Dataset Information

Tumor dynamics in patients with solid tumors treated with pembrolizumab beyond disease progression.

ABSTRACT: While many patients are treated beyond progression (TBP), the magnitude and duration of clinical benefit in these patients have not been fully quantified. Data from 799 patients with melanoma (n = 176), non-small cell lung cancer (NSCLC; n = 146), gastric cancer (GC; n = 87), head and neck squamous cell carcinoma (HNSCC; n = 112), clear-cell renal cell carcinoma (ccRCC; n = 51), and urothelial carcinoma (UC; n = 227) TBP were included. Patients had received pembrolizumab beyond confirmed progressive disease (PD) per RECIST v1.1. A subset of patients displays a 30% reduction in the sum of lesion diameters in the post-progression period (melanoma 24.4%, NSCLC 11.6%, 12.6% GC, 8.9% HNSCC, 15.7% ccRCC, and 13.2% UC). Most patients show stable target lesion dynamics in the post-progression period (melanoma, 64.8%; NSCLC, 72.6%; GC, 69.0%, 75.9% HNSCC, 72.5% ccRCC, 75.3% UC). Pembrolizumab generates meaningful efficacy in a subset of patients treated beyond RECIST v1.1 progression.

SUBMITTER: Topp BG

PROVIDER: S-EPMC11229185 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor dynamics in patients with solid tumors treated with pembrolizumab beyond disease progression.

Topp Brian G BG Channavazzala Madhav M Mayawala Kapil K De Alwis Dinesh P DP Rubin Eric E Snyder Alexandra A Wolchok Jedd D JD Ribas Antoni A

Cancer cell 20230901 9

While many patients are treated beyond progression (TBP), the magnitude and duration of clinical benefit in these patients have not been fully quantified. Data from 799 patients with melanoma (n = 176), non-small cell lung cancer (NSCLC; n = 146), gastric cancer (GC; n = 87), head and neck squamous cell carcinoma (HNSCC; n = 112), clear-cell renal cell carcinoma (ccRCC; n = 51), and urothelial carcinoma (UC; n = 227) TBP were included. Patients had received pembrolizumab beyond confirmed progres ...[more]

PMID: 37699333

Similar Datasets

Project description:BackgroundSeveral studies have evaluated the relationship between tumor mutational burden (TMB) and outcomes of immune checkpoint inhibitors. In the phase II KEYNOTE-158 study of pembrolizumab monotherapy for previously treated recurrent or metastatic cancer, high TMB as assessed by the FoundationOne CDx was associated with an improved objective response rate (ORR).MethodsWe retrospectively assessed the relationship between TMB and efficacy in participants with previously treated advanced solid tumors enrolled in 12 trials that evaluated pembrolizumab monotherapy, including 3 randomized trials that compared pembrolizumab with chemotherapy. TMB was assessed in formalin-fixed, paraffin-embedded pretreatment tumor samples by whole-exome sequencing. High TMB was defined as ≥175 mutations/exome. Microsatellite instability (MSI) phenotype was based on whole-exome sequencing results. Programmed death ligand 1 (PD-L1) expression was assessed by immunohistochemistry. The primary end point was ORR assessed per RECIST V.1.1 by independent central review. Other end points included progression-free survival (PFS) assessed per RECIST V.1.1 by independent central review and overall survival (OS).ResultsOf the 2234 participants in the analysis, 1772 received pembrolizumab monotherapy and 462 received chemotherapy. Among the pembrolizumab-treated participants, ORR was 31.4% (95% CI 27.1 to 36.0) in the 433 participants with TMB ≥175 mutations/exome and 9.5% (95% CI 8.0 to 11.2) in the 1339 participants with TMB <175 mutations/exome. The association of TMB with ORR was observed regardless of PD-L1 expression and not driven by specific tumor types or participants with very high TMB or high MSI. In the 3 randomized controlled trials, TMB was associated with ORR (p≤0.016), PFS (p≤0.005), and OS (p≤0.029) of pembrolizumab but not of chemotherapy (p≥0.340, p≥0.643, and p≥0.174, respectively), and pembrolizumab improved efficacy versus chemotherapy in participants with TMB ≥175 mutations/exome.ConclusionsTMB ≥175 mutations/exome is associated with clinically meaningful improvement in the efficacy of pembrolizumab monotherapy and improved outcomes for pembrolizumab versus chemotherapy across a wide range of previously treated advanced solid tumor types. These data suggest TMB has broad clinical utility irrespective of tumor type, PD-L1 expression, or MSI status and support its use as a predictive biomarker for pembrolizumab monotherapy in participants with previously treated advanced solid tumors.

Project description:BACKGROUNDWe previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8+ T cell radiomics score (RS) and circulating cytokines.METHODSPatients received SBRT to 2-4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines.RESULTSIn the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%)dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90-5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS.CONCLUSIONSBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy.TRIAL REGISTRATIONClinicaltrials.gov NCT02608385FUNDINGMerck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.

Dataset Information

Tumor dynamics in patients with solid tumors treated with pembrolizumab beyond disease progression.

Publications

Tumor dynamics in patients with solid tumors treated with pembrolizumab beyond disease progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets