Potential of regorafenib in late-line treatment for refractory advanced gastric cancer

Although the development of chemotherapy has actually improved the long-term outcomes in advanced gastric cancer (AGC), the survival rates remain unsatisfactory in a subset of population. Long-term survival rates for refractory AGC receiving pharmacotherapy remain poor even with newly developed drugs. It is imperative to establish the optimal therapeutic strategy for refractory AGC.

When starting AGC treatment, it is essential to evaluate the expression of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC), programmed death-ligand 1 (PD-L1) IHC (CPS: combined positive score), microsatellite instability (MSI)/mismatch repair (MMR) [MSI polymerase chain reaction (PCR) and MMR IHC] and Claudin-18 (CLDN18) IHC of a tumor in each patient. Based on the evaluations of these four biomarkers, we can select an appropriate regimen for each patient with AGC. Table 1 lists regimens that have been proven effective in previous randomized controlled trials around the world. Table 1 was modified based on Japanese Gastric Cancer Treatment Guidelines 2025 (1).

In first-line treatment, the results of HER2 expression roughly divide patients into two groups. Trastuzumab should be principally administered to patients with HER2-positive AGC (2). The KEYNOTE-811 trial recently demonstrated the efficacy of pembrolizumab in combination with chemotherapies plus trastuzumab (3). Patients with HER2-negative AGC can be classified into two groups according to the CLDN18 IHC results. For patients with CLDN18-positive AGC, zolbetuximab combined with chemotherapy can be administered as first-line treatment (4,5). In contrast, immune checkpoint inhibitors (ICIs) combined with chemotherapy are also applicable to patients with CLDN18-negative AGC. A previous trial demonstrated the favorable efficacy of ICI in patients with programmed cell death-ligand 1 (PD-L1)-positive AGC (CPS >1) (6-8).

In second-line treatment, the paclitaxel (PTX) plus ramucirumab regimen has become commonplace. Furthermore, pembrolizumab is also used in patients with high MSI. A recent trial identified the limited efficacy of trastuzumab deruxtecan (T-Dxd) in patients with HER2-positive AGC in second-line treatment (9) and another trial also demonstrated the efficacy of T-Dxd in third-line treatment for this population (10).

In third-line treatment, irinotecan (IRI) and trifluridine/tipiracil (FTD/TPI) can be used at this stage. If nivolumab has not previously been used, it can be adopted.

In fourth-line treatment, there is no effective therapeutic strategy for this late stage. However, we can apply a regimen that has not been used before. Although we do not expect a jackpot effect, we must use some regimen to improve prognosis. Recently, genomic medicine has been developed and incorporated into daily practice. In Japan, genomic medicine can be performed after standard treatments under the government insurance system. Unfortunately, fewer than 10% of patients with AGC in Japan reach a reliable regimen by genomic medicine. In addition, many of these are directed against ErbB2. Therefore, it may be more reasonable to apply genomic medicine to earlier-line treatment. It is a tailor-made treatment. By contrast, approved chemotherapeutic regimens differ from one country to another. Therefore, it is important to develop and approve as many effective drugs as possible in each country.

Regorafenib is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR1, 2, 3, as well as TIE-2) which are involved in angiogenesis. It also inhibits receptor tyrosine kinases (c-KIT, RET, B-RAF, stromal PDGFR-β, and FGFR), which are associated with carcinogenesis and tumor cell proliferation (11,12). Regorafenib is the first low-molecular-weight compound available for molecular therapy that targets molecules related to cancer proliferation. To date, its efficacy has been demonstrated in patients with non-resectable colorectal cancer (13), gastrointestinal stromal tumors (GISTs) (14), and non-resectable primary liver cancer (15). However, we must pay attention to some adverse effects. In particular, hand-foot skin reactions, hypertension, general fatigue, diarrhea and skin rashes can deteriorate patients’ quality of life (QOL). Furthermore, it is important to educate patients not to take high-fat diet while taking the medicine, as this type of diet can reduce the effectiveness of regorafenib.

The INTEGRATE phase II trial was a double-blind study in which patients were randomly assigned to either an active arm receiving regorafenib or a control arm receiving placebo. The trial first evaluated the efficacy of regorafenib for refractory AGC that had not responded to previous treatment (16). The trial successfully demonstrated effectiveness of regorafenib in prolonging PFS with acceptable incidence of adverse effects. Next, investigators focused on the therapeutic effect of regorafenib for refractory AGC at a late stage of treatment stage in the INTEGRATE IIa phase III study (17). In this study, approximately 40% of patients had received more than three lines of treatments; therefore, it is fair to say that standard treatment is no longer an option for this population. At first glance, it may appear counterintuitive to conduct a trial in such a challenging-to-treat group of patients. A previous study, the CORRECT trial (13), assessed the efficacy of regorafenib monotherapy for previously treated metastatic colorectal cancer after the last standard therapy. The CORRECT trial was conducted following an acceptable phase Ib study and due to the high unmet need in this population, in order to identify the efficacy of regorafenib. The INTEGRATE IIa phase III study was also conducted based on the acceptable results of the phase II INTEGRATE I trial and the high unmet need for patients with refractory AGC after receiving several lines of approved treatment. The INTEGRATE IIa study successfully demonstrated the efficacy of regorafenib in treating refractory AGC, improving overall survival (OS), delaying progression-free survival (PFS) and delaying deterioration of QOL while maintaining an acceptable incidence of adverse effects. Considering the details carefully, administration of regorafenib provided significant improvement of OS [hazard ratio (HR), 0.68; P=0.006]. Although the difference in median OS was minor, the difference in the estimated 1-year OS rate was 13% between two groups. The survival curve in the regorafenib group showed a gradual decline and did not intersect with that in the placebo group within 18 months. We can suppose that the effect of regorafenib, which significantly prolonged the deterioration time in QOL, influenced these results. Although the survival benefit is moderate, this is reasonable given that regorafenib was used in the late-line treatment. Surprisingly, regorafenib reduced the risk of death by 32% and the risk of progression by 48% compared to placebo in this late-line treatment. What is the mechanism by which regorafenib exerts its effect on refractory AGC in late-stage treatment? It is necessary to elucidate the biomarkers for effectiveness of regorafenib. In a previous study of regorafenib for KIT/PDGFRA wild type metastatic GIST (KP-wtGIST), the SDH-deficient GIST subset showed better clinical outcome than other KP-wtGIST. It was therefore concluded that regorafenib should be considered as an initial treatment for advanced KP-wtGIST (18). I believe that such biomarkers must be revealed through precise and meticulous evaluations of patients with refractory AGC who are treated with regorafenib.

Recently, some clinical study groups have conducted trials using regorafenib in combination with nivolumab and chemotherapy for AGC. The ongoing INTEGRATE IIb study is investigating the effectiveness of the combination therapy of regorafenib and nivolumab for OS by comparing it with the approved standard chemotherapy options for refractory AGC. Furthermore, the INTEGRATE IIb study is comparing the effectiveness of this regimen demonstrated in the phase Ib REGONIVO trial (19). Moreover, a phase II trial investigating the use of regorafenib in combination with nivolumab and chemotherapy as a first-line treatment for AGC revealed that this combination exhibits has promising anti-tumor activity and is safety for patients with AGC (20). I suppose that regorafenib plus ICIs and chemotherapy treatment has the potential to be effective against AGC, regardless of treatment-line. Another phase I/II study using regorafenib and PTX in patients with first-line refractory advanced esophagogastric carcinoma demonstrated tolerability and efficacy in this population (21). Moreover, this trial revealed that galectin-1, which acts as an autocrine negative growth factor that regulates cell proliferation, and chromosome 19q13.12-q13.2 amplification are negative predictive biomarkers of treatment response. In the INTEGRATE IIa study, the proportion of patients receiving prior ICIs was low. Although prior administration of ICIs did not influence OS between the regorafenib group and the placebo group in the forest plot analysis, it is important to determine the effect of the prior administration of ICIs on OS in sufficient numbers of patients. Many investigators must be interested in the interaction of these two drugs.

The toxicity profile identified three grade 5 toxicity (one related to study treatment and two unrelated to study treatment) and some controllable regorafenib toxicities consistent with the previous report (16). Clever toxicity managements such as regorafenib dose interruption, reduction, escalation, and initially lower regorafenib dose may provide favorable therapeutic procedure, particularly in the late-line treatment.

In the future, we can anticipate the development of regorafenib-based combination therapies for AGC, particularly for AGC at every treatment-line, as well as for late-stage refractory AGC. It is essential to determine the most effective combinations of regorafenib with ICIs and chemotherapeutic agents for each treatment line. Moreover, we must continue to evaluate predictive biomarkers of regorafenib for AGC in each treatment line and establish prophylactic treatments for the adverse effects of regorafenib to improve QOL.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-751/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-751/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2025. 7th ed. Tokyo: Kanehara & Co., Ltd.; 2025.
2. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97. [Crossref] [PubMed]
3. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 2023;402:2197-208. [Crossref] [PubMed]
4. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2023;401:1655-68. [Crossref] [PubMed]
5. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 2023;29:2133-41. [Crossref] [PubMed]
6. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40. [Crossref] [PubMed]
7. Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022;23:234-47. [Crossref] [PubMed]
8. Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1181-95. [Crossref] [PubMed]
9. Shitara K, Van Cutsem E, Gümüş M, et al. Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer. N Engl J Med 2025;393:336-48. [Crossref] [PubMed]
10. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020;382:2419-30. [Crossref] [PubMed]
11. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011;129:245-55. [Crossref] [PubMed]
12. Schmieder R, Hoffmann J, Becker M, et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer 2014;135:1487-96. [Crossref] [PubMed]
13. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303-12. [Crossref] [PubMed]
14. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295-302. [Crossref] [PubMed]
15. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66. [Crossref] [PubMed]
16. Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the Treatment of Advanced Gastric Cancer (INTEGRATE): A Multinational Placebo-Controlled Phase II Trial. J Clin Oncol 2016;34:2728-35. [Crossref] [PubMed]
17. Pavlakis N, Shitara K, Sjoquist K, et al. INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer. J Clin Oncol 2025;43:453-63. [Crossref] [PubMed]
18. Martin-Broto J, Valverde C, Hindi N, et al. REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial. Mol Cancer 2023;22:127. [Crossref] [PubMed]
19. Fukuoka S, Hara H, Takahashi N, et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol 2020;38:2053-61. [Crossref] [PubMed]
20. Cytryn SL, Moy RH, Cowzer D, et al. First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial. Lancet Oncol 2023;24:1073-82. [Crossref] [PubMed]
21. Stroes CI, Schokker S, Khurshed M, et al. A phase Ib/II study of regorafenib and paclitaxel in patients with beyond first-line advanced esophagogastric carcinoma (REPEAT). Ther Adv Med Oncol 2022;14:17588359221109196. [Crossref] [PubMed]