2024 Updates in GI Cancer Feature FLOT Combinations, Restricted FDA Approvals by PD-L1 Expression, and More

The gastroesophageal cancer field has witnessed several key data updates in 2024, and one of the most prominent revealed that FLOT (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil [5-FU]) is the preferred regimen for patients with localized adenocarcinoma, as radiation does not improve outcomes, according to Yelena Y. Janjigian, MD.¹

Findings for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) combination therapies in HER2-positive disease and the final overall survival (OS) analysis of dual HER2/PD-1 blockade in the phase 3 KEYNOTE-811 trial (NCT03615326) have also shed light on treatment approaches, and the first-line FDA approval of zolbetuximab-clzb (Vyloy) plus chemotherapy for Claudin 18.2 (CLDN18.2)—positive gastric/gastroesophageal junction (GEJ) tumors as a notable regulatory decision. Janjigian highlighted these updates and more in a presentation at the 42nd Annual Chemotherapy Foundation Symposium, an event held by Physicians’ Education Resource, LCC.¹ Janjigian is chief attending physician of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York.

FLOT Is the Preferred Regimen: Are Combinations With It Efficacious?

Janjigian stressed that radiation therapy should not be used as it’s demonstrated a lack of benefit, but with that comes new investigations of FLOT combination therapies. FLOT demonstrated superiority over radiation therapy according to data from the phase 3 ESOPEC study (NCT02509286), which showed that patients who received neoadjuvant and adjuvant FLOT experienced improved OS compared with those given neoadjuvant chemoradiation with the CROSS regimen (paclitaxel/carboplatin); the median OS was 66 months vs 37 months, respectively, and the 5-year OS rates were 50.6% vs 38.7%.²

Additionally, findings from the phase 3 TOPGEAR study (NCT01924819) showed that the addition of radiation therapy to chemotherapy did not improve OS outcomes in the perioperative setting.³ Patients who received chemotherapy (n = 288) experienced a median OS of 49 months vs 46 months among those who received chemoradiotherapy (n = 286; HR, 1.05; 95% CI, 0.83-1.31).

Building upon these findings, the phase 3 MATTERHORN trial (NCT04592913) examined neoadjuvant durvalumab (Imfinzi) plus FLOT followed by adjuvant durvalumab plus FLOT and then durvalumab monotherapy. When compared with a FLOT plus placebo regimen (n = 474), durvalumab plus FLOT (n = 474) yielded a statistically significant improvement in pathological complete response (pCR) rate in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma.⁴ Rates were 19% vs 7%, respectively (Δ, 12%; odds ratio, 3.08; 95% CI, 2.03-4.67; P < .00001).

However, data from the phase 3 KEYNOTE-585 trial (NCT03221426) showed that this patient population did not experience a statistically significant improvement in event-free survival when treated with pembrolizumab (Keytruda) plus chemotherapy vs placebo plus chemotherapy (HR, 0.81; 95% CI, 0.67-0.99; P = .0198).⁵ Furthermore, patients in the main plus FLOT cohort experienced a pCR rate of 13.0% (95% CI, 10.2%-16.3%) when given the pembrolizumab regimen (n = 502) vs 2.4% (95% CI, 1.3%-4.2%) when given the placebo regimen (n = 505; Δ, 10.6%; 95% CI, 7.4%-14.0%).

HER2 Inhibition in GEJ Adenocarcinoma

Janjigian noted that up to 30% of GEJ adenocarcinomas are HER2-positive, and 30% of HER2-positive GEJ tumors harbor co-alterations of the RTK/RAS/PI3K pathway, leading to intrinsic resistance. She added HER2 inhibition alone in the first line is insufficient to overcome this intrinsic resistance, as shown by several negative studies such as the phase 3 JACOB trial (NCT01774786).¹

The 2021 FDA approval of pembrolizumab plus trastuzumab (Herceptin), fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma based on data from the phase 3 KEYNOTE-811 trial (NCT03615326) marked an important step forward, according to Janjigian, who highlighted the restriction of this immunotherapy approval for patients with a PD-L1 combined positive score (CPS) of at least 1%.^1,6

Data from the final analysis of the KEYNOTE-811 revealed that antitumor activity was higher in patients with PD-L1 CPS at least 1% with an overall response rate (ORR) Δ of 14.7% (95% CI, 7.1%-22.2%) seen for patients treated with the pembrolizumab regimen (n = 298) vs placebo regimen (n = 296).^6,7 An ORR Δ of 12.6% (95% CI, 5.6%-19.4%) was seen in the intention-to-treat population of patients given pembrolizumab (n = 350) vs placebo (n = 348). Janjigian noted that the incidence of immune-mediate adverse effects and infusion reactions were as expected.^1,7

Several combination therapies with T-DXd in the first-line HER2-positive metastatic esophageal adenocarcinoma/gastric cancer/GEJ adenocarcinoma setting are also under investigation. Findings from the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) showed that the highest ORRs observed thus far were in the T-DXd 6.4 mg/kg plus 5-FU/capecitabine 1000 mg/m² cohort (n = 41) and the standard of care trastuzumab plus 5-FU/capecitabine plus cisplatin/oxaliplatin cohort (n=29); these respective ORRs were 78% (95% CI, 62%-90%) and 76% (95% CI, 56%-90%).⁸

OS by Microsatellite Stability Status in Gastric/GEJ/Esophageal Adenocarcinomas

Data from the phase 3 CheckMate 649 trial (NCT02872116) also demonstrated that a nivolumab (Opdivo) plus FOLFOX regimen (n = 23) bested a chemotherapy alone regimen (n = 21) for patients with microsatellite instability–high (MSI-H) disease.⁹ The median OS was 38.7 months (95% CI, 8.4–not estimable) vs 12.3 months (95% CI, 4.1-16.5), respectively (unstratified HR, 0.34; 95% CI, 0.16-0.74). Among patients with microsatellite stable disease, the median OS was 13.8 months (95% CI, 12.4-14.5) in the nivolumab plus FOLFOX arm (n = 696) vs 11.5 months (95% CI, 10.8-12.5) in the chemotherapy arm (n = 682; unstratified HR, 0.79; 95% CI, 0.71-0.89).

When broken down by CPS score, 36-month follow-up data showed that patients who experienced the most OS benefit with the nivolumab regimen vs chemotherapy regimen were those with a PD-L1 CPS of at least 10% (unstratified HR, 0.66), followed by those with a PD-L1 CPS of at least 5% (unstratified HR, 0.69). The unstratified HR for death was 0.78 among the overall population.⁹

Zolbetuximab Makes Waves in CLD18.2-Positive Disease

Janjigian noted that the OS improvement seen with zolbetuximab plus CAPOX vs the control arm in the phase 3 GLOW study (NCT03462719) was similar to that seen in the phase 3 SPOTLIGHT trial (NCT03504397) with zolbetuximab plus mFOLFOX6 (n = 283) vs placebo plus mFOLFOX6 (n = 282).^1,10,11 The median OS was 18.23 (95% CI, 16.43-22.90) vs 15.54 (95% CI, 13.47-16.53) in SPOTLIGHT (HR, 0.750; 95% CI, 0.601-0.936; P = .0053), respectively.

“OS Kaplan-Meier curves [separated] early, and sustained separation [is] important,” Janjigian said.

Janjigian added that there has been a “better ORR benefit [seen] with anti–PD-1 vs anti-CLDN18.2 [agents]…[There was] minimal/no improvement in ORR with zolbetuximab.” She noted that anti–PD-1 agents may be better for patients with proximal tumors as less OS benefit was observed with zolbetuximab for patients with GEJ tumors in a subgroup analysis. Janjigian highlighted the importance of prioritizing biomarker-based therapy with MSI-H status followed by HER2 expression, a PD-L1 CPS greater than 1%, and CLD18.2 high expressions. Additional next steps include the evaluation of CLD18.2 antibody-drug conjugates in the first- and second-line settings.

Disclosures: Dr Janjigian reported receiving funds for research support from Arcus Biosciences, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Cycle For Survival, the Department of Defense, Eli Lilly, Fred’s team, Genentech/Roche, Inspirna, Merck, NCI, Stand Up 2 Cancer, and Transcenta. She has stock options with Inspirna and has received consulting fees and travel funding from Abbvie, Amerisource Bergen, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas, AstraZeneca, Basilea Pharmaceutica, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, eChinaHealth, Ed Med Resources (OncInfo), Eisai, Inc., Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, Inc., H.C. Wainwright & Co., LLC, Imedex, Imugene, Inspirna, Lynx Health, Master Clinician Alliance, Merck, Merck Serono, Mersana Therapeutics, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Physicians’ Education Resource, LLC, Research to Practice, Sanofi Genzyme, Seagen, Silverback Therapeutics, Suzhou Liang Yihui Network Science and Technology Company, Talem Health, TotalCME, WebMD, LLC, and Zymeworks Inc.

References

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2. Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). J Clin Oncol. 2024;42(suppl 17):LBA1. doi:10.1200/JCO.2024.42.17_suppl.LBA1
3. Leong T, Smithers BM, Michael M, et al. Preoperative chemoradiotherapy for resectable gastric cancer. N Engl J Med. 2024;391(19):1810-1821.doi:10.1056/NEJMoa2405195
4. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Pathological complete response (pCR) to 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) with or without durvalumab (D) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Subgroup analysis by region from the phase 3, randomized, double-blind MATTERHORN study. J Clin Oncol. 2024;42(suppl 3):LBA246. doi:10.1200/JCO.2024.42.3_suppl.LBA246
5. 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. J Clin Oncol. 2024;42(suppl 3):247. doi:10.1200/JCO.2024.42.3_suppl.247
6. FDA amends pembrolizumab’s gastric cancer indication. FDA. Updated November 8, 2023. Accessed November 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-amends-pembrolizumabs-gastric-cancer-indication
7. Janjigian YY, Kawazoe A, Bai Y, et al. Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma. Ann Oncol. 2024;35(suppl 2):S877-S878. doi:10.1016/j.annonc.2024.08.1466
8. Janjigian YY, van Laarhoven HWM, Rha SY, et al. Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03). Ann Oncol. 2024;35(suppl 2):S878. doi:10.1016/j.annonc.2024.08.1467
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10. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 4):LBA292. doi:10.1200/JCO.2023.41.4_suppl.LBA292
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