ASH 2016 | Long-term responses with pembrolizumab in patients with R/R cHL: results of phase 1b KEYNOTE-013 study

The Annual Meeting & Exposition of the American Society of Hematology (ASH) took place in San Diego, CA, on 3–6 December 2016.

On Monday 5^th December, an oral abstract session was held between 4:30pm and 6:00pm in the “Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies Program: Oral and Poster Abstracts” category. This session was moderated by Stephen Ansell, MD, PhD, of the Mayo Clinic, and Anas Younes, MD, of the University of Texas M.D. Anderson Cancer Center.

Abstract #1108 was presented during this session, titled “Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Long-term Efficacy from the Phase 1b Keynote-013 Study” by Philippe Armand, MD, PhD, of the Dana-Farber Cancer Institute, and colleagues.

Pembrolizumab was administered intravenously at a dose of 10mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity to classical Hodgkin Lymphoma (cHL) patients who had relapsed after or ineligible for ASCT, or relapsed or refractory to treatment with BV. Safety and Complete Remission (CR) were primary endpoints, secondary endpoints included Duration of Response (DoR) and Overall Response Rate (ORR). This presentation included CR rate, ORR and DoR by Blinded Independent Central Review (BICR). At the data cut-off of June 3^rd 2016, 31 patients were evaluable for analysis with a median follow-up duration of 24.9 months (7.0–29.7). The median number of prior lines of therapy was 5 (2–15); 74% of patients had failed prior ASCT and 100% patients had failed prior BV.

• Median DoR not reached

• ORR = 58% (18/31), 6 patients (19%) achieving CR and 12 patients (39%) achieving PR

• ORR in patients with no response to ≥1 prior line of therapy = 56% (n = 27)
• ORR in patients who relapsed after ≥3 prior lines of therapy = 75% (n = 4)
• At cut-off, 3 patients (10%) remained on treatment, 5 (16%) completed 2 years of treatment, and 23 (74%) discontinued treatment

• Median PFS = 11.4 months; 6-month PFS rate = 66%; 12-month PFS rate = 48%

• Median OS was not reached; 6-month PFS rate = 100%; 12-month OS rate = 87%

The presentation concluded by stating that these results indicate that heavily pre-treated cHL patients who have failed treatment with BV can achieve long-term responses with single-agent pembrolizumab without consolidative therapy. It is highlighted that, due to this tumor’s genetic dependence on the PD-1 pathway, PD-1 blockade may offer a new treatment paradigm patients with R/R cHL.

Abstract:

Background: Patients with classical Hodgkin lymphoma (cHL) who progress after brentuximab vedotin (BV) have a poor prognosis. cHL frequently harbors genetic alterations at the 9p24.1 locus, resulting in the overexpression of the PD-L1 and PD-L2 immune checkpoint ligands. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between the PD-1 receptor and PD-L1/PD-L2, and can restore antitumor immune activity in several different tumors. Based on its likely genetically driven dependence on PD-1, cHL was included as an independent expansion cohort in the KEYNOTE-013 study (NCT01953692), a multicenter, multicohort phase 1b trial of pembrolizumab in patients with hematologic malignancies. Updated results from this cohort, including long-term efficacy, are presented.

Methods: Key eligibility criteria for the cHL cohort of KEYNOTE-013 included relapse after or ineligibility for autologous stem cell transplantation (ASCT), and relapse after or refractory to BV treatment. Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed at week 12 and every 8 weeks thereafter according to the International Harmonization Project 2007 criteria. The primary end points were safety and complete remission (CR) rate (CRR); secondary end points included overall response rate (ORR) and duration of response (DOR). Patients who achieved a CR could opt to stop treatment after 24 weeks provided that they received at least 2 doses after CR. This report includes CRR, ORR, and DOR by blinded independent central review (BICR).

Results: At the time of data cutoff on June 3, 2016, 31 patients were enrolled, and all were evaluable for analysis. Median follow-up duration was 24.9 months (range, 7.0-29.7 months). The median number of prior lines of therapy was 5 (range, 2-15), 74% of patients had failed prior ASCT, and by design 100% had failed prior BV. Per investigator review, ORR was 65%, and CRR was 19%. Per BICR, ORR was 58% (18/31), with 6 patients (19%) achieving CR and 12 (39%) partial remission; 7 patients (23%) had stable disease as their best response. Median DOR was not reached, with a range of 0.0+ to 21.4+ months (95% CI, 3.7 months to not reached) (Figure).

An analysis with hierarchical mutually exclusive categories of refractory disease (RD; defined as no response to ≥1 prior line of therapy) or relapse after ≥3 prior lines of therapy (Re ≥3) was conducted. Per BICR, the ORR was 56% in RD (n = 27 patients) and 75% in Re ≥3 (n = 4). As of the data cutoff date, 3 patients (10%) remained on treatment, 5 (16%) completed 2 years of treatment, and 23 (74%) discontinued treatment: 3 (10%) for toxicity, 14 (45%) for progressive disease, 3 (10%) per physician decision (all ultimately underwent allogeneic SCT), 1 in CR (underwent allogeneic SCT), 1 for clinical progression, and 1 who withdrew consent. Per BICR, median progression-free survival (PFS) was 11.4 months; 6-month and 12-month PFS rates were 66% and 48%, respectively. Median overall survival (OS) was not reached; 6-month and 12-month OS rates were 100% and 87%, respectively.

Conclusions: With nearly 2.5 years of median follow-up, the present results demonstrate that a subset of heavily pretreated patients who failed BV therapy can achieve a long-term response with single-agent pembrolizumab, without consolidative therapy. PD-1 blockade may offer a new treatment paradigm for patients with relapsed/refractory cHL, supporting the hypothesis that this tumor has a genetic dependence on the PD-1 pathway.