Neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy in resectable gastric and gastroesophageal junction cancer

Gastric and gastroesophageal junction (G/GEJ) cancers stand out as significant challenges in oncology due to their prevalence and their devastating burden for both the patients and the healthcare system. The development of these cancers is influenced by a complex interplay of genetic, environmental, and lifestyle factors, making them multifactorial in nature (1). This complexity underscores their status as a substantial global health concern, affecting individuals across diverse demographics and geographical regions. The prevalence of G/GEJ cancers varies significantly worldwide, with certain areas, particularly East Asia, experiencing higher incidence rates compared to others (2,3). Remarkably, the global incidence of these malignancies remains notably high, with over a million new cases diagnosed annually, placing it fifth in terms of global cancer incidence (3). One distinguishing characteristic of G/GEJ cancers is their aggressive tumoral behavior and propensity for metastasis, with studies indicating that more than one-third of these patients present with metastatic disease at the time of diagnosis (4). This significantly limits treatment options and results in poorer prognoses, with a median overall survival of less than one year in these metastatic cases (5). Consequently, these cancers contribute significantly to worldwide cancer-related mortality, ranking as the fourth leading cause of such mortality (3).

The treatment of G/GEJ cancers often necessitates a comprehensive, multimodal approach consisting of a combination of medical, radiation, and surgical oncology strategies tailored to factors such as the staging of the cancer (6). The current standard-of-care treatment option for those with early-stage resectable G/GEJ cancer is the administration of neoadjuvant chemotherapy using triple agents, FLOT chemotherapy regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel), followed by surgery (7). The response to the treatment in a notable proportion of these patients, however, is not optimal and the rates of pathological complete response (pCR), a potent indicator for long-term overall survival and recurrence-free survival, were shown to be low, being observed in only 3% to 15% of cases (8). This highlights the necessity for additional modalities in the treatment of these patients for a more favorable outcome.

The advent of targeted therapies and immunotherapies has revolutionized treatment paradigms for G/GEJ cancers. While the addition of these treatments including immune checkpoint blockade has become integral to the standard-of-care treatment protocols for patients with several tumor types, such as melanoma, bladder cancer, colorectal cancer, lung cancer, and even patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment in patients with early stage, resectable G/GEJ cancer is still being explored in small and large pivotal trials (9). This underscores the ongoing need for comprehensive research and innovative approaches to assess the safety, and efficacy of this modality in patients with resectable G/GEJ adenocarcinoma. This editorial delves into the current evidence on the intricate landscape of the use of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway inhibitors, with a focus on the findings of the PANDA trial, as a neoadjuvant therapy along with chemotherapy in the treatment of patients with resectable G/GEJ adenocarcinoma (10).

The findings from phase II of the PANDA trial underscore the safety and significant antitumor activity of neoadjuvant atezolizumab in conjunction with chemotherapy as the neoadjuvant treatment in patients with resectable G/GEJ cancer (10). Notably, the study revealed a comparable incidence of chemotherapy-related adverse events and postoperative complications when compared to prior studies utilizing standard-of-care treatments without immunotherapy, along with reports from real-world data. Moreover, all serious immune-related adverse events were manageable in the patients, with complete resolution of symptoms, and nearly all patients completed all cycles of the treatment and underwent surgery, further emphasizing the safety and feasibility of this neoadjuvant approach. Additionally, the trial demonstrated an impressive major pathological response (MPR, Mandard tumor regression grading 1 or 2) in 70% of patients, with 45% achieving pCR (Mandard tumor regression grading 1), a high rate of R0 resection, and a substantially lower rate of recurrence compared to the existing literature. These findings from addition of atezolizumab to chemotherapy in 21 patients suggests its potential efficacy in achieving significant tumor regression and reducing the risk of recurrence, indicating it may be a promising therapeutic option for patients with resectable G/GEJ cancer.

The efficacy and safety of neoadjuvant atezolizumab administration were also reported in a recently published article on the interim results of the DANTE/IKF-s633 trial (11). In this open-label phase II/III trial, 295 patients with resectable G/GEJ adenocarcinoma were randomly assigned to receive either the standard-of-care chemotherapy alone, FLOT, or chemoimmunotherapy with atezolizumab. Results from the DANTE trial showed that there were significantly higher rates of MPR and pCR in the intervention arm where the participant received atezolizumab with rates of 49% vs. 38%, and 24% vs. 15%, respectively. Besides, there were no significant differences in the rates of occurrence of adverse events and their severity, postoperative morbidity and mortality, length of hospital stay, and rates of completing neoadjuvant treatment and undergoing the surgery, even when considering reasons for treatment discontinuation between these two arms. These safety rates were, importantly, also consistent with those reported in previous trials where patients only received standard-of-care chemotherapy, underscoring that the addition of atezolizumab did not introduce any additional safety concerns (7,12). For example, compared to patients receiving FLOT with atezolizumab in the DANTE trial, patients in the FLOT arm of the pivotal FLOT4 trial had similar rates for proceeding to surgery (97% in both trials), receiving tumor surgery (97% vs. 94%), surgical morbidity (45% vs. 51%), 30-day surgical mortality (3% vs. 2%), need for reoperation (10% in both trials), and length of hospital stay (16 vs. 15 days) (7,11).

The effectiveness and safety of atezolizumab observed in these two trials align with findings from studies using other PD-1/PD-L1 inhibitors as neoadjuvant therapy in combination with preoperative chemotherapy for patients with resectable G/GEJ cancer. Notably, emerging strong evidence from various trials, importantly the recently published multicenter double-blinded phase III randomized clinical trials, KEYNOTE-585 and MATTERHORN, assessing the antitumor activity of pembrolizumab and durvalumab, respectively, underscores the potential beneficial effects of integrating this treatment modality (13,14). Additionally, promising reports from phase I/II trials on the efficacy and safety of agents such as nivolumab, sintilimab, toripalimab, tislelizumab, camrelizumab, spartalizumab, and avelumab contribute to the growing body of evidence supporting the efficacy of PD-1/PD-L1 inhibitors in this context (15-17). The consistent demonstration of favorable outcomes across various agents belonging to the PD-1/PD-L1 inhibitor class implies a class-wide therapeutic effect, independent of individual agent specificity. Nevertheless, additional investigations directly comparing the efficacy and safety profiles of distinct agents within this class are necessary to provide comprehensive insights and inform clinical decision-making accurately. Furthermore, a recently published systematic review and meta-analysis of 33 clinical trials, encompassing data from 1,074 patients with resectable G/GEJ cancer, highlighted the potential benefits of neoadjuvant immunotherapy in this patient population (18). A pooled pCR of 24% [95% confidence interval (CI): 19–28%], MPR of 49% (95% CI: 38–61%), R0 resection rate of 96% (95% CI: 95–98%), serious treatment-related adverse events rate of 28% (95% CI: 17–40%), and serious immune-related adverse events rate 19% (95% CI: 11–27%) collectively indicate the safety and efficacy of neoadjuvant immunotherapy. These findings were also yielded in another systematic review and meta-analysis on patients with resectable G/GEJ cancer undergoing neoadjuvant immunotherapy, which reported a pCR of 26% (95% CI: 20–31%), MPR of 45% (95% CI: 36–54%), and serious treatment-related adverse events rate of 35% (95% CI: 19–51%) (19).

The histopathologic regression observed in the PANDA trial, characterized by pCR and MPR rates of 45% and 70%, respectively, exceeded the reported rates from similar trials investigating other PD-1/PD-L1 inhibitors. This higher rate of pathological responses is particularly noteworthy considering that the frequency of patients with microsatellite instability, who are often associated with more favorable responses to immunotherapy, was not notably different in the PANDA trial compared to these other comparative studies (10,11,13,20). Therefore, the higher pathological rates observed in the PANDA trial despite a lower proportion of patients with microsatellite instability suggest the presence of other potential factors contributing to enhanced treatment response beyond microsatellite instability status. Furthermore, the higher rate of pCR and MPR in the PANDA trial does not seem to be attributed to the intrinsic properties of atezolizumab compared to the other members of its class, as this heightened response was not observed in the DANTE trial, which also evaluated the efficacy of atezolizumab with pCR and MPR rates of 24% and 49%, respectively. It is plausible that variations in the treatment protocols used in these trials may account for this discrepancy. Specifically, the PANDA trial employed a regimen consisting of one cycle of atezolizumab monotherapy as the induction treatment followed by four cycles of preoperative combined chemoimmunotherapy. It’s noteworthy that despite some other trials administering even higher total equivalent dosages of immunotherapy than this trial, the differences in the protocol and timing may potentially be linked to this superior effect seen on tumoral lesions. This nuanced difference in treatment approach highlights the complexity of optimizing therapeutic strategies in the context of neoadjuvant immunotherapy for patients with resectable G/GEJ cancer. Other possible explanations may include variations in patient populations, research methodology, or outcome assessment protocols (local vs. central assessment).

The translational component of the PANDA trial constitutes another crucial aspect of this study. While previous research has explored changes in the tumor microenvironment and the profile of tumor-infiltrating immune cells in the context of neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy, the specific attribution of these changes to individual components of combination therapy and the dynamics of changes following monotherapy with PD-1/PD-L1 inhibitors and subsequent combination with chemotherapy have not been thoroughly investigated before (21). In the PANDA trial, serial biopsies were collected at baseline, after the initial cycle of atezolizumab monotherapy, and subsequent to the combination therapy. This meticulous approach provided a unique opportunity to precisely assess the individual contribution of PD-L1 inhibitor therapy before its integration with chemotherapy. In this study, the pathological assessments revealed a statistically significant surge in the infiltration of CD8+ T cells following the monotherapy with PD-L1 inhibitor among responder participants; however, subsequent biopsy samples following combination therapy with chemotherapy showed no significant changes in CD8+ T cell numbers (10). Contrasting this order of administration of chemoimmunotherapy, An et al. conducted a study examining the effects of pembrolizumab and chemotherapy in patients with advanced gastroesophageal adenocarcinoma (22). In this phase II trial, chemotherapy, specifically 5-fluorouracil/platinum, was administered initially, followed by the combination of chemotherapy and pembrolizumab. Interestingly, this study showed a further remodeling of the tumor microenvironment following the addition of pembrolizumab, accompanied by a significant expansion of CD8+ T cells. Collectively, these findings, coupled with observations from the PANDA trial, provide direct evidence of the substantial contribution of PD-1/PD-L1 axis blockade to enhanced immune activation and treatment response.

Additionally, the PANDA trial unveiled a correlation between observing response, i.e., remodeling in the tumor microenvironment after the first cycle, and observing response after subsequent cycles of neoadjuvant treatment, as well as long-term clinical outcomes. This correlation was also observed in An et al.’s study between the response following the first cycle of treatment with chemotherapy alone and the response following the next cycle of treatment with chemotherapy and pembrolizumab. This observation may establish a foundation for future strategies aimed at predicting and deciding whether to continue neoadjuvant treatment. Such strategies could be based on the analysis of the tumor microenvironment following the initial cycle of chemotherapy, immunotherapy, or chemoimmunotherapy, based on the specific protocol. These efforts would contribute to the development of individualized treatment plans tailored to each patient’s unique circumstances and treatment response.

The evaluation of mismatch repair (MMR) status in patients with various types of cancer undergoing immunotherapy constitutes a critical aspect of current therapeutic investigations. Various studies are also underway to assess the impact of MMR status on treatment outcomes in patients with resectable G/GEJ cancer (23,24). Tumors with deficient MMR exhibit instability in microsatellite regions and possess a unique tumor microenvironment, often marked by heightened immunogenicity, which can elicit stronger immune response (24). The main cohort of the KEYNOTE-585 trial highlighted this significance, revealing that patients with high microsatellite instability (MSI-H) achieved a pCR rate more than four times higher (37.1%; 95% CI: 23.1% to 53.8%) compared to those without MSI-H (7.7%; 95% CI: 4.2% to 11.8%) (13). The DANTE trial also demonstrated that patients with deficient MMR/MSI-H experienced notably better histopathologic outcomes, with pCR rates more than doubling and MPR rates increasing by 1.27 times compared to their proficient MMR counterparts (11). In the PANDA trial, however, the number of patients deficient MMR was low, restricting robust interpretation of the impact of MMR status (10). Among the 21 participants included in this study, only 3 exhibited deficient MMR. Of these, one individual unfortunately passed away shortly after undergoing neoadjuvant treatment, before proceeding to surgery, due to external factors unrelated to the study. Remarkably, the remaining two participants with deficient MMR both showed a pCR, underscoring the potential therapeutic benefit in this subset despite the study’s limitations. This notably more favorable responses among these patients suggests that the presence of MSI-H may serve as a promising predictive biomarker for chemoimmunotherapy efficacy in patients with resectable G/GEJ cancer, warranting further studies with larger cohorts to validate these findings.

In addition to the findings discussed, it is pertinent to consider the evolving landscape of long-term survival outcomes in neoadjuvant immunotherapy trials for G/GEJ cancers. While the addition of immunotherapy to neoadjuvant treatment has led to significant improvements in pCR in this patient population, these improvements in the short-term pathological responses do not necessarily result in better survival outcomes. Notably, in the main cohort phase 3 trial of KEYNOTE-585, despite observing significantly higher rates of MPR and pCR, alongside markedly longer median event-free survival with a hazard ratio of 0.81 (95% CI: 0.67–0.99) in patients receiving immunotherapy, the difference in event-free survival was not statistically significant (13). Moreover, subgroup analyses based on patient and tumoral characteristics, including PD-L1 expression, did not reveal any significant differences in long-term outcomes in this study.

A similar pattern was observed among participants of the FLOT cohort of this trial, where there was a significant improvement in pCR but no significant improvement in overall survival or event-free survival (25). This observation regarding the lack of significant long-term outcomes despite a significantly higher pCR may be due to the low completion rate of adjuvant therapy in those on the pembrolizumab arm, wherein while 95% of them completed all cycles of neoadjuvant therapy, but only 45% completed adjuvant therapy. Furthermore, interestingly, the pCR was notably higher in both the pembrolizumab and placebo arms of the FLOT cohort (17.0% and 6.8%) compared to the main cohort (12.9% and 2.0%). This may suggest the potential superiority of the FLOT chemotherapy backbone over the cisplatin-based doublet backbone used in the main cohort. Notwithstanding the foregoing observations, while the overall survival rates were almost the same between the treatment arms, it’s important to highlight the preliminary nature of these findings in both the main cohort and the FLOT cohort, with ongoing follow-up being conducted to assess the survival advantage associated with pembrolizumab addition. Similarly, in the other two randomized trials, MATTERHORN and DANTE, with all receiving the FLOT backbone, despite observing higher histopathologic responses, the significance of these responses on event-free survival and overall survival has not yet been determined, pending further data (11,14). As these trials continue to mature, a comprehensive analysis of overall and subgroup survival outcomes becomes imperative. Therefore, while the initial promise of immunotherapy addition is evident, further investigation into its impact on the long-term outcomes and factors influencing long-term outcomes is essential to reevaluate the prospect of addition of immunotherapy to the neoadjuvant treatment for patients with resectable G/GEJ cancers or refine patient selection criteria (22).

While recognizing the limitations of the PANDA trial, including constraints related to its study design and single-arm nature, as well as its small sample size, its findings contribute significantly to the growing body of evidence supporting the integration of immunotherapy into the neoadjuvant treatment paradigm for resectable G/GEJ cancers. This presents a promising avenue for enhancing outcomes in this patient population. Further exploration of these treatment protocols, including the optimal timing, duration, and dosing frequency with regard to the surgery, as well as the most effective combination of immunotherapies, is imperative. Additionally, comprehensive studies are warranted to identify factors for patient selection and to predict treatment response accurately. Such endeavors are crucial for maximizing the benefits of neoadjuvant immunotherapy as part of personalized treatment approaches.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-44/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-44/coif). A.S. reports a leadership role with Autem therapeutics, Exelixis, KAHR medical and Bristol-Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics, and KAHR medical; and participation as a data safety monitoring board chair for Arcus therapeutics. The other author has no conflicts of interest to declare.

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

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