How do we improve chemoimmunotherapy in gastroesophageal adenocarcinoma?

Gastroesophageal adenocarcinoma (GEAC) continues to need advancements in management. Building on immunotherapy activity in the refractory setting, many studies using either an anti-programmed death-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) immune checkpoint agent, in combination mostly with cytotoxics, have been reported recently in patients with advanced or localized GEAC. Representative studies among these in the advanced setting are KEYNOTE-811, CHECKMATE-649, ATTRACTION-4, KEYNOTE062, KEYNOTE-859, ORIENT-16, JAVLIN Gastric 100, and RATIONALE-305 (1-8) (Table 1). Modest and heterogenous survival improvement from the immune checkpoint addition to fluoropyrimidine plus platinum is seen (1-9). These results are not as robust as those in other tumors because a smaller number of patients seems to benefit. This is either due to the inherent tumor microenvironment (TME) composition of GEAC (that we ignore entirely in the clinic) or heterogeneity of the epithelial cells [for example, chromosomal instability (CIN) that confers resistance to cytotoxics and immunotherapy]. An elaborate molecular definition of GEAC tumors is lacking. Bulk clinical observations suggest that not all patients will benefit from the addition of immune checkpoint therapy, as seen in CHECKMATE-649, an international phase 3 trial, which studied the addition of nivolumab, an anti-PD-1 agent, to upfront fluoropyrimidine plus platinum in the front-line advanced GEAC setting (2). CHECKMATE-649 showed a distinction in outcomes based on PD-L1 combined positive score (CPS) score. Those with a CPS score of ≥5 were those that derived benefit from the addition of anti-PD-1 therapy. Some of these patients will benefit a lot as there is prolonged survival and duration of response that can be seen. Similarly, in ORIENT-16, a phase 3 Chinese study, sintilimab, an anti-PD-1 agent, was added to front-line fluoropyrimidine plus platinum therapy. A more dramatic benefit was seen in advanced gastric adenocarcinoma (GAC) PD-L1 CPS ≥5 reported an objective response rate (ORR) of 63.6% and a median duration of response of 9.8 months (6). The phase 3 RATIONALE-305 showed similar activity in PD-L1 positive patients [tumor area positivity (TAP) score >5] with tislelizumab, an anti-PD-1 agent, plus investigator choice chemotherapy. ORR was 50.4% with a duration of response of 9 months. This result again highlights more impact in those with higher PD-L1 scoring. The same was seen in KEYNOTE-811 in relation to PD-L1 CPS positivity as the benefit of the addition of pembrolizumab was only in those with a CPS score ≥1 (1). With results showing ~40–50% not having shrinkage and with a duration of response of only ~9 months (2,6,8), there are intrinsic and acquired immune resistance pathways present in GEAC.

Similarly, several studies in the refractory and rechallenge setting are underway but again, none considering TME or overall molecular/immune sub-typing of GEAC. Such examples are: the PARAMUNE, INTEGRATE, LEAP, DURIGAST-PRODIGE, and CAP 02 Re-challenge trials (9-14).

Localized GEAC has also been recently investigated for its share of immune checkpoint additions in studies such as DANTE/IKF-S633, KEYNOTE 585, MATTERHORN, ATTRACTION-5, and VESTIGE (15-19). However, data is still maturing and whether this will have a robust advantage to the patients with localized GEAC is conflicting. Meaningful pathological complete response (pCR) improvement has been reported; however, time will be needed to gather survival data and pCR will correlate. The only trial currently with survival endpoints reported is the KEYNOTE 585. Final analysis of KEYNOTE 585 reported event-free survival 44.4 vs. 25.5 months, median overall survival 71.8 vs. 55.7 months, and pCR rate 13.4% vs. 2%; however, primary endpoint for event-free survival did not meet prespecified statistical significance (16). Whether certain subgroups would have survival benefits remains unanswered. As with the DANTE trial, PD-L1 CPS ≥1 was reported at 58% of the population and therefore may not be a reliable marker in the localized setting (15). All these studies have ignored the driver epithelial oncogenes and the machinery responsible for immune suppression. Current basic questions necessary to move the needle include (I) what specific patterns of innate and acquired resistance to immunotherapy or other therapy are present in GEAC; (II) what would change a “cold” TME to a host favoring TME?; and (III) what novel biomarkers, perhaps, in the blood could trigger customized therapeutics. Obtaining actionable biomarkers is necessary and how these will be determined remains unanswered as serial biopsies are not always feasible and/or patient preferred in standard practice. Additionally, how accurate blood and tissue analysis align along with how to incorporate these in clinical practice remain key areas to answer these questions.

We must applaud An and colleagues who conducted a very difficult phase 2 trial of advanced GEAC patients (n=47) (9). An and colleagues conducted a prospective single-arm sequential chemoimmunotherapy trial in patients with metastatic GEAC. The researchers performed serial sampling for deep correlative studies to build upon the authors’ prior work (serial biopsies in GEAC patients on chemotherapy do demonstrate early TME remodeling). Serial biopsies were taken from the primary tumor (day 1 before cycle 1, day 1 before cycle 2, and day 1 before cycle 7). They made an attempt to systemically study the TME before treatment and following treatment. They also tried to parse out the TME changes with cytotoxic agents versus the addition of pembrolizumab. Obtaining a clear picture of the TME holds answers on how tumor cells behave particularly after exposure to treatment to help us understand how the cancer progresses and/or responds and how to remodel the TME to make it harder for tumor growth. However, when it comes to investigating patients, the specimen collection and precisely repeating collection from the same area remains a challenge. Nevertheless, An and colleagues were able to generate wealth of information that we never had before. All patients were Korean which could impact extrapolation to the Western population as often GEAC has shown differences in epidemiology, treatment, and survival between Asian and Western countries but this may not be that important and can be sorted out in the future. The authors’ objectives were to validate prior results of TME remodeling after exposure to fluoropyrimidine plus platinum therapy and to additionally understand the contribution of pembrolizumab on standard chemotherapy, and to identify candidate pathways for future exploration.

The authors described important differences of pro-immunity and anti-immunity features seen in slow progressors and fast progressors. Slow progressors were found to have increased expression of representative genes of immunogenic cell death after a single cycle of chemotherapy alone, and a larger proportion showed remodeled TME toward immune enriched environments compared to fast progressors. The authors found T cell expansion after anti-PD-1 in slow progressors leading to questions of whether early chemotherapy induced TME remodeling determines whether anti-PD-1 will enhance response or improve prognosis. Further compelling information observed was that the CD8 T cell expansion (naive, memory, and exhausted cells) showed slow progressors following anti-PD-1 therapy. CD8 effector subsets were found in responders. The authors describe potential ways of depriving the TME of immunosuppressive signals or stimulating the induction with pro-immunity hubs. More studies similar to the one performed by An and colleagues are needed to understand how more patients can derive advantage from the current armamentarium.

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Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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