Development of combinatorial immunotherapy for patients with advanced gastric cancer from the perspective of immunosuppressive mechanisms in the tumor microenvironment
論文ID: 25-00009
詳細
論文ID: 25-00009
Combinatorial immunotherapy using anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) is being developed to overcome the limited efficacy of monotherapy with anti-PD-1 mAb for patients with advanced gastric cancer (GC). Anti-PD-1 mAb exhibits clinical efficacy by enhancing the function of cytotoxic T lymphocyte (CTL) through the inhibition of the PD-1 pathway;however, there are various immunosuppressive mechanisms that inhibit CTL function, as well as the PD-1 pathway in the tumor microenvironment (TME). Immune suppressive cells and expression of the inhibitory immune checkpoint molecules are included as main inhibitory mechanisms against CTL in the TME. On the other hand, increasing the number of CTLs enhances the efficacy of anti-PD-1 mAb, and immunogenic tumor cell death (ICD) is crucial to induce CTL through the activation of the cancer immunity cycle. In the present review, we discuss the therapeutic potential of developing combinatorial immunotherapy focusing on the inhibitory immune checkpoint molecules and immune suppressive cells in the TME, as well as on the ICD induced by radiotherapy for patients with advanced GC.
Since nivolumab was approved for 3rd or later-line treatment of unresectable advanced or recurrent gastric cancer (GC) in Japan in 2017, immunotherapy with anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb), nivolumab or pembrolizumab, has been established as one of the standard treatments in patients with advanced GC. However, the monotherapy of anti-PD-1 mAb showed limited efficacy and did not provide a favorable overall survival (OS) advantage compared to cytotoxic chemotherapy for patients with advanced GC1-8). Therefore, combinatorial immunotherapy using anti-PD-1 mAb is being developed. Currently, the combinatorial immunotherapy of nivolumab and chemotherapy is the first-line treatment for human epidermal growth factor receptor type 2 (HER2)-negative advanced GC in Asia and Japan, based on the results of the CheckMate-649 and ATTRACTION-49,10).
Anti-PD-1 mAb exhibits clinical efficacy by enhancing the function of cytotoxic T lymphocyte (CTL) through the inhibition of the PD-1 pathway in the tumor microenvironment (TME). However, in addition to the PD-1 pathway, various immunosuppressive mechanisms inhibit CTL function in the TME11,12). Among them, infiltration of immune suppressive cells and expression of the inhibitory immune checkpoint molecules, which are expressed on tumor cells, immune cells, and stromal cells, are included as main inhibitory mechanisms against CTL in the TME12-16). Inhibitory immune checkpoint molecules of particular interest include cytotoxic T-lymphocyte antigen-4 (CTLA-4), lymphocyte-activating gene-3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM-3), and T cell immunoreceptor with an immunoglobulin and tyrosine-based inhibitory motif (TIGIT). CTLA-4 inhibitors are already used in clinical practice, and inhibitors targeting LAG3, TIM-3, and TIGIT are under development in clinical trials. On the other hand, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (M2-TAMs) are notable infiltrating immune suppressive cells, which suppress CTL function, in the TME17-23). In order to enhance the clinical efficacy of immunotherapy with anti-PD-1 mAb (anti-PD-1 therapy), it is crucial to inhibit the signaling through inhibitory immune checkpoint molecules and the immunosuppressive function of these immune suppressive cells.
Increasing the number of CTLs in the TME, though activating the cancer immunity cycle, also enhances the effect of anti-PD-1 therapy, and immunogenic tumor cell death (ICD) is important for activating the cancer immunity cycle24-26). It was reported that particular cytotoxic drugs, such as platinum derivatives and anthracyclines, etc., and radiotherapy under certain circumstances induce ICD in the TME and subsequently activate the cancer immunity cycle27-30). Therefore, the combinatorial immunotherapy of anti-PD-1 therapy plus radiotherapy or chemotherapy, including these drugs, may have therapeutic potential for patients with advanced GC.
In this review, we discuss the therapeutic potential of combinatorial immunotherapy, focusing on the inhibitory immune checkpoint molecules, immune suppressive cells, and ICD induced by radiotherapy in the TME for patients with advanced GC. The clinical trials with combinatorial immunotherapy for GC cited in this manuscript and their information are summarized in Table 1.
List of clinical trials with combinatorial immunotherapy for gastric cancer cited in this manuscript.
Ref* is the reference number in the text. CTLA-4, cytotoxic T-lymphocyte antigen-4;DCR, disease control rate;EA, esophageal adenocarcinoma;ESCC, esophageal squamous cell carcinoma;GC, gastric cancer;GEA, gastro-esophageal junction adenocarcinoma;HER2, human epidermal growth factor receptor type2;LAG-3, lymphocyte-activating gene-3;mPR, major pathological response;MSI-H, microsatellite instability-high;MSS, microsatellite stable;MST, median survival time;ORR, overall response rate;OS, overall survival;pCR, complete pathological response;PD-1, programmed cell death 1;PD-L1, programed death-ligand 1;PFS, progression free survival;RFS, relapse-free survival;TIGIT, T cell immunoreceptor with an immunoglobulin and tyrosine-based inhibitory motif;TIM-3, T cell immunoglobulin and mucin domain 3;VEGFR, vascular endothelial growth factor receptor
There are two phases, which are induction and effector phases, in the induction of CTL (Fig. 1) 31,32). Anti-CTLA-4 mAb, ipilimumab, mainly acts on the induction phase to activate dendritic cells and anti-PD-1 mAb, nivolumab and pembrolizumab, acts on effector phase to attack tumor cells (Fig. 1)33-36). Therefore, the combinatorial immunotherapy using both anti-CTLA-4 mAb and anti-PD-1 mAb was expected to provide better clinical effect than monotherapy with anti-PD-1 mAb. Indeed, NO LIMIT (jRCT2080225304), a phase 2 trial, demonstrated an overall response rate (ORR) of 62.1% for first-line nivolumab plus low-dose ipilimumab in patients with microsatellite instability-high (MSI-H) advanced GC/gastroesophageal adenocarcinoma (GEA), and GERCOR NEONIPIGA (NCT04006262), a phase 2 trial, demonstrated a complete pathological response (pCR) of 58.6% for neoadjuvant nivolumab plus low-dose ipilimumab in patients with locally advanced MSI-H GC/GEA37-39). However, PRODIGE 59-FFCD 1707-DURIGAST (NCT03959293), a randomized phase 2 trial, did not show the clinical benefit of adding tremelimumab, anti-CTLA4 mAb, for FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus durvalumab, anti-programmed death-ligand 1 (PD-L1) mAb in patients with advanced GC/GEA, and AIO INTEGA (NCT03409848), a randomized phase 2 trial, showed that the combination of ipilimumab and nivolumab was similar in OS compared to the ToGA regimen in patients with untreated HER2-positive GEA40-42). Furthermore, in the CheckMate-649 (NCT02872116), randomized phase 3 trial, the ipilimumab plus nivolumab arm was discontinued due to the severe toxicities for patients with GC/GEA/esophageal adenocarcinoma (EA)43). Up to the present, the additive or synergistic effects of anti-CTLA-4 mAb on anti-PD-1 therapy are controversial. The ongoing ATTRACTION-6 (NCT05144854), randomized phase 3 trial, is investigating the superiority of adding nivolumab and ipilimumab to standard chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent GC/GEA. The results of ATTRACTION-6 are eagerly anticipated to determine the benefit of combinatorial immunotherapy with anti-CTLA-4 mAb and anti-PD-1 mAb in patients with advanced GC.
LAG3, TIM-3, and TIGITIt was reported that tumor-infiltrating CD8(+) T cells often co-express high levels of LAG3, TIM-3, and TIGIT on their surface, and these molecules have distinct functions in the regulation of CTLs (Fig. 2)44,45). Therefore, LAG3, TIM-3, and TIGIT axes have been considered as potential therapeutic targets next to PD-1 and CTLA-4 axes, and immunotherapy targeting them for patients with advanced GC is under development in clinical trials. We reported that ligands for PD-1, LAG3, and TIM-3 were expressed on GC cells and that these pathways inhibited the cytotoxic activity of tumor antigen-specific CTLs46). In addition, it has been reported that the ligands for TIGIT were also expressed on tumor cells and immune cells in the GC TME47-50). Based on these reports, immunotherapy targeting LAG3, TIM-3, and TIGIT axes has a promising therapeutic potential for patients with advanced GC.
LAG3 reduces the infiltration of CTLs in the TME through the immune suppressive function of Tregs and inhibits the proliferation and cytotoxic function of T cells51). While LAG3 binds with high affinity to major histocompatibility complex (MHC) class II, LAG3 also binds to galectin-3, Liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin), and fibrinogen-like protein 1 (Fig. 2)52-58). We reported that LAG3 ligands, MHC class II and/or LSECtin, were expressed on tumor cells in 61.6% of patients with advanced GC, of which 37.2% co-expressed PD-L146). A number of clinical trials of combinatorial immunotherapy using anti-PD-1 mAb and anti-LAG3 mAb are currently ongoing. There are two anti-LAG3 mAbs, favezelimab and relatlimab, which were used in clinical trials for patients with advanced GA59-61). Phase 1 trial of favezelimab plus pembrolizumab demonstrated that ORR was 11.3% with an acceptable safety profile for patients with advanced GC (NCT02720068)59). RELATIVITY-060 (NCT03662659), which was a randomized phase 2 trial and used nivolumab and chemotherapy with/without relatlimab, did not improve ORR by the addition of relatlimab in previously untreated advanced GC/GEA patients with LAG3 expression ≥1%60). Kelly RJ et al. conducted a phase 1b trial evaluating neoadjuvant nivolumab or nivolumab plus relatlimab with concurrent chemoradiotherapy in resectable GEA/EA or esophageal squamous cell carcinoma (ESCC) patients and reported that the nivolumab plus relatlimab arm showed relapse-free survival and OS improvement in comparison with the nivolumab arm (NCT03044613)61). A Phase 3 clinical trial would be needed to determine whether combinatorial immunotherapy using anti-PD-1 mAb and anti-LAG3 mAb with/without chemotherapy has a therapeutic benefit for patients with advanced GC.
TIM-3 is expressed at high levels on exhausted CD8(+) T cells and is often co-expressed with PD-162-65). TIM-3 also inhibits the function of T cells, and dual blockade of TIM-3 and PD-1 enhances the anti-tumor immunity64-66). Galectin-9, phosphatidylserine, high-mobility group box 1 (HMGB1), and carcinoemryonic antigen-related cell adhesion molecule 1 (CEACAM-1) were identified as ligands for TIM-3 (Fig. 2)45). We reported that CEACAM-1 was expressed on tum or cells in 67.2% of patients with advanced GC, of which 35.5% co-expressed PD-L146). Therefore, TIM-3 is also a potentially therapeutic target for immunotherapy in patients with advanced GC. Although phase 1 trials (NCT02608268 and NCT03099109) of anti-TIM-3 mAb, sabatolimab or LY3321367, with/without anti-PD-1 therapy have been conducted in patients with advanced solid tumors, including advanced GC/GEA, further investigation is necessary to evaluate the efficacy of anti-TIM-3 mAb for patients with advanced GC67,68).
TIGIT is expressed on activated T cells and natural killer (NK) cells, and its ligands are CD112 and CD155 (Fig. 2)69,70). Since TIGIT reduces the function of T cells, NK cells, and dendritic cells and enhances the immunosuppressive function of Tregs, the inhibition of the TIGIT pathway has the potential to restore the anti-tumor immunity in the TME71,72). Based on the results of a mouse model that dual blockade of PD-1 and TIGIT enhanced the anti-tumor function of CD8(+) T cells compared to PD-1 alone, several clinical trials using combinatorial immunotherapy of anti-PD-1 mAb and anti-TIGIT mAb have been performed73). Several anti-TIGIT mAb, such as vibostolimab, ociperlimab, triagolizumab, and domvanalimab, were used in clinical trials74-76). KEYVIBE-001 trial (NCT02964013), which was a phase 1 trial and used vibostolimab and pembrilizumab, showed an ORR of 13% in patients with PD-1/PD-L1 inhibitor-naïve advanced GC in the second or later line therapy74). AdvanTIG-105 trial (NCT04047862), which was a phase 1b trial and used ociperlimab and tislelizumab, anti-PD-1 mAb, with chemotherapy, showed ORR of 50.8% and disease control rate of 84.7% in patients with stage IV GC/GEA in first-line therapy75). EDGE-Gastric trial (NCT05329766), which was a phase 2 trial and used domvanalimab and zimberelimab, anti-PD-1 mAb, in combination with FOLFOX (leucovorin, fluorouracil, and oxaliplatin), showed ORR of 59% and 6-month progression-free survival (PFS) of 75% without increasing adverse events (AEs) in patients with locally advanced unresectable or metastatic GC/GEA/EA in first-line therapy76). STAR-221 (NCT05568095), which is a randomized phase 3 trial and compares the combination of domvanalimab and zimberelimab plus chemotherapy to nivolumab plus chemotherapy in patients with locally advanced unresectable or metastatic GC/GEA/EA in the first-line therapy, is currently ongoing, and its results are eagerly anticipated.
Currently, bispecific checkpoint inhibitors are in development, and several clinical trials are being conducted to evaluate their efficacy. Among them, phase 3 clinical trials were conducted using cadonilimab, a PD-1/CTLA-4 bispecific antibody, and tebotelimab, a PD-1/LAG3 bispecific antibody77,78). COMPASSION-15 (NCT05008783), which was a placebo-controlled phase 3 trial and compared cadonilimab plus chemotherapy versus chemotherapy alone in patients with GC/GEA in the first line therapy, showed that the addition of cadonilimab significantly improved OS (14.1 versus 11.1 months; hazard ratio 0.66;p < 0.001) and the safety profile was manageable77). MAHOGANY (NCT04082364) was a phase II/III trial and evaluated margetuximab, Fc-optimized anti-HER2 mAb, plus retifanlimab, anti-PD-1 mAb, with/without chemotherapy, and margetuximab plus tebotelimab with chemotherapy in patients with HER2-positive unresectable/metastatic or locally advanced GEA in the first-line therapy78). Additional benefits of teboterimab will become apparent when the results of the MAHOGANY trial are released.
Immunogenic tumor cell death and cancer immunity cycle.
Immunogenic tumor cell death (ICD) is the concept of activating dendritic cells through damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and calreticulin. The cancer immunity cycle is activated by ICD, resulting in the induction of cytotoxic T lymphocytes (CTLs). DAMPs are produced when tumor cells undergo apoptosis under certain conditions and activate immature dendritic cells. Activated immature dendritic cells uptake tumor antigens and become mature dendritic cells that present tumor antigens to CTLs. Antigen-presenting mature dendritic cells induce CTLs (induction phase), however, the CTLA-4 pathway inhibits the interaction between mature dendritic cells and CTLs. Anti-CTLA-4 monoclonal antibody (mAb) blocks this inhibition and enhances the induction of CTLs. In the tumor microenvironment, CTLs attack tumor cells;however, the PD-1 pathway blocks the interaction between CTLs and tumor cells. Anti-PD-1 mAb blocks this inhibition and enhances the cytotoxicity of CTLs. RAGE, receptor for advanced glycation end products;TLR4, toll-like receptor 4.
Immune checkpoint molecules in the effector phase.
Receptors of immune checkpoint molecules are expressed on cytotoxic T lymphocytes (CTLs), and ligands of immune checkpoint molecules are expressed on tumor cells, immune cells, and stromal cells in the tumor microenvironment. CEACAM-1, carcinoemryonic antigen-related cell adhesion molecule 1;FGL1, fibrinogen-like protein 1;HLA, human leukocyte antigen;HMGB1, high-mobility group box 1;LAG3, lymphocyte-activating gene-3;LSECtin, liver and lymph node sinusoidal endothelial cell C-type lectin;MHC class II, major histocompatibility complex class II;PD-1, programmed cell death 1;PD-L1, programed death-ligand 1;PVR, poliovirus receptor;TCR, T cell receptor;TIGIT, T cell immunoreceptor with an immunoglobulin and tyrosine-based inhibitory motif;TIM-3, T cell immunoglobulin and mucin domain 3.
Tregs, MDSCs, and M2 -TAMs are infiltrated in the TME, and these cells are involved in resistance to immunotherapy with immune checkpoint inhibitors17-23). Therefore, it is also crucial to inhibit the immunosuppressive function of these cells to enhance the clinical efficacy of anti-PD-1 therapy. We recently showed that vascular endothelial growth factor receptor 2 (VEGFR2) was expressed on infiltrating M2-TAMs and Tregs in the colorectal cancer TME, and an anti-VEGFR2 inhibitor may have therapeutic potential to control their immunosuppressive function15,79). Furthermore, Tada et al. reported that Tregs expressed VEGFR2 and the frequency of tumor-infiltrating Tregs was reduced by treatment with ramucirumab, anti-VEGFR2 mAb, in patients with advanced GC80). Since it was also reported that anti-angiogenic agents have a therapeutic potential to decrease Tregs, MDSCs, and TAMs23), the combinatorial immunotherapy using VEGF pathway-targeted therapy and anti-PD-1 therapy may be a promising treatment strategy in patients with advanced GC. Anti-angiogenic agents such as regorafenib, ramucirumab, apatinib, and lenvatinib are used in real-world clinical practice, and a lot of clinical trials of combinatorial immunotherapy using these agents and anti-PD-1 therapy are ongoing.
Regorafenib is a multikinase inhibitor targeting VEGFR1 -3 and anti-fibroblast growth factor receptor, etc., and several clinical trials using regorafenib with nivolumab were conducted. REGONIVO (NCT03406871), which was a phase 1b trial and used regorafenib plus nivolumab, showed promising clinical benefits for patients with advanced GC or colorectal cancer81). REGOMUNE (NCT03475953), which was a phase 2 trial and used regorafenib plus avelumab, anti-PD-L1 mAb, was associated with promising anti-tumor activity for patients with advanced or metastatic GC/EA or ESCC82). Cytryn SL et al. reported a phase 2 trial (NCT04757363) of regorafenib in combination with nivolumab plus FOLFOX in patients with untreated advanced GC/GEA/EA, and demonstrated that the addition of regorafenib could be safe, and 25 of 35 patients met the primary endpoint of 6-month PFS83). Based on the results of these clinical trials, INTEGRATE IIb (NCT04879368), which is a randomized phase 3 trial and uses regorafenib plus nivolumab versus standard chemotherapy in patients with refractory advanced GEA, is ongoing84).
Ramucirumab is an anti-VEGFR2 mAb, and apatinib is a tyrosine kinase inhibitor with selective inhibition of VEGFR2. Several phase 1-2 clinical trials combining anti-PD-1 therapy with these drugs have shown the potential to enhance anti-tumor activity in patients with advanced GC85-91). PARAMUNE (NCT06203600), a randomized phase 2/3 trial, is currently ongoing to evaluate the efficacy of adding nivolumab to paclitaxel plus ramucirumab in patients with advanced GC/EA with PD-L1 CPS≥192). Furthermore, anapinib was used in a neoadjuvant setting93,94). Neoadjuvant therapy with apatinib plus camrelizumab, anti-PD-1 mAb, and chemotherapy achieved 15.8% of pCR and 26.3% of major pathological response (mPR) in patients with cT4a/b and N(+) GC (phase 2 trial) (NCT03878472)93). TAOS-3B-Trial (NCT05223088), a phase 2 trial using tislelizumab combined with apatinib and SOX (oxaliplatin plus S1), showed 24% of pCR and 36% of mPR in patients with HER2-negative advanced GC with Borrmann IV, large Borrmann III type, and bulky N positive94).
Lenvatinib is a multi-kinase inhibitor against VEGFR1–3 and EPOC1706 (NCT03609359), a phase 2 trial, showed promising anti-tumor activity of lenvatinib plus pembrolizumab in patients with advanced or recurrent GC/GEA95). LEAP-015 (NCT04662710), a randomized phase 3 trial, is ongoing to evaluate the efficacy and safety of adding pembrolizumab plus lenvatinib to chemotherapy in patients with HER2-negative advanced/metastatic GEA in the first-line setting96).
Anti-PD-1 therapy exerts its efficacy by enhancing the function of CTLs in the TME. In order to increase the number of tumor antigen-specific CTLs, it is necessary to activate the cancer immunity cycle. ICD is the concept of activating dendritic cells via damage-associated molecular patterns (DAMPs), etc., which are produced when tumor cells undergo apoptosis under certain circumstances, and subsequently initiate the cancer immune cycle24-26). ICD are triggered by radiotherapy under certain conditions and by particular cytotoxic drugs such as platinum derivatives and anthracyclines, etc.27-30). In the currently used combinatorial immunotherapy of nivolumab and chemotherapy for HER2-negative advanced GC patients, the activation of the cancer immunity cycle by chemotherapy is also thought to play a crucial role in its efficacy because the oxaliplatin included in this chemotherapy regimen is one of the platinum-based drugs.
We reported that DAMPs such as HMGB1 and calreticulin were produced from tumor cells by irradiation in an experimental system using ESCC cell lines, and that cancer testis antigen-specific CTLs were induced in about 40% of patients with advanced ESCC treated with chemoradiation97,98). In addition, we recently reported that tumor antigen-specific CTLs were induced by localized non-ablative irradiation, 22.5 Gy/5fractions, in patients with advanced metastatic GC99). These results suggested that the combinatorial immunotherapy using anti-PD-1 therapy and irradiation may have therapeutic potential in patients with advanced GC.
A lot of clinical trials of combinatorial immunotherapy using anti-PD-1 therapy and radiotherapy have been conducted in many types of solid tumors. Although the PACIFIC trial (NCT02125461), KEYNOTE-A18 (NCT04221945), and CheckMate 577 (NCT02743494) demonstrated the significant clinical benefits of the addition of radiotherapy, several clinical trials did not reach the primary endpoint100-104). To the best of our knowledge, there has been only one clinical trial that examined the efficacy of combinatorial immunotherapy using anti-PD-1 therapy and radiotherapy for patients with advanced metastatic GC, the CIRCUIT trial (NCT03453164), which we conducted105). We reported the results of the CIRCUIT trial, a phase 1/2 trial, that adding radiotherapy prior to nivolumab administration may have the potential to induce prolonged median survival time and induce tumor antigen-specific CTLs99,105).
Considering the results of clinical trials of combinatorial immunotherapy using anti-PD-1 therapy and radiotherapy conducted to the present time, the condition of radiotherapy that would enhance the anti-tumor effect of anti-PD-1 therapy has not been established yet. Further development is needed to evaluate the conditions for radiotherapy that would enhance the therapeutic efficacy of anti-PD-1 therapy for patients with advanced GC.
Although the number of cases was limited, there were some reports that advanced GC patients were treated with anti-PD-1 therapy in combination with chimeric antigen receptor T-cell (CAR-T) therapy, neoantigen-specific tumor-infiltrating lymphocytes (Neo-TIL) therapy, or neoantigen-loaded dendritic cell (Neo-DC) vaccine106-108). Claudin18.2-specific CAR-T therapy showed ORR of 54.9%, median PFS of 5.8 months, and median OS of 9.0 months in patients with Claudin18.2-positive advanced GC (NCT03874897)106) Although 15 cases were treated with Claudin18.2-specific CAR-T plus toripalimab, anti-PD-1 mAb, in this phase 1 trial, its results were ORR of 26.7%, median PFS of 4.4 months, and median OS of 6.7 months, respectively106). In this cohort, the level of PD-L1 expression in the TME and the timing of anti-PD-1 mAb administration were not considered, which might also be the reason for the lack of an add-on effect of anti-PD-1 therapy. In a phase 2 clinical trial of Neo-TIL therapy for patients with metastatic gastrointestinal cancer (NCT01174121), the ORR of 34 patients treated with Neo-TIL and pembrolizumab was 23.5%, and 1 out of 34 patients had GEA107). Guo Z et al. reported a case that Neo-DC plus nivolumab induced durable complete regression of metastatic GC108). Although these combinatorial immunotherapies may be a promising treatment strategy, the number of cases should be accumulated, and the treatment methods need to be further improved.
Among the developing combinatorial immunotherapy with anti-PD-1 therapy for advanced GC patients, phase 3 trials using anti-CTLA-4 mAb, anti-TIGIT mAb, bispecific antibody targeting PD-1/LAG3, and multikinase inhibitors targeting VEGFR1-3 are ongoing, and the results of these clinical trials are highly anticipated. Furthermore, regarding cadonilimab, a PD-1/CTLA-4 bispecific antibody, a phase 3 trial (COMPASSION-15, NCT05008783) has shown a significant add-on effect to chemotherapy in patients with advanced GC, and clinical use of cadonilimab would be expected in the near future. Combinatorial immunotherapy using anti-PD-1 mAb is still under development, and it is desirable to develop new treatment strategies with fewer AEs and better clinical efficacy.
None.
The authors have no conflict of interest pertaining to this review article.
