Dostarlimab-gxly Granted Breakthrough Therapy Designation for Rectal Cancer

Dostarlimab achieved a 100% clinical complete response rate in patients with dMMR/MSI-H advanced rectal cancer, a phase 2 study found.

Dostarlimab-gxly (Jemperli) has been granted the breakthrough therapy designation by the FDA for the treatment of patients with locally advanced mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) rectal cancer, according to a press release from the developer, GSK.¹

In an analysis, dostarlimab, in patients with frontline locally advanced dMMR rectal cancer, demonstrated a 100% clinical complete response (cCR), defined as no evidence of tumors as assessed by MRI, endoscopy, PET scan, and digital rectal exam, in all 42 patients that completed treatment. At a median follow-up of 26.3 months (95% CI, 12.4-50.5), a sustained cCR was observed in the first 24 patients evaluated.

Dostarlimab previously received fast track designation for dMMR and MSI-H rectal cancer in January 2023. If approved, this would be the first approval for dostarlimab to be used in frontline dMMR/MSI-H rectal cancer, anywhere in the world.

Results from a phase 2 study (NCT04165772) investigating whether dostarlimab followed by standard chemotherapy and then standard surgery is a viable treatment for dMMR tumors informed this decision.

“Today’s designation, which is based on the unprecedented 100% clinical complete response 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,” Hesham Abdullah, senior vice president and global head of oncology for research and development at GSK, wrote in the press release.¹ “Our registrational AZUR-1 trial is continuing to study dostarlimab in this patient population.”

Regarding safety, no adverse events of grade 3 or higher were reported and the safety/tolerability profile of dostarlimab-gxly was consistent with previously known data.

The trial’s primary end point was pCR at 12 months.

Trial intervention saw patients with stage II or III MRI-staged, MSI-H/dMMR solid tumors receiving 500 mg of dostarlimab intravenously over 30 minutes once every 3 weeks, 825 mg/m² of capecitabine taken orally twice a day concurrently with radiation, and 5400 cGy of intensity modulated radiation therapy (IMRT) to the tumor and surrounding nodes and 4700 cGy to the pelvis with an integrated boost of 5400 cGy to the primary tumor and involved nodes in 27 fractions, all for up to 6 months, or nine 21-day cycles.²

Inclusion criteria include histologically confirmed locally advanced solid tumor, an ECOG performance status of 0 or 1, no evidence of distant metastases, or a tumor specimen that demonstrates dMMR by immunohistochemistry or microsatellite instability by next-generation sequencing or polymerase chain reaction, among others.

Patients were excluded from participation if they had the presence of metastatic or recurrent disease; a history of prior radiation therapy, chemotherapy, or surgery for a tumor; a diagnosis of immunodeficiency; an active immune disease requiring systemic treatment within the past 2 years or documented history of clinically severe autoimmune disease; and having received a live vaccine within 30 days of the planned study start date, among others.

Additionally, GSK’s ongoing single-arm, open-label phase 2 AZUR-1 trial (NCT05723562) is actively analyzing dostarlimab monotherapy in patients with dMMR/MSI-H locally advanced rectal cancer who have not received prior treatment.³

The trial will only include 1 experimental arm that will administer solely dostarlimab-gxly. The primary end point will be the number of patients with sustained cCR at 12 months assessed by independent central review. Secondary end points are the number of cCR’s at 24 and 36 months, as well as the number of patients with event-free survival (EFS) at 3 years, among others.

Patients with histologically confirmed stage II to III (T3-T4, N0, or T any, N+), locally advanced rectal cancer, radiologically and endoscopically evaluable disease, and a dMMR or MSI-H classified tumor will be included.

Patients will be excluded if they have distant metastatic disease, have received prior radiation or systemic therapy, or surgery for the management of rectal cancer, and if they have a history of interstitial lung disease or pneumonitis, among others.

References

1. Jemperli (dostarlimab-gxly) receives US FDA breakthrough therapy designation for locally advanced dMMR/MSI-H rectal cancer. News Release. GSK. December 16, 2024. Accessed December 16, 2024. https://tinyurl.com/2nkurvce
2. Study of induction PD-1 blockade in subjects with locally advanced mismatch repair deficient solid tumors. ClinicalTrials.gov. Updated April 23, 2024. Accessed December 16, 2024. https://tinyurl.com/58mfnjwe
3. A study of dostarlimab in untreated dMMR/​MSI-H locally advanced rectal cancer (AZUR-1). ClinicalTrials.gov. Updated September 9, 2023. Accessed December 16, 2024. https://tinyurl.com/ykkdrkem