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Pre-Surgery Immunotherapy, This Time With an Anti-LAG3/PD-1 Duo, Wows Again at ESMO


NEW YORK – All 19 patients with non-metastatic DNA mismatch repair-deficient (dMMR) colorectal cancer responded to neoadjuvant treatment with Bristol Myers Squibb's Opdualag (nivolumab plus relatlimab) in the Phase II NICHE-3 trial, researchers reported at the European Society for Medical Oncology Congress on Sunday.

Especially after response data from the NICHE-2 study, testing BMS's Opdivo (nivolumab) plus Yervoy (ipilimumab) in the neoadjuvant setting, wowed gastrointestinal oncologists last year, data from NICHE-3 reignited discussions among oncologists at ESMO about the best way to treat this biomarker-defined group of colorectal cancer patients from the onset.

Opdualag, the brand name under which BMS markets the combination of its PD-1 inhibitor nivolumab and the anti-LAG-3 agent relatlimab, is a newer approach in immune checkpoint inhibition. The treatment scored its first approvals from the US Food and Drug Administration and European Commission last year in metastatic melanoma. But oncologists are testing the combination out in different tumor types and settings, including pre-surgery. The NICHE-3 study, which started before oncologists had final disease-free survival data from NICHE-2, is the latest example of this.

Yara Verschoor, an oncologist at the Antoni van Leeuwenhoek Hospital at the Netherlands Cancer Institute, presented the initial data from NICHE-3 at ESMO. Out of 19 patients with locally advanced, dMMR colorectal cancer, 100 percent responded to neoadjuvant Opdualag by the time they underwent surgery and 79 percent had a pathologic complete response. Eighty-nine percent of patients had a major pathologic response, defined as having 10 percent or fewer viable tumor cells. Initially, 74 percent of patients had node-positive disease, Verschoor noted, but because none had lymph node metastases in their surgical resection specimens, there was no need for post-surgery chemotherapy.

Only one patient experienced a grade 3 immune-related adverse event, and the majority of the grade 1 to grade 2 immune-related adverse events seen among 14 patients were infusion-related reactions.

While news of a "100 percent response rate" is exciting for oncologists and patients, Verschoor cautioned that "it's too early to draw conclusions based on this limited sample size."

Having met the prespecified criteria that at least 15 out of the first 19 patients treated respond, the trial can expand and enroll another 40 patients. This second stage is currently ongoing, Verschoor said, adding that her team expects to present data from the full cohort next year.

Filling the shoes of NICHE-2

During this same meeting a year ago, when oncologists learned that 95 percent of non-metastatic, dMMR colorectal cancer patients had a major pathologic complete response to neoadjuvant Opdivo and Yervoy in the NICHE-2 trial, they responded with a standing ovation.

In that trial, the combination of the anti-PD-1 and anti-CTLA4 inhibitor yielded a 67 percent pathologic complete response rate. BMS hasn't reported the disease-free survival rate from that earlier trial yet, but given the latest NICHE-3 data, oncologists are already wondering: is it better to combine Opdivo with relatlimab or Yervoy?

While melanoma studies of Opdualag suggest improved toxicity, according to Verschoor, there are few, if any, head-to-head trials comparing the efficacy of these agents in any cancer type.

This question could be particularly tough to answer in neoadjuvant dMMR colorectal cancer. Even though the 79 percent pathologic complete response rate in NICHE-3 "seems to be numerically higher than in the NICHE-2 study's 67 percent pathologic complete response," Verschoor said, "it will be very difficult to directly compare" two studies given different treatment doses and varying intervals between immunotherapy cycles and immunotherapy and surgical resection.

In a discussion of NICHE-3, Raghav Sundar, a gastrointestinal oncologist at the National University Cancer Institute in Singapore, raised another important question for this patient population: might they benefit from neoadjuvant anti-PD-1 treatment alone?

Studies evaluating single-agent neoadjuvant immunotherapy, like the MD Anderson Cancer Center-led trial of Merck's anti-PD-1 blockbuster Keytruda (pembrolizumab) in this setting, are still ongoing, but have had encouraging early readouts.

What's more, studies in other tumor types, like non-small cell lung cancer, have suggested minimal benefit from neoadjuvant Opdualag compared to Opdivo alone.

BMS, meanwhile, is bullish about Opdualag's activity across cancer types and in earlier treatment lines, and may not be motivated to run head-to-head trials comparing Opdualag against its other immunotherapies. Even though such a comparison could help oncologists identify the best treatment approach for patients, it might diminish the revenue potential for one of BMS's products. It's likely that oncologists will have to look to academic-sponsored trials to answer their questions.

But perhaps more pressing than the question of which immunotherapy approach is best for neoadjuvant dMMR colorectal cancer is the fact that, so far, none of these drugs have been approved in this earlier stage of disease at all. The National Comprehensive Cancer Network guidelines do recommend oncologists "consider" neoadjuvant Keytruda, Opdivo, or Opdivo plus Yervoy if dMMR/microsatellite instability-high non-metastatic colorectal cancer patients have locally advanced cancers, but the treatments aren't approved in these settings.

"Use of single-agent or combination immune checkpoint inhibitors as a neoadjuvant therapeutic strategy for early-stage MSI-high/dMMR colon cancer is rapidly emerging and should commence consideration of regulatory approval in the near future," Sundar said, noting that breast cancer oncologists routinely give their high-risk, early-stage triple-negative breast cancer patients FDA-approved Keytruda plus chemo before they undergo surgery.

In the long run, Sundar remains optimistic that, someday, certain colorectal cancer patients may be able to avoid surgery altogether. Of course, far more research in larger patient populations with longer follow-up will be needed, but given the negative impact colorectal cancer surgery has on patients' quality of life, the thought of sparing the organ is certainly motivating for the field.