Chemo-immunotherapy on localized gastroesophageal/gastric adenocarcinoma—hope or delusion?

Gastroesophageal junction (GEJ) and gastric cancer (GC) rank as the fifth most prevalent neoplasm among both males and females, according to the latest findings from the GLOBOCAN database (1). Presently, the primary curative treatment option for localized GEJ and GC remains surgical intervention (2). However, owing to the notable recurrence rates, particularly in the form of distant metastases, a combination of fluoropyrimidine and oxaliplatin chemotherapy was the first incorporation in the adjuvant setting to enhance survival outcomes.

A meta-analysis has underscored the advantages of this approach, revealing that the 5-year overall survival (OS) rate in the surgery-only group stood at 49.6%, whereas in the adjuvant chemotherapy group, it rose to 55.3%. Furthermore, the median OS significantly improved from 58.8 to 93.6 months [hazard ratio (HR) =0.82] (3).

Due to the considerable toxicity and treatment discontinuation rates associated with chemotherapy post-gastrectomy, attention has shifted toward a perioperative treatment approach, therefore allowing an adequate exposure to chemotherapy cycles. The initial positive outcome demonstrating an improvement in OS with this strategy was observed in the MAGIC trial, which utilized a combination of 5-fluorouracil (5-FU), cisplatin, and epirubicin (ECF protocol) administered in 21-day cycles for a total of 3 cycles before and 3 cycles after surgery.

This resulted in an increase in the 5-year OS rate from 23% to 36.3% (4). However, the efficacy of anthracyclines was called into question due to the lack of benefit observed in subsequent studies involving these agents in the treatment of advanced GEJ/GC patients (5). Conversely, taxanes began to exhibit superior clinical efficacy. This observation was encapsulated in a meta-analysis that also highlighted a less toxic adverse events profile (6).

As a result, taxanes underwent testing in the localized setting through the FLOT4 study, a trial that utilized a combination of 5-fluorouracil, oxaliplatin, and docetaxel administered every 2 weeks for 4 cycles before and 4 cycles after surgery. This regimen demonstrated superiority compared to the ECF protocol, with the authors reporting an improvement in the median OS from 35 months in the ECF/ECX (epirubicin, cisplatin, capecitabine) group to 50 months in the FLOT group (HR =0.77) (7).

Interestingly, a large real-world study failed to demonstrate an OS benefit when comparing FLOT (52.1 months) to ECF (46.4 months), with a P value of 0.577 (8).

Although FLOT is the current standard of care, the disadvantage lies in its limiting toxicity, particularly in the postoperative setting, where less than half of the patients actually complete the 8 cycles of the protocol (9). Consequently, it is pertinent to consider that most of the benefit of using the FLOT protocol is derived from the neoadjuvant phase and the improvement of the pathological complete response (pCR), which was improved from 6% to 16% in the FLOT4 trial (10). Furthermore, the impact of the adjuvant treatment after a pCR remains uncertain. A study including only Asian population with pCR after neoadjuvant treatment for GEJ/GC failed to demonstrate a statistical benefit from the adjuvant chemotherapy (11). Additionally, a meta-analysis analyzing specifically the correlation between pCR (ypT0 and ypN0) and event-free survival (EFS) reported a significant benefit in the 3-year OS rate with a risk reduction (RR) of 0.43 (95% confidence interval: 0.25–0.72; P=0.002) comparing the patients with pCR to the patients without pCR (12).

In order to enhance the outcomes of localized disease, considering the observed improvements in OS and progression-free survival (PFS) with immune checkpoint inhibitors in the first-line setting for advanced diseases as demonstrated in the CheckMate-649 (13) and Keynote-859 (14) studies, the logical next step was to investigate the combination of immunotherapy with perioperative chemotherapy. An important aspect to highlight is the significance of programmed cell death 1 ligand 1 (PD-L1) expression as a predictive biomarker for the benefits of immunotherapy. A higher level of PD-L1 expression corresponds to a greater impact of immunotherapy agents. However, it is essential to note that there is currently no standardized method for assessing PD-L1 expression. Thus far, the combined positive score (CPS) has been the most commonly used method, although there is no universally agreement upon cut-off point, as evidenced by findings from a comprehensive meta-analysis (15).

The first results of a phase III trial assessing the combination of pembrolizumab with chemotherapy was the Keynote-585 study. In this study, there were two options for the chemotherapy: cisplatin + 5-FU and FLOT. The initial interim analysis concerning the main cohort of cisplatin-based treatment yielded disappointing results. Although the complete pCR rate was increased from 6% to 12.9%, a result lower than the 16% of pCR seen in the FLOT4 trial, there were no statistically significant differences in the median EFS with a P value of 0.0198 (pre-specified significance threshold was P<0.0178). The control arm had a median EFS of 25.3 months, falling short of the 30 months in the FLOT4 study (16). A posterior update of the Keynote-585 trial, focusing on the FLOT cohort, reported a pCR rate of 17% with a 2-year OS of 72%, surpassing the 59% 2-year OS of the FLOT4 trial. However, both median EFS and OS for this cohort are still immature (17).

Most recently, two new players have emerged in the boardgame, but this time using only FLOT as chemotherapy backbone. One of them, known as the MATTERHORN trial, investigated the use of durvalumab in combination with perioperative chemotherapy. The first interim analysis revealed an improvement of the pCR rate from 7% to 19% with the addition of durvalumab. The results of median EFS and OS are eagerly awaited (18).

The most recent trial to be published is the DANTE trial, which investigates the combination of perioperative chemotherapy with atezolizumab. In the overall population, the pCR rate increased from 14% to 23%. Notably, this represents the highest pCR rate reported thus far in the experimental arms of the chemo-immunotherapy strategy. When stratifying the results based on the CPS value, as specified in the trial protocol, it is noteworthy that the benefit in terms of pCR rate was observed independently of the CPS value. However, as anticipated, this benefit exhibited a direct correlation with the CPS value. The increase in pCR percentage with atezolizumab in subgroups with CPS <1, CPS >1, CPS >5, and CPS >10 was 6%, 10%, 8%, and 18%, respectively (19). Interestingly, the most substantial benefit of immunotherapy was observed in the group with CPS >10, a finding akin to the observations in advanced disease studies (14).

Several distinctions among the three trials concerning perioperative chemo-immunotherapy could have impacted their outcomes, as delineated in Table 1. Keynote-585 notably excluded Siewert type 1 GEJ tumors, distinguishing it from the other trials. Furthermore, it exhibited the lowest proportion of cT2 tumors, comprising only 5% of its cohort. Regarding PD-L1 expression, the DANTE trial had the smallest percentage of participants with CPS greater than 1, with only 56% meeting this criterion. In contrast, the MATTERHORN trial, utilizing a novel PD-L1 scoring methodology known as tumor area positivity (TAP), reported a TAP score exceeding 1 in 90% of its patients. It is worth noting that recent research has indicated a high concordance rate of over 85% between CPS and TAP when assessed by pathologists. However, a stratified analysis of the concordance ratio based on PD-L1 expression levels revealed a linear correlation, implying that the agreement may fluctuate more prominently in samples with low PD-L1 expression levels compared to those with high PD-L1 expression levels (20). The PD-L1 quantification is useful because it seems to be a predictive factor for pCR, but with different methodologies of testing used in different trials, the harmonization is in the agenda of scientific societies to standardize patient healthcare and generate real-world data.

An important predictive biomarker for response to immunotherapy is the microsatellite instability (MSI) high status, the percentage of these patients in the trials described in the manuscript is less than 10% (Table 1). The subgroup analysis showed a more expressive benefit in the arms with chemo-immunotherapy as expected, which opens the question if these patients really need chemotherapy; however, at the moment there is only retrospective data and a phase 2 single arm trial using only immunotherapy in localized GEJ and GC with MSI-high status (21). More robust data in this small specific population is needed. MSI-high seems to be correlated with higher CPS/TAP values; however, trials did not report this parameter.

Although infiltrative histology is more common in the Asian population, a retrospective study reported there was no difference in the CPS >1 status, using the 22c3 PharmaDx assay, between the Asian and western patients. In addition, the expression of PD-L1 was not associated with OS in the two groups (22). Moreover, the last update of the MATTERHORN trial that presented the results on pCR comparing different regions showed that the results of the Asian population were similar to the global population, nonetheless these results were not stratified by CPS level (23).

Concerning the safety profile of these trials, the most common grade 3 and 4 chemotherapy-related toxicities in the FLOT4 trial were neutropenia (51%), diarrhea (10%), and nausea (7%) (7). On the other side, in the most recent trials the grade 3 and 4 toxicities related to chemotherapy had a better control as reported in the Keynote-585 trial with neutropenia (14%), nausea (6%) and diarrhea (4%), in the DANTE trial with neutropenia (5%), nausea (8%) and diarrhea (13%) and for last in the MATTERHORN trial with neutropenia (20%) and diarrhea (5%) (17-19). Furthermore, the addition of immunotherapy did not increase the surgical morbidity, the grade 3–4 postoperative complications rates that lead to treatment discontinuation were 9% vs. 8%, as shown in the DANTE trial (19).

The accessibility to immunotherapy in low-and-middle-income countries depends on reimbursement coverage from health insurance companies and is not disponible in the public health system. The main limitation is the cost of drugs, therefore in the short-term local health authorities focus on the development of adequate infrastructures for the hosting of clinical trials and advocates promote patient support programs and health policy changes (24).

In summary, the combination of immunotherapy with chemotherapy has shown encouraging outcomes by elevating the pCR rate in GEJ and GC. However, as per the currently available data, this increase in the pCR rate has not translated into improvements in EFS and OS. We anticipate the final results of ongoing trials such as DANTE and MATTERHORN trials for further insights and validation of these findings.

Acknowledgments

Funding: None.

Footnote

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

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-34/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-34/coif). M.P.S.A. has received support for attending Brazilian Oncology Congress 2023 from Roche and support for attending Brazilian Oncology Congress 2022 from Novartis. 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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