NRG Oncology Study Determines Total Neoadjuvant Therapy with Pembrolizumab and Chemoradiotherapy is Safe, but May Not be Beneficial for Patients with Locally-Advanced Rectal Cancer

January 16 2021

PITTSBURGH, PA – The NRG Oncology phase II clinical trial NRG-GI002 was designed to assess a total neoadjuvant treatment that included the addition of the immunotherapy drug pembrolizumab to capecitabine, and radiotherapy in patients with locally-advanced rectal cancer (LARC) following (m)FOLFOX6 (oxaliplatin, leucovorin calcium, fluorouracil) therapy. The goal was to determine whether the added immunotherapy causes any unexpected adverse events and if it can improve the efficacy of the total neoadjuvant treatment. Researchers on this trial determined that this combination was successfully used to treat this patient population safely and without unexpected short-term toxicities. However, the addition did not appear to offer any statistically significant improvement in downstaging of the cancer at the time of surgery. The results were presented at the virtual edition of the American Society of Clinical Oncology’s (ASCO) Annual Gastrointestinal Cancers Symposium in January 2021.

“The primary focus of NRG-GI002 was to demonstrate an improvement in the Neoadjuvant Rectal Cancer (NAR) score, which is used to measure the success of treatment in downstaging rectal tumors and is a surrogate for overall survival. Our results demonstrated a mean NAR score of 14.08 for patients on the control arm versus 11.53 for patients on the experimental arm (smaller is better), the difference of 2.55 was not statistically significant” stated Osama E. Rahma, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, and the Lead Author of this arm analysis and associated NRG-GI002 manuscript. “Although the NRG-G002 did not meet its primary endpoint, it further validated the power of using the Neoadjuvant Platform to investigate novel agents in this disease setting. The availability of resected surgical tissue from this study will allow us to study the effect of the chemoradio-immune therapy combination on the tumor microenvironment to inform future studies that aim to overcome resistance to immunotherapy in colorectal cancer”.

NRG-GI002 is a master platform study that accrued 185 patients to this portion of the study and randomly assigned them to receive either chemoradiotherapy on the control arm or the addition of pembrolizumab on the experimental arm. All patients received (m)FOLFOX6 for 4 months, followed by chemoradiotherapy with capecitabine with or without pembrolizumab for 3 weeks for six doses. All treatment was followed by surgery at 8-12 weeks after the final dose of radiotherapy. The primary endpoint was to evaluate improvements in the NAR score. NRG-GI002 also investigated secondary endpoints such as overall survival, disease-free survival, toxicity, pathological complete response, complete clinical response, therapy completion, negative surgical margins, sphincter function, and assessment of molecular or radiographic predictors of response and distant failure. The overall and disease-free survival will be presented in the future when the data is mature and may still demonstrate that this intervention benefits patients in the long-term, just not evident at the time of pathologic downstaging. The side effects were similar between the experimental and control arm. The addition of pembrolizumab did not result in increased immune related adverse events on the experimental arm.


This project was supported by grants U10CA180868, UG1-189867, and U24-196067 from the National Cancer Institute (NCI).

Citation

Rahma OE, Yothers G, Hong TS, Russell MM, You YN, Parker W, Jacobs SA, Colangelo LH, Lucas PC, Gollub MJ, Hall WA, Kachnic LA, Vijayvergia N, Wolmark N, George TJ. (2021, January). NRG-GI002: A Phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally-advanced rectal cancer (LARC): Pembrolizumab experimental arm (EA) primary results. Paper presented at the annual Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology. Virtual meeting platform.

About NRG Oncology

NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network.

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