Updates of two key phase III trials presented at the 2024 ASCO Gastrointestinal Cancers Symposium showed the benefit of adding a checkpoint inhibitor to standard perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) in locally advanced, resectable gastric and gastroesophageal junction cancers. FLOT chemotherapy is a standard of care in operable tumors, and PD-1 blockade plus chemotherapy has become standard first-line therapy in metastatic disease. The MATTERHORN¹ and KEYNOTE-585² trials took the chemoimmunotherapy approach into the perioperative setting.

MATTERHORN evaluated the anti–PD-L1 agent durvalumab plus FLOT in 948 patients. In the previously reported interim analysis, the addition of durvalumab significantly improved the pathologic complete response rate by 12%, based on rates of 7% with FLOT and 19% with durvalumab plus FLOT (odds ratio = 3.08; P < .00001).³Yelena Y. Janjigian, MD, of the Memorial Sloan Kettering Cancer Center, New York, presented a deeper dive into the findings, reporting pathologic complete response rates based on geographic region, country, and subgroups, essentially validating this approach globally.¹

“We’ve demonstrated that the addition of durvalumab showed consistent improvement in pathologic complete responses vs placebo, across the globe.”

— Yelena Y. Janjigian, MD

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“MATTERHORN is the first global phase III study that successfully randomly assigned patients to receive perioperative durvalumab plus FLOT in patients with resectable gastric and gastroesophageal junction cancers. We’ve demonstrated that the addition of durvalumab showed consistent improvement in pathologic complete responses vs placebo, across the globe,” Dr. Janjigian said, noting that in Asia, three-drug chemotherapy “has historically not been the norm.”

Kohei Shitara, MD

Salah-Eddin Al-Batran, MD

Similarly, KEYNOTE-585 demonstrated a clear increase in pathologic complete responses with perioperative pembrolizumab plus FLOT vs FLOT alone, but more modest improvements in survival were seen in an exploratory analysis of the cohort whose chemotherapy backbone was FLOT.² The addition of pembrolizumab led to a doubling in pathologic complete response rate, and event-free survival was not reached in patients receiving pembrolizumab plus FLOT, but overall survival remained similar, according to Kohei Shitara, MD, of the National Cancer Center Hospital East in Kashiwa, Japan. The study’s first author was Salah-Eddin Al-Batran, MD.

About MATTERHORN

Patients were recruited from Europe (53%), Asia (19%), South America (19%), and North America (9%) and were stratified by geographic region (specifically, Asia vs all other regions). They were randomly assigned to receive four doses of FLOT plus two doses of durvalumab or placebo preoperatively. After surgery, they received these regimens again, followed by 10 doses of durvalumab or placebo as maintenance. The primary endpoint was event-free survival; these results are pending.

In addition to the 12% increase in pathologic complete response, the main analysis also showed the combined complete and near-complete pathologic response rate was also significantly improved by approximately 12%, based on rates of 14% in the control arm and 27% in the durvalumab arm (odds ratio = 2.19; P < .00001). Also of note, a higher percentage of individuals treated with durvalumab plus FLOT achieved T0 stage (23% vs 11%) and N0 stage (52% vs 36%) after surgery. The study showed that, globally, “FLOT is feasible,” Dr. Janjigian added, based on the observation that 97% of patients completed preoperative treatment, and 63% completed adjuvant therapy.

Consistent Benefit Across Regions and Subgroups

In exploratory analyses, the addition of durvalumab to perioperative FLOT consistently improved pathologic complete response rates across geographic regions. Although the Asian population had more patients with lymph node positivity and T4 stage tumors, these patients derived benefit from durvalumab that was nearly identical to the non-Asian populations; absolute improvements were 13% (odds ratio = 3.96) and 12% (odds ratio = 2.92), respectively. The improvements in pathologic complete responses were consistent across Europe and South America, with an even greater increase (21%) observed in the North American cohort (odds ratio = 4.93), she reported.

“The difference in event-free survival favored perioperative pembrolizumab plus FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel].”

— Kohei Shitara, MD

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Similarly, benefit was observed across virtually all prespecified subgroups, with the exception of patients with PD-L1 expression < 1%. Outcomes were better with durvalumab in both microsatellite-high and non–microsatellite-high subgroups.

About KEYNOTE-585

The randomized, double-blind, phase III KEYNOTE-585 trial compared perioperative pembrolizumab plus chemotherapy vs placebo plus chemotherapy. In a recent analysis of the main cohort, whose backbone was a cisplatin-based doublet, the addition of pembrolizumab significantly improved the pathologic complete response rate from 2.0% to 12.9% (P < .00001).⁴ Event-free survival was numerically—though not significantly—improved (44.4 vs 25.3 months; hazard ratio [HR] = 0.81; P = .0198), based on a P value for significance of .0178. Thus, the study findings are technically negative.

The main study included 804 patients assigned to receive neoadjuvant pembrolizumab (at 200 mg) or placebo plus a cisplatin-based doublet chemotherapy every 3 weeks for 3 cycles, followed by surgery and then adjuvant pembrolizumab or placebo for 11 cycles. A smaller group of 203 patients received FLOT as the chemotherapy backbone. Preoperative FLOT and pembrolizumab were given every 2 weeks for 4 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus FLOT for 4 cycles, then pembrolizumab or placebo as maintenance for 11 cycles. This group constituted the FLOT cohort, whose findings were presented at the conference.

Outcomes With Pembrolizumab Plus FLOT

In the FLOT cohort, the pathologic complete response rate was more than doubled with pembrolizumab vs placebo, at 17% vs 7%, respectively. Moreover, at a median follow-up of 31.6 months, the median event-free survival was not reached for the pembrolizumab arm and was 30.9 months for the placebo arm (HR = 0.79; 95% confidence interval [CI] = 0.52–1.22). At 24 months, event-free survival rates were 66% and 57%, respectively, and at 36 months, they were 59% and 47%, respectively. Overall survival rates, however (though still immature), were nearly identical, 72% and 73%, respectively, at 24 months and 62% and 67%, respectively, at 36 months (HR = 1.04; 95% CI = 0.66–1.66), Dr. Shitara reported.

“The difference in event-free survival favored perioperative pembrolizumab plus FLOT,” he said. “The event-free survival and overall survival times in the control arm align well with what was previously observed in the FLOT-4 study.” 

DISCLOSURE: Dr. Janjigian has received fees for consulting and travel from AmerisourceBergen, Arcus Biosciences, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Imedex, Imugene, Lynx Health, Merck, Merck Serono, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, RGENIX, Seagen, Silverback Therapeutics, and Zymeworks and has stock options with RGENIX. Dr. Shitara reported financial relationships with AbbVie, Amgen, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda, and Janssen.

REFERENCES

1. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Pathological complete response to 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) with or without durvalumab in resectable gastric and gastroesophageal junction cancer: Subgroup analysis by region from the phase 3 randomized, double-blind MATTERHORN study. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract LBA246. Presented January 18, 2024.

2. Al-Batran SE, Shitara K, Folprecht G, et al: Pembrolizumab plus FLOT vs FLOT as neoadjuvant and adjuvant therapy in locally advanced gastric and gastroesophageal junction cancer: Interim analysis of the phase 3 KEYNOTE-585 study. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 247. Presented January 18, 2024.

3. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: LBA73 Pathological complete response to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric and gastroesophageal junction cancer: Interim results of the global, phase III MATTERHORN study. Ann Oncol 34(suppl 2):S1315-S1316, 2023.

4. 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. December 19, 2023 (early release online).

EXPERT POINT OF VIEW

The invited discussant of the KEYNOTE-585 and MATTERHORN trials was Alexander G. Raufi, MD, of Brown University Legorreta Cancer Center and Rhode Island Hospital, Providence. “Both studies demonstrate that neoadjuvant chemoimmunotherapy increases downstaging and improves pathologic complete response rates compared with chemotherapy alone,” but that is not sufficient to change the standard of care, he said.

Alexander G. Raufi, MD

Dr. Raufi noted that in the main cohort analysis of KEYNOTE-585, there was no statistically significant event-free survival or overall survival difference. The main cohort likely received an inferior cisplatin-based doublet, he added; the 20% of patients who received FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) in the current analysis did demonstrate a trend toward better event-free survival, but this did not translate into any improvement in overall survival for any subgroup, he pointed out.

“Insufficient adjuvant treatment likely played a role,” Dr. Raufi said, noting that adjuvant therapy was completed by only 45% of those given pembrolizumab plus FLOT and by 54% of the control arm. “We know dose intensity matters,” he said, adding that a possible lack of benefit in patients with a combined positive score (CPS) < 5 or < 10 could affect outcomes.

In MATTERHORN, the addition of durvalumab to FLOT increased pathologic complete response rates and enhanced downstaging, consistently across global regions. However, the data for this study are not complete, he said.

Clinical Implications

Neither study changes current practice, according to Dr. Raufi. MATTERHORN lacks survival data, and KEYNOTE-585 did not demonstrate a meaningful increase in cure rates. “Unfortunately, we have yet to see improvements in event-free and overall survival, which we need before this can be adopted into the standard of care,” he commented.

However, Dr. Raufi is hopeful MATTERHORN may show a survival benefit. All patients received the superior chemotherapy backbone, FLOT, compared with only about 20% of those in KEYNOTE-585, and 63% as opposed to 45% completed adjuvant therapy.

“But what if MATTERHORN is negative?” he asked. “Do we shift our focus over to populations who are more likely to benefit? Perhaps patients with less advanced disease? Perhaps those with a PD-L1 CPS ≥ 10? Do we think about moving over to total neoadjuvant therapy? Ultimately, we will need to identify more effective, novel combinations to truly cure this disease.” 

DISCLOSURE: Dr. Raufi reported no conflicts of interest.