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Use of Pembrolizumab in Advanced Pleural Mesothelioma: Results From KEYNOTE-158


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The largest single-arm trial evaluating pembrolizumab in relapsed malignant pleural mesothelioma has demonstrated an “impressive” duration of response, according to a presentation during the virtual edition of the International Association for the Study of Lung Cancer (IASLC) 2020 North America Conference on Lung Cancer.1 The median duration of response was 14.3 months in the 10 patients with a partial response, and these responses were seen regardless of PD-L1 expression status. The results from the KEYNOTE-158 study showed an overall response rate of 8.5%.


“Pembrolizumab is still an attractive option in relapsed disease, but more research is needed to improve patient selection for this approach.”
— Melina E. Marmarelis, MD, MSCE

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Discussant of the abstract, Melina E. Marmarelis, MD, MSCE, of Abramson Cancer Center at the University of Pennsylvania, Philadelphia, called the results on duration of response “surprising and impressive.”

“Given the favorable toxicity profile, the duration of response, and limited treatment options in the second-line treatment of malignant pleural mesothelioma, pembrolizumab is still an attractive option in relapsed disease, but more research is needed to improve patient selection for this approach,” Dr. Marmarelis said.

Lead study author, Timothy A. Yap, MBBS, PhD, FRCP, a medical oncologist and physician-scientist, who is Associate Professor at The University of Texas MD Anderson Cancer Center, Houston, noted that the median overall survival with second-line chemotherapy or targeted therapy in malignant pleural mesothelioma is approximately 7 to 8 months.


“The median duration of response in the 10 responders in the overall patient population was 14.3 months.”
— Timothy A. Yap, MBBS, PhD, FRCP

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In a previous related study, KEYNOTE-028,2 pembrolizumab demonstrated an overall response rate of 20%, a median progression-free survival of 5.5 months, and a median overall survival of 18.7 months in patients with PD-L1–positive mesothelioma.

Study Details

KEYNOTE-158 is a phase II, multicohort study in rare cancers, including malignant pleural mesothelioma. Dr. Yap and colleagues enrolled patients who met the following eligibility criteria: failure of, disease progression on, or intolerance to at least one line of standard therapy for unresectable and/or metastatic disease; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and Eastern Cooperative Oncology Group performance status of 0 or 1. Provision of a tumor sample for biomarker assessments was also mandated, and any PD-L1 status was permitted. PD-L1 positivity was defined as a PD-L1 Combined Positive Score (CPS) of at least 1, and PD-L1 negativity was defined as a PD-L1 CPS of less than 1.

Pembrolizumab was administered intravenously at a standard dose of 200 mg every 3 weeks for 35 cycles (approximately 2 years) or until disease progression, intolerable toxicity, investigator decision, or participant withdrawal.

The primary endpoint of the study was overall response rate per RECIST version 1.1 by central review. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Patients were assessed for response every 9 weeks for 12 months and every 12 weeks thereafter.

Median Duration of Response of 14.3 Months

As Dr. Yap reported, a total of 118 participants with previously treated advanced malignant pleural mesothelioma were enrolled. At data cutoff in June 2019, the median study follow-up was 38.5 months. The median age of patients was 68 years, and the majority were men.

In addition, 65% of patients had a PD-L1–positive tumor, and 1% had microsatellite instability–high disease. The majority of patients had received at least two prior lines of therapy.

The overall response rate was 8.5%, said Dr. Yap. Among those who responded, six patients (7.8%) had PD-L1–positive tumors, and four patients (12.9%) had PD-L1–negative tumors.

KEY POINTS

  • Pembrolizumab demonstrated antitumor activity in previously treated participants with advanced mesothelioma, regardless of PD-L1 status.
  • Responses were durable, with a median duration of response of 14 months.

Of note, said Dr. Yap, the median duration of response in the 10 responders in the overall patient population was 14.3 months. The estimated percentages of patients with an ongoing response at 6 months and 12 months were 70% and 60%, respectively.

Of the 109 patients with postbaseline tumor assessments by RECIST version 1.1, 17 patients (15.6%) had a reduction of at least 30% in their target lesions.

At data cutoff, 115 of 118 patients (97%) had died or experienced disease progression, and 103 of 118 patients (87%) had died due to any cause. The estimated rates of progression-free survival at 6 months and 12 months were 27% and 11%, respectively. The median overall survival with pembrolizumab was 10 months, with approximately 45% of patients expected to be alive at 12 months.

Finally, toxicity was consistent with previous studies evaluating pembrolizumab monotherapy. Treatment-related adverse events occurred in 69% of patients, said Dr. Yap, but most were grade 1 or 2. Treatment discontinuation due to treatment-related adverse events occurred in 11% of patients, and one patient died of treatment-related apnea. 

DISCLOSURE: Dr. Marmarelis holds stock or other ownership interests in Bluebird Bio, Gilead Sciences, Johnson & Johnson, Merck, Pfizer, and Portola Pharmaceuticals; has received honoraria from Novocure and Targeted Oncology; has an immediate family member who has received honoraria from Health Advances; has served as a consultant or advisor to AstraZeneca and Boehringer Ingelheim; has received institutional research funding from AstraZeneca, Lilly, and Trizell; has been reimbursed for travel, accommodations, or other expenses by Boehringer Ingelheim and Novocure; and has held other relationships with Novartis. Dr. Yap has received research support (paid to institution) from AstraZeneca, Bayer, Pfizer, Tesaro, Jounce, Eli Lilly, Seattle Genetics, Kyowa, Constellation, EMD Serono, Ipsen, Forbius (Formation Biologics), and Vertex Pharmaceuticals; has served on scientific advisory boards for Pfizer, Atrin, Bayer, Cybrexa, I-Mab, and Seattle Genetics; and has consulted for Aduro, Almac, AstraZeneca, Atrin, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Janssen, Merck, Pfizer, Roche, Seattle Genetics, and Vertex Pharmaceuticals.

REFERENCES

1. Yap TA, Nakagawa K, Fujimoto N, et al: Pembrolizumab for advanced mesothelioma: Results from the phase 2 KEYNOTE-158 study. 2020 North America Conference on Lung Cancer. Oral Abstract Session 1. Presented October 16, 2020.

2. Ott PA, Bang Y, Piha-Paul SA, et al: T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol 37:318-327, 2019.


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