5; DAKO 28-8) and FGFR2 expression (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abcam EPR24075-418). Patients were treated with nivolumab and CAPOX using the same criteria as in the CheckMate-649 study.

The primary endpoint was the 1-year PFS rate and secondary endpoints included median PFS, PFS2, OS, objective response rate, and toxicity.

Seventy-four patients were screened, and 23 were enrolled (31%). The median follow-up was 17.3 months. The 1-year PFS rate was 30.4%, with a median PFS of 6.0 months. The median OS was 15.1 months. Patients with moderate FGFR2 expression (2+) and a CPS score of 20 had numerically better OS results. Twenty-two percent of patients responded to therapy, including 1 complete response. The toxicity profile was consistent with previously reported data.

Eighty-three percent of patients received second-line ramucirumab and paclitaxel, with a median PFS2 of 5.9 months.

The NIVOFGFR2 study did not meet its primary endpoint, and the PFS results were inferior to those obtained in the CheckMate-649 study. However, OS was very similar, possibly due to the influence of subsequent lines of therapy.

It will be interesting to see the results of large trials of compounds directed against the extracellular domain of FGFR2, such as bemarituzumab and alofanib, and their combination with immunotherapy [6,7].”

Provided by Ilya Tsimafeyeu, Director at Bureau for Cancer Re­search.

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References:

1. Elimova E, Shitara K, Moehler MH, et al. Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4-year follow-up of CheckMate 649. ASCO Annual Meeting 2024; Abstract 4040.

2. Lin D, Quan W, Garretson M, et al. Updated quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of nivolumab plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (GC/GEJC/EAC): 4-year (yr) follow-up from CheckMate 649 (CM 649).

3. Tsimafeyeu I, Raskin G. Challenges of FGFR2 Testing in Gastric Cancer. Oncol Rev. 2023 Dec 14;17:11790.

4. Ruan R, Li L, Li X, et al. Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment. Mol Cancer. 2023 Mar 25;22(1):60. doi: 10.1186/s12943-023-01761-7

5. Tsimafeyeu I, Musayeva G, Mahmudova S, et al. Overall survival results from the phase 2 NIVOFGFR2 study of first-line nivolumab plus CAPOX in patients with FGFR2-positive, PD-L1-positive metastatic gastric cancer. ASCO Annual Meeting 2024; Abstract 4042.

6. Wainberg ZA, Kang YK, Lee KW, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial. Gastric Cancer. 2024 May;27(3):558-570.

7. Tsimafeyeu I, Statsenko G, Vladimirova L, et al. A phase 1b study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer. Invest New Drugs. 2023 Apr;41(2):324-332.