A 100% response rate suggests dostarlimab is ‘definitive’ therapy for rectal cancer
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Key takeaways:
- Dostarlimab conferred clinical complete responses in all patients treated during a phase 2 trial..
- Circulating tumor DNA results indicate treatment may work rapidly.
CHICAGO — A phase 2 study evaluating dostarlimab in adults with mismatch repair-deficient locally advanced rectal cancer has maintained a 100% clinical complete response rate at a median follow-up of almost 18 months.
The data, presented at ASCO Annual Meeting, also showed half of the individuals enrolled have sustained a clinical complete response for at least 1 year.
“We are incredibly excited about the results,” Andrea Cercek, MD, gastrointestinal oncologist, section head of colorectal cancer and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center, told Healio.
“Treatment with dostarlimab was definitive,” she added. “None of the patients needed any additional intervention beyond immunotherapy. No one needed radiation or rectal surgery, which have a negative impact on quality of life.”
Background and methodology
Roughly 5% to 10% of patients with locally advanced rectal cancer have a mismatch repair-deficient (dMMR) biomarker, according to background information Cercek presented.
“It’s less sensitive to chemotherapy, and we initially noticed this when we were treating patients with locally advanced rectal cancer with total neoadjuvant therapy,” Cercek said during her presentation. “When we started with chemotherapy, we noticed that actually 30% of these patients had progression of disease. And at the same time, mismatch repair-deficient metastatic colorectal cancer was known to be very sensitive to immune checkpoint blockade.”
This led Cercek and colleagues to examine if neoadjuvant PD-1 blockade could potentially replace one of or all of chemotherapy, radiation and surgery.
They enrolled 48 adults with stage II/III dMMR rectal cancers into the phase 2 study (58% women; 77% white; 79% tumor stage III or IV; 85% node positive; 51% positive for Lynch syndrome).
Participants received 500 mg IV dostarlimab (Jemperli, GSK), an anti-PD-1 monoclonal antibody, every 3 weeks for 6 months and evaluation. If they had a complete clinical response, they would continue follow-up every 4 months. If study participants had residual disease, they would go on to standard-of-care chemoradiation and surgery as needed.
Overall response rate and pathologic or complete clinical response 12 months following PD-1 blockade served as the study’s primary endpoints, with safety as the secondary endpoint.
Researchers presented data on ORR in June 2022, which Healio previously reported on, showing 14 consecutive patients had a clinical complete response to dostarlimab alone.
“Based on these data, the NCCN guidelines actually incorporated PD-1 blockade into neoadjuvant therapy for mismatch repair-deficient rectal cancer last year [May 2023], but the trial has been ongoing,” Cercek said during her presentation.
Results and next steps
At a median follow-up of 17.9 months (0.3-50.5), each of the 42 patients who received dostarlimab and underwent subsequent evaluation had a complete clinical response to therapy.
“The majority of patients achieve a [complete clinical response] right at 6 months, but we do have a handful who have a [complete clinical response] at the 3-month evaluation, but they continue dostarlimab for the full 6 months of therapy,” Cercek said during her presentation. “There is an 8-week window of observation after completion of dostarlimab, and another handful of patients that achieve that clinical complete response at the end of that evaluation.”
Additionally, at a median follow-up of 26.3 months, 24 patients have achieved a sustained complete clinical response lasting at least 1 year.
“We have not seen any local regrowths in these patients,” Cercek said.
Researchers evaluated complete clinical responses in a multitude of ways, including rectal MRI, endoscopy, biopsies, circulating tumor DNA (ctDNA) and PET-CT.
Rectal MRIs and endoscopy both showed a complete clinical response in a median of just over 6 months, but ctDNA had a median of 1.38 months (95% CI, 1.38-2.76).
No patients experienced grade 3 or worse treatment-related adverse events. The most common adverse events included rash/dermatitis (21%), pruritus (13%), fatigue (11%) and hypothyroidism (11%).
Cercek said future research should investigate this immunotherapy approach in all rectal cancers.
“Mismatch repair-deficient rectal cancer treatment with dostarlimab alone leads to unprecedented durable complete responses, without the need for rectal surgery,” Cercek told Healio. “There is an ongoing global confirmatory study, AZUR1, which has the exact same design, and will change the standard of care worldwide.”
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Cercek A, et al. Abstract 3512. Presented at: ASCO Annual Meeting; May 31-June 4, 2024; Chicago.
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