Experimental rectal cancer drug caused all patients' tumors to disappear in a trial

The New England Journal of Medicine (NEJM):

Locally advanced rectal cancer is typically managed with multimodal therapy, including chemotherapy, radiation, and surgery.

Owing to the complications of surgery and the high frequency of pathological complete response, interest in organ-sparing nonoperative management is increasing.

Approximately 5 to 10% of rectal adenocarcinomas are mismatch-repair deficient, and these tumors have been shown to respond poorly to standard chemotherapy regimens.

The results were published on June 5, 2022 in the New England Journal of Medicine and presented at the American Society of Clinical Oncology 2022 annual meeting.

Key findings

Patients with locally advanced rectal cancer and tumors with deficient mismatch repair (dMMR) have shown a remarkable response to treatment with the programmed cell death-1 (PD-1) inhibitor Dostarlimab.

A total of 16 patients have been enrolled and treated. Of these patients, 12 have been enrolled for longer than 6 months and have completed the nine planned cycles (6 months) of dostarlimab.

Results among the 12 patients with at least 6 months follow-up showed a complete response among all patients, with no evidence of tumor on biopsy, digital rectal exam, endoscopic visualization, fluorodeoxyglucose-PET or MRI. The other 4 patients are responding to treatment.

Fig. Evolution of Endoscopic and Radiographic Response in Representative Patients Treated with Dostarlimab.

No patients experienced disease progression or recurrence, and no patients required chemoradiation or surgery. Moreover, researchers did not observe any serious grade 3 or higher adverse events.

Authors initiated a phase 2 study to investigate the overall response and frequency of sustained clinical complete response to neoadjuvant treatment with dostarlimab, a PD-1 inhibitor.

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Single-Agent Dostarlimab

For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.

Dostarlimab is approved by the US Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.

All patients had mismatched repair-deficient stage 2 or 3 rectal adenocarcinoma.

Efficacy

The criteria for the primary end point of overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy have been met. The percentage of patients with a clinical complete response was 100% in 12 consecutive patients who have completed 6 months of therapy.

In this study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled authors to omit both chemoradiotherapy and surgery and to proceed with observation alone.

In this study, single-agent dostarlimab was remarkably effective in mismatch repair–deficient, locally advanced rectal cancer, providing a clinical complete response in all 12 patients who have completed treatment to date.

Although the results of this study is promising, especially given that 12 consecutive patients all had a clinical complete response, the study is small and represents the experience of a single institution. These findings must be reproduced in a larger prospective cohort that balances academic and community practices and ensures the participation of patients from a diverse set of racial and ethnic backgrounds.

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Abstract

Background

Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.

Methods

We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.

Results

A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, ¹⁸F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.

Conclusions

Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response.

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