September 12 2024
NRG-GI004/S1610: Colorectal Cancer Metastatic dMMR/MSI-H Immuno-therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/Bevacizumab/Atezolizumab Combination Versus Single Agent Atezolizumab in the First-line Treatment of Patients With Deficient DNA Mismatch Repair (dMMR)/Microsatellite Instability-high (MSI-H) Metastatic Colorectal Cancer
The COMMIT Study (NRG-GI004/SWOG S1610) is an ongoing research project within the NRG Oncology gastrointestinal portfolio of clinic trials that investigates the addition of atezolizumab immunotherapy to the mFOLFOX6/bevacizumab chemotherapy regimen for patients with microsatellite instability-high (MSI-H), also known as DNA mismatch repair deficient (dMMR) metastatic colon cancer. This group of patients represent about 5% of the metastatic colorectal cancer population. While immunotherapy has been shown to be beneficial in this subgroup, almost half of the patients treated with immunotherapy alone will have cancer progression in the first year of treatment. The COMMIT Study aims to improve these results by testing the combination of immunotherapy plus anti-angiogenesis (diminishing the vascular supply to the cancer cells) plus chemotherapy. The trial plans to enroll 120 patients and has recently surpassed the milestone of enrolling its 100th patient. NRG Oncology interviewed Dr. Caio Max Sao Pedro Rocha Lima, one of the Principal Investigators of the COMMIT Study at Wake Forest University Baptist Health, to provide insights, on this important clinical trial to the accruing sites.
Can you provide some background about the study and why it was created?
Answer: The KEYNOTE-177 trial showed that patients with MSI-H/dMMR metastatic colorectal cancer have better progression free survival with checkpoint inhibitors compared to chemotherapy alone (n engl j med 383;23, 2020). However, more patients in the pembrolizumab group than in the first-line chemotherapy group had progression of disease as the best response (29.4% vs. 12.3%). Also, despite the improved progression free survival, at one year nearly half (46%) of the patients had progressed on single agent pembrolizumab. Thus, it appears that an important subgroup within the MSI-H/dMMR population does not benefit from immune checkpoint inhibitors.
The COMMIT trial builds on these findings and tests the hypothesis of whether combining mFOLFOX 6 plus bevacizumab with atezolizumab improves progression-free survival and overall survival compared to atezolizumab alone.1 Chemotherapy can induce immunogenic cell death and modulate the tumor microenvironment, potentially increasing the efficacy of immunotherapy.2
Chemotherapy-Induced Immunogenic Cell Death (ICD) is an important observation and part of the background for combining chemotherapy to immunotherapy, as already shown to be sound in NSCLS, SCLC, gastroesophageal, breast, among other solid tumors. ICD refers to a process where certain chemotherapeutic agents, (like oxaliplatin and 5FU - components of FOLFOX – both induce cell death and simultaneously stimulate the immune system to recognize and attack cancer cells.3 This observation may be even more relevant in cancers with high microsatellite instability or deficient mismatch repair, as these tumors are more likely to respond to immunotherapy to start with. A very interesting paper titled, Paradigms on Immunotherapy Combinations with Chemotherapy,4 expands on the potential interactions between chemotherapy and immunotherapy, and I believe it is worth your time to check it out.
Combining bevacizumab with checkpoint inhibitors may also enhance the anti-tumor response. Vascular endothelial growth factor (VEGF) can directly trigger T regulatory cells (T-reg) proliferation, increase myeloid-derived suppressor cells infiltration, and it may promote cytotoxic T-cell exhaustion by up-regulating suppressive immune checkpoint molecules, such as PD-L1. 5,6 Bevacizumab, by inhibiting VEGF-VEGFR pathway, stimulates the maturation of dendritic cells and reduces the expansion of T-reg lymphocytes and myeloid-derived suppressor cells thus contributing to immune effector cells activation. Moreover, the vasculature normalization allows an increase in cytotoxic T-cell tumor infiltration.
Can you explain the design of the study and the treatments being tested?
Answer: The COMMIT Study is designed to evaluate the efficacy of combining atezolizumab with the mFOLFOX6/Bevacizumab regimen compared to atezolizumab as a single agent in patients with dMMR /MSI-H metastatic colorectal cancer. This design will help us answer important and clinically meaningful questions in this population, including whether the addition mFOLFOX6/bevacizumab to atezolizumab improves survival, progression free survival, and responses compared to atezolizumab alone. The study is also evaluating potential toxicities from the addition of FOLFOX + bevacizumab to atezolizumab over single agent atezolizumab.
How does this trial compare to the ATOMIC (A021502) Trial?
Answer: Both trials focus on patients with dMMR/MSI-H colorectal cancer. However ATOMIC is treating patients with stage III disease while COMMIT is for those with stage IV. Both trials investigate the addition of atezolizumab to standard treatment regimens: FOLFOX in the adjuvant setting for ATOMIC and FOLFOX + bevacizumab in the metastatic setting for COMMIT. Both are phase III trials aiming to improve clinically important outcomes that may lead to change in the current standard of care for the dMMR/MSI-H patients with stage III (ATOMIC) and stage IV (COMMIT).
Correlative studies from both trials will help us better understand mechanisms of resistance as well as cancer susceptibility to treatments studied. Since COMMIT and ATOMIC (A021502) both have similar treatment arms (except for no bevacizumab in the study arm of ATOMIC), they will join forces in the translational work. This joint effort will allow us to correlate laboratory findings to clinical practice, eventually leading to personalized strategies as we uncover resistance mechanisms and identify predictive biomarkers. It is anticipated that these two studies will lead to significant contributions in the overall management of patients with dMMR /MSI-H colorectal cancer.
What have amendments changed regarding the study and what is the status of the trial currently?
Answer: Community oncologists deal with practical challenges (e.g., patient comorbidities, resource limitations). The recent amendment to the COMMIT protocol better mirrors patients seen by community oncologists and bridges the gap between clinical trials and real-world practice. It will benefit both accrual and generalizability.
Specifically, the changes made to the eligibility criteria include the allowance for one cycle of FOLFOX + bevacizumab prior to study enrollment to allow for MMR or MSI testing to result, more liberal hepatic and renal function allowances, among others, that will increase the patient population pool for the study without compromising safety.
This broader representation ensures that trial results are applicable to a wider range of patients. Community oncologists are more likely to participate when the trial design aligns with their daily practice. Plus, results from a more diverse patient pool enhance the study’s external validity and the findings become more relevant to the broader oncology community. I believe we all appreciate the amendment.
We just achieved the 100th patient enrollment, a milestone for the study. We need 20 more patients enrolled. Unfortunately, patient accrual has been slower than desired. We are looking forward to all trial sites’ engagement to pull this through.
Are there any ‘frequently asked questions’ you receive about this study and, if so, what are the common answers for those?
“Giving pembrolizumab is efficacious in this population, so why add chemo?”
Answer: In Keynote-177, 46% of patients progressed in 1 year and more patients in the pembrolizumab group than in the first-line chemotherapy group had progression of disease as the best response (29.4% vs. 12.3%). Clearly not all patients benefit, and this study is testing how to improve outcomes for more patients.
“I treat my patients with dMMR metastatic colon cancer with the combination of ipilimumab and nivolumab”
Answer: Indeed, CheckMate 8HW trial for previously untreated MSI/dMMR metastatic colorectal cancer demonstrated significant benefit for nivolumab plus ipilimumab over chemotherapy. However, results comparing nivolumab plus ipilimumab to single agent nivolumab were not yet available. Thus, single agent checkpoint inhibitor is still a standard of care option as in the COMMIT trial whereas the addition of FOLFOX + bevacizumab to atezolizumab remains a valid study strategy to improve efficacy in this patient population.
RESOURCES
Available COMMIT Study Patient-Facing Materials:
Prior COMMIT Study Articles:
References
- Li Y, Du Y, Xue C, Wu P, Du N, Zhu G, Xu H, Zhu Z. Efficacy and safety of anti-PD-1/PD-L1 therapy in the treatment of advanced colorectal cancer: a meta-analysis. BMC Gastroenterol. 2022 Oct 10;22(1):431. doi: 10.1186/s12876-022-02511-7. PMID: 36217119; PMCID: PMC9549670.
- Grothey A. Pembrolizumab in MSI-H-dMMR Advanced Colorectal Cancer - A New Standard of Care. N Engl J Med. 2020 Dec 3;383(23):2283-2285. doi: 10.1056/NEJMe2031294. PMID: 33264550.
- Jiang M, Zeng J, Zhao L, Zhang M, Ma J, Guan X, Zhang W. Chemotherapeutic drug-induced immunogenic cell death for nanomedicine-based cancer chemo-immunotherapy. Nanoscale. 2021 Oct 28;13(41):17218-17235. doi: 10.1039/d1nr05512g. PMID: 34643196.
- Salas-Benito D, Pérez-Gracia JL, Ponz-Sarvisé M, Rodriguez-Ruiz ME, Martínez-Forero I, Castañón E, López-Picazo JM, Sanmamed MF, Melero I. Paradigms on Immunotherapy Combinations with Chemotherapy. Cancer Discov. 2021 Jun;11(6):1353-1367. doi: 10.1158/2159-8290.CD-20-1312. Epub 2021 Mar 12. PMID: 33712487.
- Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996 Oct;2(10):1096-103. doi: 10.1038/nm1096-1096. Erratum in: Nat Med 1996 Nov;2(11):1267. PMID: 8837607.
- Osada T, Chong G, Tansik R, Hong T, Spector N, Kumar R, Hurwitz HI, Dev I, Nixon AB, Lyerly HK, Clay T, Morse MA. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother. 2008 Aug;57(8):1115-24. doi: 10.1007/s00262-007-0441-x. Epub 2008 Jan 10. PMID: 18193223; PMCID: PMC4110970.
Other referenced studies
André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr. KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699. PMID: 33264544.