competitive landscape gastric cancer

Zolbetuximab (anti-CLDN18.2; Astellas)

First-line (1L) zolbetuximab + chemotherapy in patients (pts) with claudin 18.2 (CLDN18.2)+, HER2–, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: A pooled final analysis of SPOTLIGHT + GLOW
(Abstract 1438P; Kang et al.)

Final pooled analysis of the P3 SPOTLIGHT and GLOW studies showed continued efficacy benefit and consistent safety for zolbetuximab + chemotherapy in 1L HER2-, CLDN18.2+ GC/GEJ adenocarcinoma which continue to support Astellas’ regulatory submissions. This study has the potential to fragment the 1L HER2- patient population ahead of the STAR-221 data readout.

• Key Takeaways
  • Zolbetuximab presents a direct threat to STAR-221 in 1L HER2- GC/GEJ adenocarcinoma as it has the potential to fragment the patient population ahead of the STAR-221 data readout.
    • ~38% 1L HER2- patients are CLDN18.2+, and Astellas will have to invest in marketing shaping to encourage testing
  • The P3 pooled results (OS HR 0.77; PFS HR 0.71) appear to be numerically similar to data from the ITT populations from BMS’s CheckMate 649 (OS HR 0.79; PFS HR 0.80) and Merck’s KEYNOTE-859 (OS HR 0.78; PFS HR 0.76) studies
    • Considering the similar efficacy to current anti-PD1 SoC, it is unclear whether zolbetuximab will be utilized in the PD-L1 all-comers patient population or mainly utilized in the PD-L1 low/ negative patient population
  • The pooled data continues to support Astellas’ ongoing regulatory submission for zolbetuximab + chemotherapy for 1L treatment of patients with CLDN18.2+, HER2-, unresectable GC/GEJ adenocarcinoma. This regimen is already approved for use in Japan and UK with an EMA approval expected in Q4 2024 while FDA approved Astellas' Vyloy (zolbetuximab-clzb) + chemo for gastric/GEJ adenocarcinoma
• Study information
  • P3 SPOTLIGHT (NCT03504397): zolbetuximab 800/600 mg/m² + mFOLFOX6 vs. placebo + mFOLFOX6, 1L HER2- CDLN18.2+ LA GC/GEJ adenocarcinoma
    • N= 566
    • Data cut-off: September 8, 2023
  • P3 GLOW (NCT03653507): zolbetuximab 800/600 mg/m² + CAPOX vs. placebo + CAPOX, 1L HER2- CDLN18.2+ GC/GEJ adenocarcinoma
    • N= 498
    • Data cut-off: January 12, 2024
  • 1EP: PFS
  • 2EP: OS, TTCD in GHS/QoL, PF, OG25-Pain, ORR, DOR, safety, PROs
  • Pooled analysis
• Pooled Efficacy (zolbetuximab + chemo vs placebo + chemo)
  • mPFS (mos): 9.2 vs 8.2 (HR 0.71)
  • mOS (mos): 16.4 vs 13.7 (HR 0.77)
  • ORR: 45 % vs 44%
  • mDOR (mos): 8.1 vs 6.5
• Pooled Safety
  • Gr3+ TEAEs: 81 % vs 75%
    • Nausea: 13% vs 5%
    • Vomiting: 14% vs 5%
  • TRAEs leading to dose interruption of zolbetuximab or placebo: 54% vs 19%
  • TRAEs leading to discontinuation of zolbetuximab or placebo: 11% vs 3%
  • TRAEs leading to death: 2% vs 2%

Rilvegostomig (AZD2936; PD1/TIGIT bi-specific antibody; AstraZeneca)

First-line rilvegostomig (rilve) + chemotherapy (CTx) in patients (pts) with HER2-negative (HER2–) locally advanced unresectable or metastatic gastric cancers: First report of GEMINI-Gastric Substudy 2
(Abstract 1422P; Rivera Herrero et al.)

First time efficacy data from the single-arm P2 GEMINI-Gastric Substudy 2 demonstrated encouraging efficacy for rilvegostomig (PD1 x TIGIT bsAb) + chemotherapy in 1L HER2- advanced gastric cancers, with an ORR and mPFS numerically higher than current anti-PD1 SoC benchmarks. Encouraging activity of rilvegostomig in UGI, especially in the PD-L1 CPS ≥5 population, may further increase confidence in the TIGIT MoA in upper Gl cancers

•      Key Takeaways
  • Initial efficacy data from this presentation indicate encouraging activity of rilvegostomig in UGI and may help increase confidence in the TIGIT MoA in upper Gl cancers
    • Although no plans have been announced, data from this study may lead to an initiation of a pivotal trial in 1L HER2- locally advanced unresectable or metastatic GC/ GEJ adenocarcinoma that could compete with DOM/ZIM in the future
  • Although cautious interpretation of the data is warranted due to the small sample size, ORR and mPFS of rilvegostomig + FOLFOX/XELOX of 63% and 8.3 mos appears to be numerical higher to current benchmarks of P3 CheckMate 649 (58%, 7.7 mos) and P3 KEYNOTE-859 (51%, 6.9 mos)
    • In particular, numerically higher efficacy data was observed in the CPS ≥5 cohort reinforcing the TIGIT MOA’s promise in this subpopulation
  • The regimen was generally well tolerated with the most common treatment-related adverse events observed with the rilvegostomig regimen being nausea, neutrophil count decrease, anemia, and platelet count decrease
• Study information
  • P2 GEMINI-Gastric (NCT05702229): rilvegostomig + XELOX or FOLFOX, 1L HER2- GC/GEJ adenocarcinoma
  • N=40 pts (N=27 in rilvegostomig + XELOX cohort, N= 13 rilvegostomig + FOLFOX)
    • Data cut off: Jul 04, 2024
  • 1EP: ORR (analyzed by baseline PD-L1 combined positive score (CPS) <5 vs ≥5), PFS at 6 mos
  • 2EP: Safety, PFS, DoR
• Efficacy
  • mPFS (mos): 8.3 (6 mo PFS rate: 73.3%)
    • PD-L1 CPS ≥5: 11.1
    • PD-L1 CPS <5: 7.1
  • cORR: 63%
    • PD-L1 CPS ≥5: 81% (CR: 2 pts)
    • PD-L1 CPS <5: 50%
  • CR rate: 5.0% (2 patients, both with PD-L1 CPS ≥5)
  • mDoR (mos): 5.8
    • PD-L1 CPS ≥5: 12.2
    • PD-L1 CPS <5: 5.8
  • All patients had disease control; none had primary progressive disease
• Safety
  • Gr 3+ TRAE rilve related: 10% (overall 43%)
  • Gr 3+ TEAE: 58%
  • All grade/G3+ TRAEs:
    • Nausea: 58% / 3%
    • Neutrophil count decreased: 50% / 13%
    • Anemia: 35% / 3%
    • Platelet count decreased: 35% / 3%
• The GEMINI-Gastric trial also evaluates rilvegostomig + AZD0901 (CLDN18.2 ADC) + CT (Substudy 4) for which we are yet to see the data.
  • in May 2024, AstraZeneca noted plans to launch up to 10 pivotal combination trials across solid tumor indications, including GI cancers, within the next 12-18 months, and thus we could expect to see a lot more activity from AstraZeneca in the near future

Bemarituzumab (FGFR2b mAb; Amgen)

Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) protein overexpression and biomarker overlap in patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC)
(Abstract 1420P; Sato et al.)

In-line with Amgen’s previous estimates, data from a single Japanese cohort demonstrates that FGFR2b overexpression (2+/3+ staining) in advanced GC/GEJ was observed in 28.9% of tested tumors. Findings further suggest that FGFR2b overexpression is more prevalent in the PD-L1 low/negative patient population which could limit positioning of Amgen’s bemarituzumab + chemotherapy regimen to this subpopulation.

• Key Takeaways
  • Data from a single Japanese cohort (N=128) demonstrates that FGFR2b overexpression (2+/3+ staining) in advanced GC/GEJ was observed in in 28.9% of tested tumors, with 10.9% meeting the higher threshold for expression (≥10% 2+/3+)
    • 13.5% of samples showed an overlap of FGFR2b overexpression and PD-L1 CPS ≥5 while 31% of samples showed an overlap of FGFR2b overexpression and PD-L1 CPS <5, suggesting that FGFR2b overexpression is more prevalent in the PD-L1 low/negative patient population.
  • Considering the overlap of expression of FGFR2b and PD-L1, anti-FGFR2b therapies in combination with chemo might be limited to CPS low/negative (<5) patient subpopulations 
    • Amgen’s P3 FORTITUDE-101 (bemarituzumab + chemo) and FORTITUDE-102 (bemarituzumab + nivolumab + chemo) trials in 1L HER2- FGFR2b+ G/GEJ are currently ongoing with interim data from FORTITUDE-101 expected to readout in 1H 2025
• Study information
  • Study aimed to provide clinical and molecular characterization of FGFR2b expression in advanced GC/GEJC and its overlap with other biomarkers of interest e.g., HER2, PD-L1, MMR and CLDN18.2
    • Data was collected from a Japanese cancer center's electronic medical records
  • Eligibility: unresectable/metastatic GC/GEJC, histologically confirmed adenocarcinoma, no prior systemic chemotherapy for advanced disease, and archived tissue specimen available
  • FFPE samples tested via IHC for FGFR2b [clone FPR2-D] and PD-L1 [clone 28-8]; FGFR2b defined as any 2+/3+ staining or ≥10% 2+/3+
  • PD-L1 stratified by CPS (≥5 vs <5)
  • HER2, MMR, and CLDN18.2 assessed, with CLDN18.2 defined as ≥75% cells with 2+/3+ staining
• Results
  • 547 tumor specimens tested for FGFR2b and PD-L1; 500 were evaluable for FGFR2b.
    • Sub-cohort described in poster: 128 GC/GEJC patients with tumor samples collected ≤1.5 years before study initiation
  • Estimated FGFR2b prevalence:
    • Any 2+/3+: 28.9%
      • Among these, 40% noted as not eligible for currently approved targeted therapies
    • ≥10% 2+/3+: 10.9%
  • No differences in patient/tumor characteristics between FGFR2b any 2+/3+ and FGFR2b 0/1+ groups
  • Biomarker prevalence:
    • Estimated prevalences of FGFR2b any 2+/3+ were: 16.6% HER2-positive, 0% dMMR, 11.4% PD-L1 CPS ≥5, and 31.0% CLDN18.2-positive
    • In FGFR2b any 2+/3+ samples:
      • HER2 negative: 89.2%
      • PD-L1 CPS ≥5: 13.5%
      • PD-L1 CPS <5: 83.8%
      • CLDN18.2-positive: 35.1%
      • CLDN18.2-negative: 64.9%