From the Journals

Pembrolizumab shows promise for relapsed/refractory PMBCL



The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.

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