Nonoperative Management of Mismatch Repair—Deficient Tumors

Author(s): Andrea Cercek, M.D.¹; Michael B. Foote, M.D.¹; Benoit Rousseau, M.D., Ph.D.¹; J. Joshua Smith, M.D., Ph.D.²; Jinru Shia, M.D.³; Jenna Sinopoli, N.P.¹; Jill Weiss, B.S.¹; Melissa Lumish, M.D.⁴; Lindsay Temple, B.A.¹; Miteshkumar Patel, M.S.¹; Callahan Wilde, B.A.¹; Leonard B. Saltz, M.D.¹; Guillem Argiles, M.D.¹; Zsofia Stadler, M.D.¹; Oliver Artz, Ph.D.¹; Steven Maron, M.D.¹; Geoffrey Ku, M.D.¹; Ping Gu, M.D.¹; Yelena Y. Janjigian, M.D.¹; Daniela Molena, M.D.²; Gopa Iyer, M.D.¹; Jonathan Coleman, M.D.²; Wassim Abida, M.D.¹; Seth Cohen, M.D.¹; Kevin Soares, M.D.²; Mark Schattner, M.D.¹; Vivian E. Strong, M.D.²; Rona Yaeger, M.D.¹; Philip Paty, M.D.²; Marina Shcherba, M.D.¹; Ryan Sugarman, M.D.¹; Paul B. Romesser, M.D.⁵; Alice Zervoudakis, M.D.¹; Avni Desai, M.D.¹; Neil H. Segal, M.D., Ph.D.¹; Imane El Dika, M.D.¹; Maria Widmar, M.D.²; Iris Wei, M.D.²; Emmanouil Pappou, M.D., Ph.D.²; Gerard Fumo, M.D.⁶; Santiago Aparo, M.D.⁷; Mithat Gonen, M.D.⁸; Marc Gollub, M.D.⁹; Vetri S. Jayaprakasam, M.B., B.S.⁹; Tae-Hyung Kim, M.D.⁹; Julio Garcia Aguilar, M.D., Ph.D.²; Martin Weiser, M.D.²; Luis A. Diaz, Jr., M.D.¹

Source: N Engl J Med 2025;392:2297-2308

Dr. Maen Hussein's Thoughts

Two cohorts, one for patients with colon cancer and the second for all other patients. Of the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at two years was 92%. Only 20-months follow up for now. It will be interesting to see how this goes with future updates but seems promising.

BACKGROUND

Among patients with mismatch repair—deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.

METHODS

We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.

RESULTS

A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.

CONCLUSIONS

Among patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.)

Author Affiliations

¹Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York; ²Department of Surgery, Memorial Sloan Kettering Cancer Center, New York; ³Department of Pathology, Memorial Sloan Kettering Cancer Center, New York; ⁴Department of Oncology, Case Comprehensive Cancer Center, Cleveland; ⁵Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York; ⁶Department of Oncology, Hartford HealthCare, Hartford, CT; ⁷Department of Oncology, Baptist Health Miami Cancer Institute, Miami; ⁸Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York; ⁹Department of Radiology, Memorial Sloan Kettering Cancer Center, New York

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Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C–Mutated Tumors

A promising anti TP53 agent demonstrated an overall response rate of 20%, increasing to 30% in patients with KRAS wild type disease. Nausea and vomiting were the most commonly reported adverse events. While early, this agent may warrant continued attention as additional data emerge.

PROs vs clinician-reported adverse events in a large clinical trial: findings from the phase 3 POLARIX study Open Access

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