Microsatellite Instability-high Solid Tumors Research Articles

Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study

We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200mg every 3weeks. The most common cancer type is colorectal cancer (n= 71). With a median follow-up of 22.5months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.

Clinical efficacy and biomarker analysis of pucotenlimab (HX008) in patients with previously treated advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A single-arm, multicenter, phase 2 study.

799 Background: Pucotenlimab is a humanized IgG4 anti-PD-1 monoclonal antibody with an engineered Fc domain. We aim to assess the efficacy and safety of pucotenlimab, and potential predictive biomarkers of response in patients with previously treated advanced microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors. Methods: In this single-arm, multi-center, phase 2 study, eligible patients had locally advanced or metastatic, centrally confirmed MSI-H or dMMR solid tumors treated with at least one prior systemic therapy. Patients received pucotenlimab 200mg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by the independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Besides, patients’ PD-L1 expression, blood neutrophil to lymphocyte ratio (NLR), germline HLA-I genotyping, loss of heterozygosity (LOH) of HLA-I genes, tumor mutational burden (TMB), and genetic alterations in the tumor revealed by next-generation sequencing were investigated to identify potential predictors of efficacy. Results: 100 patients with MSI-H or dMMR solid tumors were enrolled. Colorectal cancer (n=71) and gastric cancer (n=10) were the most common cancer types. The median follow-up duration was 22.5 months (range: 0.3-37.4) at data cutoff (December 4, 2021). The ORR was 49.0% (95% CI 38.86%-59.20%), and the 12-month progression-free survival (PFS) rate was 56.1% (95% CI 45.63%-65.24%) based on IRC’s assessment. Both the median PFS and median duration of response were not reached. Pucotenlimab was well tolerated. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 18 patients, most commonly anemia, leukocytopenia, and hypertension. For the biomarker analysis, patients with NLR <4 at the second treatment cycle, TMB≥32.5 muts/Mb (the lower 35th TMB-percentile), or mutations in the KMT2D gene showed significantly higher ORR. Conclusions: Pucotenlimab demonstrated durable antitumor activity and manageable safety for previously treated patients with advanced MSI-H/dMMR solid tumors. KMT2D gene mutation, along with NLR and TMB, warrants further investigation as predictive biomarkers. Clinical trial information: NCT03704246 .

Does detection of microsatellite instability-high (MSI-H) by plasma-based testing predict tumor response to immunotherapy (IO) in patients with pancreatic cancer (PC)?

607 Background: Immunotherapy (IO) is known to have robust anti-tumor activity in patients with MSI-H solid tumors. However, clinical trials investigating IO activity have used tissue-based testing to determine MSI-H status. Pancreatic tumor biopsy often does not provide sufficient tumor tissue for MSI testing. We investigated if the MSI-H status detected by plasma-based circulating tumor DNA (ctDNA) testing predicts robust response to IO in patients with PC. Methods: Genomic results from a well-validated plasma-based ctDNA assay (Guardant360[G360]) performed as part of routine clinical care between October 1, 2018 and September 7, 2021 in patients with PC were queried to identify patients with MSI-H tumors. Patient characteristics, tumor characteristics, treatment details, and outcomes were reported by ordering clinicians where available. The data cut-off date was September 1, 2021. Results: A total of 52 patients with PC who had MSI-H tumors on G360 were identified. Clinical outcomes data were available for 10/52 (19%) patients who were included for analysis. This patient cohort had a median age of 68 years (range: 56-82); 80% were male and 80% of patients had metastatic disease. 9/10 patients received IO: 3 in the first-line, 3 in the second-line, 3 in the third-line setting; most received pembrolizumab (8/9) while 1 received ipilimumab plus nivolumab. The median duration of IO was 8 months (range: 1-24). The overall response rate was 77% (7/9) and 6 of the 7 responders continue to show response at the time of data cut-off after a median follow-up of 21 months (range:11-33). The median progression-free survival and overall survival were not reached in the IO-treated cohort. Tissue-based MSI testing results were concordant with plasma-based G360 results in 5 of 6 patients (83%) who had tissue-based test results available. The patient with the discordant result was MSI-H by G360 but had intact mismatch repair protein expression by immunohistochemistry. This patient received neoadjuvant IO followed by surgery and the resected specimen confirmed pathological complete response. Conclusions: The detection of MSI-H status by plasma-based ctDNA testing is highly concordant to tissue-based testing and predicts robust and durable response to IO in patients with PC. The use of a well-validated plasma-based ctDNA analysis may expand the identification of MSI-H tumors in patients with PC and enable treatment with IO resulting in improved outcomes.

Characteristics and outcomes of real-world (RW) patients (pts) with microsatellite instability-high (MSI-H) solid tumors treated with pembrolizumab monotherapy (P) after FDA approval.

3060 Background: The first tumor-agnostic, biomarker-based FDA approval in oncology was P in May 2017 for pts with MSI-H or mismatch repair (MMR) deficient tumors. 1 yr overall survival (OS) was >70% for colorectal cancer (CRC) and >60% for non-CRC in P-treated MSI-H clinical trial pts (Le 2019; Marabelle 2019). As tumor-agnostic therapies are a new paradigm, it is important to assess their use and effectiveness in routine clinical practice. We examined characteristics and outcomes of RW pts with MSI-H solid tumors who received P after May 2017. Methods: Pts with MSI-H solid tumors who received P after May 2017 were selected from the Flatiron Health-Foundation Medicine (FH-FMI) clinico-genomic database, a nationwide de-identified EHR-derived database linked to comprehensive genomic profiling (CGP) data. Pts with 2+ visits in the FH network from 01/2011-09/2019 with CGP prior to P use were included. Clinical characteristics were assessed at first P use. Time to treatment discontinuation (TTD) and OS from first P use were estimated with Kaplan-Meier analyses of all pts and the largest tumor types. Results: 33,395 pts had a solid tumor tested for MSI by CGP, of which 557 (1.7%) were MSI-H (median age 68 yrs; 34% male). 129 MSI-H pts across 33 tumor types received first P after May 2017. CRC (N=36) and Endometrial cancer (N=39) were most common. 52 pts (40%) had a concurrent MMR alteration (MLH1, MSH2, MSH6 or PMS2); median TMB was 32.2 mut/mb (IQR 20.9-47.5). Median number of therapies prior to P was 1; median time from CGP to first P use was 3 mos. Table shows OS and TTD. Conclusions: In this RW study, P use was observed across 33 MSI-H tumor types. Median OS exceeded 1 yr across all pts and in CRC, Endometrial, and Other cohorts. 1 yr OS rate was consistent with P trial outcomes. Further study should evaluate whether effectiveness differs across diseases, MSI testing method, or other genomic attributes to improve treatment selection. [Table: see text]