Expert Point of View: John C. Krauss, MD

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Invited discussant John C. Krauss, MD, Medical Oncology Director of the Multidisciplinary Colorectal Cancer Clinic, Rogel Cancer Center of the University of Michigan, Ann Arbor, said he was impressed by the “rapidity with which the NRG-GI002 trial accrued,” which was about 10 months.1 “Equally impressive is the number of patients who made it through therapy,” he added. More than 90% completed FOLFOX (fluorouracil, leucovorin, oxaliplatin), more than 80% completed capecitabine plus radiotherapy, and the majority went on to receive potentially curative surgery. Three-quarters received pembrolizumab essentially as planned.

John C. Krauss, MD

John C. Krauss, MD

Dr. Krauss reminded listeners of what the neoadjuvant rectal (NAR) score represents; it takes into consideration nodal status, clinical tumor status, and pathologic tumor status and arithmetically creates a mean score that is associated with outcome. In the NSABP R-04 trial, the 5-year overall survival was 92% for those with an NAR up to 8 (low); 89% for those with an NAR between 8 and 16 (intermediate); and 68% for those with an NAR of more than 16 (high).2 “Unfortunately, the study found no significant difference in NAR score for the control group vs the pembrolizumab group. It also showed no difference in other endpoints,” he said.

Lessons Learned From Melanoma

“What can we do differently?” asked Dr. Krauss. Perhaps, the field could learn from the experience of checkpoint inhibitors in metastatic melanoma.

“We know with metastatic melanoma that the early combination of ipilimumab and nivolumab is superior to ipilimumab or nivolumab alone, and perhaps as many as 40% of patients are having a long-term cure with this combination,” Dr. Krauss said. “We know that ipilimumab/nivolumab works better in patients with microsatellite-instable colorectal cancer. In an update of CheckMate 142 presented at this meeting, 84% of patients had a reduction in tumor from baseline.3 Finally, we know that ipilimumab/nivolumab may cause some responses in patients with mismatch repair–proficient early-stage colorectal cancer as well.4 Clearly, this work is something to be built on. Perhaps, we need to apply ipilimumab/nivolumab rather than just PD-1 inhibition alone,” he concluded.

Combination Therapy Under Study

Interesting avenues are being explored for both mismatch repair–deficient and the more common mismatch repair–proficient colorectal cancers, he noted. For example, Dr. Rahma and his team are evaluating the combination of the angiopoietin-2 inhibitor trebananib with pembrolizumab, which in patients with early-stage disease “has produced some impressive responses,” he reported.5

As for locally advanced rectal cancer, NRG-GI002 showed that total neoadjuvant therapy can be delivered safely and may serve as a useful platform for studying these types of novel strategies, Dr. Krauss commented. 

DISCLOSURE: Dr. Krauss has received research funding from Cardiff Oncology; has received institutional research funding from AbbVie, ACCRU, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Boston Biomedical, Hutchison MediPharma, Ignyta, Isofol Medical, Novartis, NSABP Foundation, and Tempest Therapeutics.


1. Rahma OE, Yothers G, Hong TS, et al: NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy in locally advanced rectal cancer—Pembrolizumab experimental arm primary results. 2021 Gastrointestinal Cancers Symposium. Abstract 8. Presented January 16, 2021.

2. George TJ, Allegra CJ, Yothers G: Neoadjuvant rectal (NAR) score: A new surrogate endpoint in rectal cancer clinical trials. Curr Colorectal Cancer Rep 11:275-280, 2015.

3. Lenz HJ, Lonardi S, Zagonel V, et al: Subgroup analyses of patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer treated with nivolumab plus low-dose ipilimumab as first-line therapy: Two-year clinical update. 2021 Gastrointestinal Cancers Symposium. Abstract 58. Presented January 15, 2021.

4. Chalabi M, Fanchi LF, Dijkstra KK, et al: Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26:566-576, 2020.

5. Rahma OE, Cleary JM, Ng K, et al: Phase Ib study to test the safety and activity of pembrolizumab (anti-PD-1) and trebananib (angiopoietin-2 inhibitor [Ang-2]) in patients with advanced solid tumors: Updated analysis of the colorectal cancer cohort. 2021 Gastrointestinal Cancers Symposium. Abstract 155.

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Study Reports Little Benefit to Adding Pembrolizumab to Neoadjuvant Therapy for Locally Advanced Rectal Cancer

The addition of pembrolizumab to neoadjuvant chemotherapy and radiotherapy (ie, total neoadjuvant therapy) failed to improve a rectal cancer–specific surrogate for survival in patients with locally advanced disease in the phase II NRG-GI002 trial.1

As reported at the 2021 Gastrointestinal Cancers...