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Association of Tumor Mutational Burden With Response to Pembrolizumab in Previously Treated Patients With Advanced Solid Tumors


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A prospective biomarker analysis of the multicohort phase II KEYNOTE-158 trial reported by Marabelle et al in The Lancet Oncology found that patients with previously treated advanced solid tumors were more likely to respond to pembrolizumab monotherapy if they had high tissue tumor mutational burden.

Study Details

The study involved patients with advanced unresectable or metastatic tumors (eligible types included anal, biliary, cervical, endometrial, neuroendocrine, salivary, small cell lung, thyroid, and vulvar, as well as mesothelioma) who were enrolled between January 2016 and June 2019. Patients had to have disease progression on or intolerance to one or more lines of standard therapy, as well as measurable disease on Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) on independent central radiologic review.

“[High tumor mutational burden status] identifies a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy. Tissue tumor mutational burden could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.”
— Marabelle et al

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Patients received pembrolizumab at 200 mg every 3 weeks for up to 35 cycles. The efficacy population for the current analysis consisted of patients with evaluable tissue tumor mutational burden data who were enrolled at least 26 weeks before data cutoff in June 2019. High tissue tumor mutational burden status was defined as ≥ 10 mutations/Mb. The primary endpoint was the proportion of patients with objective response according to RECISTv1.1 on independent central review.

Key Findings

A total of 1,050 of 1,066 patients (98%) were enrolled by at least 26 weeks before data cutoff. Of these patients, 790 (75%) were evaluable for tumor mutational burden. Of the 790 patients, 102 (13%) were classified as having high tissue tumor mutational burden, and 688 (87%) did not have high tissue tumor mutational burden (< 10 mutations/Mb). Median follow-up was 37.1 months.

Objective responses were observed in 30 of 102 patients (29%, 95% confidence interval [CI] = 21%–39%) in the high tumor mutational burden group and 43 of 688 (6%, 95% CI = 5%–8%) of those classified as not having high tumor mutational burden. A complete response was observed in 4 (4%) vs 11 (2%) patients. An additional 14% vs 33% had stable disease.

The median duration of response was not reached in the high tumor mutational burden group (range = 2.2+ to 34.8+ months) and was 33.1 months (4.0–35.7+ months) in those without high tumor mutational burden as of data cutoff.

An objective response was observed in 24 of 68 patients (35%) with both a high tumor mutational burden and PD-L1–positive tumors (Combined Positive Score ≥ 1) and in 6 of 29 patients (21%) without a high tumor mutational burden and PD-L1–negative tumors. Among patients without a high tumor mutational burden, an objective response was observed in 33 of 383 (9%) with PD-L1–positive tumors and 9 of 274 (3%) with PD-L1–negative tumors.

Median progression-free survival was 2.1 months (95% CI = 2.1–4.1 months) in the high tumor mutational burden group and 2.1 months (95% CI = 2.1–2.2 months) in those without a high tumor mutational burden. Median overall survival was 11.7 months (95% CI = 9.1–19.1 months) vs 12.8 months (95% CI = 11.1–14.1 months).   

The investigators concluded: “[High tumor mutational burden status] identifies a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy. Tissue tumor mutational burden could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.”

Aurélien Marabelle, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit thelancet.com.


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