NEW YORK – Findings from a small study suggest that patients with early-stage mismatch repair-deficient rectal adenocarcinoma can achieve a complete clinical response to anti-PD-1 immunotherapy alone and potentially forego more toxic chemotherapy and radiation or invasive surgeries.
Therapy for early-stage rectal cancer "is pretty gruesome," explained Luis Diaz, a medical oncologist and head of the solid tumor oncology division at Memorial Sloan Kettering. "The question we had was could we replace chemotherapy, chemotherapy and radiation, surgery, or all three in a scenario where we knew that immunotherapy works quite well, and that's in mismatch repair deficient [tumors]?"
In a late-breaking abstract presented at the American Society of Clinical Oncology's annual meeting in Chicago on Sunday, MSK medical oncologist Andrea Cercek shared findings from that effort: a prospective Phase II clinical trial of Tesaro and GlaxoSmithKline's anti-PD-1 immune checkpoint blocking drug Jemperli (dostarlimab) in 18 individuals with mismatch repair-deficient stage II or III rectal adenocarcinoma.
"There's been growing interest in the field of rectal cancer for non-operative management of patients who achieved a clinical complete response to chemotherapy and radiation," Cercek explained.
However, since the 5 percent to 10 percent of rectal cancer patients with mismatch repair deficiencies tend to fare poorly on chemotherapy, the field has also been motivated to explore immunotherapy as an alternative in this subgroup.
Most of the immunotherapy research to date in this subgroup has focused on metastatic patients, however. Two years ago, at this same meeting, researchers co-led by Diaz presented data from the KEYNOTE-177 trial, in which metastatic colorectal cancer patients with high microsatellite instability (a biomarker that reflects perturbed mismatch repair function) on Merck's checkpoint inhibitor Keytruda (pembrolizumab) lived on average twice as long without their disease progressing compared to those on investigators' choice of chemotherapy or a chemotherapy-based regimen with Genentech's Avastin (bevacizumab) or Eli Lilly's Erbitux (cetuximab). The US Food and Drug Administration approved this indication in 2020.
The latest research provides insights into immunotherapy efficacy earlier in cancer patients' disease trajectory. "Our hypothesis was that in mismatch repair-deficient, locally advanced rectal cancer, we could utilize PD-1 blockade to be able to either replace chemotherapy alone, replace chemotherapy and radiation, or replace chemo, radiation and surgery," Cercek reported at the ASCO meeting.
The anti-PD-1 drug was given intravenously every three weeks for six months. The team initially planned to offer chemotherapy, radiation, and/or surgery for rectal cancer patients who did not respond to the immune checkpoint blockade. But patients who fully responded to the treatment based on endoscopic exams, magnetic resonance imaging, and PET scans done at six months had the option of continuing with observation and skipping chemotherapy, radiation, and surgery.
All 14 patients treated so far have had a clinical complete response and none has required further treatment, Cercek said. No severe treatment-related toxicities, namely grade 3 or higher severe adverse events, were reported.
Details on the first 12 cases, who have been followed for at least six months, were published in the New England Journal of Medicine on Sunday. The follow-up time for these and other patients treated so far ranges from less than one month to almost two years. The investigators are continuing to track how well treatment response holds in patients, and they expect to share further details on the durability of the immunotherapy effects next spring.
The results are especially promising since conventional treatments for non-metastatic rectal cancer can have significant side effects and are inconsistently effective in rectal cancers. Some patients experience sexual dysfunction, bowel/bladder dysfunction, and other side effects stemming from pelvic radiation, for example, while surgeries can leave patients reliant on an ostomy.
"While a cure is frequently achieved with this combination," Cercek said, "radiation and surgery, in particular, have life-altering consequences."
Hanna Sanoff, a cancer researcher from the University of North Carolina Lineberger Comprehensive Cancer Center, who was not involved in the study, called the new rectal cancer results "amazing."
"It's a small subset of rectal cancer patients that this would apply to, but we, for years, have been able to cure people — not everybody, but many — but with a lot of toxicity," she said, noting that rectal cancer treatments are often more debilitating than treatments for other forms of colorectal cancer. "If we can have a treatment where they can get six months of immunotherapy and nothing else … that would be such a big improvement."
Sanoff also lauded the team for the comprehensive approaches used to follow patients and ensure their ongoing safety after treatment.
In an editorial accompanying the new NEJM study, she pointed to the need for larger studies of mismatch repair-deficient rectal cancer cases, along with additional analyses of potential toxicities and adverse events associated with immunotherapy.
"It's a small trial, so we need to see what it looks like in a bigger setting, a bigger population, but this will definitely be part of the standard of care in some way in the near future," Sanoff said.
Commenting on the findings at the ASCO conference, the Dana-Farber Cancer Institute's Kimmie Ng noted that the MSK team is "attempting to replace every component of standard of care in favor of a biomarker-driven approach of anti-PD-1 therapy alone for patients with [mismatch repair]-deficient rectal cancer."
While a randomized control trial would typically be needed to change clinical care, she argued that it will likely be difficult to use that approach to compare the anti-PD-1 treatment to standard-of-care therapies in the mismatch repair-deficient rectal cancer setting.
It takes a long time to enroll patients with this disease type, Ng said. But perhaps more importantly, she suggested that the latest results make it unlikely patients will want to be randomized to a standard-of-care arm. Instead, Ng speculated that many clinicians will look at the new data and opt to use immunotherapy off-label in their patients.
Given such considerations, she called for longer follow-up of patients in the current study, along with larger studies involving patients enrolled at centers with less experience treating colorectal cancer.
"We need to confirm that the high clinical complete response rates and the complex non-operative management of rectal cancer can be replicated in all cancer care settings," she said, adding that more extensive analyses of immunotherapy response biomarkers will be needed in the future.
Investigators are still puzzling over why the anti-PD-1 response in early-stage rectal cancers look so much better than the data reported on such drugs when given to mismatch repair-deficient colorectal cancer patients with more advanced disease.
While such questions remain, to Diaz, the results from this study raise the possibility that early-stage cancer patients with mismatch repair-deficient tumors may benefit significantly from front-line checkpoint-blocking immunotherapy, potentially allowing them to avoid further treatment.
"We're trying to look for indications that will impact patient care immediately," Diaz said, adding that this research underscores the importance of biomarker analysis in patients with early-stage disease. In the current study, investigators relied on immunohistochemistry to assess mismatch repair status, based on loss of MLH1, MSH1, MSH6, or PMS2 expression in the tumor, coupled with sequencing-based microsatellite instability testing to ensure that tumors had rampant mutations, as expected.
"I hope this gets people into thinking, 'Let's take our best drugs in the advanced setting and start bringing them in as early as possible,'" he suggested. "In the advanced [rectal cancer] setting, we get a response rate of 10 percent, whereas in the early setting we get a response rate of 100 percent."
In particular, the findings have prompted MSK investigators to consider testing out first-line anti-PD-1 therapy in mismatch repair-deficient tumors in other solid cancer types — an approach they expect to test in a larger, tissue-agnostic trial in the future.
The FDA has approved immunotherapies in a histology-agnostic fashion, but patients can only access checkpoint inhibitors in this way right now after they're out of other options. In 2017, the agency approved Keytruda as a tissue-agnostic option for patients with any type of refractory solid tumor if they had MSI-high or mismatch repair-deficient tumors. Last year, the agency also approved Jemperli for patients with mismatch repair-deficient solid cancers who have failed other therapies and have no satisfactory alternatives.
Immunotherapies like Keytruda and Jemperli are thought to work especially well in these biomarker-defined tumors because mismatch repair deficiencies interfere with effective DNA mending mechanisms, and these tumor genomes are studded with somatic mutations that lead to altered proteins prone to be picked up by the immune system once the immune checkpoints involving PD-1 or related players are knocked back.
Now, though, investigators are seeing the potential for using mismatch repair deficiency status as a biomarker to guide treatment in the front line, Diaz said. "It introduces the concept of what we're calling 'immuno-ablative therapy,'" a strategy centered on using early immunotherapy to destroy mismatch repair-deficient cancers, which make up an estimated 3 percent to 4 percent of solid tumors.
If that hypothesis pans out, Cercek explained, it could open the door to more effective care for all mismatch repair-deficient cancers, particularly in places lacking easy access to chemotherapy, radiation, or surgery.
"We're starting to expand beyond colorectal cancer in the same way that we did with metastatic disease, in a tumor-agnostic way," Diaz said. "As you go down the different tumor types, there are small subsets that have [mismatch repair deficiency], but in total … it represents a big piece of the pie."