In interim results from the KEYNOTE-158 trial, pembrolizumab (Keytruda) monotherapy demonstrated durable antitumor activity, manageable safety, and improved overall survival (OS) in patients with advanced cervical cancer. Accordingly, the U.S. Food and Drug Administration has granted accelerated approval of the monoclonal antibody for use in patients with advanced programmed death-ligand 1 (PD-L1)–positive cervical cancer who have disease progression during or after chemotherapy.
Hyun Cheol Chung, MD, PhD, of Yonsei University College of Medicine in Seoul, South Korea, and colleagues reported an objective response rate (ORR) of 12.2% (95% CI 6.5-20.4), with three complete and nine partial responses. All 12 responses occurred in patients with PD-L1–positive tumors, for an overall response rate of 14.6% (95% CI 7.8-24.2%).
In addition, as shown in the study online in the Journal of Clinical Oncology, 14.3% (95% CI 7.4%-24.1%) of responses were in women who had received one or more lines of chemotherapy for recurrent or metastatic disease.
The investigators reported better OS than with other regimens used in this setting: a median of 9.4 months in the overall cohort and 11 months in the PD-L1–positive group. In contrast, a recent phase III study reported post-progression OS after first-line chemotherapy or chemotherapy plus bevacizumab (Avastin) of 7.1 and 8.4 months, respectively.
The open-label phase II KEYNOTE-158 basket study investigated the antitumor activity and safety of pembrolizumab monotherapy in multiple advanced solid tumor types.
The treatment cohort consisted of 98 patients from 42 sites in 17 countries, enrolled during January to August 2016. Patients received pembrolizumab 200 mg every 3 weeks for 2 years or until disease progression, intolerable toxicity, or physician or patient decision to stop.
Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks afterwards. The primary endpoint was ORR assessed with Response Evaluation Criteria in Solid Tumors (version 1.1) by independent central radiologic review. Safety was the secondary endpoint.
The median age of patients was 46 (range 24-75), and 65.3% had an Eastern Cooperative Oncology Group performance status of 1. Eighty-two patients (83.7%) had PD-L1–positive tumors (combined positive score ≥1), 15 were negative, and 77 had previously received one or more lines of chemotherapy for recurrent or metastatic disease.
Median follow-up was 10.2 months (range of 0.6-22.7 months), with responses usually occurring within 2.1 months, the researchers reported. They said the median duration of response was not reached (range of 3.7 to more than 18.6 months), but 50% of responses were ongoing at the time of data cutoff, and response rates were similar or superior to those observed with other therapeutic options in this setting.
"Response duration is a key consideration when assessing the clinical value of cancer therapies, and durability of response exceeded that observed with other agents available for the second-line or greater treatment of cervical cancer," the authors wrote.
Treatment-related adverse events occurred in 65.3% of patients, the most common being hypothyroidism (10.2%), decreased appetite (9.2%), and fatigue (9.2%). Treatment-related grade 3-4 adverse events occurred in 12.2% of patients.
"These results show that treatment with pembrolizumab offers a clinically meaningful therapeutic option for a subset of patients with previously treated advanced cervical cancer," Chung and co-authors wrote. They added that as the first immunotherapy approved for advanced gynecologic malignancy, the antibody is currently being tested in a clinical trial combining it with cisplatin chemotherapy and radiotherapy.
Asked for her perspective on the KEYNOTE-158 findings, Stephanie V. Blank, MD, of Icahn School of Medicine at Mount Sinai in New York City, who was not involved with the research, noted that PD-L1 inhibitors are also being studied in women with advanced cervical cancer who have not been previously treated, so these agents will possibly eventually be used earlier in the disease course.
"Although a more robust response has been seen in patients testing positive for PD-L1 in general, there may be other predictive biomarkers of response yet to be discovered," she told MedPage Today. "At present, approval is for cervical cancer patients who test positive for PD-L1 expression based on one specific test, and it is possible that this indication may be broadened as we learn more."
She added that other agents are still in evaluation, and data on these should be available soon. She said she has been using other immunotherapy agents at her center in clinical trials that specify a particular agent, but so far only pembrolizumab has been approved for this subgroup of cervical cancer patients.
"Immunotherapy is a very exciting approach for advanced and recurrent cervical cancer, a disease for which our treatment options are limited," Blank said. "It seems to work quite well in a subset of patients, and when it works, responses are durable. Determining which patients are most likely to benefit and how best to assess that benefit will allow us to use these drugs most effectively."
The study was supported by Merck Sharp & Dohme.
Chung reported financial relationships with Lilly, Foundation Medicine, Merck, Taiho Pharmaceutical, Celltrion, Eli Lilly, Quintiles, Bristol-Myers Squibb, Merck Serono, GlaxoSmithKline, Willeke Ros, Pfizer, and Roche; several co-authors also reported ties to various private-sector companies, including employment and ownership interests.
Blank reported having no competing interests to declare.
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