Recent data suggest that PD-1 and its ligands, PD-L1/PD-L2, mediate immune evasion in chronic lymphocytic leukemia (CLL). However, pembrolizumab alone is ineffective in patients with CLL (objective response rate [ORR], 0%; median progression-free survival [PFS], 2.4 months).1 However, in 5 patients with relapsed/refractory (R/R) CLL, 3 responded to the combination of ibrutinib plus nivolumab.2 It appears that a key interaction exists between PI3K signaling and immune checkpoint surveillance, by which inhibition of PI3K decreases PD-L1 tumor expression. Thus, one could hypothesize synergistic activity with PD-1 + P13K blockade. At ASH 2017, the authors reported on the safety and activity of umbralisib, a next-generation, highly-specific PI3K-delta inhibitor, in combination with pembrolizumab and the glycoengineered anti-CD20 monoclonal antibody ublituximab in R/R CLL, representing the first reported combination of a PD-1 inhibitor with a PI3K-delta inhibitor.3
This was a phase 1, multicenter study to assess the safety of pembrolizumab in combination with umbralisib and ublituximab in patients with R/R CLL. Treatment involved 3 stages: patients received umbralisib (800 mg daily) and ublituximab (900 mg 3 of 4 weeks) for the first 2 cycles (induction), and pembrolizumab (dose-level 1, 100 mg; dose-level 2, 200 mg) was then initiated every 3 weeks in combination with umbralisib daily and ublituximab (900 mg week 2 of cycles 4 and 6) for cycles 3 through 6 (consolidation). Upon completion of cycle 6, patients continued umbralisib 800 mg daily until progressive disease or unacceptable toxicity (maintenance). The primary end point was safety of pembrolizumab, umbralisib, and ublituximab; efficacy was a secondary end point.
A total of 10 patients were initially treated—9 with CLL and 1 with Richter’s transformation (RT). At ASH 2017, the authors reported on the 9 CLL patients who were evaluable for safety and efficacy. The patients had a median of 1 prior therapy, 56% had been treated with a Bruton’s tyrosine kinase (BTK) inhibitor (ibrutinib or acalabrutinib) prior to study enrollment, and all had been refractory to BTK therapy; 78% had ≥1 high-risk genetic features (del17p, del11q, TP53 mutation, NOTCH1 mutation, or complex karyotype).
Observed adverse events included neutropenia, cough, leukopenia, and decreased appetite. Increases in expected grade ≥3 PI3K-delta–associated toxicities, including pneumonitis, colitis, and transaminitis, were not observed. The ORR was 75% for the non–BTK-refractory patients and 60% in BTK-refractory patients. Proportions of the major T-cell subsets (including Tregs) and PD-1 levels did not change appreciably during therapy.
The authors concluded that the triplet combination of umbralisib, ublituximab, and pembrolizumab was well-tolerated, with durable responses in CLL patients refractory to BTK inhibitor therapy. Enrollment is ongoing in both the CLL and RT cohorts.
- Ding W, et al. Blood. 2017;129:3419-3427.
- Jain N, et al. Blood. 2016;128:59 (ASH 2016 abstract).
- Mato AR, et al. ASH 2017. Abstract 3010.