Dr. Yelena Y. Janjigian, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, has outlined critical future directions for immunotherapy in gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma, emphasizing the importance of moving these treatments to earlier disease stages.
"For all immune checkpoint blockade, we need to bring it to [patients with] earlier-stage [disease]," Dr. Janjigian stated. She expressed optimism about forthcoming data from the phase 3 MATTERHORN study (NCT04592913), which is evaluating a FLOT (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil)-based combination with the anti–PD-L1 agent durvalumab (Imfinzi) in patients with resectable gastric/GEJ cancer.
Radiation Therapy Shows No Survival Benefit
In a significant development that challenges conventional treatment approaches, Dr. Janjigian highlighted results from two recent phase 3 trials—TOPGEAR (NCT01924819) and ESOPEC (NCT02509286)—both published in the New England Journal of Medicine. These studies conclusively demonstrated that radiation therapy does not improve survival in patients with gastric and GEJ cancers.
"Radiating the gastroesophageal junction or stomach will not help your patients live longer," Dr. Janjigian emphasized. This finding represents a paradigm shift in treatment strategy, suggesting that clinicians should focus on systemic approaches rather than localized radiation therapy.
Optimizing Treatment Strategies
For HER2-positive disease, Dr. Janjigian noted that the combination of trastuzumab (Herceptin), immunotherapy, and chemotherapy is appropriate in the first-line setting. However, not all combination approaches have proven successful. The phase 3 LEAP-015 trial (NCT04662710), which evaluated pembrolizumab (Keytruda) plus lenvatinib (Lenvima) in previously untreated, locally advanced, unresectable or metastatic, HER2-negative gastroesophageal adenocarcinoma, did not meet its primary endpoint of overall survival.
Dr. Janjigian strongly advocated for the FLOT regimen as the optimal therapy in the perioperative setting, particularly when combined with immunotherapy. "If the patient is not able to get FLOT, if you want to dose reduce once you get started or drop docetaxel, that's okay," she advised, offering practical guidance for clinical implementation.
She explicitly cautioned against using the CROSS regimen—paclitaxel plus carboplatin with radiation—for adenocarcinoma, stating she hasn't used this approach in over six years.
Addressing Systemic Disease
A critical insight from Dr. Janjigian's commentary is the recognition of gastric cancer as a systemic disease. She advised against rushing patients to surgery if an R0 resection (complete removal of all cancer with no cancer cells seen at the margins of the removed tissue) is not possible, noting that radiation will not improve outcomes in such cases.
"You need to prolong systemic therapy, perhaps starting with either a triplet with immunotherapy or a doublet with immunotherapy. Only once the disease biology declares itself could you consider doing surgery," she explained.
Dr. Janjigian clarified that while radiation may increase R0 resection rates, this does not translate to survival benefits because of the systemic nature of the disease. "If you do not recognize that, you are doing your patients a disservice," she stated.
Future Research Directions
Ongoing research is focusing on several key areas:
- Refining combination approaches in the first-line setting
- Bringing immunotherapy to the perioperative setting
- Exploring novel approaches for second- and later-line treatments for patients who have experienced disease progression after receiving immunotherapy
Dr. Janjigian noted that treatment based on the phase 3 CheckMate649 trial (NCT02872116) may not work for every patient, highlighting the need for additional treatment options beyond the frontline setting. She mentioned promising approaches such as off-the-shelf natural killer T-cell therapies and next-generation CTLA-4 inhibitors.
The evolving treatment landscape for gastric, GEJ, and esophageal cancers reflects a shift toward systemic approaches that address the fundamental biology of these diseases, with immunotherapy playing an increasingly important role across multiple disease stages.
