Andrea Cercek, M.D., Melissa Lumish, M.D., Jenna Sinopoli, N.P., Jill Weiss, B.A., Jinru Shia, M.D., Michelle Lamendola-Essel, D.H.Sc., Imane H. El Dika, M.D., Neil Segal, M.D., Marina Shcherba, M.D., Ryan Sugarman, M.D., Ph.D., Zsofia Stadler, M.D., Rona Yaeger, M.D., et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. NEJM June 5, 2022. DOI: 10.1056/NEJMoa2201445
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.
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.
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.
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. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.)
Hanna K. Sanoff, M.D., M.P.H. Improving Treatment Approaches for Rectal Cancer. NEJM. June 5, 2022 DOI: 10.1056/NEJMe2204282
A second paradigm shift in colorectal cancer — the transition from chemotherapy to immunotherapy as primary treatment for metastatic mismatch repair–deficient cancers — presents a potential means to allow these patients to consider nonoperative approaches. In the KEYNOTE-177 trial, in which the immune checkpoint inhibitor pembrolizumab was compared with standard chemotherapy, treatment with pembrolizumab resulted in a longer duration of cancer control and a greater chance for cancer regression than standard chemotherapy.
Cercek and colleagues now report in the Journal the results of a small but compelling study that brings these two treatment advances together. In this study, immunotherapy with the programmed death 1 (PD-1) inhibitor dostarlimab was followed by nonoperative care in patients with mismatch repair–deficient stage II or III rectal cancer. Twelve patients received dostarlimab for 6 months with careful monitoring of clinical response by magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, and endoscopy. Patients who did not have a complete response were to receive subsequent standard radiation therapy and chemotherapy; however, all 12 patients had complete tumor resolution with dostarlimab. At a median follow-up of 1 year, none of the 12 patients had needed other treatment, and none had had cancer regrowth. None of the patients had adverse events of grade 3 or higher.
These results are cause for great optimism, but such an approach cannot yet supplant our current curative treatment approach. The end point presented, clinical complete response, is an imperfect surrogate for long-term cancer control. Patients who have a clinical complete response after chemotherapy and radiation therapy have a better prognosis than those who do not have a clinical complete response, yet cancer regrowth occurs in 20 to 30% of such patients when the cancer is managed nonoperatively. Furthermore, although responses to PD-1 inhibition can last for years, only 55% of patients treated with pembrolizumab for mismatch repair–deficient metastatic colorectal cancer in the KEYNOTE-177 trial were reported to be alive without cancer progression at 12 months; responses lasted longer among the patients who had an initial strong response, but only approximately 70% had an ongoing response 3 years later.6 These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early- and late-stage disease. In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure.
Whether the results of this small study conducted at Memorial Sloan Kettering Cancer Center will be generalizable to a broader population of patients with rectal cancer is also not known. In order to provide more information regarding which patients might benefit from immunotherapy, subsequent trials should aim for heterogeneity in age, coexisting conditions, and tumor bulk. Enrollment of patients from diverse communities could address variations in the composition of the gut microbiome, which are known to influence response to immunotherapy. Diversity in the clinical practice setting is also critical to ensuring that this is a safe approach to implement on a large scale. Safe nonoperative management involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging. Such expertise is not available in all communities, and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.
Despite these uncertainties, Cercek and colleagues and their patients who agreed to forgo standard treatment for a promising but unknown future with immunotherapy have provided what may be an early glimpse of a revolutionary treatment shift. Although the incidence of severe toxic effects (i.e., adverse events of grade 3 or higher) with PD-1 inhibitors is usually higher than that seen in this study — closer to 10% — lasting consequences are uncommon. Thus, if immunotherapy can be a curative treatment for rectal cancer, eligible patients may no longer have to accept functional compromise in order to be cured.
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