Single-agent dostarlimab-gxly elicited a clinical complete response rate of 100% with no evidence of residual tumor in patients with stage II/III mismatch repair–deficient locally advanced rectal cancer.
Results from a phase 2 clinical trial (NCT04165772), showed that single-agent dostarlimab-gxly (Jemperli) elicited a clinical complete response (cCR) rate of 100% with no evidence of residual tumor among 14 patients with stage II/III mismatch repair–deficient (dMMR) locally advanced rectal cancer.1,2
“No patients have required chemotherapy, radiation, or surgery [and] there has been no disease recurrence observed during the follow-up period,” Andrea Cercek, MD, said in a presentation of the data. “Longer follow-up is certainly required to establish the durability of this treatment. In conclusion we believe these data provide the framework for immunoablative therapies. It highlights the clinical impact of biomarker-driven therapy, in other words of moving precision medicine into early-stage disease.” Cercek is section head of colorectal cancer and codirector of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center in New York, New York, where the trial was conducted.
The median follow-up for the analysis was 6.8 months (range, 0.7-23.8). “The majority of our patients [achieve cCR] at 6 months, but we did have a few at 3 months as well. [We have] quite a bit of a range from 0.7 to nearly 24 months and all patients remain disease free,” Cercek said.
“Standard of care for T3, T4, or node-positive rectal cancer involves trimodality therapy,” explained Kimmie Ng, MD, MPH, associate chief of the Division of Gastrointestinal Oncology, director of the Young-Onset Colorectal Cancer Center, codirector of the Colon and Rectal Cancer Center, and director of Translational Research in the Division of Gastrointestinal Oncology at Dana-Farber Cancer Center in Boston, Massachusetts in a discussion of the data.
“However, because components of the standard of care may lead to significant morbidity and quality-of-life issues, many recent studies have tried to eliminate components of the standard of care while still maintaining efficacy,” said Ng, who is also an associate professor of medicine at Harvard Medical School.
Approximately 5% to 10% of rectal cancers are dMMR, which confers resistance to chemotherapy. Investigators hypothesized that PD-1 blockade may replace chemotherapy, chemotherapy and radiation, or replace the trimodality approach of chemotherapy, radiation, and surgery.
Patients enrolled on the trial received the PD-1 monoclonal antibody dostarlimab at 500 mg intravenously every 3 weeks for 6 months, equaling 9 total cycles. At baseline and through treatment, patients were closely monitored and assessed for response at 6 weeks, 3 months, and 6 months. At these key timepoints patients underwent endoscopic and digital rectal exams. Upon treatment completion at 6 months patients then underwent comprehensive radiologic and endoscopic evaluation including tumor biopsy collection and T2-weighted and diffusion-weighted MRI of the rectum, 18F-fluorodeoxyglucose positron emission tomography, and CT scan of the chest, abdomen, and pelvis.
A cCR was defined as no evidence of residual tumor on both the digital and endoscopic rectal exams and on the rectal MRI results. Specifically, there must be visual evidence of primary rectal tumor disappearance on a normal digital exam and lack of signal on diffusion-weighted imaging with scar on T2-weighted imaging. Further, each target lymph node must have decreased short axis to less than 0.5 cm diameter.
If patients achieved cCR they entered a nonoperative follow-up window and underwent evaluation every 4 months. Patients with residual disease would proceed to chemoradiation until cCR was observed. If this was not achieved patients would proceed to surgery. Target enrollment is 30 patients.
The primary objective was overall response rate of PD-1 blockade with or without chemoradiation and pathologic complete response (pCR) or cCR at 12 months following treatment with dostarlimab with or without chemoradiation. Secondary outcomes include safety and tolerability.
The null hypothesis was that an overall response rate would be less than 25%, a numerical determination made based on the response rate to neoadjuvant chemotherapy of patients with dMMR colon cancer which is approximately 7%. “The rejection of null hypothesis required a response of 11 or more patients,” Cercek said.
At the time of the presentation 18 patients had been accrued to the trial. A majority were women (67%) and had a median age of 54 years (range, 26-78). In terms of tumor staging 22% had T1/2 tumors and 78% had T3 or T4 tumors. The mean tumor mutational burden was 67 mut/Mb (range, 36-106).
A majority (94%) of patients had node-positive disease and 100% of patients had BRAF V600E wild-type disease, which Cercek noted during a question-and-answer session is because these are patients with left-sided tumors.
“What I’d like to highlight is that the majority of these patients had big bulky tumors [with] 94% node positive,” Cercek said. “The standard of care for these patients would have very likely required all 3 modalities—chemotherapy, radiation and surgery.”
Cercek presented an overview of the first 2 patients enrolled and treated with dostarlimab. The first patient was a woman aged 38 years who presented with a large, node-positive tumor. “After completion of 6 months of [dostarlimab], we noted disappearance of tumor on endoscopy, and no evidence of tumor on MRI; she achieved a cCR, which was a very exciting start to the trial.”
The second patient was a woman aged 30 years who presented with approximately 3 months of rectal bleeding, a change in the caliber of her stool, and pelvic pain for approximately 2 weeks prior to diagnosis. Cercek noted that she subsequently received a diagnosis with Lynch syndrome. A clear response was noted at 6-week follow-up, but Cercek added that a clinical benefit was observed as well. “After just 2 doses, she felt significantly better, her bowels had normalized, and she no longer had pelvic pain. At 3 months, she achieved a cCR [on endoscopy] and on MRI she had a near complete response, so there was still some visible tumor there. On PET [evidence of disease] had also completely disappeared. Her final examination, after completion of 6 months of therapy was notable for a cCR and I’m very happy to say that this has been sustained now in follow-up for nearly 2 years.”
In terms of safety no grade 3 or 4 adverse events were observed. “This has the potential to be translated rapidly into areas where access to modern chemotherapy and even more importantly, radiation and surgery may not be available,” Cercek said in her concluding remarks.
In August 2021, dostarlimab was approved by the FDA for the treatment of patients with dMMR recurrent or advanced solid tumors who have progressed on or following prior therapy and who have no satisfactory treatment options.3
“Neoadjuvant dostarlimab for 6 months represents a promising new treatment for patients with stage II/III dMMR rectal cancer [and] larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival end points are needed,” Ng said. “It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatment for our patients.”