The FDA’s recent accelerated approval of dostarlimab for these patients serves as an important reminder of the absolute necessity to perform MSI/dMMR testing on all patients with newly diagnosed, locally advanced rectal cancer.

This unique molecular subgroup has the best opportunity to achieve successful outcomes not only with non-operative management, but also with avoidance of the potential toxicities associated with chemotherapy and radiation. While longer-term follow-up is essential to gain a clearer picture of disease-free survival and local relapse rates 3 to 5 years down the road with this strategy, the use of dostarlimab as a single agent represents an appropriate and attractive standard of care for eligible patients at the current time.

Importantly, ‘eligibility’ in this context should include not only those patients who have no contraindications to immunotherapy, but also those who have access to and will be diligent about the close follow-up surveillance necessary to ensure durable and complete clinical response. Outstanding questions still remain, including optimal duration of therapy. For example, could shorter duration achieve equivalent results, and may dual immune checkpoint inhibition or other novel immune-based combinations confer any additional advantage?

Disclosures: Ko reports advisory or independent data monitoring roles with and research funding to his institution from AltruBio Inc., Apexigen, Bristol Myers Squibb, Celgene, Erytech, Five Prime Therapeutics, Genentech/Roche, Imugene, Ipsen, LEAP Therapeutics, Merck, Natera, SynCoreBio, Syneos Health, Turning Point Therapeutics and TYME Technologies.

The FDA approval of dostarlimab for these patients changes the conversation we have with them on day 1. For decades, a curative plan has meant chemotherapy, radiation and surgery, with consequences that can last a lifetime: infertility, sexual dysfunction, bowel dysfunction and, for some, a permanent ostomy. More recently, organ-preservation approaches using chemotherapy and radiation without surgery have spared some patients an operation and improved their quality of life, but chemotherapy and radiation carry lasting effects of their own. As rectal cancer is increasingly diagnosed in younger adults, these burdens fall on people who are building careers and families. A path that may spare them all three of these treatments is extraordinary.

What stood out to me in the AZUR-1 trial data is durability. Among the 116 patients evaluable by independent central review, 47% achieved a sustained clinical complete response. Another one-third had a complete response but had not yet reached 12 months of follow-up, and at a median follow-up of more than 2 years, no patient with a complete or near-complete response progressed. I was also struck that out of the 15 patients who went to surgery because imaging suggested an incomplete response, 12 had a pathologic complete response. Our tools for assessing response are still catching up to the therapy. Improving them should be a research priority.

This is an accelerated approval, and it is not a new standard for rectal cancer as a whole. It applies only to stage II/III tumors that are mismatch repair deficient, roughly 5% to 10% of rectal cancers. For the large majority of patients, whose tumors are mismatch repair proficient, immunotherapy alone has not shown this kind of benefit. Standard multimodal therapy remains their path to cure. I worry that headlines promising no surgery and no chemo will lead patients to question treatment they need, and we owe them clarity about who this is for. Even for eligible patients, we don’t yet know the long-term risk of relapse. Confirmatory data and the full results will be important to evaluate, including how well these outcomes hold up for patients with dMMR rectal cancer treated outside of a clinical trial.

The bigger question now is whether every patient who could benefit will actually reach this treatment. Because the eligible group is so small, finding them depends on testing at diagnosis, before anyone starts chemoradiation, for every patient with rectal cancer in every care setting. Organ preservation also requires close surveillance with MRI and endoscopy for years. That is often far easier to deliver at an academic center than in a rural community clinic hours away from a specialist. If we don’t build the testing and surveillance infrastructure, this breakthrough will widen disparities instead of closing them.

The science is here. Now our systems have to get it to patients.

Disclosures: Jain reports no relevant financial disclosures.

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