Yelena Y. Janjigian, MD
The GLOW study’s invited discussant, Yelena Y. Janjigian, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, New York, said the GLOW findings are “practice-changing,” validating that high claudin-18.2 (CLDN18.2) expression as an important biomarker in advanced gastric or gastroesophageal adenocarcinoma.1 “Both GLOW and SPOTLIGHT2 met their primary and secondary endpoints, and that’s great. These breakthroughs are major,” she said, but cautioned that clinical testing for CLDN18.2 expression should wait until we have an approved immunohistochemistry assay.
In both trials, Kaplan-Meier overall survival curves showed early and sustained separation. Although follow-up is short for GLOW, the SPOTLIGHT trial demonstrated durability of this benefit, with 36-month overall survival of 21%, vs 9% in the control arm. This survival rate is similar to that observed with nivolumab and chemotherapy in the combined positive score [CPS] ≥ 5 subset of CheckMate 649, as Dr. Janjigian reported at the 2023 ASCO Gastrointestinal Cancers Symposium.3 “I want to tell you how important it is that for gastric cancer, we are now able to report 3-year survival rates,” she commented.
Biomarker Testing Critical in Gastric Cancer
With the results of the GLOW and SPOTLIGHT studies, CLDN18.2, which is expressed in 35% of gastric adenocarcinomas, joins other biomarkers that guide treatment decisions in this cancer: HER2 (20% of tumors), microsatellite instability–high (MSI-H; 5% stage IV, 20% stage I–III), Epstein-Barr virus (3%), and PD-L1; 80% with CPS ≥ 1, 60% with CPS ≥ 5). Along with CLDN18.2, overexpression of fibroblast growth factor receptor 2b (30%), which can be targeted by the monoclonal antibody bemarituzumab, is expected to join the biomarker list. Tumor sequencing for rare mutations occasionally reveals other targets.
Prioritizing Treatment
Dr. Janjigian offered thoughts on prioritizing biomarkers and their accompanying therapeutics in the first-line setting. “I think MSI-H is clearly the most important biomarker...,” she said, citing median overall survival of 26 months with nivolumab plus chemotherapy in MSI-H patients in CheckMate 649.4 Second is HER2 overexpression, most recently based on KEYNOTE-811,5 where the addition of pembrolizumab to trastuzumab plus chemotherapy increased response rates by 23%, with no increase in toxicity. “After that, everything is up for grabs,” she said.
A PD-L1 CPS ≥ 5 is an important biomarker, shown also in CheckMate 649, where treatment with nivolumab resulted in a 3.3-month gain in overall survival4 and a 15% gain in response rate vs chemotherapy alone. For CLDN18.2-positive patients with a CPS ≥ 5 who received zolbetuximab plus chemotherapy, the gain was less, and the response rate was not improved.
CLDN18.2 and PD-L1 CPS ≥ 5 overlap in about 20% of cases, and one could question which treatment approach to take in these patients. Because of what appears to be a somewhat greater benefit with immunotherapy, Dr. Janjigian said she favors this as a first choice in these patients, “particularly since they cannot get it in later lines,” she noted. “High CLDN18.2 expression clearly should come after PD-L1 CPS ≥ 5 in prioritizing the biomarkers.”
Managing Gastrointestinal Side Effects
Nausea and vomiting are the main side effects of zolbetuximab. To improve tolerability, Dr. Janjigian recommended slowing the infusion speed, splitting the infusion over 2 days, and using prophylactic antiemetics. Dr. Janjigian added that zolbetuximab plus chemotherapy may be a preferred option for patients with CLDN18.2-high tumors and prior gastrectomy, who do not experience the nausea and therefore may tolerate treatment better.
Looking Ahead
Zolbetuximab is just the beginning for CLDN18.2-based strategies in the clinic, Dr. Janjigian predicted. In development is TST001, which reportedly has higher affinity, higher antibody-dependent cellular cytotoxicity, and more activity at lower doses than zolbetuximab and is showing synergy with anti–PD-1 agents. Beyond that are human IgG1-engineered antibodies, bispecific antibodies, and antibody-drug conjugates.
DISCLOSURE: Dr. Janjigian has received fees for consulting and travel reimbursement from Amerisource Bergen, 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.
REFERENCES
1. Xu RH, Shitara K, Ajani JA, et al: Zolbetuximab + CAPOX in 1L claudin-18.2+/HER2− locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: Primary phase 3 results from GLOW. 2023 March ASCO Plenary Series. Abstract 405736. Presented March 22, 2023.
2. Shitara K, Lordick F, Bang YJ, et al: Zolbetuximab + mFOLFOX6 as first-line treatment for patients with claudin-18.2+/HER2− locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. 2023 ASCO Gastrointestinal Cancers Symposium. Abstract LBA292. Presented January 19, 2023.
3. Janjigian YY, Shitara K, Moehler MH, et al: Nivolumab plus chemotherapy vs chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: 3-year follow-up from CheckMate 649. 2023 ASCO Gastrointestinal Cancers Symposium. Abstract LBA291. Presented January 19, 2023.
4. 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 398:27-40, 2021.
5. Janjigian YY, Kawazoe A, Yañez P, et al: The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 600:727-730, 2021.
