FDA Grants Breakthrough Therapy Designation to Dostarlimab for dMMR/MSI-H Rectal Cancer

The FDA has granted breakthrough therapy designation to dostarlimab-gxly (Jemperli) for the treatment of patients with locally advanced mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) rectal cancer.1

The designation is supported by findings from a phase 2 collaborative study (NCT04165772) between GSK and Memorial Sloan Kettering Cancer Center, which showed that frontline treatment with dostarlimab led to a 100% clinical complete response (cCR) rate in all 42 patients with locally advanced dMMR rectal cancer who completed treatment with the agent, with a median follow-up of 17.9 months (range, 0.3-50.5).1,2 cCR was defined as no evidence of tumors as assessed by magnetic resonance imaging, endoscopy, PET scan and digital rectal exam.1 Additionally, in the first 24 patients evaluated, a sustained cCR of 12 months was seen with a median follow-up of 26.3 months (range, 12.4-50.5).1,2

The safety and tolerability profile of dostarlimab was largely consistent with the known safety profile of the PD-1 inhibitor.1 No grade 3 or higher adverse effects (AEs) occurred in this trial.1,2 The trial continues to evaluate enrolled patients.1

“[This] designation, which is based on the unprecedented 100% cCR rate of dostarlimab reported to date, supports a path to help change the treatment paradigm for patients with locally advanced dMMR/MSI-H rectal cancer, who face long-term adverse quality of life effects. Our registrational [phase 2] AZUR-1 trial [NCT05723562] is continuing to study dostarlimab in this patient population,” Hesham Abdullah, senior vice president, Global Head Oncology, R&D, GSK, stated in a news release.

To be eligible for enrollment patients needed to have received a diagnosis of stage II or III rectal cancer with confirmed dMMR per immunohistochemistry. Eligible patients received 500 mg of intravenous dostarlimab every 3 weeks for 6 months.2 After completing treatment, patients underwent radiologic and endoscopic evaluation. Patients with residual disease proceeded to chemoradiation and those with a cCR underwent nonoperative follow-up every 4 months. Patients with residual disease after chemoradiation underwent surgery and those with cCR entered nonoperative follow-up every 4 months.

The primary end points were the objective response rate of dostarlimab alone or in combination with chemoradiation and pathologic complete response or cCR rate for 12 months after completing dostarlimab as a single agent or in combination with chemoradiation.

Investigators also evaluated the time to cCR via rectal MRI, endoscopy, biopsy, circulating tumor DNA (ctDNA), and PET-CT. Overall, the median time to cCR was 6.22 months (95% CI, 6.18-6.45). The median times with rectal MRI, endoscopy, biopsy, ctDNA, and PET-CT were 6.15 months (95% CI, 6.09-6.25), 6.18 months (95% CI, 3.62-6.22), 1.41 months (95% CI, 1.38-2.73), 1.38 months (95% CI, 1.38-2.76), and 2.76 months (95% CI, 2.73-6.18), respectively.

Regarding safety, the most frequent any-grade AEs were pruritus (13%), rash/dermatitis (21%), diarrhea (9%), nausea (9%), fatigue (11%), fever (6%), and hypothyroidism (11%).

The registrational AZUR-1 trial, which is ongoing in locally advanced dMMR/MSI-H rectal cancer, will further evaluate the efficacy and safety of dostarlimab monotherapy, building on earlier findings from this supported collaborative study.1,3

References

1. Jemperli (dostarlimab) receives US FDA breakthrough therapy designation for locally advanced dMMR/MSI-H rectal cancer. News release. GSK. December 16, 2024. Accessed December 18, 2024. https://www.gsk.com/en-gb/media/press-releases/jemperli-dostarlimab-receives-us-fda-breakthrough-therapy-designation-for-locally-advanced-dmmrmsi-h-rectal-cancer/
2. Cercek A, Sinopoli JC, Shia J, et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2024;42(suppl 17):LBA3512. doi:10.1200/JCO.2024.42.17_suppl.LBA3512
3. Cercek A, Bachet JB, Capdevila J, et al. Phase II, single-arm, open-label study of dostarlimab monotherapy in previously untreated patients with stage II/III dMMR/MSI-H locally advanced rectal cancer. J Clin Oncol. 2023;41(suppl 16):TPS3639. doi:10.1200/JCO.2023.41.16