Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma

Abstract

Purpose: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade.

Methods: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity.

Results: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. 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 study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.

Conclusion: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

FIG 1.

Study flow. (*) KEYNOTE-013. (†) KEYNOTE-170. (‡) Clinical progression refers to patients who, based on clinical signs and symptoms or pathologic findings, had malignant neoplasm progression but did not have progression according to the protocol-specified imaging response criteria (International Working Group 2007) or for whom imaging was not able to be performed for assessment.

FIG 2.

Antitumor activity in patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) treated with pembrolizumab. Percent change from baseline in target lesion size for evaluable patients by central review in (A) KEYNOTE-013 and (B) KEYNOTE-170 and treatment exposure and duration of response in (C) KEYNOTE-013 and (D) KEYNOTE-170. Eighteen patients in KEYNOTE-013 and 40 patients in KEYNOTE-170 were evaluable (had at least 1 postbaseline disease imaging assessment). Patients had stable disease (SD) unless otherwise indicated. CR, complete response; PD, progressive disease; PR, partial response.

FIG 3.

Survival in patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) treated with pembrolizumab. (A) Progression-free survival measured from first dose to first documented disease progression or death from any cause among 21 patients (KEYNOTE-013) and 53 patients (KEYNOTE-170) with rrPMBCL who received pembrolizumab. The estimated rates of patients alive and progression free at 12 months were 47% (KEYNOTE-013) and 38% (KEYNOTE-170), with median progression-free survival times of 10.4 months (95% CI, 3.4 months to not reached) among patients in KEYNOTE-013 and 5.5 months (95% CI, 2.8 to 12.1 months) among patients in KEYNOTE-170. (B) Overall survival measured from first dose to death from any cause. The estimated rates of overall survival at 12 months were 65% (KEYNOTE-013) and 58% (KEYNOTE-170), with median overall survival times of 31.4 months (95% CI, 4.9 months to not reached) among patients in KEYNOTE-013 and not reached (95% CI, 7.3 months to not reached) in KEYNOTE-170.

FIG 4.

Association between 9p24.1 status, PD-L1 expression, and progression-free survival. (A, left, top) Photomicrograph of a representative sample stained for programmed cell death-1 ligand (PD-L1) protein expression by chromogenic immunohistochemistry (positive staining indicated by brown coloration) and strong PD-L1 expression by the malignant cells (modified H-score, 240). (A, left, bottom) Photomicrograph of the same sample analyzed for PDL1/PDL2 copy number by fluorescence in situ hybridization (FISH; red = PDL1; green = PDL2; yellow = PDL1/PDL2 fused; aqua = pericentromeric chromosome 9) and PDL1/PD2 amplification within nuclei of the malignant cells (classified as amplified). (A, right) Distribution of PD-L1 H-scores across 36 patients (excluding rearrangements) according to PDL1/PDL2 status. P = .038 was determined by the Kruskal-Wallis rank-sum test. (B) Progression-free survival of 42 patients for whom PD-L1 H-score was determined and divided according to those with an H-score of 0 (blue line), H-score of 1-99 (red line), and H-score of ≥ 100 (green line). P = .029 was determined by the log-rank test. Cox regression with hazard ratios (HRs), 95% CIs, and Wald P values are also shown using patients with an H-score of 0 as the reference.

FIG A1.

Kaplan-Meier estimate of response duration by central review in patients with relapsed or refractory primary mediastinal large B-cell lymphoma treated with pembrolizumab.