Third- and later-line systemic therapy in metastatic gastric cancer: a persistent unmet need

Most gastric cancer patients present with locally advanced or metastatic disease (1), where systemic chemotherapy combining a fluoropyrimidine with a platinum agent is the usual backbone of first-line palliative treatment. Despite recent advances with the addition of monoclonal antibodies—including checkpoint inhibitors, anti-human epidermal growth factor receptor 2 (HER2), and anti-claudin monoclonal antibodies—virtually all patients eventually will experience disease progression. After the failure of first-line therapy, irinotecan-based or taxane-based regimens are predominantly used as standard treatment for HER2-negative disease. Ramucirumab, a vascular endothelial growth factor receptor (VEGFR) monoclonal antibody, has demonstrated increased efficacy when combined with chemotherapy in this setting for relapsed patients (2-4). However, it is important to note that clinical trials in the second-line setting typically report median overall survival (mOS) of only around 5–6 months (2-4).

Some patients will survive long enough to experience disease progression to second-line regimens while maintaining sufficient performance status to receive further treatment. For these patients, treatment options remain very limited. In 2019, the Food and Drug Administration approved trifluridine/tipiracil for this setting (5) based on the results of the TAGS trial (6), a phase III study that compared trifluridine/tipiracil with placebo in patients who had received two or more lines of chemotherapy, demonstrating an improvement in overall survival (OS) (Table 1). Until then, no third-line treatments had been approved globally. Furthermore, checkpoint inhibitors have been integrated into first line settings limiting their relevance in later lines of treatment. Similarly, the use of anti-HER2 antibodies (e.g., trastuzumab and fam-trastuzumab deruxtecan) are now preferred options to be used in first- (9,10) and second-line (11) therapies, highlighting the significant unmet need for effective treatment options in third and later lines.

In this context, the original design of the Australasian Gastro-Intestinal Trials Group INTEGRATE II study aimed to compare regorafenib (an oral multikinase inhibitor with prior efficacy in refractory settings of other gastrointestinal malignancies, such as colorectal cancer) with a placebo. However, changes in clinical practice led to its modification, resulting in the study being divided into two parts: INTEGRATE IIa (8) and INTEGRATE IIb (NCT04879368). The INTEGRATE IIa (8) was a randomized, double-blind, placebo-controlled trial that enrolled advanced adenocarcinoma or undifferentiated carcinoma of the gastroesophageal junction (GEJ) or stomach with at least 2 prior lines of therapy for recurrent or metastatic disease. They were randomized 2:1 to receive 160 mg of oral regorafenib or placebo once per day on days 1 to 21 of each 28-day cycle. The median time since diagnosis at enrolment was over 20 months, which in itself exceeds the mOS reported in most first-line clinical trials, highlighting a highly selected population of patients with tumors that are either less aggressive or more responsive to previously administered therapies. Only 7% (regorafenib) and 16% (placebo) of patients had HER2-positive tumors and prior immunotherapy was received by 26% of patients in the regorafenib arm and 27% in the placebo arm.

The study primary endpoint was OS, and it was met: mOS 4.5 vs. 4 months [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.52 to 0.90; P=0.006], with a 12-month survival rates of 19% vs. 6%. There was no clear subgroup that appears to derive greater benefit, although there was a surprisingly trend to smaller treatment effect in Asian patients. Comparable efficacy was observed with both trifluridine-tipiracil (6) and apatinib, (7) an orally active VEGFR-2 inhibitor not available in the United States. It is important to mention that data on apatinib are conflicting, as the phase III ANGEL trial published in 2019 showed that OS was not significantly better with apatinib against placebo (12).

Secondary end points of the INTEGRATE trial included median progression-free survival [mPFS: 1.8 vs. 1.6 months (HR 0.53; 95% CI: 0.40 to 0.70; P<0.0001)], objective response rate (ORR 2.4% vs. 0), health-related quality of life (QoL) and safety. Detailed QoL results were not published, but time to deterioration in global QoL was significantly prolonged with regorafenib (HR 0.68; 95% CI: 0.52 to 0.89; P=0.004). Regarding safety, the most common adverse events (AEs) reported in the regorafenib arm were (grade 1/2, 3 and 4 respectively): palmar-plantar erythrodysesthesia (31%; 9%; 0%), mucositis (20%; 1%; 0%), diarrhea (18%; 4%; 0%), and hypertension (14%; 8%; 0%). It is unclear how the toxicity, safety, and QoL outcomes would be affected if a dose escalation approach had been chosen, as commonly used in metastatic colorectal cancer (mCRC), following the results of the ReDOS trial (13), which demonstrated comparable efficacy and a lower incidence of AEs with this alternative approach.

The goal of any palliative systemic therapy, regardless of the treatment line, is to improve overall survival and/or QoL. Regorafenib has demonstrated improved OS without negatively impacting QoL compared with placebo in this group of heavily pretreated patients. Therefore, in such a scenario of limited options, regorafenib may emerge as another treatment choice. Its advantage lies in a toxicity profile distinct from cytotoxic therapies, which is particularly significant for patients who have been on chemotherapy since diagnosis and may not tolerate further cytotoxic treatment with trifluridine/tipiracil. However, to date, regorafenib has not been compared against an active treatment arm. The INTEGRATE IIb study (NCT04879368), also a global phase III trial, is currently evaluating the combination of low-dose regorafenib and nivolumab versus standard chemotherapy in pretreated advanced gastroesophageal cancers. Additionally, only a minority of patients in that cohort have received modern first-line treatments such as nivolumab, pembrolizumab, trastuzumab, fam-trastuzumab deruxtecan, or zolbetuximab. Real-world data will be helpful to assess whether regorafenib would still demonstrate superiority over placebo in the current treatment landscape.

Despite the statistically significant benefits observed with both trifluridine/tipiracil (6) and regorafenib (8) in later lines of therapy, their low response rates, short mPFS, and modest OS gains highlight the need for enrolling patients in clinical trials whenever available and feasible. Additionally, with improvements in affordability and processing time advance stage patients should also undergo next-generation sequencing (NGS) to explore potential actionable mutations that may inform novel treatment strategies.

Acknowledgments

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.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-268/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-268/coif). J.M.P. reports receiving honoraria from ALCRESTA, Ferranova, AstraZeneca, ADVOCARE international, and J&J worldwide. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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