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Neoadjuvant Pembrolizumab in Localized Microsatellite Instability–High/Deficient Mismatch Repair Solid Tumors
TAKE-HOME MESSAGE
- In this phase II open-label clinical trial, patients with localized unresectable or high-risk resectable microsatellite instability–high (MSI-H)/deficiency mismatch repair (dMMR) solid tumors were treated with neoadjuvant pembrolizumab for 6 months prior to surgical resection. The majority of patients (54%) had colon adenocarcinoma. Among 49% of patients who underwent surgery, pathologic complete response (pCR) was observed in 65% of patients (lower than the study goal of 80%). Among patients with colorectal cancer, the pCR rate was 79%. Among 18 patients who did not undergo surgery, only 2 had progression. No new safety signals were observed.
- These findings indicate that neoadjuvant pembrolizumab in patients with a diverse range of MSI-H/dMMR solid tumors results in a high pathologic complete response rate, suggesting that this may be a good approach for dMMR tumors to enable organ preservation.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space.
METHODS
This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry.
RESULTS
A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression.
CONCLUSION
Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.
Additional Info
Disclosure statements are available on the authors' profiles:
Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors
J. Clin. Oncol 2023 Jan 09;[EPub Ahead of Print], K Ludford, WJ Ho, JV Thomas, KPS Raghav, MB Murphy, ND Fleming, MS Lee, BG Smaglo, YN You, MM Tillman, C Kamiya-Matsuoka, S Thirumurthi, C Messick, B Johnson, E Vilar, A Dasari, S Shin, A Hernandez, X Yuan, H Yang, WC Foo, W Qiao, D Maru, S Kopetz, MJ OvermanFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Ludford et al reported the results of a phase II study evaluating neoadjuvant pembrolizumab in multiple microsatellite instability–high (MSI-H)/deficiency mismatch repair (dMMR) solid tumors, published in the Journal of Clinical Oncology. The results contribute to the growing data supporting neoadjuvant immunotherapy in early-stage MSI-H/dMMR solid tumors.1-4 Although the responses observed in the study are robust, the heterogeneity of treatment approaches used (which include nonoperative management and surgery as well as variable duration of therapy), the questions of the durability of response and the potential for nonoperative management remain. Some relevant signals seem to emerge from the study, such as the fact that localized pancreatic cancer appears to be less sensitive to neoadjuvant immunotherapy and may require intensified or potential combination therapy. However, it is unclear whether the latter is related to the treatment approach or the biology of the disease.
In conclusion, before neoadjuvant immunotherapy for all localized dMMR solid tumors can be incorporated into clinical practice, further clinical trial data are needed to clarify critical aspects of patient management such as optimal patient selection, response evaluation, the possibility of nonoperative management, the durability of response, and appropriate follow-up guidelines.
References