New targets and strategies in treatment of metastatic gastric cancer

ABSTRACT

Introduction

Gastric cancer is a common type of cancer and one of the leading causes of cancer-related deaths. Unfortunately, the number of cases has been rising in recent years. Since this cancer often does not show symptoms in its early stages, most people are diagnosed when the disease is already advanced (stage 3 or 4). At this stage, survival rates are low, with most patients living about 12 months on average.

Treatment options

For advanced gastric cancer, the most commonly used treatments are chemotherapy combinations that include oxaliplatin and fluoropyrimidine. Another option is irinotecan, which can be used instead of oxaliplatin. However, older drugs like anthracyclines and docetaxel are no longer widely used. A newer combination of oxaliplatin, fluoropyrimidine, leucovorin, and docetaxel has fewer side effects compared to older treatments.

Recent advances

In recent years, researchers have discovered new ways to target gastric cancer. These include therapies that combine antibodies with drugs, therapies that use multiple antibodies, and immunotherapies that help the immune system fight cancer. These new treatments, when added to chemotherapy, offer hope for improving survival rates in people with advanced gastric cancer.

1. Introduction

Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer-related deaths worldwide. The incidence of gastric cancer is increasing in recent years with the highest incidences seen in Asia, Eastern Europe, and Latin America. The patients with gastric and gastroesophageal junction (GEJ) tumors are generally diagnosed in locally advanced or metastatic stage due to asymptomatic course in the early stages of the disease. Overall survival (OS) is approximately 12 months with chemotherapy in metastatic gastric and GEJ cancer.

Platinum- and fluoroprymidine-based doublet chemotherapy are used as the first-line treatment. As oxaliplatin-based doublet chemotherapies such as mFOLFOX6 or CAPOX have similar efficacy with lower adverse effects, these regimens are preferred to cisplatin-based doublet chemotherapies [1,2]. The combination of irinotecan and 5-fluorourasil (5-FU) is also used in the first-line treatment of gastric cancer [3]. Although ECF or EOF chemotherapy regimens that include antracyclines such as epirubicine or doxorubicine have been used in the past for the first-line treatment of gastric cancer, these regimens are not preferred in these days [4,5]. Similarly, the combination of docetaxel, cisplatin, and 5-FU has been used in the past but is not preferred nowadays because of high rates of adverse effects [6]. Recently, the combination of oxaliplatin, 5-FU, leucovorin, and docetaxel (FLOT or TFOX) is more preferred because of lower rates of adverse effects [7,8].

New treatment agents that affect via different pathways that are found with biomarker analyses such as targeted therapies, antibody-drug conjugates (ADCs), and immune checkpoint inhibitors (ICIs) are promising. The benefit of the addition of trastuzumab (monoclonal antibody (mAb) against human epidermal growth factor reseptor-2 (HER2)) to chemotherapy in patients with HER2-amplificated or HER2-overexpressed tumors was shown [9]. The presence of high-level T cell infiltration in tumor microenvironment after treatment with trastuzumab was observed in pre-clinical trials, and it was thought that a synergistic effect could be achieved with dual inhibition of HER2 and immune checkpoints [10]. The presence of this synergistic effect was shown in the clinical trial with the addition of anti-PD1 pembrolizumab to trastuzumab-doubled chemotherapy [11].

Margetuximab is also an HER2-targeted IgG1 mAb that has enhanced affinity for Fc gamma receptor (FcgRIIIa). It affects via increasing antibody dependent cellular cytotoxicity mediated by natural killer cells [12]. Translational studies gave rise to the thought that margetuximab may be affected via both innate and adaptive immunity [13]. For this reason, it is foreseen that margetuximab and ICI may be more effective when they are used together.

Unresponsiveness or resistance to mAbs such as trastuzumab may develop [14]. Thus, bispecific antibodies (BsAbs) which are different from traditional mAbs were developed. BsAbs affect by binding to two different antigens in tumor cells or immune cells [15]. This dual attachment easies cell–cell interaction and provides close contact between immune cells and tumor cells. BsAbs that target both Claudin-18.2 (CLDN 18.2) and programmed cell death ligand-1 (PD-L1) were developed as well as BsAbs that target HER2 or CLDN 18.2 separately, and the early-phase studies of these BsAbs are ongoing [16].

ADCs are compounds of cytotoxic drug components bonded to mAbs with a linker [17]. Antibodies recognize their antigens localized on tumor cell surfaces and constitute antigen–antibody conjugates that cause cell death as a result of internalization and release of the cytotoxic drug. The linkers in the structure of ADCs limit the off-target toxicity and provide transmission of the cytotoxic drug to cancer cells [17,18]. Trials with fam-trastuzumab deruxtecan (T-DXd) (anti-HER2 ADC) and ADCs that target CLDN 18.2 in gastric cancer patients are ongoing.

2. The first-line treatments in metastatic gastric cancer

2.1. HER2-positive tumors

OS benefit with the addition of trastuzumab to first-line standard chemotherapy in HER2-positive metastatic gastric/GEJ cancer was shown in TOGA trial [9]. The combination of cisplatin, 5-FU, and trastuzumab has become the standard first-line treatment of HER2-positive gastric cancer patients after this trial. It was shown in retrospective studies that the combination of 5-FU, irinotecan, and trastuzumab could be used in patients who were not eligible for platinum-based chemotherapy [19]. However, no further benefit has been observed with the combination of other HER2-targeted molecules with chemotherapy in the first-line setting. In TRIO-13/LOGIC study, the addition of lapatinib to CAPOX regimen did not provide any additional benefit [20]. Similarly, in JACOB trial, the addition of pertuzumab to the combination of cisplatin, 5-FU, and trastuzumab did not provide any further benefit [21].

In the phase III KEYNOTE-811 trial, the answer to the question of how the first-line treatment approach for metastatic gastric cancer which was positive for both HER2- and PD-L1 has been investigated. The researchers explored whether the addition of pembrolizumab to the combination of trastuzumab with doubled chemotherapy would bring additional benefits. It was announced in ESMO 2024 that a statistically significant benefit in both PFS and OS has been provided with the addition of pembrolizumab in PD-L1 positive gastric cancer patients [22]. The addition of pembrolizumab to the combination of trastuzumab-chemotherapy for the treatment of HER2-positive and PD-l positive (CPS ≥ 1) metastatic gastric cancer patients has been approved by EMA after this study.

There are ongoing clinical researches that are investigating whether the addition of new immunotherapy agents to chemotherapy-anti-HER2 combinations would provide further benefit. The phase III HORIZON GEA-01 study (NCT05152147) compares three different treatment arms that include chemotherapy (CAPOX or cisplatin-5-FU), the combination of chemotherapy with zanidatamab (bispecific mAb that targets HER2), and the combination of chemotherapy, zanidatamab, and tislelizumab (anti-PD-1 mAb). In the four-armed phase II/III MOHAGANY (NCT04082364) trial, the combination of margetuximab (anti-HER2 antibody, ADCC), retifanlimab, and chemotherapy, the combination of margetuximab, tebotelimab, and chemotherapy, the combination of margetuximab and chemotherapy, and the combination of trastuzumab and chemotherapy (CAPOX or mFOLFOX) are being compared in the first-line setting. A summary of clinical trials with anti-HER2 agents is shown in Table 1.

Table 1.

First-line trials of HER2-targeted agents for advanced gastric cancer patients with HER2-positive disease.

Completed Trials	Phase	Regimens	Primary Endpoint	Results	Other Data
TOGA	III	Cisplatin +5FU + Trastuzumab vs Cisplatin + 5FU	OS	Positive mOS 13.8 vs 11.1 mo mPFS 6.7 vs 5.5 mo	None
TRIO-13/LOGIC	III	CAPOX + Lapatinib vs CAPOX	OS	Negative	Positive for PFS mPFS 6.0 vs 5.4 mo
JACOP	III	Cisplatin +5FU + Trastuzumab + Pertuzumab vs Cisplatin +5FU + Trastuzumab	OS	Negative	None
KEYNOTE-811	III	Doublet CT + Trastuzumab + Pembrolizumab vs Doublet CT + Trastuzumab	PFS, OS	Positive mOS 20.0 vs 16.8 mo mPFS 10.0 vs 8.1 mo	For PD-L1 positive mOS 20.1 vs 15.7 mo mPFS 10.9 vs 7.3 mo
Ongoing Trials
HORIZON-GEA-01 (NCT05152147)	III	Zanidatamab + CT vs Zanidatamab + Tislelizumab +CT vs CT CT: CAPOX or Cisplatin + 5FU	PFS		None
MAHOGANY (NCT04082364)	II/III	Margetuximab + Retifanlimab + CT vs Margetuximab + Tobetelimab + CT vs Margetuximab + CT vs Trastuzumab + CT CT: CAPOX or FOLFOX	ORR	ORR 53% fort he first 53 patients	This study was closed because of the results of KeyNote-811 Trial
PRODIGE 51- FFCD-GASTFOX	III	FOLFOX vs TFOX	PFS	Positive mPFS 7,59 vs 5,98 mo	None

5FU: 5-Fluorourasil; OS: Overall survival; mo: months; CAPOX: Capecitabine+Oxaliplatin; PFS: Progression-free survival; CT: Chemotherapy.

2.2. HER2-negative tumors

2.2.1. Immunotherapy

In CheckMate 649 study, it has been seen that the addition of nivolumab to chemotherapy (CAPOX or mFOLFOX) in patients with PD-L1 CPS ≥5 prolonged both PFS (7.7 vs 6.5 months) and OS (14.4 vs 11.1 months). No PFS or OS benefit has been observed with the addition of nivolumab to chemotherapy in patients with CPS <5. It has also been shown in this study that the combination of nivolumab and ipilimumab (mAb that targets CTLA-4) did not provide a significant benefit compared to chemotherapy [23]. In a similar study (ATTRACTION-4) that was performed in Asia, although a significant PFS benefit (10.4 vs 8.3 months) was observed with the addition of nivolumab to chemotherapy (CAPOX or S-1 plus oxaliplatin regimens), the OS was found to be similar (17.4 vs 17.1 months). It is defined in this trial that administration of immunotherapy to 27% of the patients in the chemotherapy arm after exclusion from the study might affect OS [24]. In phase III ORIENT-16 study, it was observed that PFS and OS were better with the addition of sintilimab (anti-PD-1) to CAPOX in PD-L1 CPS > 5 patients [25].

The addition of nivolumab to first-line platinum-fluoropirimidine-based chemotherapy in HER2-negative, PD-L1 CPS ≥5 metastatic gastric cancer patients is approved by EMA with this data. FDA approved usage of nivolumab with chemotherapy independent of PD-L1 status in this group of patients.

The phase III KEYNOTE-062 was the first study that investigated the benefit of the addition of pembrolizumab to standard chemotherapy in PD-L1-positive metastatic gastric cancer patients, but no benefit could be shown. It was determined that pembrolizumab monotherapy was noninferior compared to chemotherapy in terms of OS in PD-L1 CPS >1 patients [26]. Unlike this trial, PFS, OS, and ORR benefits have been shown in all patients with the addition of pembrolizumab to first-line chemotherapy in the phase III KEYNOTE 859 study. However, in subgroup analysis, it was observed that the main benefit was seen in patients with high PD-L1 CPS. Pembrolizumab combined with chemotherapy was approved by EMA in PD-L1 CPS ≥1 patients after these findings [27].

The results of phase III RATIONALE-305 study were reported in ASCO GI 2023. It has been observed in this trial that the addition of tislelizumab (anti-PD-1) to first-line chemotherapy provided both PFS and OS benefit in PD-L1 positive advanced gastric cancer patients [28].

The patients with metastatic gastric and GEJ cancer were randomized to nivolumab + relatlimab (anti LAG-3) + chemotherapy and nivolumab + chemotherapy in phase II RELATIVITY-060 study. This is a negative study, and the primary endpoint (ORR) has not been met [29].

The biomarkers that may predict the efficacy of immunotherapy in gastric cancer are PD-L1 positivity rate, microsatellite instability (MSI) status, and high tumor mutational burden (TMB-H). It has been shown that immunotherapy provided a significant OS benefit in MSI-H patients compared to microsatellite stabile subgroups in the meta-analysis of four randomized clinical trials (KEYNOTE-062, CheckMate-649, Javelin Gastric-100 ve KEYNOTE-061) [30]. The clinical trials of immunotherapies are summarized in Table 2. The role of intratumoral lymphocyte infiltration and EBV positivity has not been clearly established in predicting immunotherapy response.

Table 2.

First-line trials of immunotherapy agents for the treatment of patients with advanced gastric cancer.

Trials	Phase	Regimens	Primary Endpoint	Results	Other Data
CHECKMATE-649	III	Nivolumab + CT vs CT CT: CAPOX or FOLFOX	PFS, OS	Positive for PFS and OS PFS: 7.7 vs 6.5 mo OS: 14.4 vs 11.1 mo	Positive for CPS ≥ 5 (Less beneficial for CPS < 5)
ATTRACTION-04	III	Nivolumab + CT vs CT CT: CAPOX or Oxaliplatin+S1	PFS, OS	Positive for PFS PFS: 10.4 vs 8.3 mo	OS was similar
ORIENT-16	III	Sintilimab + CAPOX vs CAPOX	OS	Positive mOS 15.2 vs 12.3 mo mPFS 7.7 vs 5.8 mo	Positive for CPS ≥ 5
KEYNOTE-062	III	Pembrolizumab + Cisplatin + 5FU vs Cisplatin +5FU	PFS, OS	Negative	Also negative for CPS ≥ 10
KEYNOTE-859	III	Pembrolizumab + CT vs CT	OS	Positive mOS 12.9 vs 11.5 mo	Also positive for PFS mPFS 6.9 vs 5.6 mo Better benefit for CPS ≥ 1
RATIONALE-305	III	Tislelizumab + CT vs CT	OS	Positive mOS 17.2 vs 12.6 mo	Also positive for PFS mPFS 7.2 vs 5.9 mo
RELATIVITY-060	II	Nivolumab + Relatlimab + CT vs CT	ORR	Negative

CT: Chemotherapy; CAPOX: Capecitabine + Oxaliplatin; FOLFOX: 5-Fluorourasil + Oxaliplatin; OS: Overall survival; PFS: Progression-free survival; mo: months; 5FU: 5-Fluorourasil.

2.2.2. Targeted therapies

2.2.2.1. Anti-Claudin-18.2 therapies

CLDN 18.2 is a tight junction protein that is commonly expressed in normal gastric mucosa cells. Cell polarity disappears during malign transformation, and CLDN 18.2 emerges on the surface of cancer cells, making CLDN 18.2 more accessible for antibody [31]. Zolbetuximab is a first-in-class IgG1 chimeric mAb and shows its efficacy by biding to CLDN 18.2.

No meaningful correlation has been determined between CLDN 18.2 positivity and HER2 and PD-L1 in metastatic gastric cancer patients. HER2 positivity rate was found to be 15% in both CLDN 18.2-positive and negative patient groups. CLDN 18.2 positivity rate was found to be 38.4% in HER2-negative metastatic gastric cancer patients. CLDN 18.2 positivity is seen at the same rate in gastric and GEJ cancer. CLDN 18.2 positivity is seen more frequently in women (43%) than men (36%). Higher CLDN 18.2 positivity has been determined in tumors that have diffuse-type histology (48.3%) than intestinal-type histology (38.8%) [32].

The benefit of adding zolbetuximab (mAb that targets CLDN 18.2) to EOX regimen in patients with locally advanced-metastatic gastric and GEJ adenocarciona and CLDN 18.2-positive with IHC (CLDN 18.2 overexpression ≥40% of tumor cells) was investigated in a randomized phase II FAST study. It was observed that the addition of zolbetuximab to chemotherapy provided improvement in both PFS (7.5 vs 5.3 months) and OS (13 vs 8.4 months) and that ORR was better (39% vs 25%) [33]. It was investigated whether the addition of zolbetuximab to chemotherapy provides further benefit in two different phase III trials after this phase II study.

First-line mFOLFOX + zolbetuximab treatment has been compared to mFOLFOX in patients with HER2-negative and CLDN 18.2-positive (CLDN 18.2 overexpression ≥75% of tumor cells in a central laboratory) metastatic gastric cancer in the randomized phase III SPOTLIGHT study. Asian and non-Asian patients were included in this trial. The results showed that addition of zolbetuximab to chemotherapy provided a statistically significant benefit in both PFS (median 10.6 vs 8.6 months) and OS (median 18.2 vs 15.5 months) compared to chemotherapy alone. SPOTLIGHT trial has shown that HER2, PD-L1, and mismatch repair prevalence were similar in both CLDN 18.2-positive and -negative patient groups [34].

A total number of 507 metastatic gastric cancer patients with HER2-negative and CLDN 18.2-positive disease were randomized to CAPOX + zolbetuxiamb vs CAPOX arms as a first-line treatment in the phase III GLOW trial. This trial met its primary endpoint PFS (median 8.2 vs 6.8 months) and secondary endpoint OS (median 14.39 vs 12.16 months). Since there is only 5% increase in ORR with the addition of zolbetuximab to chemotherapy, it is thought that PFS and OS benefit of zolbetuximab might be the result of prolonged tumor stabilization period rather than tumor shrinkage affect [35].

When SPOTLIHT and GLOW trials are analyzed together, a survival advantage in CLDN 18.2-positive and HER2-negative patients was shown in both trials and CLDN 18.2 was validated as a new target. After these findings, FDA approved zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative CLDN 18.2-positive gastric or GEJ adenocarcinoma [36]. With these progresses, testing CLDN 18.2 expression became a necessity and zolbetuximab combined with chemotherapy had its place in the first-line treatment of metastatic gastric cancer. Zolbetuximab may be the preferred option for the patients with PD-L1-negative or low positive (CPS < 5) and CLDN 18.2-positive tumors. This suggestion is because of limited benefit of anti-PD1 agents in patients with PD-L1 CPS < 5. Immunotherapy may be preferred to zolbetixumab in PD-L1 CPS high and CLDN 18.2-positive patients.

More than one molecular target may coexist in some patients. When the overlapping rate of CLDN 18.2 and PD-L1 expression was investigated, PD-L1 was found to be positive (PD-L1 CPS > 5) in 17% of CLDN 18.2-positive patients in the subgroup analysis of GLOW and SPOTLIGHT trials (35). The efficacy and safety of zolbetuximab + nivolumab with chemotherapy is being evaluated in ILUSTRO (NCT03505320) study as a first-line treatment for patients with HER2-negative CLDN 18.2-positive locally advanced or metastatic gastric/GEJ adenocarcinoma.

Osemitamab (also known as TST001), AB011, MIL93, ASKB589, and ZL1211 are newly developed anti-CLDN 18.2 mAbs that specifically bind with high affinity to the extracellular sites of CLDN 18.2 [32]. Furthermore, CLDN 18.2 may be a target for various therapeutic methods including BsAbs, ADCs, and chimeric antigen receptor T cells beyond mAbs.

2.2.2.2. FGFR2b inhibitors

Fibroblast growth factor receptor (FGFR) pathway plays a very important role in the growth and development of cancer cells, and the overexpression of proteins in this pathway may lead to disease progression [37]. It has been observed that FGFR2b was overexpressed in approximately 30% of HER-2-negative metastatic gastric cancer patients [38].

Bemarituzumab blocks the binding of FGF to its receptor. FGFR2b is a specific first-in-class mAb. Bemarituzumab inhibits cancer cell proliferation by blocking FGFR2b signaling specifically, and the increased affinity of bemarituzumab to natural killer cells enhances antibody-dependent cell cytotoxicity against tumor cells that express FGFR2b [39].

First-line mFOLFOX + bemarituzumab was compared to mFOLFOX + placebo in patients with FGFR2b-positive metastatic gastric and GEJ cancer in the randomized phase II FIGHT trial. Median PFS (mPFS) was found to be 9.5 and 7.4 months, respectively (p: 0.07). Median OS (mOS) was found as 19.2 months in mFOLFOX + bemarituzumab arm and 13.5 months in mFOLFOX + placebo arm. It has been observed that the efficacy of bemarituzumab was more pronounced in the patient group with FGFR2b >10%, and mPFS was 14 vs 7.3 months, and mOS was 24.7 vs 11.1 months [40]. Although the phase II FIGHT trial did not meet the primary end point PFS, the positive effect on OS is promising, and two separate phase III studies are still ongoing. The efficacy of bemarituzumab + mFOLFOX6 regimen in HER2-negative and FGFR2b-positive metastatic gastric/GEJ cancer patients with no prior treatment is being evaluated in the phase III FORTITUDE-101 (NCT05052801) trial and the efficacy of bemarituzumab + mFOLFOX6 + nivolumab in phase III FORTITUDE-102 (NCT05111626) trial. The clinical trials that evaluate these new targeted agents are summarized in Table 3.

Table 3.

First-line trials of new targeted agents for the treatment of patients with advanced gastric cancer.

Trials of Anti- CLDN18.2 Agents	Phase	Regimens	Primary Endpoint	Results	Other Data
FAST	IIb	Zolbetuximab + EOX vs EOX	PFS	Positive for PFS and OS mPFS 7.5 vs 5.3 mo mOS 13 vs 8.3 mo	CLDN18.2 positivity ≥ 40% of tumor cells (2+, 3+ by IHC)
SPOTLIGHT	III	Zolbetuximab + FOLFOX6 vs FOLFOX6	PFS	Positive for PFS and OS mPFS 10.6 vs 8.6 mo mOS 18.2 vs 15.5 mo	CLDN18.2 positivity ≥ 75% of tumor cells by IHC
GLOW	III	Zolbetuximab + CAPOX vs CAPOX	PFS	Positive for PFS and OS mPFS 8.2 vs 6.8 mo mOS 14.3 vs 12.1 mo	CLDN18.2 positivity ≥ 75% of tumor cells by IHC
Trials of FGFR2b Inhibitors
FIGHT	II	Bemarituzumab + FOLFOX vs FOLFOX	PFS	Positive for PFS and OS mPFS 9.5 vs 7.4 mo mOS 19.2 vs 13.5 mo	FGFR2b positivity ≥ 10% 2+, 3+ by IHC; amplification at ctDNA
Ongoing Trials of FGFR2b Inhibitors
FORTITUDE-101 (NCT05052801)	III	Bemarituzumab + FOLFOX vs FOLFOX	OS		FGFR2b positivity ≥ 10% 2+, 3+ by IHC; amplification at ctDNA
FORTITUDE-102 (NCT05111626)	III	Bemarituzumab + Nivolumab + FOLFOX vs Nivolumab + FOLFOX	OS		FGFR2b positivity ≥ 10% 2+, 3+ by IHC; amplification at ctDNA

CLDN18.2: Claudin 18.2; EOX: Epirubicin + Oxaliplatin + Capecitabine; PFS: Progression-free survival; OS: Overall survival; mPFS: median progression-free survival; mo: months; mOS: median overall survival; IHC: Immunohistochemistry; FOLOFX6: 5-Fluorourasil + Oxaliplatin; CAPOX: Capecitabine + Oxaliplatin.

2.2.2.3. Anti-angiogenic agents

Lenvatinib is a multikinase inhibitor that is affected by the vascular endothelial growth factor receptor 1–3 (VEGFR 1–3), FGFR 1–4, PDGFRα, and RET pathways [41]. In the phase III EPOC 1706, the efficacy of lenvatinib plus pembrolizumab was investigated in the first- and second-line treatment of metastatic gastric cancer [41]. The promising results of this trial (ORR 69%) led to initiation of phase III LEAP-015 (NCT 04662710) that investigates the efficacy of lenvatinib plus pembrolizumab plus chemotherapy [42].

2.2.2.4. Targeting the TME

DKN-01 is an anti-Dickkopf-1 (DDK1) mAb that targets Wnt signaling pathway. DKK1 accelerates tumor growth by composing an immunosuppressive tumor microenvironment [43,44]. The phase II DisTinGuish trial investigates the efficacy of DKN-01 plus tislelizumab plus chemotherapy in the first-line treatment of HER2-negative metastatic gastric cancer. The results of this ongoing trial are promising with an mPFS of 11.3 months and mOS of 19.5 months [45].

TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a receptor localized on the surface of T cells a natural killer cells [46] and causes immune cell inactivation like PD-1. The combination of anti-TIGIT and anti-PD-1 agents has shown a potential synergistic effect depending on this mechanism [47]. The phase II EDGE-gastric trial investigates the efficacy of zimberelimab (anti-PD-1) plus domvanalimab (anti-TIGIT) plus FOLFOX regimen in the first-line treatment of metastatic gastric cancer patients (NCT 05329766) [48]. After the interim analysis of this trial, phase III STAR-221 trial is initiated in the first-line treatment of metastatic gastric cancer (NCT 05568095) [49]. The trial compare zimberelimab plus domvanalimab plus chemotherapy with nivolumab plus chemotherapy [49].

3. Second-line and subsequent treatments in metastatic gastric cancer

The aim of second-line treatment for metastatic gastric/GEJ cancer is to control disease, improve quality of life, and prolong survival. Survival benefits of multi-agent chemotherapy combination regimens that did not include targeted agents could not be shown in the second-line treatment. Moreover, the toxicity due to the combination of different chemotherapeutic agents has been more frequent and more serious compared to single-agent chemotherapy [6,7]. For this reason, single-agent chemotherapy is an acceptable option for the second-line treatment of metastatic gastric cancer patients. If the patient is a candidate to receive treatment, performing tumor agnostic tests (TMB, dMMR or NTRK fusions) will be a good approach in this group of patients. The choice of second-line treatment for the patients with good performance status is determined by considering the first-line treatment that the patient has received whether there are molecular changes and patient preference.

3.1. Immunotherapies

3.1.1. Pembrolizumab

In the phase III KEYNOTE-181 trial, pembrolizumab was compared to systemic chemotherapy (researcher choice paclitaxel, docetaxel or irinotecan) in the second-line treatment. The survival results are similar in this study, where 628 locally advanced/metastatic patients with SCC (63% of the patients) or esophageal or GEJ adenocarcinoma were randomized [50]. Although there was a survival benefit in favor of pembrolizumab in SCC patients with CPS ≥10 in the unplanned subgroup analysis, the benefit was unclear in patients with adenocarcinoma. OS and PFS have been found to be similar in the phase III KEYNOTE-061 in which pembrolizumab was compared to paclitaxel in the second-line treatment.

Pembrolizumab is a treatment option for SCC patients with high PD-L1 expression (CPS ≥ 10). Pembrolizumab is not approved in USA for the treatment of refractory gastric/GEJ adenocarcinoma with high PD-L1 expression. Pembrolizumab is also not approved for the third-line treatment of GEJ adenocarcinoma with any PD-L1 expression level.

Many nonrandomized phase II trials such as KEYNOTE-158 evaluated single-agent pembrolizumab in patients who have progressed after first-line treatment. These trials showed a very encouraging ORR in MSI-H patients and demonstrated a special effectiveness of immunotherapy in this MSI-H population [51,52]. Pembrolizumab was approved by FDA in 2017 and EMA in 2022 for the patients with MSI-H or dMMR tumors that progressed after first-line treatment based on these data. One of the predictor biomarkers of the efficacy of immunotherapy in gastric cancer is TMB. TMB-H is defined as the TMB ≥10 mutation/megabase [53].

3.1.2. Nivolumab

The benefit of nivolumab has been investigated in phase III study (ONO-4538, ATTRACTION-2) in which 493 metastatic gastric/GEJ cancer patients who have progressed after two or more lines of standard chemotherapy were randomized to nivolumab (3 mg/kg) or placebo independent of PD-L1 expression [54]. Median OS with nivolumab was found to be statistically significantly better than placebo (5.3 vs 4.1 months). Nivolumab has been approved in Japan for gastric cancer patients who had disease progression after chemotherapy regardless of the number of previous regimens or PD-L1 expression.

3.1.3. Avelumab

A total number of 371 patients who had progressive disease after two lines of systemic therapy have been randomized to avelumab (PD-1 inhibitor) or clinician’s choice of systemic treatment (weekly paclitaxel or irinotecan monotherapy) in phase III JAVELIN Gastric 300 study. PFS or OS benefit of avelumab could not be shown in this study [55].

Immunotherapy can only be recommended in the second-line if it was not used in the first-line setting. PD-L1 targeted immunotherapy can be preferred instead of chemotherapy in the second-line treatment of the patients who progressed under first-line platinum-based chemotherapy. Anti-PD-1 immunotherapy is generally not recommended for the second or subsequent-line treatment of the patients who had progressive disease under prior PD-L1 targeted therapy.

3.2. Second and subsequent line treatments in HER2-positive patients

The benefit of continuing trastuzumab as a second-line treatment could not be shown in phase II trial (paclitaxel vs paclitaxel + trastuzumab) [56]. Similarly, the addition of lapatinib to paclitaxel (paclitaxel + lapatinib vs paclitaxel) in the second-line treatment did not provide any additional benefit in phase III TyTAN study. The benefit of continuation of anti-HER2 treatment (ado-trastuzumab-emtansine compared to taxane) could also not be shown in phase II/III GATSBY study [57,58]. Loss of HER2 expression after first-line treatment might lead to negative results in these studies [59]. For this reason, second-line treatment with trastuzumab, lapatinib or ado-trastuzumab emtansine is not recommended in HER2-positive gastric/GEJ adenocarcinoma patients who had progressive disease after receiving first-line chemotherapy-trastuzumab.

T-DXd is an ADC composed of mAb trastuzumab and a topoisomerase-I inhibitor deruxtecan. When T-DXd was used as a second-line treatment, ORR has been found 42% and CR 5% in the single arm nonrandomized phase II DESTINY-Gastric 02 trial that was performed in USA and Europe [60]. All patients in this trial were those who had disease progression under first-line platinum-based chemotherapy + trastuzumab and whose HER2 positivity was confirmed with re-biopsy. T-DXd provided PFS and OS benefit as third- or subsequent-line treatment in the patients who have received two lines of treatment (HER2-positive, who received trastuzumab) in the randomized phase II DESTINY-Gastric01 study [61]. FDA has approved T-DXd for locally advanced or metastatic HER2-positive gastric/GEJ adenocarcinoma patients who have received prior trastuzumab-based treatment after DESTINY-Gastric01 trial.

3.3. Second and subsequent line treatments in patients with HER2-negative disease in repeat biopsy

The preferred second-line treatment options include paclitaxel + ramucirumab or T-DXd for the patients that tumor HER2 status cannot be confirmed with biopsy. Since the two regimens have equivalent effectiveness, the treatment choice is determined by considering patient preferences and comorbidities of the patient. For example, paclitaxel + ramucirumab are preferred because of the ILD risk of T-DXd in patients who have lung problems. However, T-DXd should be preferred for the treatment of patients who have clinically meaningfull neuropathy or who are not candidates for anti-angiogenic agents such as ramucirumab. Single-agent chemotherapy (e.g., irinotecan, paclitaxel, docetaxel) may be used for the patients who are thought to be unable to tolerate these regimens.

3.3.1. Anti-VEGF treatments

3.3.1.1. Ramucirumab

Ramucirumab is a recombinant mAb from IgG1 class that blocks receptor activation by binding VEGFR-2. Three hundred and fifty-five patients who have been priorly treated for metastatic gastric/GEJ adenocarcinoma have been randomized to BSC + ramucirumab or placebo arms as a second-line treatment in phase III REGARD study [62]. mPFS (2.1 vs 1.3 months) and mOS (5.2 vs 3.8 months) were found to be statistically significantly better for the patients who have been treated with ramucirumab.

Six hundred and sixty-five metastatic gastric/GEJ adenocarcinoma patients who had progression after first-line platinum and fluoropyrimidine-based combination treatment were randomized to weekly paclitaxel + ramucirumab vs paclitaxel arms as second-line treatment in phase III RAINBOW trial [63]. This trial showed survival benefits with significantly better mOS (9.6 vs 7.4 months) with the addition of ramucirumab.

One hundred and ten metastatic GEJ adenocarcinoma patients who had progressive disease after first-line platinum-fluoroprimidine-based chemotherapy were randomized to second-line FOLFIRI + ramucirumab or paclitaxel + ramucirumab in phase II RAMIRIS study [64]. While PFS and OS were similar, ORR was found to be better in FOLFIRI + ramucirumab arm compared to paclitaxel + ramucirumab arm (22% vs 11%). FOLFIRI + ramucirumab may be preferred to ramucirumab + paclitaxel in the gastric/GEJ adenocarcinoma patients with neuropathy or who were treated with prior taxanes.

3.3.1.1.1. Apatinib

Apatinib (rivoceranib) is a tyrosine kinase inhibitor that blocks VEGFR2 specifically and it has been approved in China for the second-line treatment of advanced gastric cancer, but this agent is not available in USA or Europe. The data regarding its activity in advanced gastric cancer are conflicting. Efficacy could not be shown for apatinib used after unsuccessful two lines of chemotherapy in the preliminary report of placebo-controlled phase III ANGEL study [65].

3.3.1.1.2. Regorafenib

Patients who received at least two lines of treatment were randomized to oral multi-targeted tyrosine kinase inhibitor regorafenib or placebo arms in the phase III INTEGRATE IIa study. Better survival with regorafenib was first reported in ASCO GI 2023 cancer symposium [66]. Regorafenib + nivolumab vs standard chemotherapy is being compared in a similar patient group in the phase III INTEGRATE IIb trial (NCT04879368) which is still ongoing.

4. Conclusion

It has been shown that survivals are prolonged with targeted therapies that show effectiveness via different pathways and are chosen according to the results of some biomarker analysis and the combinations of ICIs with chemotherapy in the treatment of metastatic gastric cancer. FGFR-2b and CLDN 18.2 are promising biomarkers for the management of metastatic gastric cancer. Thus, the assessment of CLDN 18.2 expression and FGFR-2b status may be considered as well as other new molecular targets including HER2, PD-L1 CPS, and MSI to decide the first-line treatment of metastatic gastric cancer patients.

Trastuzumab is used with chemotherapy in HER2-positive gastric cancer patients. The benefits of immunotherapy (pembrolizumab) used with chemotherapy-trastuzumab in HER2- and PD-L1-positive gastric cancer patients have been shown. The effect of ICIs such as nivolumab with chemotherapy in PD-L1 positive gastric cancer patients is mainly evident in patients with PD-L1 CPS ≥ 5. Targeting the new pathway CLDN 18.2 prolongs survival, and FGFR-2b is a promising target to improve the survival in HER2-negative patients that constitute the main part of gastric cancer.

The treatment of gastric cancer rapidly develops with the new technology treatment options such as ADCs and BsAbs. With these innovative modalities, it is aimed to target tumor cells with immune cells as well as to decrease adverse effects. There are some limitations of this current study. First, although more comprehensive data about the approved drugs for the treatment was given, new technology treatment agents (such as ADCs and BsAbs) could not be discussed in detail, as the trials are still ongoing. Second, we could not present data on the choice of treatment in patients who may be candidates for more than one targeted therapy with the results of molecular analysis (e.g., both positive for HER2 and CLDN 18.2 or positive for both CLDN 18.2 and PD-L1). Third, we could not explain whether the existing treatments against each new molecular target should be used combined or in which order if they would be used sequentially. Future planned studies are needed to find the answer to unknown questions and to better define the precise sequence for every new targeted treatment.

5. Future perspective

We eagerly wait for new technology agents for the treatment of metastatic gastric cancer including various combinations. These combinations may consist of ICI+ICI regimens, ICI+ICI+targeted agents, ICI+ICI+targeted agents + chemoteherapy, targeted agents + chemoterapy. Discovery of new molecular targets may lead to the discovery of new agents targeting these molecular pathways, and gastric cancer is a promising disease for this kind of innovation. When we look behind to the past 10 years, the coming 10 years give us hope for better outcomes for this dismal disease.

Funding Statement

This paper was not funded.

Article highlights

• The combination of anti-HER2 agents with ICIs is a promising strategy for the first-line treatment of HER2 positive metastatic gastric cancer patients.

• New molecular targets such as CLDN 18.2 and FGFR2b may be the major factors in treatment decisions for metastatic gastric cancer.

• Various combination therapies may be considered for the treatment of HER2 negative and HER2 positive metastatic gastric cancer patients (e.g., ICI + targeted agents, targeted agents + chemotherapy).

• For patients with dual positive results for targeted therapies (e.g., PD-L1 positive and CLDN 18.2 positive, PD-L1 positive and FGFR2b positive), new combinations may be developed.

• Obtaining adequate and sufficient tissues at the time of diagnosis is much more important than ever.

Author contributions

Melih Simsek: Conceptualization, writing – review and editing, writing – original draft. Haci Mehmet Turk: Conceptualization, supervision. The authors have written, substantially revised, and critically reviewed the article together, and they have agreed on the journal to which the article will be submitted. The authors also reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage. The authors agree to take responsibility and be accountable for the contents of the article and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosures

No writing assistance was utilized in the production of this manuscript.

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Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.