PD-L1 Provides Valid Biomarker for Nivolumab/Chemo in Gastric Cancer

CASE

• A 60-year-old man had abrupt 10-pound weight loss, dyspepsia, bloating after meals, and loss of appetite. All symptoms got worse over the next 3 months​.
• Family history: father deceased at age 50 due to gastric cancer
• Medical history: overweight, hypertension​
• Esophagogastroduodenoscopy (EGD) showed 2-cm protruding mass in the body of the stomach, without ulceration.​
• Biopsy revealed poorly differentiated adenocarcinoma.​
• Molecular testing: HER2/neu negative; mismatched repair proteins (MMRp) were microsatellite stable; PD-L1 combined positive score was 5%​
• CT of abdomen and chest revealed a gastric polypoid mass and thickening; no ascites; 2 lesions seen in the left lung lower lobe.​
• Lung biopsy confirmed metastatic adenocarcinoma consistent with gastric primary cancer.
• PET/CT confirmed metastatic disease​.
• Diagnosis: stage IV gastric adenocarcinoma
• The patient was started on FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) plus nivolumab (Opdivo).

Targeted Oncology: What are some of the trials that make up relevant data for the use of nivolumab and chemotherapy in this patient population?

MICHAEL GIBSON, MD, PhD​: Despite all the [approved] options for these patients, the data to support them are very repetitive. For patients with esophageal squamous cell carcinoma, [the trial that led to the approval of nivolumab and chemotherapy for these patients was] CheckMate 648 [NCT03143153].¹ In both squamous and non-squamous disease KEYNOTE-590 [NCT03189719] led to the approval for pembrolizumab [Keytruda] plus chemotherapy.²

What was notable from the CheckMate 649 (NCT02872116) study outcomes?

The randomization of this trial was straightforward; [patients were on either] chemotherapy alone or nivolumab plus or minus chemotherapy, and the primary end points [were overall survival (OS) and progression-free survival (PFS) in patients with a PD-L1 combined positive score (CPS) of 5 or more].³ At 3-years [of follow-up], the median OS and PFS [in the combination arm] were higher for those with a CPS of 5 or more [compared with] the entire randomized population.⁴ [This was at 14.4 months (95% CI, 13.1-16.2) vs 13.7 months (95% CI, 12.4-14.5) and 8.3 months (95% CI, 7.0-9.3) vs 7.7 months (95% CI, 7.1-8.6), respectively].⁴ This showed the validity of CPS as a marker for this patient population.

Michael Gibson, MD, PhD​

Associate Professor of Medicine

Director of Translational Research for Head and Neck Oncology

Vanderbilt University Medical Center​

Nashville, TN​

How are the patient’s quality-of-life outcomes impacted by this combination?

Quality-of-life [measurements have] tremendous importance...and these were collected in the CheckMate 649 trial.... As the treatments went on, the numbers [corresponding to the patient's] quality of life got better.⁵ Looking at safety, just like in all the immunotherapy vs chemotherapy studies, the difference in toxicity is in the immune-related adverse events [irAEs]....³ There are irAEs that go away with [extra treatment] and there are ones that don’t.... I would be curious to see data that suggests the patients who are treated with prednisone got better [compared with] those who didn't, but I haven't been able to find those sort of data presented in that way.

References:

1. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. FDA. News Release. May 31, 2022. Accessed February 28, 2024. http://tinyurl.com/4my6bb54

2. FDA approves pembrolizumab for esophageal or GEJ carcinoma. FDA. News Release. March 22, 2021. Accessed February 28, 2024. http://tinyurl.com/y8khh4yz

3. 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(10294):27-40. doi:10.1016/S0140-6736(21)00797-2

4. Janjigian YY, Ajani JA, Moehler M, et al. First-line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III CheckMate 649 trial. J Clin Oncol. 2024: JCO2301601. doi:10.1200/JCO.23.01601

5. Moehler M, Xiao H, Blum SI, et al. Health-related quality of life with nivolumab plus chemotherapy versus chemotherapy in patients with advanced gastric/gastroesophageal junction cancer or esophageal adenocarcinoma from CheckMate 649. J Clin Oncol. 2023;41(35):5388-5399. doi:10.1200/JCO.23.00170