Neoadjuvant dostarlimab is a promising treatment option in locally advanced dMMR rectal cancer

1. All neoadjuvant dostarlimab patients had a clinical complete response and no patients needed any additional treatments at the study data cutoff.

2. There were no adverse events of grades 3 or higher. Most common adverse events of any grade were dermatitis, pruritus, fatigue, and nausea.

Evidence Rating Level: 2 (Good)

Study Rundown: Immune checkpoint inhibitors have had great success as a first-line treatment for patients with mismatch repair-deficient (dMMR) metastatic colorectal cancer. This study explored the efficacy and safety of neoadjuvant dostarlimab (a PD-1 inhibitor) on dMMR patients with locally advanced rectal cancer. Patients were only assigned to a treatment group. All patients who completed 6 months of dostarlimab had a clinical complete response. After 12 months of completion of dostarlimab treatment, no patients had evidence of recurrence or progressive diease. Pathological complete response was another endpoint but could not be evaluated as no patients had to undergo surgical resection. Most common adverse events of any grade were dermatitis, pruritus, fatigue, and nausea. There were no adverse events of grades 3 or higher. Limitations to this study include its small sample size and the fact it only observed dMMR patients, which comprise a very small subset of rectal cancer patients. A longer follow-up is also needed to assess the duration of response. The strengths of this study are that all patients had a clinical complete response and that dostarlimab may potentially omit both chemotherapy and surgery as treatments for this rare subtype of rectal cancer. Overall, dostarlimab shows tremendous promise for the treatment of surgically resectable rectal cancer and may change the current treatment landscape drastically.

Click to read the study in NEJM

Relevant Reading: Advances and challenges in treatment of locally advanced rectal cancer

In-Depth [prospective cohort]: This prospective phase II study included 16 dMMR patients with locally advanced rectal cancer. Of those 16 patients, only 12 have been enrolled for longer than 6 months. Clinical complete response after 6 months of dostarlimab was 100% (95% confidence interval [CI], 74 to 100). After 12 months of completion of dostarlimab treatment, none had recurrence of their cancer. By potentially bypassing surgery and chemotherapy, dostarlibumab may be able to negate all the negative health outcomes that can result from them, such as problems with fertility, sexual health, bowel and bladder. Since no resections were performed, pathological complete response was not evaluated. Most common adverse events of any grades were dermatitis (31% of patients), pruritus (25%), fatigue (25%), and nausea (19%). No adverse events of grades 3 or higher occurred. Overall, dMMR rectal showed high sensitivity to PD-1/PD-L1 blockade and further trials including more follow-up data will help shape the changes in approaching locally advanced rectal cancer.

Image: PD

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