KEYNOTE-585: disappointing results for perioperative pembrolizumab in gastric cancer

Investigators recently reported interim results from the KEYNOTE-585 trial, an ambitious global phase III trial adding pembrolizumab to perioperative chemotherapy in clinical stage T3–4, node positive or negative gastric and gastroesophageal junction (GEJ) cancer (1). Despite promising improvements in pathologic complete response with the addition of pembrolizumab to perioperative chemotherapy, the trial failed to improve the co-primary endpoint of event free survival, or the secondary endpoint of overall survival compared to perioperative chemotherapy alone.

KEYNOTE-585 built on trials demonstrating that adding an immune checkpoint inhibitor to first line chemotherapy in metastatic gastric cancer improves response to therapy, progression free and overall survival. One of the first trials reported, KEYNOTE-062, failed to improve survival with the addition of pembrolizumab to first line chemotherapy in metastatic gastric and GEJ cancer (2). However, subsequent positive trials for pembrolizumab reported improvements in response, progression free, and overall survival, including KEYNOTE-590 in esophageal and GEJ adenocarcinoma (3), and more recently KEYNOTE-859 in gastric and GEJ adenocarcinoma (4). However, the benefit in progression free and overall survival for pembrolizumab in metastatic disease is limited to patients testing microsatellite instability (MSI) high, or to patients with combined positive scores (CPS) for programmed death-ligand 1 (PD-L1) ≥10% (KEYNOTE 590) or ≥1% (KEYNOTE-859). A number of other immune checkpoint inhibitors added to first line chemotherapy in metastatic gastric cancer achieved similar improvements in metastatic disease in response, progression free, and overall survival, including nivolumab (5,6), sintilimab (7), and tislelizumab (8), with the benefits again dependent on positive expression of PD-L1. The tislelizumab trial improved overall survival and progression free survival when added to chemotherapy but there was no improvement in response rate. ATTRACTION-4 indicated improvements in response and progression free survival for the addition of nivolumab to first line chemotherapy but it did not achieve any improvement in overall survival.

In Asia, the standard of care for postoperative adjuvant chemotherapy is either a platinum agent or docetaxel combined with a fluorinated pyrimidine, after D2 resection of pathologic stage III or node positive gastric cancer (9,10). In the West perioperative chemotherapy is the preferred approach with the triplet FLOT regimen (5-FU/leucovorin/oxaliplatin/docetaxel) (11). Given the proven survival benefit for chemotherapy added to surgery in gastric cancer, expectations were high about the potential for immune checkpoint inhibitors to enhance adjuvant therapy.

KEYNOTE-585 adopted the Western approach of perioperative chemotherapy. The main cohort of 804 patients was treated with perioperative cisplatin combined with 5-FU or capecitabine (CF), and an additional 203 patient cohort was treated with FLOT. Patients were randomized to placebo or to the addition of pembrolizumab during perioperative chemotherapy, followed by additional months of adjuvant pembrolizumab after chemotherapy completion. In the main CF treated cohort, 76% were stage III, 75% had CPS ≥1%, 9% were MSI high, and 75% were treated with capecitabin/cisplatin. The results from KEYNOTE-585 are outlined in Table 1. The observed pathologic complete response to CF alone was lower than expected, 2%, but was significantly increased up to 12.9% with the addition of pembrolizumab, a difference of 10.9% [95% confidence interval (CI): 7.5 to 14.8; P<0.00001] achieving one of the trials primary endpoints. The greatest incremental increase in pathologic complete response over chemotherapy alone was seen in MSI high cancers (37.1%) compared to non MSI high cancers (7.7%). There was a numeric increase in median event free survival for the addition of pembrolizumab compared to chemotherapy alone in the main CF cohort (44.4 vs. 25.3 months) which did not reach statistical significance [hazard ratio (HR) 0.81, 95% CI: 0.67 to 0.99; P=0.0198]. Event free survival trended better with pembrolizumab for the MSI high (HR 0.59, 95% CI: 0.24 to 1.47) and PD-L1 CPS ≥10% patients (HR 0.70, 95% CI: 0.46 to 1.04) compared to the non MSI high (HR 0.88, 95% CI: 0.71 to 1.11) and CPS <10% patients (HR 0.85, 95% CI: 0.67 to 1.09). The secondary endpoint of overall survival revealed no difference with (60.7 months) or without pembrolizumab (58.0 months, HR 0.90, 95% CI: 0.73 to 1.12; P=0.174). The trial was therefore declared negative for the outcomes of either event free or overall survival. In a recent abstract publication from KEYNOTE-585 for the FLOT cohort of patients, similar outcomes were reported: there was an incremental improvement in pathologic complete response rate for pembrolizumab added to chemotherapy over chemotherapy alone (17.0% vs. 7.0%) but no significant difference in either event free survival (HR 0.79, 95% CI: 0.52 to 1.22) or overall survival (HR 1.04, 95% CI: 0.66 to 1.66).

Other recently reported phase 2 and 3 trials support the observed increase in pathologic complete response with the addition of an immune checkpoint inhibitor to perioperative chemotherapy over chemotherapy alone. These trials are outlined in Table 1. These include the addition of atezolizumab to perioperative FLOT on the Dante trial (12), durvalumab added to perioperative FLOT on the Matterhorn trial (13), and the addition of toripalimab to perioperative S-1 or capecitabine plus oxaliplatin (14). All trials showed a statistically significant incremental increase in pathologic complete response rate with the addition of a checkpoint inhibitor to perioperative chemotherapy, ranging from an increase of 9% to 15%. Of the two larger trials, Dante and Matterhorn, Dante was an open label randomized phase 2 trial treating 295 patients with the primary focus on pathologic outcome and pathologic complete response rate, and Matterhorn was a double-blind placebo-controlled trial treating 948 patients with the primary endpoint of event free survival and the rate of pathologic complete response rate was a secondary endpoint. Mature results for event free and overall survival from the largest of these trials, the Matterhorn trial, are anxiously awaited.

Despite the lack of success with pembrolizumab added to perioperative chemotherapy in gastric cancer, KEYNOTE-585 is a landmark accomplishment for successfully conducting the first global trial of a novel adjuvant therapy in gastric cancer, and the first to evaluate the contribution of an immune checkpoint inhibitor to perioperative chemotherapy. Although investigators were disappointed in the overall low rates of pathologic complete response to chemotherapy alone for both the FLOT and CF cohorts, in a nearly 1,000-patient global trial these rates of response likely reflect more the reality of responses observed to these regimens in real world practice.

Although positive, the incremental benefits of adding an immune checkpoint inhibitor in metastatic gastric cancer are modest at best when looking at all patients treated on these trials. However, there is an enriched benefit for MSI and CPS high patients. What explains the failure of pembrolizumab to improve event free or overall survival in locally advanced gastric cancer? Although there was no clear difference in event free survival for CPS patients <1% or ≥1%, event free survival trended superior for pembrolizumab in the MSI high and in the CPS ≥10% patients, which accounted for 9% and 27% of patients respectively. Is there a potential benefit for perioperative pembrolizumab in these patients? There was also concern that the use of 5-FU or capecitabine plus cisplatin as the neoadjuvant regiment may have led to inferior outcomes in both the pembrolizumab and placebo control arms. However, in the small cohort of patients treated with the superior FLOT regimen, there also was no significant improvement in event free or overall survival in this subset for treatment with pembrolizumab. Higher rates of toxicity with FLOT make this a more difficult backbone to build upon in the future with the addition of other potential novel targeted agents.

The negative results for pembrolizumab may not be surprising when we also consider the negative results recently reported for the postoperative adjuvant trial of nivolumab. The ATTRACTION-5 trial, reported in abstract form and outlined in Table 1, treated 755 patients with pathologic stage III gastric cancer with postoperative adjuvant chemotherapy alone with either S-1 or capecitabine oxaliplatin, with or without the addition of one year of nivolumab (15). The trial failed to improve the primary endpoint of 3-year event free survival for chemotherapy alone (65.3%) vs. the addition of nivolumab (68.4%, HR 0.90). Two subsets emerged who may potentially benefit from nivolumab, including the 37% with pathologic stage IIIC cancer, and the small minority of patients (11%) testing positive for tumor expression of PD-L1. MSI status was not evaluated on this trial and may confound any interpretation of outcomes in small patient subsets.

What explains the inability of either pembrolizumab or nivolumab to achieve a survival benefit in perioperative or adjuvant therapy in gastric cancer? We have learned in gastric and other gastrointestinal (GI) malignancies that agents improving response, progression free, and overall survival in metastatic disease do not always result in survival improvement in the adjuvant setting. Possible explanations include tumor heterogeneity, the different tumor microenvironments in metastatic versus micro metastatic disease, and treatment agent exposure promoting the growth of resistant cancer cells. We also need to keep in perspective that the survival benefit for immune checkpoint inhibitor therapy in metastatic gastric cancer is modest, with only a small subset of patients gaining long term benefit. Perhaps the margin of benefit of currently available immune checkpoint inhibitor therapy in metastatic disease is not yet great enough to translate into a significant survival benefit as adjuvant therapy.

Although the greatest benefit for response and event free survival in KEYNOTE-585 was seen in MSI high patients, the optimal approach to patients with MSI high locally advanced gastric cancer is increasingly coming into question. Recent retrospective and pooled analyses of outcomes with surgery alone and adjuvant chemotherapy in MSI high gastric cancers report superior survival in MSI high patients treated with surgery alone without adjuvant chemotherapy (16). These studies also suggest a potential detriment with adjuvant chemotherapy treatment over surgery alone. Given the high degree of activity for immune checkpoint inhibitors in MSI high cancers, pilot trials have now evaluated the use of combined anti PD-L1 or programmed cell death-1 (PD-1) inhibitors with anti cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors as preoperative therapy followed by surgery, without chemotherapy. In two recent phase 2 trials high rates of pathologic complete response and near complete response have been observed (17,18). These encouraging results will engender ongoing trials. The high rate of pathologic complete response seen opens the door for nonoperative management in patients with MSI high cancers who appear to achieve a clinical complete response, potentially obviating the need for chemotherapy and potentially even surgery.

From KEYNOTE-585 we have learned that it is safe and feasible to combine pembrolizumab with perioperative chemotherapy in gastric cancer. We have learned that improving pathologic response is not a reliable predictor of improvement in either event free or overall survival. Identifying the optimal group of patients with biomarker selection will be the strategy to move immune checkpoint inhibitors forward in the adjuvant and neoadjuvant space. The emerging technology of circulating tumor DNA for the early detection of minimal residual disease to identify high risk patients will clearly move into clinical trial design. Also, how to best exploit existing and emerging drug targets, including human epidermal growth factor receptor 2 (HER2), claudin 18.2, and fibroblast growth factor receptor (FGFR), potentially in combination with immune checkpoint inhibitors, will be the subject of the next generation of adjuvant therapy trials.

Acknowledgments

Funding: The study was supported by MSK Cancer Center Support Grant/Core Grant (No. P30 CA008748).

Footnote

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

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-57/coif). The author has no conflicts of interest to declare.

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References

1. Shitara K, Rha SY, Wyrwicz LS, et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol 2024;25:212-24. [Crossref] [PubMed]
2. Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol 2020;6:1571-80. [Crossref] [PubMed]
3. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759-71. [Crossref] [PubMed]
4. Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1181-95. [Crossref] [PubMed]
5. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40. [Crossref] [PubMed]
6. Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022;23:234-47. [Crossref] [PubMed]
7. Xu J, Jiang H, Pan Y, et al. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA 2023;330:2064-74. [Crossref] [PubMed]
8. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ 2024;385:e078876. [Crossref] [PubMed]
9. Park SH, Lim DH, Sohn TS, et al. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial Ann Oncol 2021;32:368-74. [Crossref] [PubMed]
10. Kakeji Y, Yoshida K, Kodera Y, et al. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer 2022;25:188-96. [Crossref] [PubMed]
11. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:1948-57. [Crossref] [PubMed]
12. Lorenzen S, Götze TO, Thuss-Patience P, et al. Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial. J Clin Oncol 2024;42:410-20. [Crossref] [PubMed]
13. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. LBA73 Pathological complete response (pCR) to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Interim results of the global, phase III MATTERHORN study. Ann Oncol 2023;34:S1315-6. [Crossref]
14. Yuan S, Nie RC, Jin Y, et al. Perioperative PD-1 antibody toripalimab plus SOX or XELOX chemotherapy versus SOX or XELOX alone for locally advanced gastric or gastro-oesophageal junction cancer: Results from a prospective, randomized, open-label, phase II trial. J Clin Oncol 2023;41:4001. [Crossref]
15. Terashima M, Kang YK, Kim YW, et al. ATTRACTION-5: A phase 3 study of nivolumab plus chemotherapy as postoperative adjuvant treatment for pathological stage III (pStage III) gastric or gastroesophageal junction (G/GEJ) cancer. J Clin Oncol. 2023;41:4000. [Crossref]
16. Pietrantonio F, Miceli R, Raimondi A, et al. Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability As a Biomarker in Gastric Cancer. J Clin Oncol 2019;37:3392-400. [Crossref] [PubMed]
17. André T, Tougeron D, Piessen G, et al. Neoadjuvant Nivolumab Plus Ipilimumab and Adjuvant Nivolumab in Localized Deficient Mismatch Repair/Microsatellite Instability-High Gastric or Esophagogastric Junction Adenocarcinoma: The GERCOR NEONIPIGA Phase II Study. J Clin Oncol 2023;41:255-65. [Crossref] [PubMed]
18. Pietrantonio F, Raimondi A, Lonardi S, et al. INFINITY: A multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). J Clin Oncol 2023;41:358. [Crossref]