乌鸦传媒

Single-agent pembrolizumab (Keytruda) produced durable responses and encouraging survival in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL), according to long-term follow-up of a prospective study.

After a median follow-up of 48.7 months, 53 heavily treated patients had an overall response rate (ORR) of 41.5%, including complete responses (CRs) in 20.8%. Duration of response had yet to be reached. A third of patients remained progression-free at 4 years, and the 4-year overall survival (OS) rate was 45.3%. No patient who achieved a CR had relapsed or progressed to stem cell transplant (SCT).

Grade 3/4 adverse events (AEs) occurred in 22.6% of patients, but no grade 5 AEs occurred, reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy, and co-authors in .

"Given the long duration of follow-up after treatment, the durable responses were strongly suggestive of a curative potential for pembrolizumab in this subgroup [with CR] and supported observation rather than SCT for complete responders," the authors wrote in conclusion. "In addition, the depth of radiographic response appears to be the strongest predictor of outcome to date, which is similar to the response data observed with PD-1 inhibitors in Hodgkin lymphoma."

"The results of KEYNOTE-170 confirmed that PD-1 blockade is an effective and safe treatment option for R/R PMBCL, and an ongoing study ... is currently testing its role as first-line therapy," they added.

The trial had the longest follow-up to date of any study of PMBCL treated with a checkpoint inhibitor and provided several findings that should help inform treatment decisions, wrote Lisa Giulino-Roth, MD, of Weill Cornell Medical College in New York City, in an .

"First, there were a significant subset of patients who converted from a PR [partial response] to a CR (7 of 18 patients with an initial PR)," Giulino-Roth noted. "Second, among the 11 patients who achieved a CR, all remained in a CR at the time of data lockout without consolidative stem cell transplant or other additional therapy. This is a remarkable response in a heavily pretreated population ... Given the aggressive nature of PMBCL, with most relapses occurring early, this finding suggests that single-agent pembrolizumab may be curative in a subset of patients who achieve a CR."

"Last, in a post hoc analysis, patients with primary refractory disease (n=16) had inferior outcomes, with an ORR of 25% and no patients achieving a CR. In this higher-risk group, additional therapy beyond single-agent pembrolizumab is likely needed," she added.

The results firmly establish checkpoint inhibition as a third-line option for PMBCL, and the "next big question" is whether the drugs have a role in the second- or even first-line setting, she said.

The findings also added to those from the CheckMate 436 trial that evaluated PD-1 inhibitor nivolumab (Opdivo) plus brentuximab vedotin (Adcetris) after autologous SCT. That trial showed an ORR of 73%, despite brentuximab's limited in R/R PMBCL; duration of response was not reached.

A rare aggressive lymphoma that predominantly affects younger women, PMBCL has more similarities to classical Hodgkin lymphoma than non-Hodgkin lymphoma, including frequent amplification and translocation at 9p24.1, resulting in overexpression of PD-L1 and PD-L2. Those features provided a rationale for evaluating PD-1/L1 inhibition in PMBCL, along with the limited treatment options for patients with R/R disease, Zinzani and co-authors noted.

In a of R/R PMBCL, single-agent pembrolizumab resulted in an ORR of 41% and a duration of response that had yet to be reached after 11.3 months of follow-up. Evaluation of pembrolizumab continued in the phase II KEYNOTE-170 trial. Collectively, data from the phase I trial and initial results from KEYNOTE-170 for FDA approval of pembrolizumab as third-line treatment for R/R PMBCL.

Because PMBCL has few salvage options, long-term outcomes from KEYNOTE-170 remained a salient issue, which Zinzani and colleagues addressed in the report after 4 years of follow-up. The 53 patients had received a median of three prior lines of therapy, and 16 (30.2%) had primary refractory disease. All the patients had received rituximab (Rituxan), a third had prior radiotherapy, and a fourth had previous autologous SCT.

The trial's primary objective was ORR. Investigator-assessed best overall response (BOR) was CR in 11 (20.8%) patients and PR in 11. Six patients (11.3%) had a BOR of stable disease. Among 18 patients initially found to have a PR, eight retained that status during follow-up and three had progressive disease, in addition to the seven who subsequently converted to CR. The median time to CR was 2.7 months (range 2.2-5.5 months).

For all responding patients, the estimated 48-month response rate was 80.6%.

Four of 16 patients with primary refractory disease achieved PR with pembrolizumab, and no patient had a CR. Patients without primary refractory disease had an ORR of 46.9%.

The most commonly reported all-grade AEs were neutropenia (18.9%), asthenia (9.4%), hypothyroidism (7.5%), and fatigue and pyrexia (5.7% each). Four patients discontinued pembrolizumab because of treatment-related AEs.