In a phase II study testing the PD-1 inhibitor dostarlimab in locally advanced mismatch repair–deficient rectal cancer, 100% of evaluable patients experienced a clinical complete response without needing other therapies. Standard treatment for the disease, which includes chemotherapy, radiation therapy, and surgery, can lead to bowel, urinary, and sexual dysfunction, infertility, and permanent ostomy, but the study's findings suggest that neoadjuvant checkpoint blockade could spare patients these life-altering adverse events.

For many patients with rectal cancer, standard treatment with chemotherapy, radiation therapy, and surgery can knock out the disease. However, this regimen can have life-altering consequences, such as bowel, urinary, and sexual dysfunction; infertility; and permanent ostomy. Seeking to prevent these problems, researchers have been searching for therapeutic alternatives for patients with early-stage tumors—and based on findings from a phase II trial, one has come to the fore.

Because checkpoint blockade has proven highly effective in people with metastatic mismatch repair–deficient (dMMR) rectal cancer, researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, tested the PD-1 inhibitor dostarlimab (Jemperli; GSK) in patients with stage II/III dMMR disease, which afflicts 5% to 10% of people with rectal cancer and is often resistant to chemotherapy. The team's findings were presented at the 2022 American Society of Clinical Oncology Annual Meeting in June, with most of the data published simultaneously (N Engl J Med 2022;386:2363–76).

In the trial, dostarlimab replaced chemotherapy in the standard treatment regimen, with chemoradiotherapy and surgery slated to follow 6 months later—except for patients demonstrating a clinical complete response (cCR). At the meeting, Andrea Cercek, MD, reported that after a median of 6.8 months, all 14 evaluable patients (of 18 accrued to date) experienced a cCR.

“The majority of these patients had big, bulky tumors,” said Cercek, meaning that they “would likely require all three treatment modalities: chemotherapy, radiation, and surgery.” However, “we have not had to radiate anyone, and no one has gone to surgery.” In addition, no patients experienced grade 3 or 4 adverse events, and disease recurrence was not reported during follow-up, she noted.

The study “highlights the clinical impact of biomarker-driven therapy—in other words, of moving precision medicine into early-stage disease,” said Cercek.

“The 100% clinical complete response rate is unprecedented in rectal cancer,” remarked invited discussant Kimmie Ng, MD, of Dana-Farber Cancer Institute in Boston, MA. “The possibility of eliminating pelvic radiation for our patients is huge,” she added.

Despite the small number of patients, the trial's findings are scientifically plausible, Ng said. Studies have shown that checkpoint blockade may be more effective in early-stage cancer due to greater T-cell infiltration and less systemic immunosuppression—and it's yielded high response rates in other tumor types, including lung cancer and melanoma. Plus, in the NICHE trial, patients with localized dMMR colon cancer had a higher response rate to the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb [BMS]) and the CTLA4 inhibitor ipilimumab (Yervoy; BMS) when given preoperatively than patients with dMMR metastatic colorectal cancer in other trials.

So, might dostarlimab change stan­dard of care for these patients? The answer, said Ng, is “not yet” because the study has several limitations. For example, it has no control group, and given the impressive results, “off-protocol use of neoadjuvant immunotherapy is likely to occur…and the willingness of patients to [enroll in] a randomized study will be questionable.” In addition, follow-up and duration of response are relatively short, with just half of patients monitored beyond a year, and other endpoints, such as 3-year disease-free survival and overall survival, weren't reported. Data from multiple institutions are also needed, she said, because all the patients were enrolled at MSKCC, which has “extensive expertise in nonoperative management of rectal cancer.”

Even so, Ng praised the research. Although it “may seem bold at first, especially in a potentially curative setting, [the] study is supported by strong data showing high efficacy of checkpoint blockade for treatment of MMR-deficient metastatic colorectal cancer.” –Suzanne Rose

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©2022 American Association for Cancer Research
2022
American Association for Cancer Research