When rectal cancer progresses locally, oncologists fight back with a series of treatments. Chemotherapy and radiation therapy are followed by surgery, a treatment option that can be curative. But this multi-pronged attack has left patients with other complications, so clinicians have been looking for a way to treat rectal cancer that does require surgery. A clinical trial testing GlaxoSmithKline’s immunotherapy has early clinical trial results suggesting the drug may be able to offer patients an alternative.
The clinical trial enrolled patients with rectal cancer characterized by deficiency in mismatch repair (dMMR), a mutation in a gene that is involved in repairing errors when DNA is replicated in cells. Mismatch repair-deficient cancers do not respond well to chemotherapy, but tumors with this mutation that have spread beyond the original cancer site do respond to a type of immunotherapy called checkpoint inhibitors.
Scientists at Memorial Sloan Kettering Cancer Center wanted to see if the use of the approved GSK checkpoint blocker drug dostarlimab (marketed as Jemperli) could replace some or all of the chemotherapy, radiation and surgery regimens that are standard of care for rectal cancer. The clinical trial started by replacing Jemperli’s chemotherapy. So far, this is the only treatment patients need.
To date, the Phase 2 study has enrolled 18 patients. Results from the 12 patients with at least 6 months of follow-up showed that they all achieved clinical complete remission, meaning no detectable signs of cancer.These results are post Published June 5 in the New England Journal of Medicine. Andrea Cercek, co-director of the MSK Sloan Young-Onset Colorectal and Gastrointestinal Cancer Center and one of the study’s two principal investigators, presented data from two other patients at the June 5 annual meeting and added in total The results of two patients were added. American Society of Clinical Oncology (ASCO).
“We’re obviously very excited, we’ve treated 14 patients so far,” Cercek said. “All 14, 100 percent had a complete clinical response to dostarlimab alone. We didn’t have to irradiate anyone, and no one had surgery.”
Jemperli is an antibody designed to block PD-1, a so-called “checkpoint” protein on T cells that prevents them from recognizing tumors. Blocking PD-1 enables T cells to target and destroy cancer cells. The checkpoint inhibitor class includes blockbusters such as Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo. Jemperli joined their market last year, winning First FDA Approval for Advanced Endometrial Cancer Characterized by dMMR. A few months after making the regulatory decision, the agency Expand the drug’s approval to cover all solid tumors with the dMMR gene signature. GlaxoSmithKline through its acquisition of Jemperli Acquired Tesaro in 2018The drug remains a relatively new contributor to GSK’s revenue, with sales of £5 million ($6.2 million) last year, according to the company’s annual report.
Kimmie Ng, associate director of the Division of Gastrointestinal Oncology at the Dana Farber Cancer Institute, provided additional perspective on the MSK research following Cercek’s presentation. Due to the small sample size and short median follow-up time, the data are still at an exploratory stage, Ng said. Longer follow-up of these patients is required. Ng pointed to data from another rectal cancer study, noting that the vast majority of tumor regeneration can occur within two years of completing chemotherapy and radiation therapy, known as neoadjuvant therapy, designed to prevent cancer from returning. Other limitations include the lack of a control arm and results from a single agency. The only data so far are complete responses, and there are no other data on survival or other outcomes.
While a randomized and well-controlled study could answer some of these questions, Ng doubts it would work. This mutation is extremely rare in rectal cancer, making it difficult to recruit enough patients for such studies. Another challenge, given the current results, is the willingness of study participants to be randomly assigned to a control group. Still, for the therapy to change the standard of care, Ng said larger sample sizes and longer follow-up periods are needed to provide data on more measures, such as three-year disease-free survival and organ preservation. Expanding clinical trials to include other institutions will help show that results can be replicated in all cancer care settings. Even so, Ng said the results so far are clinically meaningful.
“The 100 percent clinical complete response rate is unprecedented in rectal cancer, and the potential to reduce morbidity by eliminating pelvic radiation and surgery for our patients is enormous,” she said.
Complications after rectal cancer surgery include bowel and bladder dysfunction, sexual dysfunction, and infertility. Also, after surgery, many patients require a permanent stoma, an opening in the abdomen to allow waste to leave the body. Side effects listed on the Jemperli drug label include fatigue, nausea, diarrhea, anemia, and constipation. To date, Jemperli has not reported any serious adverse reactions in rectal cancer studies. To make drugs an alternative to surgery, it is critical to identify predictive biomarkers to guide clinicians in making treatment decisions, Ng said. An estimated 5 to 10 percent of rectal cancers have dMMR mutations, Cercek said.
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