Pembrolizumab Generates Sustained Responses in Relapsed/Refractory PMBCL

Pembrolizumab (Keytruda) produced sustained antitumor activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to data from the final analysis of the phase 2 KEYNOTE-170 trial (NCT02576990) published in Blood.¹

At a median follow-up of 48.7 months san(range, 41.2-56.2), findings showed that patients treated with pembrolizumab monotherapy (n = 53) achieved an investigator-assessed objective response rate (ORR) of 41.5% (90% CI, 30.0%-53.7%), including a 20.8% complete response (CR) rate. Among those who achieved a CR, the median time to CR was 2.7 months (range, 2.0-5.5) and the median duration of CR was not yet reached (NR; range, 33.7+ to 50.0+). Notably, the median duration of response (DOR) was NR (95% CI, NR-NR) and the estimated rate of continued responders at 48 months was 80.6%.¹

No patients who achieved a CR progressed or receivedconsolidation stem cell transplant or subsequent therapy at data cutoff. Among patients who initially experienced a partial response (PR; n = 18), 7 improved to a CR, 8 stayed in PR, and 3 experienced progressive disease.

The median progression-free survival (PFS) was 4.3 months (95% CI, 2.8-13.8), with a 48-month PFS rate of 33.0%. The median overall survival (OS) was 22.3 months (95% CI, 7.3-NR) with 45.3% of patients remaining alive at 48 months.

Previous findings from KEYNOTE-170 supported the FDA accelerated approval of pembrolizumab. On June 13, 2018, the agent gained approval for the treatment of adult and pediatric patients with refractory PMBCL, or patients who have relapsed following at least 2 prior lines of therapy.²

KEYNOTE-170 was an open-label, non-randomized trial that enrolled adult patients with PMBCL who experienced disease progression following, or were ineligible for, autologous stem cell therapy. Eligible patients also needed to have undergone a minimum of 2 prior lines of therapy. After enrollment, all patients were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks for a maximum of 35 cycles, or until disease progression, unacceptable toxicity, or withdrawal.¹

The co-primary end points were ORR by blinded independent central review and safety. Secondary end points consisted of ORR, DOR, PFS, and OS according to investigator assessment.¹

At baseline, the median age of enrolled patients was 33 years (range, 20-61). Most patients were female (57%), had an ECOG performance status of 1 (57%), and did not undergo prior transplantation (74%).3 The median number of prior lines of therapy was 3 (range, 2-8); all patients received prior rituximab (Rituxan), 32.1% underwent prior radiation; and 26.4% were treated with prior stem cell transplant.¹

Additional findings from a post-hoc analysis of the trial showed that among 16 patients with primary refractory PMBCL, the ORR was 25.0% and the median DOR was NR (95% CI, 11.1-NR). Patients who did not have primary refractory disease (n = 37) achieved an ORR of 46.9%, including 11 CRs, and a median DOR of NR (95% CI, NR-NR).

At the conclusion of treatment with pembrolizumab, 7 patients subsequently underwent stem cell transplantation with 5 being treated with autologous transplantation and 2 receiving an allogeneic transplant. One patient progressed following autologous stem cell transplantation, 1 experienced a PR, 1 achieved stable disease, and 3 experienced progressive disease. After allogeneic transplantation, 2 patients achieved a PR.¹

In the overall population, 24.5% of patients completed 2 years of treatment with pembrolizumab. The remaining 75.5% of patients discontinued treatment due to disease progression (34.0%), clinical progression (22.6%), adverse effects (AEs; 11.3%), and physician’s decision (5.7%). One patient discontinued before 2 years following CR.

In terms of safety, any-grade treatment-related AEs (TRAEs) were reported in 56.6% of patients. The most common any-grade TRAEs included neutropenia (18.9%), asthenia (9.4%), hypothyroidism (7.5%), fatigue (5.7%), and pyrexia (5.7%). Grade 3 or 4 TRAEs occurred at a rate of 22.6% and included neutropenia (13.2%), asthenia (1.9%), and increased aspartate aminotransferase (1.9%).

Serious TRAEs were reported in 7.5% of patients and 1 patient had to discontinue treatment due to a serious TRAE, although no deaths were attributed to TRAEs. Death due to AEs unrelated to treatment occurred in 3 patients, caused by myocardial infarction, cardiac tamponade, and Aspergillus infection. Immune-mediated AEs consisted of hyperthyroidism (n = 2), hypothyroidism (n = 4), pneumonitis (n = 1), and thyroiditis (n = 1). One instance of grade 4 immune-mediated pneumonia was reported.¹

Investigators concluded that PD-1 blockade with pembrolizumab was a safe and effective treatment providing durable responses for patients with relapsed/refractory PMBCL. Another PD-1 inhibitor, nivolumab (Opdivo), is being evaluated with chemoimmunotherapy as a first-line therapeutic option for patients with PMBCL in an ongoing phase 3 trial (NCT04759586).¹

References

1. Zinzani PL, Thieblemont C, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170. Blood. 2023;142(2):141-145. doi:10.1182/blood.2022019340
2. FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL. News release. FDA. June 13, 2018. Accessed July 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-treatment-relapsed-or-refractory-pmbcl
3. Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol. 2019;37(34):3291-3299. doi:10.1200/JCO.19.01389