Dosing Schedule Factors into Chemo/ICI Choice in Upper GI Cancer

Frontline treatment of metastatic gastrointestinal cancers has several elements that can affect treatment choice. If a biopsy does not support use of certain targeted treatments, several trials support the use of chemotherapy plus immune checkpoint inhibitor (ICI), with better responses expected in patients with higher PD-L1 combined positive score (CPS). During a virtual Case-Based Roundtable event, Yelena Y. Janjigian, MD, moderated a discussion about a patient with stage IV gastric adenocarcinoma and what treatment could be selected. Janjigian, chief of the gastrointestinal oncology service and Carroll and Milton Petrie Chair at Memorial Sloan Kettering Cancer Center, asked participants about their reasoning for using a particular ICI and their impressions of the use of dual ICI in this setting.

CASE SUMMARY

• A 60-year-old man with abrupt 10-pound weight loss, dyspepsia, bloating after meals, and loss of appetite, and all symptoms worsening over the past 3 months​
• Family history: father deceased age 50 (gastric cancer)​
• Medical history: overweight, hypertension
• Esophagogastroduodenoscopy showed 2-cm protruding mass in the body of the stomach without ulceration​.
• Biopsy revealed poorly differentiated adenocarcinoma​.
• Molecular testing: HER2/neu negative; mismatch repair proficient/microsatellite stable; PD-L1 CPS – 5; Claudin18.2 less than 75%​
• CT of abdomen and chest revealed a gastric polypoid mass and thickening; no ascites; 2 lesions in the left lung lower lobe​.
• Lung biopsy confirmed metastatic adenocarcinoma consistent with gastric primary ​
• Diagnosis: stage IV gastric adenocarcinoma

DISCUSSION QUESTIONS

• Which chemotherapy regimen do you prefer? ​
  • At which dosing/administration schedule? ​
  • Given synchronously with ICIs?
• What factors influence your decision regarding which ICI to use in first-line chemotherapy?

Kamal Sahu, MD: With the CPS of 5, I think the patient will be pretty responsive to immunotherapy. I’m used to using chemotherapy along with immunotherapy, so chemotherapy plus nivolumab [Opdivo] is my go-to first choice in this case.

Yelena Y. Janjigian, MD: Out of pembrolizumab [Keytruda], tislelizumab [Tevimbra], or nivolumab , how do you decide which one to use?

Ike Onwere, MD: It is [sometimes] based on giving the FOLFOX [leucovorin, fluorouracil, and oxaliplatin] every 2 weeks. It’s just easier to give nivolumab every 2 weeks than pembrolizumab, so I typically do an every-2-weeks regimen.

Janjigian: Yes, me too. Otherwise, you have to remember to dose pembrolizumab every 6 weeks. Asynchronous pembrolizumab is also tricky. I decide based on [if] I want to give chemotherapy every 2 weeks or every 3 weeks and then decide on chemotherapy based on this.

Do you see any of these drugs behaving differently, or do you think they’re all the same? Do you believe in different effects of these anti–PD-1 [agents]?

Igor Genkin, MD: I don’t see any major differences.

Karam Al-Issa, MD: It seems like pembrolizumab has fewer episodes of autoimmune toxicity compared with nivolumab, but maybe I’m biased because a lot of times we use ipilimumab plus nivolumab, so that makes things more complicated. I use pembrolizumab a little bit more, because our order sets already include the pembrolizumab every 6 weeks. I like the every-6-weeks regimen for patients, and I tend to use a little bit more pembrolizumab than nivolumab.

Janjigian: And you do pembrolizumab with FOLFOX?

Al-Issa: Yes.

Janjigian: I find that pembrolizumab every 6 weeks or nivolumab every 4 weeks is associated with some more mild but symptomatic skin and joint toxicity. [There is] not a big difference in major immune-related adverse events, but the minor stuff is in my experience slightly noticeable because you give a higher dose of immunotherapy.

Fayez Estefan, MD: Looking at the clinical trial results for the chemotherapy with tislelizumab, incidence of AEs was lower compared with the other trial. This is a cross-trial comparison, and we should probably not do that, but [it seemed] better tolerated than nivolumab. I’ve never used that, but it’s something that I noticed from reviewing the data.

Janjigian: I think some of it is the way that the AEs are attributed, either treatment related or all AEs. The way to compare the AEs best is the absolute increase [vs the control] within each study, as opposed to [cross trial]. But overall, the drugs have very similar AEs profiles.

Kok Hoe Chan, MD: I think it’s pretty comparable for all 3 trials regarding the use of the immunotherapy in the frontline setting. I do not have any patients with squamous cell carcinoma, because I think that’s pretty rare in the United States.

Changqing Xie, MD: These 3 trials play an important role nowadays [showing] that immunotherapy does something, no matter if it’s adenocarcinoma or squamous. For nivolumab/ipilimumab alone compared with nivolumab plus chemotherapy…the progression-free survival between the nivolumab/ipilimumab is shorter compared with the nivolumab plus chemotherapy in the CheckMate 648 study [NCT03143153], but the overall survival [rate at 5 years] is much better compared with nivolumab plus chemotherapy.¹

Janjigian: There’s the initial flip on the survival curves…. I think the duration of response is better.

_{DISCLOSURES: Janjigian previously reported research funding from Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Fred’s Team, Genentech/Roche Lilly, Merck, National Cancer Institute and Rgenix; serving as a consultant or in an advisory role for Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Imugene, AstraZeneca, Lilly, Merck, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Seattle Genetics, Pfizer, Rgenix, AmerisourceBergen, Arcus Biosciences, Geneos, GlaxoSmithKline, Imedex, Lynx Health, Peerview, Silverback Therapeutics and Zymeworks; receiving stock options from Rgenix; and nonfinancial relationships with Clinical Care Options, Axis Medical Education and Research to Practice.}

_REFERENCE

_{1. Chau I, Ajani J, Doki Y, et al. 2106P - Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): 5-year follow-up from CheckMate 648. Ann Oncol. 2025;36(suppl 2):S1187-S1188. doi:10.1016/j.annonc.2025.08.2726}