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.

The immune landscape and response to immune checkpoint blockade therapy in lymphoma

“…In both studies, no patient who achieved CR relapsed during follow-up. 89 As expected, PD-L1/2 SVs were common among evaluable biopsy specimens, and the presence of PD-L1 SVs (copy gains and amplifications) was associated with increased PD-L1 protein expression, which itself predicted for prolonged PFS in pembrolizumab-treated patients. 89 Finally, anti-PD-1 therapy has also demonstrated impressive activity in small numbers of patients with r/r PCNSL and PTL, although no prospective clinical trials have been completed.…”

“…89 As expected, PD-L1/2 SVs were common among evaluable biopsy specimens, and the presence of PD-L1 SVs (copy gains and amplifications) was associated with increased PD-L1 protein expression, which itself predicted for prolonged PFS in pembrolizumab-treated patients. 89 Finally, anti-PD-1 therapy has also demonstrated impressive activity in small numbers of patients with r/r PCNSL and PTL, although no prospective clinical trials have been completed. 90 The discovery of recurrent PD-L1 SVs in PCNSL and PTL was instrumental in providing the initial support for the use of PD-1 blockade in these rare, poor-prognosis DLBCLs.…”

The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

“…Furthermore, they also demonstrated that CD38 knock out tumors exhibit delayed growth when compared to CD38 + wild-type tumors in wild-type mice and that in tumor-bearing mice, combination of anti-CD38 antibody and anti-PDL-1 acts synergistically to suppress tumor growth and dissemination. These findings support the use of this combination in the clinical setting in the attempt to overcome resistance to checkpoint blockade, especially in those tumors where PD-1/PDL-1 inhibitors are especially effective, such as r/r cHL or primary mediastinal B-cell lymphoma (PMBCL) [94][95][96][97]. So far, this combination has been investigated in MM, where patient recruitment has been completed and final results are being elaborated (clinicaltrials.gov), and is currently being tested in HL/NHL (Table 1).…”

Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion

“…22 In previous studies, we and others defined common transcriptional signatures and key signaling and immune evasion pathways in these cancers. 11,14,[91][92][93][94] We used mirror bar plots ( Figure 7A) to compare the frequencies of the recurrent genetic alterations in cHL (Figure 4) to those in PMBL. 22 Like cHL, PMBL exhibited recurrent alterations of B2M, TNFAIP3, CSF2RB, XPO1, STAT6, GNA13, and chromosomes 2p/2p15 (2p16.1), 6p21.32, 6q23.3, and 9p/9p24.1 (Figure 7A), highlighting the shared genetic features of these diseases.…”