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Pembrolizumab demonstrates ‘robust’ activity in relapsed, refractory primary mediastinal large B-cell lymphoma
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SAN DIEGO — Pembrolizumab demonstrated considerable antitumor activity among patients with relapsed or refractory primary mediastinal large B-cell lymphoma, according to results of the KEYNOTE-013 and KEYNOTE-170 studies presented at ASH Annual Meeting and Exposition.
The results served as the foundation for FDA accelerated approval of pembrolizumab (Keytruda, Merck) for these patients in June.
Patients with relapsed or refractory primary mediastinal large B-cell lymphoma typically receive treatments similar to those administered to patients with diffuse large B-cell lymphoma. However, effective treatment options are limited and outcomes often are poor.
Primary mediastinal large B-cell lymphoma — unlike DLBCL — often harbors genetic abnormalities that lead to overexpression of PD-L1 and PD-L2, indicating it should be sensitive to PD-1 blockade, according to study background.
Results of the phase 1b KEYNOTE-013 study showed pembrolizumab was associated with frequent and durable responses.
Philippe Armand, MD, PhD, senior physician, director of clinical research for the lymphoma program and chair in lymphoma research at Dana-Farber Cancer Center, and colleagues conducted the phase 2 KEYNOTE-170 study to build on the phase 1 findings and also examine correlative biomarkers of response.
At ASH, Armand presented updated results of all patients in KEYNOTE-013, as well as the first full analysis of patients in KEYNOTE-170.
The KEYNOTE-13 analysis included 21 patients with relapsed or refractory primary mediastinal large B-cell lymphoma who received a median three prior lines of therapy. Thirteen patients (62%) were ineligible for autologous stem cell transplant; the other eight failed or refused transplant.
The KEYNOTE-170 included 53 patients with elapsed or refractory primary mediastinal large B-cell lymphoma who received at least two prior therapies (median, 3). Of this group, 39 (74%) were ineligible for autologous stem cell transplant due to chemorefractoriness. The other 14 patients relapsed after transplant.
In KEYNOTE-013, the initial 10 patients received pembrolizumab 10 mg/kg every 2 weeks. The other 11 patients in that trial, as well as all patients on KEYNOTE-170, received pembrolizumab 200 mg/kg every 3 weeks for up to 2 years.
Investigators used archival or fresh tumor tissue obtained prior to pembrolizumab initiation to conduct correlative studies.
Objective response rate by blinded independent central review served as the primary endpoint for KEYNOTE-170. Secondary endpoints included PFS, OS, duration of response, safety and tolerability. Response by Lugano 2014 criteria and biomarker analyses served as exploratory endpoints.
In KEYNOTE-013, researchers reported an ORR of 48% (95% CI, 26-70), with 33% of patients achieving complete response. After median follow-up of 29.1 months (range, 0.6-49.6), median duration of response was not reached (range, 1.9+ months to 39.8+ months). To patients who were in response at 2 years remained in complete response after further 12- and 18-month follow-up off therapy.
Researchers reported median PFS of 10.4 months (95% CI, 3.4-not reached) and a 12-month PFS rate of 47%. Median OS was 31.4 months and 65% of patients remained alive at 12 months.
No new safety signals emerged in KEYNOTE-013.
In KEYNOTE-017, researchers reported an ORR of 45% (95% CI, 32-60), with 13% of patients achieving complete response. After median follow-up of 12.5 months (range, 0.1-25.6), median duration of response had not been reached (range, 1.1+ months to 22+ months). No patient who achieved a complete response had relapsed.
Researchers reported median PFS of 5.5 months (95% CI, 2.8-12.1) and a 12-month PFS rate of 38%. Median OS had not been reached (95% CI, 7.3-not reached), and 58% of patients remained alive at 12 months.
Thirty patients (57%) experienced treatment-related adverse events. The most common included neutropenia (19%), hypothyroidism (8%), asthenia (8%) and pyrexia (6%).
Twelve patients (23%) experienced grade 3 or grade 4 treatment-related adverse events, including 5 (9%) who developed grade 3 neutropenia and two (4%) who developed grade 4 neutropenia.
Six patients (11%) experienced an immune-mediated adverse event, including one (2%) who had grade 4 pneumonitis. No treatment-related deaths occurred.
“Together with the longer follow-up results of KEYNOTE-013, KEYNOTE-170 — the largest prospective clinical trial in relapsed or refractory primary mediastinal large B-cell lymphoma — establishes the robust antitumor activity of pembrolizumab in this disease,” Armand and colleagues wrote. “[The results show] exceptionally durable responses and survival in responding patients.” – by Mark Leiser
Reference:
Armand P, et al. Abstract 228. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosure: Armand reports research funding from Adaptive Biotechnologies, Affimed, Bristol-Myers Squibb, Merck, Otsuka, Roche and Tensha Therapeutics, and consultant roles with Affimed, Bristol-Myers Squibb, Infinity, Merck and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.