The innovation that helped produce a dramatic leap forward in survival outcomes among patients across the spectrum of hematologic malignancies during the past decade has been continuing at a rapid pace, with the emergence of novel agents and therapeutic strategies with the potential to change treatment paradigms anew.
Thus far, the adoption of new therapies has been most pronounced in the chronic lymphocytic leukemia (CLL) field, where recently approved agents have been quickly integrated into treatment guidelines and clinical practice. The drug discovery pipeline is brimming with additional novel candidates for the treatment of patients with blood cancers, including new targeted drugs identified through the unfolding molecular characterization of these tumors.
The Pharmaceutical Research and Manufacturers of America reported that approximately 28% of 836 oncology drugs and vaccines in all stages of development are being evaluated in leukemias, multiple myeloma, and lymphomas. In recent weeks, OncLive
has interviewed leading researchers in those three categories about some of the promising therapies under development. While there are too many drugs under study to offer a complete picture, here is an overview of the experts’ outlook in certain subtypes of these malignancies.
Chronic Lymphocytic Leukemia
The PI3K inhibitor idelalisib (Zydelig) and the BTK inhibitor ibrutinib (Imbruvica) made a dramatic impact on the CLL field when they were approved in 2013 and 2014, respectively. Since then, several next-generation PI3K and BTK inhibitors, including duvelisib (IPI- 145), TGR-1202, ONO-4059, and ACP-196, have demonstrated promising data in early trials, suggesting that the newer agents may build on the success of the targeted therapies introduced in the past two years.
In addition, the novel Bcl-2 inhibitor, venetoclax (ABT-199), which received a breakthrough therapy designation from the FDA for patients with 17p deletion CLL in May 2015, has also shown potential.
In a phase II study for patients with relapsed or refractory CLL harboring the 17p deletion, venetoclax met its primary endpoint for overall response rate (ORR). Full study results have not been presented; however, previous studies have shown an ORR of 79% with venetoclax in CLL, with 26% of patients experiencing a complete response, and 53% of patients experiencing a partial response.
Venetoclax is likely to be the next inhibitor approved in CLL, according to Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and an associate professor of Medicine at Harvard Medical School.
“This drug is in very advanced clinical development and has shown excellent response rates in the order of 80% to 90% in relapsed refractory CLL,” said Brown. “Complete remission rates from 25% to 40% were observed in the combination study with rituximab. It is somewhat unique in its ability to induce complete remissions compared to other Bcl-2 inhibitors. It is in a number of registration trials, as well as combination therapy trials.
“I am very excited about ABT-199 as a novel class of inhibitors that affects Bcl-2, particularly because some of its mode of action suggests that it may be synergistic with and work well in combination with ibrutinib,” Brown added. “This could perhaps form the backbone for a potential combination therapy that is free of chemotherapy.”
In the PI3K inhibitor category, duvelisib is the most advanced in terms of clinical development. Duvelisib inhibits the delta isoforms of PI3K, as does idelalisib, and it also targets the gamma isoform. “The data with duvelisib look quite good so far,” Brown said. “In the follow-up of the phase I story, approximately 66% were still in remission at 2-years PFS [progression-free survival]. That drug is in registration trials that are ongoing.”
Another PI3K inhibitor exhibiting potential is TGR-1202, which is a delta-specific agent. “That is a next-generation molecule with a different structure, which we hope might reduce some of the hepatotoxicity that is seen with other PI3K inhibitors,” said Brown. “Efficacy data are still early and relatively immature, but the response rates with that drug in CLL look promising.”
In the realm of new BTK inhibitors, Brown points to two agents, ONO-4059 and ACP-196. “ONO-4059 had very promising phase I data a couple of years ago, and we are now awaiting additional trials,” said Brown.
“Unfortunately, no clinical data have been reported on [ACP-196]. However, [ACP-196] has a very extensive trial portfolio, including two phase III studies designed for potential registration that have been initiated. Notably, they are doing a head-to-head trial of ACP-196 versus ibrutinib in patients with relapsed CLL. It will be very interesting to see how these registration trials for these additional inhibitors develop over the next few years.”