Dostarlimab Benefit Signaled for Patients with MRD, Locally Advanced Rectal Cancer

Maged Khalil, MD

Single-agent anti-PD-1 therapy with neoadjuvant dostarlimab (Jemperli) showed high sensitivity in patients with mismatch repair deficient (MRD), locally advanced rectal cancer in a phase 2 confirmatory clinical trial (NCT04165772).¹

“There is now a drug for this population with the mismatch protein deficiency that avoid the use of chemoradiation and surgery, and improves not only cure their disease, but improve their quality-of-life, particularly those young populations, said Maged Khalil, MD, a hematologist and medical oncologist on the GI cancer multidisciplinary consultation team at Lehigh Valley Topper Cancer Institute of Leigh Valley Health Network, a Memorial Sloan Kettering Cancer Center (MSK) partner, in an interview with Targeted Oncology™.

The key goal of the MSK-sponsored study was to assess the overall response rate of dostarlimab when administered at 500 mg every 3 weeks for 6 months followed by radiation at a total dose of 5040 cGy given in 28 fractions plus standard-dose capecitabine, which was followed by total mesorectal excision. The other end point was sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response.

A 100% (95% CI, 74%-100%) clinical complete response rate was achieved with neoadjuvant dostarlimab in 12 patients who received the agent for 6 months. Investigators reported that the median time to rectal MRI was 16 days (range, 8-26), and the median time to endoscopy was 20 days (range, 14-28) post dostarlimab.

Responses occurred rapidly, and symptoms of disease were resolved within 9 weeks of starting dostarlimab in 81% of patients. Moreover, an endoscopic complete response occurred in 5 patients, and 2 patients had a radiographic complete response to the anti-PD-1 therapy.

Seventy-five percent of patients (95% CI, 48%-92%) experienced adverse events (AEs) of any grade. No cases of grade 3 or higher AEs were observed. The most common grade 1 or 2 AEs were rash or dermatitis (31%), pruritus (25%), fatigue (25%), and nausea (9%). One patient in the study developed thyroid-function abnormalities.

In the interview, Khalil discussed historic issues with treating MRD, locally advanced rectal cancer, and the subgroups in the most need for new treatment options. Khalil also provided insight on a phase 2 clinical trial with results that have shifted the landscape.

TARGETED ONCOLOGY: Can you discuss the questions surrounding treatment options and sequencing treatment for MRD, locally advanced rectal cancer?

Khalil: Patients with rectal cancer stage II and III have been treated regardless of their MMR status with chemoradiation, and chemotherapy followed by surgery – an approach known as total new adjuvant therapy, or TNT. Patients with MRD, locally advanced rectal cancer, did not respond to chemotherapy as well as MRP patients, however they still have to go through the same treatment with chemo and chemoradiation, and likely end up having a life-time ostomy bag.

What should oncologists know about MRD locally advanced rectal cancer and patient outcomes?

Before June of 2022, patients with mismatch repair deficient disease were not treated any different than patients with mismatch repair protein proficient disease. Basically, they were treated with standard of care chemoradiation followed by surgery. We knew about metastatic colorectal cancer that was treated with anti-PD1 therapy, and many drugs were approved for that setting. We all were waiting for this kind of trial for the mismatch repair protein deficient early-stage rectal cancer.

Most MRD tumors are resistant to chemotherapy and they respond better to immunotherapy, but without clinical trials, those patients were all treated the same.

What is important to note about the phase 2 study of single-agent PD-1 blockade for the treatment of MRD locally advanced rectal cancer?

It’s hard to find a word to express the magnitude of impact these results will have on rectal cancer treatment for this cohort of patients. This is a paradigm-shifting study. We're seeing increased incidences of rectal cancer in young people, including women in their childbearing years.

Current rectal cancer treatment can cause serious impacts on these young people’s quality of life leading to impaired GI and GU functions and sterility.

What are the implications of the study findings?

There is now a drug for this population with the mismatch protein deficiency that helps avoid the use of chemoradiation and surgery, as well as improves not only the disease outcome but also maintains normal quality-of-life, particularly for those young populations.

Some oncologists wait for confirmatory evidence before using a new drug. What advice do you have for those who are using dostarlimab for the first time?

Oncologists should make sure that their pathologist tests for mismatch repair protein and microsatellite instability. They must insist and make sure because everybody deserves that chance. This should be ordered for every new rectal cancer patient who is stage II and III.

_REFERENCE:

_{Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med. 2022; 386(25):2363-2376. doi: 10.1056/NEJMoa2201445}