For most people with locally advanced rectal cancer, treatment means radiation, chemotherapy and a major operation that can leave a permanent stoma or lasting bowel, bladder and sexual dysfunction. On October 19, the US Food and Drug Administration approved a drug that, for one genetically defined slice of patients, can replace all of it. Whether it works for 68 percent or 47 percent of them depends on who is counting.

What the FDA approved

The agency granted accelerated approval to dostarlimab (Jemperli, GSK) for adults with stage II or III locally advanced rectal cancer that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), as determined by an FDA-authorized test, according to the agency's announcement. GSK called it the first and only immunotherapy approved in the US for that group. Dostarlimab blocks PD-1, a signal cancer cells use to evade immune attack.

The decision came ahead of its scheduled action date, biopharma trade press reported. Accelerated approval means the drug was cleared on an early signal of benefit, usually a measure other than survival, with confirmatory evidence still to come.

How the trial worked

The evidence comes from AZUR-1, a multicenter, single-arm, open-label trial in 154 previously untreated patients, the FDA said. Patients received dostarlimab every three weeks for six months, Benzinga reported. Those who reached a clinical complete response, meaning no detectable cancer on scans, endoscopy and examination, entered a nonoperative management period and were monitored for recurrence every four months for two years and every six months after that.

The main goal was a sustained clinical complete response at 12 months, or cCR12, judged by an independent central review.

The two numbers

Investigator assessment gave a cCR12 rate of 68 percent (98 of 144 evaluable patients, 95 percent confidence interval 60 to 76), per the FDA and GSK. That is the figure in most headlines. The independent central review put it at 47 percent, according to a trade report on the trial, with the data still maturing, Benzinga noted.

The gap is large, and it is worth reading carefully. Public reporting does not explain it in detail. What is stated is that the independent review is the trial's primary analysis, that the data are still maturing, and that another 38 participants have already achieved a clinical complete response but are still moving through the 12-month window, according to GSK. Reviewers can also judge the same scans and endoscopies differently when a response is defined by the absence of visible disease, which may play a part.

Other measures are more favorable. In an overall view, about 71 percent of treated patients received dostarlimab alone with no further treatment and no progression, per a nursing news summary of the FDA label. Among 15 patients who had surgery after dostarlimab because imaging suggested an incomplete response, 12 turned out to have no cancer on pathology. The objective response rate was 82 percent.

What it means for patients, and what it does not

For eligible patients, the appeal is plain. Avoiding chemoradiation and surgery can protect fertility, bowel control and sexual function. The first signals came from a small study at Memorial Sloan Kettering, where all 12 initial patients had complete responses, as reported in the New England Journal of Medicine in 2022.

But AZUR-1 is a single-arm trial. It does not show that skipping surgery and chemoradiation is as good for survival as standard care, because no one was randomized to standard care. The FDA's accelerated pathway implies that confirmation is still needed. Follow-up is also short for a disease where recurrence can appear years later. Among 27 patients followed for at least three years, one had a recurrence, and it was local, Pharmacy Times reported. That is encouraging and still a very small group.

Safety adds a caution. Jemperli was permanently discontinued because of adverse reactions in 3 percent of patients, according to the product announcement. Immunotherapy side effects can affect any organ, and some are permanent.

A small population

This drug will reach a minority. The FDA says published estimates suggest about 3 percent of locally advanced rectal cancers are dMMR or MSI-H, while GSK cites 5 to 10 percent across rectal cancers, Pharmacy Times noted. That gap in estimates matters for planning, and it is a reminder that the single most important step is testing. A patient who is never tested for mismatch repair status never gets to this choice.

The same biomarker is reshaping other cancers. We recently covered the FDA's approval of Tecentriq for stage III dMMR colon cancer, where the benefit is in preventing relapse after surgery. The rectal approval aims at something different: replacing surgery altogether. The evidence standards differ too. Compare it with the survival-based case behind the EMA's backing of daraxonrasib for pancreatic cancer, where the headline number is overall survival from a randomized trial. Here the headline number is a response that must hold up over time.

What to watch

GSK plans to present full interim AZUR-1 data at the European Society for Medical Oncology Congress this month, per biopharma reporting. Those data should show how the investigator and independent-review numbers move as follow-up lengthens.

If the independent figure climbs toward the investigator figure, the approval will look conservative. If it stays well below, doctors will have to explain to patients that the chance of avoiding surgery is closer to one in two than to two in three. Either way, patients should be told which number applies, and who measured it.

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