Neoadjuvant Pembrolizumab Associated with Limited Side Effects and High Clinical Activity in Patients with Localised dMMR Solid Tumours

Findings from a single-centre, phase II clinical study demonstrate that neoadjuvant pembrolizumab is safe and feasible, and results in a high rate of pathologic complete response (pCR) in patients with a range of localised dMMR solid tumours. Although the pCR rate of 65% was lower than the study goal of 80%, the majority of resected patients without pCR demonstrated pathologic downstaging and in patients with colorectal cancer, the pCR was 79%. High rates of pathologic, radiographic, and endoscopic response have implications for organ-sparing strategies. The findings are published by Dr. Kaysia Ludford of The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 9 January 2023 in the Journal of Clinical Oncology.

dMMR/MSI-high arise most commonly in colorectal, endometrial, and gastric cancers. In addition, dMMR tumours are more commonly seen in early-stage disease. Localised dMMR cancers are currently treated as proficient mismatch repair/microsatellite stable tumours. However, both preclinical and clinical data have suggested that dMMR cancers demonstrate less benefit from chemotherapy compared with proficient mismatch repair cancers.

Anti–PD1 therapy significantly improves clinical outcomes in advanced/metastatic dMMR/MSI-high solid cancers. However, its role for localised dMMR cancers is not fully defined, but has demonstrated promising results in colorectal and gastro-oesophageal cancers.  Neoadjuvant immunotherapy is appealing since the intact primary tumour provides a source of antigens for immune priming and expansion of activated tumour-specific T cells. Furthermore, it’s promising not only as a highly active when coupled with surgery, but also may enable non-operative management.

In this phase II open-label, single-centre study conducted among patients with localised unresectable or high-risk resectable dMMR/MSI-high tumours who were treated with pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue treatment for 1 year followed by observation. To continue on study, patients were required to have radiographic or clinical benefit. The coprimary endpoints were safety and pCR. Key secondary endpoints were response rate and organ-sparing at 1 year for patients who declined surgery. Exploratory analyses included interrogation of the tumour immune microenvironment using imaging mass cytometry.

A total of 35 patients were enrolled, including 27 patients with colorectal cancer and 8 patients with non-colorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 patients (49%) who underwent surgery, the pCR rate was 65%. Ten patients elected to receive 1 year of pembrolizumab followed by surveillance without surgical resection with median follow-up of 23 weeks. An additional 8 patients did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course and subsequent follow-up, progression events were seen in 6 patients of whom 4 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, meaning that more CD15-positive granulocytic cells within the tumour microenvironment with proximity to cytotoxic CD8-positive T cells, as well as T cell exhaustion, may predict for lack of (or loss of) treatment response.

This study adds to the growing body of evidence that endorses the role of anti–PD1 therapy in dMMR/MSI-high gastrointestinal cancers. One of the most intriguing findings from this prospective study is the suggestion that neoadjuvant PD1–based treatment may represent a definitive approach for dMMR solid tumours enabling organ preservation. The radiographic response rate of 82% is notably higher than the response rates seen in clinical studies of PD1–based treatment for metastatic dMMR cancers. In patients with luminal cancers, endoscopic evaluation provided a valuable adjunct for complementing radiographic response evaluation.

In an accompanied editorial article, drs Kristen K. Ciombor and Cathy Eng of the Vanderbilt-Ingram Cancer Center in Nashville, TN, US wrote that although excellent safety and efficacy signals were seen in this study of neoadjuvant immunotherapy, more data are needed before this treatment approach is established as a ubiquitous standard of care for all patients with localised dMMR/MSI-high solid tumours. Collection of additional data from well-designed, prospective, multicentre studies will be essential to help answer the critical questions and guide best treatment of patients with tumours that harbour this genomic signature.

The study was previously presented at ESMO 2021 Congress.

The study was supported by CCSG P30 CA016672, SPORE P50CA221707, Merck, and Kavanagh Family Foundation.

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