Brave new world—new and emerging treatments for gastric cancer

Background

Gastric cancer (GC) is one of the most common cancers worldwide, ranking 5th in global incidence (1). There are regional variations with regard to incidence and anatomical location. Within United States (US) and Western populations, there has been an increase in proximal and junctional adenocarcinoma with a concurrent reduction in non-cardia/distal GC. This shift has underlying aetiological drivers with proximal ‘western’ GC being associated with obesity and reflux while, for distal GC, the major driver is helicobacter pylori. As we shall discuss, these global differences impact on biology and behaviour and must be taken into account when interpreting clinical trial data. The initial foothold for chemotherapy in GC was established, in the metastatic setting, by studies which proved a (modest) benefit compared to supportive care alone and, in the perioperative setting, by the MAGIC study (2). Since then, efforts to build on chemotherapy did not have a major impact on survival times and—with the exception of human epidermal growth factor receptor 2 (HER2)-directed treatments with trastuzumab (3) or more recently trastuzumab deruxtecan (T-DXd) (4)—clinical trials evaluating so-called targeted therapies in GC were on the whole disappointing. There is now however a strong sense within the field that this has changed. New targets have emerged most notably claudin 18.2 and fibroblast growth factor receptor 2b (FGFR2b), with zolbetuximab and bemarituzumab (5) likely to be approved in the near future. The immune checkpoint inhibitor (ICI) class of drugs have had an enormous impact on the entire field of oncology and 2021 saw the first landmark studies in GC which have seen ICIs become part of the standard of care. In this review, we will discuss the impact to date of the ICI class in this disease with a focus on the advanced disease setting, and also discuss new and emerging targets and treatment strategies in GC.

Immunogenicity of GC

The immune system plays a significant role in cancer development and evolution (6,7). The Cancer Genomic Atlas (TCGA) project grouped GC into four distinct subtypes, two of which—microsatellite instable (MSI) and Epstein-Barr virus (EBV)-related—could be characterized as ‘immunogenic’ based on expression of immune-relevant genes (8). Validation of this has been seen in the striking efficacy of ICI drugs in both these subtypes with—in the MSI-high group—pathologic complete response (pCR) rates of 59% and—in the EBV group—objective radiologic responses have been seen in high numbers but all EBV positive tumors also have high programmed death-ligand 1 (PD-L1) combined positive score (CPS). Due to a lack of data at the present time, routine testing of all GCs for EBV is not recommended due to the overlap with PD-L1 positive tumors (9,10). More broadly, the extent to which the immune system reacts in response to a cancer can be inferred indirectly by pathologic variables such as tumor-infiltrating lymphocytes (TILs) and expression of PD-L1. A meta-analysis of over twenty studies found a strong correlation between presence of TILs—specifically non-regulatory T (Treg) TILs—and survival which points to an active immune role even when no immune drug is being employed (11). Treatment can of course impact on this and this is hugely important to consider in the non-MSI-high/EBV scenarios where we try to combine the ICI class with standard chemotherapy. Certain chemotherapeutic agents (e.g., oxaliplatin) appear to be more immunogenic than others (12). It is perhaps one of the disappointing aspects of the huge number of ongoing studies interrogating the combination of immune drugs with chemotherapy (or radiation) that the chemotherapy backbone, in terms of dose and schedule, is the same as that which negotiated the dose-limiting toxicity constraints of traditional trial design.

Immune approaches

First-line, ICI chemotherapy combinations

In 2021, KEYNOTE-590 became the first randomized phase 3 study in gastroesophageal cancer to demonstrate a meaningful improvement in overall survival (OS) with the addition of an ICI—pembrolizumab—to chemotherapy [5-fluorouracil (5-FU) and cisplatin] in comparison with chemotherapy alone (13). The study met its primary endpoint overall and this was consistent across the pre-specified subtypes including the 27% of patients who had adenocarcinoma and the 12% with a Siewert type 1 gastroesophageal junction (GEJ) tumor. For this subgroup, OS was longer with the addition of pembrolizumab to chemotherapy {median 11.6 [95% confidence interval (CI): 9.7–15.2] vs. 9.9 (95% CI: 7.8–12.3) months; hazard ratio (HR): 0.74, 95% CI: 0.54–1.02}. Subsequently, at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Symposium further updated results were presented. These demonstrated that median OS in the esophageal squamous cell carcinoma (ESCC) cohort was 12.6 months (HR: 0.73, 95% CI: 0.61–0.88) in comparison with 11.6 months in those with adenocarcinoma (HR: 0.73, 95% CI: 0.55–0.99). Of note, the updated data demonstrated better OS regardless of histopathology, which had not been seen in the earlier results (14). The US Food and Drug Administration (FDA) approval for this regimen however is limited to esophageal [both ESCC and esophageal adenocarcinoma (EAC)] and Siewert class 1 GEJ tumors. KEYNOTE-590 did not enrol any GCs and to date, pembrolizumab has not been licensed for this indication. However, this may imminently change with the recent presentation of the positive results from the phase III KEYNOTE-859 trial at the European Society for Medical Oncology (ESMO) virtual plenary session in February 2023, comparing pembrolizumab plus chemotherapy to chemotherapy alone as first-line therapy in gastric and GEJ adenocarcinoma (15).

Similarly, both CheckMate-649 and ATTRACTION-4 investigated the addition of nivolumab to chemotherapy in the first-line setting with a focus on adenocarcinoma (16,17). CheckMate-649 has three arms comparing nivolumab in combination with oxaliplatin-based chemotherapy, with ipilimumab and nivolumab and with chemotherapy alone. The primary endpoint assessable in patients whose tumors were PD-L1-postive (defined on amendment as a CPS of five or more). N=1,581 patients were randomized, and about 60% demonstrated PD-L1 CPS of ≥5. The majority of patients were non-Asian (76%) and—in contrast to the KEYNOTE-590 study mentioned above—most (70%) had GC. Nivolumab in combination with oxaliplatin based chemotherapy resulted in significant improvements in OS (HR: 0.71, 98.4% CI: 0.59–0.86, P<0.0001) and progression-free survival (PFS) (HR: 0.68, 98.4% CI: 0.56–0.81, P<0.0001) vs. chemotherapy alone in the enriched population (PD-L1 ≥5) although improvement was also seen with a PD-L1 CPS ≥1 who were enrolled. Updated results were presented at ESMO 2021, to include the ipilimumab and nivolumab arm. A secondary endpoint of OS in PD-L1 CPS ≥5 in the combined immunotherapy arm in comparison with chemotherapy was not met, and this calls into question the role—if any—of CTLA-4 inhibition as a strategy moving forwards in gastric or GEJ cancers (18). Although the US FDA approved the addition of nivolumab without limitation to CPS ≥5, the National Comprehensive Cancer Network (NCCN) has given category 1 evidence to CPS ≥5 but only category 2B evidence for those patients with CPS ≥1. In comparison, the European Medicines Agency (EMA) has only afforded approval where CPS ≥5. ATTRACTION-4, like CHECKMATE 649, combines nivolumab with oxaliplatin-based chemotherapy—but in an Asian population and the primary endpoints were applied regardless of PD-L1 expression albeit with four stratification blocks for CPS (19). Ninety percent of participants had GC. While the addition of nivolumab improved PFS [10.45 (95% CI: 8.44–14.75) vs. 8.34 (95% CI: 6.97–9.40) months] OS data was not different [17.45 (95% CI: 15.67–20.83) vs. 17.15 (95% CI: 15.18–19.65) months], a finding that many ascribe to the high numbers of patients who received an ICI as part of subsequent therapy.

Interim analysis results from ORIENT-16 were presented at ESMO 2021, comparing sintilimab, a programmed cell death protein 1 (PD-1) inhibitor, in combination with chemotherapy vs. chemotherapy alone (20). In total, 61.1% of patients had a CPS ≥5. Median OS was greater for sintilimab plus chemotherapy vs. chemotherapy alone both in those with CPS ≥5 (18.4 vs. 12.9 months; HR: 0.660, 95% CI: 0.505–0.864, P=0.0023) and for all patients (15.2 vs. 12.3 months; HR: 0.766, 95% CI: 0.626–0.936, P=0.0090). Greater median PFS was also observed for sintilimab plus chemotherapy vs. chemotherapy alone with CPS ≥5 (HR: 0.628, 95% CI: 0.489–0.805, P=0.0002) and again in all patients (HR: 0.636, 95% CI: 0.525–0.771, P<0.0001).

Similarly, positive interim analysis results from the PD-L1 positive population from the phase III Rationale 305 trial were presented at ASCO Gastrointestinal in January 2023 (21). A total of 274 patients with PD-L1 positive unresectable and previously untreated gastric or GEJ adenocarcinoma were randomized to either tislelizumab, an anti-PD1 monoclonal antibody, or placebo, in combination with chemotherapy. Chemotherapy was investigator chosen, either oxaliplatin plus capecitabine or cisplatin and 5-FU. The experimental arm demonstrated improved median OS vs. chemotherapy alone, at 17.2 vs. 12.6 months (HR: 0.74, 95% CI: 0.59–0.94, one-sided P=0.0056), in addition to superior median PFS (7.2 vs. 5.9 months; HR: 0.67, 95% CI: 0.55–0.83). Higher overall response rates (ORRs) were also seen in the tislelizumab arm with 50.4% vs. 43%.

Finally, results from KEYNOTE-859 were presented as the ESMO 2023 virtual plenary, cementing the role of up-front chemotherapy with immunotherapy in previously untreated HER2-negative gastric or GEJ adenocarcinoma. A total of 1,579 patients were randomized to either pembrolizumab or placebo 3 weekly for up to 35 cycles with chemotherapy [5-FU with cisplatin or capecitabine with oxaliplatin (CAPOX)]. At median study follow-up of 31 (range, 15.3–46.3) months, median OS was 12.9 months in the pembrolizumab arm in comparison with 11.5 months in the placebo arm (HR: 0.78, 95% CI: 0.70–0.87, P<0.0001). Median PFS was also greater in the immunotherapy arm at 6.9 vs. 5.6 months with placebo (HR: 0.76, 95% CI: 0.67–0.85, P<0.0001). Pembrolizumab with chemotherapy demonstrated an of ORR of 51.3% in comparison with 42.0% for those receiving placebo with chemotherapy (P=0.00009). Efficacy in the full intention-to-treat (ITT) cohort was presented with results largely consistent across the subgroups including PD-L1 CPS status, however specific subgroup analysis data for the PD-L1 subgroups will be presented at a later date (15).

ICI monotherapy

The entry point for the ICI class into the clinic has been either as a combination with chemotherapy in the front-line setting or as monotherapy in patients who had been previously treated (often with multiple lines of therapy). The initial data were for pembrolizumab in this latter setting. KEYNOTE-012 (22) was a phase 1b trial in Asia in PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or GEJ and had a response rate of 22%. This led to a larger, phase 2 study—KEYNOTE-059—which investigated third or later line pembrolizumab in previously treated metastatic GC (23). The ORR was 15.5% and 6.4% in those with PD-L1 positive and negative tumors respectively, with positivity being defined as greater or equal to one. As a result, pembrolizumab was approved by the US FDA in September 2017 for this indication, however approval was later withdrawn in 2021 following a recommendation by the Oncology Drugs Advisory Committee (ODAC). The ODAC recommendation was informed by the results of two pembrolizumab studies, KEYNOTE-062 (24)—a front-line study discussed below—and KEYNOTE-061 (25), which compared pembrolizumab with paclitaxel in patients with PD-L1-positive (defined as CPS ≥1) advanced gastric/GEJ cancer that had progressed on first-line chemotherapy. The median OS was 9.1 (95% CI: 6.2–10.7) and 8.3 (95% CI: 7.6–9.0) months for pembrolizumab and paclitaxel respectively with median PFS favoring paclitaxel 4.1 vs. 1.5 months.

Similarly, nivolumab also first demonstrated activity in previously treated gastric and GEJ malignancies in the ATTRACTION-2 study (26). This was a phase III study in an Asian population randomizing n=493 patients to nivolumab or placebo and demonstrated a modest improvement in median PFS (1.61 vs. 1.45 months; HR: 0.60, P<0.0001) and OS (5.26 vs. 4.14 months; HR: 0.63, P<0.0001). The landmark endpoints demonstrate a 12-month OS rate in favor of nivolumab (26.6% vs. 10.9%). ORR was 11.2% (vs. 0% in the placebo group), with a median duration of response (DOR) of 9.53 months. A retrospective multivariate analysis by Kim et al. showed that PD-L1 positivity and low neutrophil-lymphocyte ratio were predictors of benefit (27). Longer follow-up showed that the median OS of responders (n=32) was 26.7 months with a 3-year survival rate of 35.5% (28). However, although Japan afforded regulatory approval for nivolumab in this indication regardless of PD-L1 status in October 2017, these data were insufficient for EMA approval.

Encouraging pre-clinical data exists to support the investigation of combined immune checkpoint inhibition in GCs (29,30), and dual cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-L1 inhibition is established in the first-line management of other malignancies including melanoma and renal cell carcinoma (31,32). CheckMate-032 evaluated the safety and efficacy of single agent nivolumab or combination nivolumab with ipilimumab at different dose and schedules in n=160 patients with advanced esophagogastric cancer (33). Results demonstrated promising effectiveness with durable responses and encouraging long-term OS results in addition to a tolerable toxicity profile in all three schedules evaluated. As would be expected, adding anti-CTLA-4 inhibition did increase toxicity. These encouraging results prompted more comprehensive investigation in the phase III CheckMate-649 study discussed below (34). Another anti-CTLA-4 combination of durvalumab and tremelimumab was also assessed in a randomized multicentre phase II study in patients with advanced GEJ/G cancers and whilst response rates were low the 12-month OS rates were similar to those reported in CheckMate-032 (35).

The difficulty of displacing chemotherapy from its front-line position was seen in KEYNOTE-062. N=763 patients were randomized to pembrolizumab alone, pembrolizumab with chemotherapy or chemotherapy alone, in the first-line setting in unresectable or metastatic gastric and GEJ cancer with PD-L1 CPS ≥1 (24). Though pembrolizumab alone seemed to have benefit in PD-L1 CPS >10 this was not formally evaluated/pre-specified and neither pembrolizumab or pembrolizumab plus chemotherapy was superior to chemotherapy for the OS and PFS end points tested. Of concern though was the fact that though the 12-month survival was the same for the pembrolizumab-alone arm there seemed to be worse survival in the first few months of treatment due to the lack of chemotherapy in patients who were either slow to respond or would never respond to the ICI.

The other disappointing negative study evaluating a role for monotherapy in the front-line setting—this time in the maintenance setting—was the phase III Javelin Gastric 100 study of maintenance avelumab (36). This was a global (23% Asian), open-label study patients with untreated, unresectable, HER2-negative, gastric or junctional tumors who had not progressed after 12 weeks of up front oxaliplatin-based chemotherapy. In total, 499 of 805 patients met the criteria for randomization to receive maintenance avelumab or continue chemotherapy. Median OS was 10.4 (95% CI: 9.1 to 12.0) vs. 10.9 (95% CI: 9.6 to 12.4) months and 24-month OS rate was 22.1% vs. 15.5% with avelumab vs. chemotherapy, respectively. There was no benefit seen in the pre-specified PD-L1-positive population but in an exploratory analysis of those who were PD-L1-positive population by CPS—taking into account not just tumor cells but the immune microenvironment—median OS was 14.9 (95% CI: 8.7 to 17.3) months with avelumab vs. 11.6 (95% CI: 8.4 to 12.6) months with chemotherapy (Table 1).

Ongoing IO trials of note

Anti-vascular endothelial growth factor (anti-VEGF)

The combination of anti-angiogenic agents with ICIs has received a lot of attention in recent years with an increased understanding of the role of VEGF and other ‘pro-angiogenic’ mediators in maintaining an immune-suppressed microenvironment which facilitates immune-escape (37). The combination of lenvatinib—a multikinase inhibitor against VEGFR1, 2, and 3, fibroblast growth factor receptor (FGFR)1, 2, 3, and 4, platelet-derived growth factor receptor (PDGFR) alpha, c-Kit and rearranged during transfection (RET)—and pembrolizumab in particular has shown promising activity in endometrial and liver cancer (38,39). The LEAP-015 trial (NCT0466271) is a randomized phase III study evaluating this combination in patients with advanced/metastatic gastroesophageal adenocarcinoma (40). Safety run-in data was presented at ESMO 2022 which assessed the tolerability, safety and efficacy of the combination. N=15 patients were enrolled with an ORR of 73% demonstrated and a disease control rate of 93% (41). Part 2 of the study, which is open-label and randomized, is currently enrolling.

T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT)

TIGIT is an immune checkpoint which inhibits activation of T cells and natural killer cells and has been shown to play a role in tumor immune-surveillance (42). As such, the biologic rationale for anti-TIGIT antibodies in GC is similar to that for anti-PD-1 therapy (43). Pre-clinical studies have revealed a synergistic anti-tumor effect by combining anti-TIGIT antibodies with anti-PD-L1 ICIs, and up to 80 clinical trials are currently underway investigating anti-TIGIT antibodies across a host of solid tumors and hematological malignancies. Although phase II data for anti-TIGIT antibody in combination with anti-PD-L1 therapy in non-small cell lung cancer has been recently presented and shows greater promise in those with greater levels of PD-L1 expression (44), trials assessing anti-TIGIT therapy in combination with anti-PD-1/PD-L1 therapy in GC are currently in very early stages. These include SKYSCRAPER-11, a phase 2 trial which proposes to evaluate the safety and efficacy of tiragolumab (anti-TIGIT) and atezolizumab in patients with advanced solid tumors where anti-PD-1 therapy would be considered appropriate therapy (45), in addition to gastric/GEJ adenocarcinoma specific studies NCT04933227 (46) which looks at atezolizumab plus tiragolumab and chemotherapy in the first-line advanced disease setting and NCT05702229 (47), which will assess anti-TIGIT therapy with anti-PD-1 therapy.

Lymphocyte activation gene 3 (LAG-3)

LAG-3 is an immune checkpoint mediator limiting effector T-cell function and has been demonstrated to show expression in gastric carcinomas. CA224-060 is a phase II study which has completed recruitment and intends to assess the efficacy of relatlimab with nivolumab and chemotherapy in the first-line treatment of gastric and gastroesophageal adenocarcinoma (48).

Chimeric antigen receptor T-cell (CAR-T)

CAR-T works by utilizing viral vectors to introduce CARs to T-cells, thereby allowing the T-lymphocytes to identify tumor-associated antigens (such as surface glycoproteins) without the need for processing and presentation in context of major histocompatibility molecules (49). It has been used to great success in some hematological malignancies however as yet has not established a formal role in solid organ malignancies. Given the proposed promise of claudin 18.2 as a target in GC, which is outlined in greater detail below, CAR-T therapy using genetically engineered T-lymphocytes expressing claudin 18.2-targeted CAR has been developed. Interim phase I data has been published in previously treated claudin 18.2 positive cancers, including 28 patients with GC or GEJ cancer (50). In the GC cohort, an ORR of 57% (95% CI: 37.2%, 75.5%) was seen. In total, 42.9% of the gastric/GEJ cancer patients had received prior anti-PD-1 or anti-PD-L1 therapy previously. Additionally, although early phase data, an ORR of 70% was seen across all malignancy types in those without PD-L1 expression. As such, this represents an area of great promise for both immunogenic and low PD-L1 GC, notwithstanding the expense and toxicity of CAR-T therapy in its current form.

Perioperative/neoadjuvant use of ICIs

We have seen in lung cancer that the benefits of ICI seem to be greater when given earlier in the treatment paradigm, specifically pre-operatively (51). Neoadjuvant administration of ICIs is appealing for a variety of immunological reasons, with a potential increased efficiency of priming against in-situ tumor antigens leading to activated T-cells and better surveillance after surgery (52). In addition, the immune response is not complicated by the dramatic changes in VEGF levels and other mediators of wound healing that will occur in the days and weeks after surgery. In the GC area CHECKMATE 577 was practice-changing, though it enrolled patients with esophageal or GEJ cancer (with 71% having adenocarcinoma) (53). The Dante trial evaluated atezolizumab in combination with fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy with interim results presented at ASCO 2022 (54). 295 patients were randomized with the addition of immunotherapy demonstrating greater downsizing (pT0 23% vs. 15% and pN0 in 68% vs. 54%). Centrally assessed pCR was seen in 46% vs. 24% in those with a PD-L1 CPS ≥10, though in all-comers comparable pCR rates were seen in both arms. A number of other studies in the peri-operative setting have not yet reported. EORTC VESTIGE, is a phase II study assessing adjuvant ipilimumab and nivolumab vs. chemotherapy in patients with gastric or EAC who have had a poor response to neoadjuvant chemotherapy and have incomplete (R1) resection or metastatic lymph nodes (N+) (55). KEYNOTE-585 is an ongoing phase III trial evaluating pembrolizumab in combination with perioperative chemotherapy in those with resectable gastric/GEJ adenocarcinoma (56), although it must be highlighted that FLOT, which represents the current standard of care chemotherapy, is not mandatory. MATTERHORN is a randomized controlled phase III study investigating peri-operative FLOT ± durvalumab (57). Omitting the chemotherapy completely in the subset of patients with MSI-high GC was evaluated by the NEONIPIGA phase II study (58). This trial evaluated neoadjuvant ipilimumab (1 mg/kg every 6 weeks) for two cycles in combination with nivolumab 240 mg every 2 weeks for six cycles, followed by surgery then nivolumab 480 mg every 4 weeks for nine cycles. N=32 patients were enrolled, and all had complete endoscopic response with tumor free biopsies. Three patients did not proceed to surgery, two of whom refused and a further patient had metastatic disease at inclusion. Of the 29 that proceeded to surgery, all had a R0 resection and 58.6% had pCR. This continues to recruit as a phase II trial (Table 2).

Non-immune/immune-adjacent approaches

While there are continued advances in the immune-based therapy in GC, targeted therapy in this field has not quite kept the pace with a couple of exceptions. Over a decade ago, the ToGA trial demonstrated improved OS by adding trastuzumab to chemotherapy in the approximately 20% of gastroesophageal adenocarcinomas that are HER2-positive (3). Building on that success and introducing an antibody drug conjugate (ADC) to the GC treatment paradigm for the first time is T-DXd, an ADC consisting of an anti-HER2 antibody linked to a cytotoxic topoisomerase I inhibitor (4). DESTINY-Gastric01 is an open-label randomized phase 2 trial assessing T-DXd against chemotherapy in HER2-positive advanced GC previously treated with at least two lines of systemic therapy, including trastuzumab. N=125 patients were randomized 2:1 to T-DXd or chemotherapy. ORR of 51% with T-DXd was noted in comparison to 14% with chemotherapy (P<0.001). OS was 12.5 months in the T-DXd cohort vs. 8.4 months with chemotherapy [HR: 0.59, 95% CI: 0.39–0.88, P=0.01]. A phase 3 trial is currently recruiting. In a similar vein, DESTINY-Gastric03 is a phase 1b/II dose escalation and dose expansion trial with multiple arms investigating T-DXd as a single agent in addition to in combination with chemotherapy and/or anti-PD-1/PD-L1 therapy (59). Promising preliminary data demonstrating ORR of 50% was presented at ASCO Gastrointestinal in February 2022 and further results are eagerly awaited.

The fibroblast growth factor (FGF)/FGFR pathway plays a role in both angiogenesis and tumor cell proliferation. Alterations in the FGF/FGFR pathway, including FGFR2 gene amplification and FGFR2 overexpression, have been noted in gastroesophageal adenocarcinomas. It therefore represents another potential therapeutic target in GC. Bemarituzumab represents a first-in-class monoclonal antibody specific to the FGFR2b receptor, blocking FGF binding, and has demonstrated modest single agent activity in FGFR2b overexpressed advanced gastroesophageal adenocarcinoma with ORR of 17.9% (95% CI: 6.1–36.9%) (60). FIGHT is a randomized, doubled blind phase 2 trial investigating bemarituzumab in combination with modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) vs. mFOLFOX6 with placebo in the first-line setting in FGFR2b overexpressed GC (5). Thirty percent [275] of N=910 tumors evaluated for inclusion were FGFR2b positive. N=155 patients were randomized to either mFOLFOX6 with bemarituzumab or placebo, with median PFS of 9.5 months in the bemarituzumab arm in comparison with 7.4 months in the placebo arm (HR: 0.68, 95% CI: 0.44–1.04, P=0.07). OS was the secondary endpoint, with median not yet reached in bemarituzumab arm and 12.9 months in the placebo arm (HR: 0.58, 95% CI: 0.35–0.95, P=0.03). Phase 3 data is awaited.

Furthermore, in the context of targeted therapy in GC, it is important to look again at claudin 18.2. Claudins are transmembrane proteins which form part of the tight junctions at the apical region of polarized endothelial or epithelial cells (61). Changes in their expression can result in alteration to signalling pathways and tumorigenesis. Claudin 18.2 is expressed only in the gastric epithelia, with prominent expression maintained in GC and aberrant expression seen in other malignancies (62). As such, it represents a potential target in the treatment of GC. A number of agents targeting claudin 18.2 are under development internationally however zolbetuximab from Astellas is currently at the forefront in terms of clinical development. It is a chimeric monoclonal immunoglobulin antibody that binds claudin 18.2 to bring about tumor cell death (63). Zolbetuximab monotherapy demonstrated only modest activity in advanced claudin 18.2 positive gastric/GEJ cancer in the second-line setting, with ORR of just 9% and marginally better ORR of 14% in those with moderate to high claudin 18.2 expression in ≥70% of tumor cells (64). Combination therapy looks to offer more efficacy. The FAST trial was a phase II randomized control trial assessing zolbetuximab with epirubicin, oxaliplatin, and capecitabine (EOX) vs. EOX alone in the first-line setting in claudin 18.2 positive advanced gastric, GEJ and esophageal adenocarcinoma. Inclusion criteria required moderate to strong claudin 18.2 expression in ≥40% of tumor cells and centrally assessed by immunohistochemistry. Of 730 patients that were screened, 686 had tumor samples amenable to central assessment, and of these 334 (49%) met the claudin 18.2 expression inclusion criteria. Median PFS was greater with zolbetuximab + EOX than EOX [7.5 (95% CI: 5.6–11.3) vs. 5.3 (95% CI: 4.1–7.1) months]. Zolbetuximab + EOX also demonstrated a greater median OS and reduction in risk of death, compared with EOX [13.0 (95% CI: 9.7–18.7) vs. 8.3 (95% CI: 6.9–10.2) months; HR: 0.55, 95% CI: 0.39–0.77, P<0.0005]. SPOTLIGHT and GLOW are two phase III randomized control trials currently in progress assessing mFOLFOX with zolbetuximab and CAPOX with zolbetuximab respectively (65,66). Data from the phase III Spotlight trial was presented at ASCO Gastrointestinal on Thursday Jan 19th 2023 by Shitara as late breaking abstract LBA292 (67). It assesses zolbetuximab plus mFOLFOX 6 vs. placebo plus mFOLFOX6 and reports statistically significant improvements in PFS and OS in the zolbetuximab arm. Median PFS with zolbetuximab + mFOLFOX6 was 10.61 vs. 8.67 months in the placebo arm (HR: 0.751, P=0.0066). Additionally, improved OS was also reported with zolbetuximab + mFOLFOX (median 18.23 vs. 15.54 months; HR: 0.750, P=0.0053). While the incidences of serious treatment related AEs were similar in both arms (44.8% vs. 43.5%), there were higher rates of nausea and vomiting in the zolbetuximab arm.

Finally, in the realms of non-immune approaches, brief consideration should be given to the notable advances over the past two decades in the prevention, early detection and enhanced surgical intervention in GC. As mentioned, considerable regional variations exist in the incidence of GC internationally, with considerably higher incidence in Asian populations than in the western world (68). Japan and South Korea demonstrate amongst the highest incidence internationally of GC and have both introduced population-based screening programmes, although the implementation of screening recommendations is noted to vary on a national level and, as with almost any new therapeutic or intervention, there are concerns about sustainability from a cost perspective (69). Significant advances have also been made, again particularly in the East Asian world, with novel and progressive surgical techniques. Minimally invasive interventions, such as endoscopic mucosal dissection (ESD) which can include the use of artificial intelligence (AI), and stomach sparing surgical techniques propose to offer improved quality of life outcomes for patients (70), At present, long-term survival data is outstanding, however such surgical advances may well play a role in the currently still evolving perioperative systemic therapy paradigm in GC.

Conclusions

There has been much progress in the management of GC over the past two decades. The role of chemotherapy has been refined and has steadily increased the proportion of patients cured by surgery. In the advanced disease setting, notwithstanding the disappointments of multiple targeted therapies, anti-HER2 treatments have been genuinely impactful and continue to evolve. More recently, we have seen the potential for immune-based approaches and already the standard of care has changed in the perioperative and advanced disease settings. This is not surprising given the heterogenous clinicopathologic subtypes and knowledge of their respective immunogenicity as evidenced by the prognostic relevance of finding tumor-reactive lymphocytes embedded in the tumor. Ongoing clinical trials seek to further these advances with many exciting strategies such as combining multikinase inhibitors like lenvatinib which can target multiple immune related pathways with PD-1 inhibitors and CAR-T therapy which, though in early stages of investigation, have demonstrated promising preliminary results. Other targeted therapies are showing promising early results, with agents under investigation targeting FGFR2b in addition to claudin 18.2. However, as treatments advance questions remain about their optimal use. Further clarity is needed regarding predictive biomarkers for ICIs, with limitations to using PD-L1 including its heterogeneity of expression, variation in assays and optimal cut-off levels. With the evolution of newer agents with alternative specific targets, similar questions may well develop with regard to FGFR2b and claudin 18.2 expression and assessment. Regardless, with continued advances in immune-based, immune-adjacent and non-immune therapeutic approaches in GC the future holds promise for better outcomes and improved survival.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Adam Yopp and Matthew Porembka) for the series “Multimodal Management of Gastric and Gastroesophageal Cancers” published in Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-13/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-13/coif). The series “Multimodal Management of Gastric and Gastroesophageal Cancers” was commissioned by the editorial office without any funding or sponsorship. The authors have no other 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.

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/.

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