Combination and precision: ingredients for success in advanced gastric cancer

Patients with metastatic gastric cancer have poor prognosis with overall survival (OS) remaining less than 2 years despite recent updates in standard practice (1). While there have been significant advances in first- and second-line settings, developing novel therapies for more advanced disease has been challenging. By incorporating more effective therapies earlier in the disease course, a growing number of patients may be candidates for systemic treatment options beyond the second line, highlighting the critical need for drug development. Currently, trifluridine/tipiracil is the only agent approved in the United States for patients whose disease progressed on two prior lines of therapy. This approval was based on the results from a global phase 3 study, TAGS, that randomized patients who have received at least two prior lines of therapies to either oral trifluridine/tipiracil or placebo. Treatment with trifluridine/tipiracil resulted in significant improvement in OS [median OS 5.7 vs. 3.6 months; hazard ratio (HR) 0.69] (2). Efficacy was sustained regardless of prognostic factors, such as performance status, number of previous treatment lines, HER2 status, number of metastatic sites and age.

The ANGEL study evaluated activity of rivoceranib, a selective VEGFR2 tyrosine kinase inhibitor (TKI), in a patient population similar to that enrolled in the TAGS study (3). Antiangiogenic agents have established activity in the management of this disease. Ramucirumab [a monoclonal antibody against vascular endothelial growth factor receptor-2 (VEGFR2)], in combination with paclitaxel, is a preferred second-line regimen in a biomarker non-select patient population (4). However, the results of studies with antiangiogenic agents have been mixed, likely affected by patient selection, treatment setting, and tumor heterogeneity (5,6). Small molecule TKIs targeting vascular endothelial growth factor (VEGF) signaling have been under active investigation in this disease for several years but are yet to yield actionable results. In the ANGEL study, participants (n=460) were randomized 2:1 to receive either rivoceranib plus best supportive care (BSC) or placebo plus BSC. Among intention-to-treat population, primary endpoint of median OS was not statistically different between the rivoceranib and placebo cohorts [5.78 vs. 5.13 months; HR 0.93, 95% confidence interval (CI): 0.74–1.15]. Improvements were observed with secondary outcomes of median PFS (2.83 vs. 1.77 months; HR 0.58, 95% CI: 0.45–0.79) and objective response rate (ORR) (6.87% vs. 0%), though margin of benefit was minimal. Rivoceranib had expected toxicities that are typical for other TKIs targeting angiogenesis, including anorexia, hypertension, proteinuria, diarrhea, and palmar-plantar erythrodysesthesia syndrome. While the study results are disappointing, several interesting observations can be made about the presented data. The study was able to enroll patients with disease progression after several lines of therapy, and it helped demonstrate that earlier use of active regimens may positively impact the ability to receive treatment in later-line settings. This phenomenon, unfortunately, was not observed in recent phase 3 trials, where only about 50% of patients were able to receive subsequent therapies after progression on the first-line treatment (1,7,8). Therefore, the ANGEL study also enrolled patients who had favorable disease to allow clinical trial participation very late in the course of their illness. The latter may, at least in part, explain better than expected outcomes of the control group with OS of 5.13 months in the whole study population and 4.73 months in those with ≥4 lines of therapy. Although further lines of therapy can affect OS results, both experimental and control groups had a similar number of patients receive subsequent treatments. It is also important to note recent results from a similar study, phase 3 INTEGRATE IIa (NCT02773524), that compared regorafenib, a TKI directed against angiogenic, stromal, and oncogenic kinases, to placebo in an analogous setting. Although INTEGRATE IIa demonstrated a statistically significant improvement in median OS (4.5 vs. 4.0 months; HR 0.70), it is questionable whether these results translate into relevant clinical benefit (9).

While single agent TKIs have little potential in advanced gastric cancer, combination strategies do hold promise in this disease. Several prior studies demonstrated synergism between antiangiogenic agents and immune checkpoint inhibitors. Inhibition of both programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) and VEGF pathways may enhance T-cell mobilization and enable anti-tumor activity within tumor microenvironment (10). In the phase 1b REGONIVO trial, treatment with regorafenib and nivolumab resulted in 40% response rate among 25 evaluable patients (11). Lenvatinib and pembrolizumab demonstrated promising activity as well (12). Ongoing phase 3 LEAP-015 trial is investigating combination of lenvatinib and pembrolizumab with chemotherapy in the first-line setting (NCT04662710).

Treatments for advanced gastric cancer are increasingly becoming more personalized, and biomarker-based approaches are now widely accepted. In advanced disease, treatment selection based on HER2 status, PD-L1 (combined positive score; CPS), microsatellite instability (MSI) status or mismatch repair (MMR) protein expression has become standard practice (7,8,13-15). These approaches have been shown to improve patient outcomes. Trastuzumab deruxtecan, a HER2-directed antibody drug conjugate, is the only targeted agent approved for use in late lines (16,17). Hopefully more biomarker-based strategies can be utilized in late lines to help mitigate unnecessary toxicities in pretreated patients, as well as address an unmet need for improved treatment efficacy. Importantly, there are several new biomarkers that are under active investigations across treatment lines. Overexpression of CLDN18.2, a tight junction protein which is normally expressed on gastric epithelial cells, has been found in close to a third of advanced gastroesophageal cancers (1,18). Treatment with zolbetuximab, a chimeric immunoglobulin G1 (IgG1) monoclonal antibody targeted against CLDN18.2, in combination with chemotherapy resulted in OS improvement in treatment-naïve, HER2-negative, locally advanced or metastatic gastric or gastroesophageal adenocarcinoma patients in two phase 3 trials (1,19). Claudin-directed bispecific antibodies, drug conjugates and even cellular therapies are in the developmental pipeline (20). Bemarituzumab, a monoclonal antibody against FGFR2b, demonstrated positive results in the randomized phase 2 FIGHT trial (NCT03694522) in combination with chemotherapy for tumors with FGFR2 overexpression by IHC or gene amplification (21). Ongoing phase 3 studies FORTITUDE-101 (NCT05052801) and FORTITUDE-102 (NCT05111626) will further validate this positive signal, and numerous trials are looking fibroblast growth factor receptor (FGFR) inhibition with TKIs.

There are several opportunities for combination strategies with TKIs, and some are already under active investigations as discussed earlier. Management of advanced gastric cancer requires further utilization of biomarker-based paradigms. Appropriate patient selection is key to both maximize benefits and minimize unnecessary treatment toxicities.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-53/coif). N.V.U. reports receiving grants from the University of Wisconsin, Carbone Cancer Center (P30 CA014520), research support from Arcus/Gilead, Ipsen; and consulting for Astellas, AZ, Pfizer, BMS, Ipsen, Elevation Oncology, Merck, BeiGene, Eisai, Arcus, holding stock or stock options in Exact Sciences, Natera. The other author has no conflicts of interest to declare.

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