September’s Paper of the Month looks into the findings from a phase 2 trial (NICHE-3) investigating neoadjuvant nivolumab and relatlimab in locally advanced, mismatch repair deficient colon cancer.
This trial focused on the pathological response rate of patients with mismatch repair deficient colon cancer: does neoadjuvant nivolumab/relatlimab result in pathological response?
Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial
Peter G M de Gooyer, Yara L Verschoor, Lauren D W van den Dungen, Sara Balduzzi, Hendrik A Marsman, Marnix H Geukes Foppen, Cecile Grootscholten, Simone Dokter, Anne G den Hartog, Wieke H M Verbeek, Karlijn Woensdregt, Joris J van den Broek, Steven J Oosterling, Ton N Schumacher, Koert F D Kuhlmann, Regina G H Beets-Tan, John B A G Haanen, Monique E van Leerdam, Jose G van den Berg, Myriam Chalabi
Nat Med. 2024, September 2024, online ahead of print
What is known about the subject?
Approximately 15% of all non-metastatic colon cancers are mismatch-repair deficient (dMMR) , which is defined by a defective DNA mismatch repair system, with resultant highly immunogenic and hypermutated tumours. The FOxTROT study showed a pathologic response rate of 7% in dMMR tumours after neoadjuvant chemotherapy. [1]
In contrast, dMMR tumors have been shown to respond exceptionally well to neoadjuvant anti PD-1 plus anti-CTLA-4 treatment, resulting in high pathological response rates. The combination of nivolumab/relatlimab has shown high efficacy in early stage and advanced melanoma, with low toxicity for the patients. [2-4]
What the study adds?
In this study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg), followed by surgery within 8 weeks of enrollment, between December 2022 and April 2024. 3/59 patients only received the first cycle of nivolumab/relatlimab. The study's primary outcome was pathologic response, defined as < 50% residual viable tumour.
The median age was 65 years (21-85) and 19% had Lynch syndrome. Although most patients had stage III disease, and 68% of patients had cT4 tumors on preoperative CT scans, the pathological response rate was 57/59 patients (97%; 95% CI 88-100%). In forty patients (68%) a complete pathological response rate was found (95% CI:54-79%). After a median follow-up of 8 months (2-19) , one patient had disease recurrence. The most common immune-related adverse events were reactions related to infusions, thyroid dysfunction and fatigue. Grade 3-4 adverse events occurred in 10% of patients.
Implications for colorectal practice
Neoadjuvant nivolumab/relatlimab results in high rates of pathological responses. Routine MMR testing may have considerable benefits for patients, especially in cT4/cN+ disease if this treatment is (to become) available in the patient’s health care system. The relatively low grade 3-4 toxicity, combined with the clinical ineffectiveness of chemotherapy, support the neoadjuvant use of nivolumab/relatlimab over systemic chemotherapy in the clinical context of dMMR colon cancer.
References
- Dion Morton, Matthew Seymour, Laura Magill, Kelly Handley, James Glasbey, Bengt Glimelius , Andy Palmer, Jenny Seligmann, Søren Laurberg , Keigo Murakami, Nick West, Philip Quirke, Richard Gray; FOxTROT Collaborative Group. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J Clin Oncol 2023;41, 1541-1552.
- Rodabe N Amaria, Michael Postow, Elizabeth M Burton, Michael T Tetzlaff, Merrick I Ross, Carlos Torres-Cabala, Isabella C Glitza, Fei Duan, Denái R Milton, Klaus Busam, Lauren Simpson, Jennifer L McQuade, Michael K Wong, Jeffrey E Gershenwald, Jeffrey E Lee, Ryan P Goepfert, Emily Z Keung, Sarah B Fisher, Allison Betof-Warner, Alexander N Shoushtari, Margaret Callahan, Daniel Coit, Edmund K Bartlett, Danielle Bello, Parisa Momtaz, Courtney Nicholas, Aidi Gu, Xuejun Zhang, Brinda Rao Korivi, Madhavi Patnana, Sapna P Patel, Adi Diab, Anthony Lucci, Victor G Prieto, Michael A Davies, James P Allison, Padmanee Sharma, Jennifer A Wargo, Charlotte Ariyan , Hussein A Tawbi. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature 2022:611, 155-160.
- Georgina V Long, F Stephen Hodi, Evan J Lipson, Dirk Schadendorf, Paolo A Ascierto, Luis Matamala, Pamela Salman, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen J Gogas, Christopher D Lao, Juliana Janoski De Menezes, Stéphane Dalle, Ana Arance, Jean-Jacques Grob, Sarah Keidel, Anadil Shaikh, Anne Marie Sobiesk, Sonia Dolfi, Hussein A Tawbi. Overall survival and response with nivolumab and relatlimab in advanced melanoma. NEJM Evid. 2023:2, EVIDoa2200239.
- Jedd D Wolchok, Vanna Chiarion-Sileni, Rene Gonzalez, Piotr Rutkowski, Jean-Jacques Grob, C Lance Cowey, Christopher D Lao, John Wagstaff, Dirk Schadendorf, Pier F Ferrucci, Michael Smylie, Reinhard Dummer , Andrew Hill, David Hogg, John Haanen, Matteo S Carlino, Oliver Bechter, Michele Maio, Ivan Marquez-Rodas, Massimo Guidoboni, Grant McArthur, Celeste Lebbé, Paolo A Ascierto, Georgina V Long, Jonathan Cebon, Jeffrey Sosman, Michael A Postow, Margaret K Callahan, Dana Walker, Linda Rollin, Rafia Bhore, F Stephen Hodi, James Larkin. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 2017:377, 1345-1356.
