NEW YORK – GlaxoSmithKline's checkpoint inhibitor Jemperli (dostarlimab) spared 80 percent of patients with earlier-stage solid tumors characterized by mismatch repair deficiency (dMMR) from needing surgery, a study has shown.
At the American Association for Cancer Research's annual meeting, researchers from Memorial Sloan Kettering Cancer Center said their research suggests that this immunotherapy may be a new tissue-agnostic frontline treatment option for the 2 percent to 3 percent of patients with dMMR solid tumors and could greatly improve their quality of life. With early-stage tumors, standard chemotherapy, radiation, and surgery can be curative, but with consequences. Patients may need to have their stomachs removed, require a colostomy bag, or lose a kidney.
"There are a lot of negative effects on the quality of life of these patients in survivorship, and what we found was that immunotherapy alone replaced the need for surgery," Andrea Cercek, attending and section head of colorectal cancer at MSK and coleader of the study, said in presenting the data at the meeting.
The analysis was funded by Swim Across America, GSK, Stand Up to Cancer, Haystack Oncology, the Simon and Eve Colin Foundation, the Dalton Foundation, and grants from the US National Institutes of Health and the National Cancer Institute, showcasing the importance of funding investigator-initiated research, which can be practice changing.
The study involved 103 patients with stage II and III resectable dMMR cancers — 49 with rectal cancer and 54 with other types of tumors — who received Jemperli in the neoadjuvant setting. All 49 rectal cancer patients experienced a complete response on the immunotherapy, and 35 out of 54 (65 percent) of those with other types of tumors, including gastroesophageal, hepatobiliary, genitourinary, and gynecologic cancers, had complete responses. The majority, 82 out of 84 patients with complete responses, or 80 percent of everyone included in the analysis, decided to skip surgical resection of their tumors.
"This is absolutely fascinating data," Ryan Corcoran, director of the Tucker Gosnell Center for Gastrointestinal Cancers at Massachusetts General Hospital, who was not involved in the research, said at the meeting. "The opportunity for patients to receive potentially curative immunotherapy without needing to go through surgery or other morbid therapies is just truly remarkable … and it's exciting to see it might offer options for all tumors."
Motivated by the fact that the 5 percent to 10 percent of rectal cancer patients with dMMR tumors fare poorly on chemotherapy, MSK researchers a few years ago began exploring whether neoadjuvant immunotherapy may be a chemo-free alternative. Not only does the latest data lend further support to such a strategy, it also presents the possibility that patients with other types of dMMR tumors may receive neoadjuvant immunotherapy in the curative setting and forgo more toxic systemic treatments.
Tissue-agnostic treatments, premised on the ability to be given to patients with any type of cancer based on a common biomarker, so far have been largely relegated to the metastatic setting, typically after patients have exhausted other options. The first such approval in 2017 was for Merck's checkpoint inhibitor Keytruda (pembrolizumab) for patients with unresectable or metastatic solid tumors with high microsatellite instability (MSI-high) and dMMR, after they've progressed on other drugs. Then, in 2020, the US Food and Drug Administration approved Keytruda again as a treatment for any refractory or metastatic solid tumor with a high tumor mutational burden.
Both tissue-agnostic approvals are based on research showing that an overabundance of genomic mutations in the tumor creates an immunogenic environment highly responsive to checkpoint inhibition. After Keytruda's success in the tumor-agnostic setting, Jemperli was similarly approved for recurrent or advanced dMMR solid tumors that have failed other treatments.
The data presented at the AACR on Sunday, however, shows not only that the tissue-agnostic approach works in metastatic patients after they've exhausted other treatment options but also that it could be a frontline option for a subset of patients with earlier-stage disease.
"From our perspective, we believe the data supports testing all early-stage cancers for mismatch repair deficiency or microsatellite instability, since it could have a dramatic impact on the treatment of their disease," said Luis Diaz, a gastrointestinal medical oncologist and head of the solid tumor division at MSK and senior author on a New England Journal of Medicine paper detailing the results from this study. "This is most important in tumors where mismatch repair is common, like colorectal, gastric, bladder, biliary, stomach, and esophageal cancers. These outcomes should not give anyone pause in testing" for dMMR.
The aim of neoadjuvant treatment is to shrink the tumor to prevent its spread and to reduce the need for invasive surgery. There were only five recurrences across both cohorts in this study. Among rectal cancer patients, 96 percent were alive without recurrence at two years of follow-up, and in those with other types of dMMR tumors, 85 percent were recurrence-free at two years. At this time, four rectal cancer patients with complete responses have not seen their cancer return for five years.
In the non-rectal tumor cohort, 19 out of the 54 patients, most commonly those with prostate and gastrointestinal cancers, had an incomplete response on neoadjuvant immunotherapy. Sixteen of these patients underwent surgery, and evaluation of the tumor showed evidence of regression in 13 patients and three had pathologic complete response in the primary tumor but residual disease in their lymph nodes. Cercek pointed out that nearly all 19 incomplete responders had a high degree of MSI at baseline, and genomic analysis of pre- and posttreatment tumor tissue showed that a few patients didn't respond as well to neoadjuvant immunotherapy because their tumors lost dMMR.
In the NEJM paper, Diaz and colleagues noted that the reason 35 percent of patients with non-rectal tumors didn't achieve complete response is unclear but hypothesized that underlying tumor heterogeneity or the microbiome could have played a role. "It is possible that a longer duration of treatment or the administration of combination immune checkpoint blockade would have led to a complete response in these patients," the authors suggested in the paper.
GSK is working on gaining Jemperli's approval as a frontline treatment for earlier-stage locally advanced, dMMR rectal cancer, and conducting the registrational AZUR-1 trial. In the meantime, the National Comprehensive Cancer Network already recommends six months of checkpoint inhibitor treatment in this setting based on early data from Diaz's group. However, the current standard of care also includes chemo plus radiation to shrink the tumor followed by surgery to remove residual cancer cells in the intestine or surrounding tissue, which can be curative but can also lead to sexual dysfunction and infertility.
Diaz said that a "quick approval" for Jemperli in early-stage dMMR rectal cancer "could immediately help thousands of patients" and "dramatically improve their quality of life." He noted that several MSK patients with rectal cancer in this study have been able to have children naturally, where previously they would not have been able to conceive.
As to GSK's plans to expand Jemperli's histology-agnostic approval to dMMR patients with early-stage solid tumors, a spokesperson said the firm is "closely assessing the data from cohort 2" but didn't reveal any specifics around regulatory strategy. In the NEJM paper, Diaz and his team noted that their work provides a foundation for larger studies to confirm the long-term benefit of Jemperli, especially in non-rectal tumors. "We believe, a tumor-agnostic approach for approval should be pursued," Diaz said.
One practical hurdle with a tissue-agnostic approach is that it's not easy to monitor early-stage cancer patients for recurrence using endoscopy if they have, for example, pancreatic cancer. In the study, in cases where endoscopy wasn't feasible, MSK researchers relied on imaging to monitor for recurrence, which they acknowledged in the paper isn't "as definitive as [findings] seen in tissue."
"That is the biggest challenge, monitoring for a complete response especially in those where the tumor cannot be visualized with endoscopy," Diaz said. "This is where an advanced diagnostic with circulating tumor DNA will be important."
In their study, researchers used imaging and endoscopic assessments as well as ctDNA to track patients' responses to Jemperli and monitor for recurrence. The median time it took for imaging or endoscopic assessments to determine a complete response was around six months, and the median time to see a negative biopsy was 1.5 months. However, among 52 patients who had a complete response and could be evaluated for ctDNA, using Quest's tumor-informed Haystack MRD test, median time to clearance of ctDNA was 1.4 months. Researchers also reported "substantial concordance" between what biopsies and ctDNA testing showed, with nearly 90 percent agreement between the two techniques.
Haystack MRD involves sequencing a patient's tumor tissue and a matched normal sample and developing a tumor-specific, personalized assay based on identification of 50 patient-specific somatic mutations. This ctDNA approach, Cercek said, "was a reliable liquid biopsy and a marker of response and recurrence" in this study.
The takeaway from this study, in Diaz's view, is that "ctDNA can effectively detect and monitor early-stage tumors and will help significantly with management of these cases" by indicating, "for example, who should go forward with surgery versus who can safely be watched." But it's still early days, he noted, for ctDNA monitoring, and these approaches need further study.
Lastly, amid the backdrop of significant government cuts to life sciences research, Massachusetts General Hospital's Corcoran highlighted that this practice-changing study was investigator initiated, and asked Cercek to comment on the importance of funding such research. It's "incredibly expensive" to generate even preliminary findings and manage patients in studies with long follow-up, Cercek said, adding that without the funding her group receives from the NIH, industry, and charitable groups, "we really can't get studies done."