Bringing Immunotherapy to Earlier Stages of Gastric/GEJ Cancer

CancerNetwork® spoke with Yelena Y. Janjigian, MD, chief attending physician of the Gastrointestinal Medical Oncology Service at Memorial Sloan Kettering Cancer Center, about the unmet need durvalumab (Imfinzi) in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) would help reduce in patients with resectable locally advanced gastric and gastroesophageal junction (GEJ) cancers.

Janjigian began by explaining that the regimen was seeking to address a need for perioperative targeted therapy in this patient population. She contextualized the feasibility of the durvalumab plus FLOT regimen by highlighting findings from the phase 3 CheckMate 577 study (NCT02743494), where adjuvant nivolumab (Opdivo) reduced the risk of cancer recurrence in patients with high-risk disease and residual lymph nodes or tumors at the time of surgery.¹ These results supported the FDA approval of nivolumab for resected esophageal or GEJ cancerin May 2021.²

Additionally, Janjigian further expressed that neoadjuvant therapy before surgery was observed to benefit multiple disease states, and that neoadjuvant treatment biologically expands the T-cell population and helps survey cancer post-surgery. She then explained that in certain disease states, such as microsatellite instability–high (MSI-H) tumors, organ preservation without surgery may be feasible. She further remarked that the presence of positive data for therapy in the perioperative setting can serve to shift the paradigm for this patient population.

Furthermore, Janjigian speculated that organ preservation may be possible for complete responders to neoadjuvant immunotherapy with gastric or GEJ cancers, highlighting previous data which showed that chemotherapy in combination with immunotherapy has treated metastatic cancers and has been approved in stage IV disease.³ She concluded by iterating that the phase 3 MATTERHORN trial (NCT04592913) was seeking to assess immunotherapy in early-stage disease with curative intent, even before surgery.

Transcript:

The unmet need that that this regimen is helping to address is perioperative targeted therapy. [When] it’s chemoradiation followed by surgery, and if [the patient has] high-risk disease for recurrence with residual lymph node or residual tumor at the time of surgery, we know that adjuvant nivolumab helps reduce risk of cancer recurrence. That’s based on the phase 3 CheckMate 577 data.¹ It is FDA-approved in that high-risk population.

In every other solid tumor—lung cancer, bladder cancer, [breast cancer], and other diseases—we know that doing neoadjuvant therapy before surgery helps patients have a better outcome [and] potential downstaging. In fact, the T-cell population biologically expands and helps survey the cancer even after surgery. In some diseases, we are now moving toward a non-operative approach, especially for [MSI-H] tumors. If there’s a complete response, perhaps you can do organ preservation and not have surgery. To have a positive study in the perioperative therapy setting––before surgery for gastric and esophageal adenocarcinoma––is truly remarkable because it can change the paradigm. We can shift the paradigm.

We can treat the patient as soon as they are diagnosed and not wait to give them immunotherapy after surgery. Also, perhaps it is within our lifetime that we can do organ preservation, where people can keep their organs and not live with lifelong sequela of having a major operation, especially if they had a complete response. We know that immunotherapy has worked in metastatic disease and that regimen, the 2-drug combination [of leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX)] plus immunotherapy has been approved for some time in stage IV disease. The unmet need that the phase 3 MATTERHORN study is addressing is bringing immunotherapy to early-stage disease in a curative setting and doing it even before surgery.

References

1. Kelly RJ, Ajani JA, Kuzdal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125
2. FDA approves nivolumab for resected esophageal or GEJ cancer. FDA. May 20, 2021. Accessed March 12, 2025. https://tinyurl.com/4wcvk3ud
3. FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. FDA. April 16, 2021. Accessed March 12, 2025. https://tinyurl.com/3f67jdtp