Top Takeaways from ASH: Kinase inhibitors emerge as key therapies in ‘sea change’ of targeted medicine

Among the evolving novel therapies highlighted at the annual American Society of Hematology Annual Meeting and Exposition in Orlando, Fla. was the use of small molecule kinase inhibitors to treat lymphoma.

Experts were particularly excited by promising results reported on the oral Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica; Pharmacyclics, Janssen) as an adjunct or as monotherapy, as well as on the second generation BTK inhibitor ACP-196.

Combination Therapy

In patients with previously-untreated follicular lymphoma, a combination of ibrutinib and rituximab (Rituxan; Genentech, Biogen Idec) demonstrated good safety and robust clinical activity.

“This combination was well-tolerated, with an overall response rate of 82% and complete response rate of 27%,” Steven I. Park, MD, associate professor of medicine in the division of hematology/oncology, University of North Carolina School of Medicine, and director of the UNC Lineberger Lymphoma Oncology Program, told Healio.com.

The phase 2 data from Nathan Fowler, MD, at the University of Texas MD Anderson Cancer Center in Houston, and colleagues, suggest an alternative to common approaches of rituximab and either bendamustine (Treanda, Cephalon) or CHOP therapy in this treatment-naive population. But Park said it is too early to tell.

“Certainly, the response rates look promising, but we need a longer follow-up to determine whether this combination will be useful in the front-line setting for follicular lymphoma,” Park said.  

Joshua Brody, MD, director of the Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai Hospital, New York, shared similar sentiments. 

“This was new and exciting because ibrutinib is so well-tolerated that some doctors already use it a lot for other diseases,” Brody said. “Now maybe it can become, in the future, a standard therapy for follicular lymphoma. We are still some time away, but this was good evidence towards that.”

Single Agent

Ibrutinib as monotherapy has already been shown to be highly effective in treating chronic lymphocytic leukemia, Park noted.

Brody was equally excited by the first-ever phase 3 data on ibrutinib in patients with previously-treated mantle cell lymphoma, demonstrating the therapy was superior to the standard mTOR inhibitor temsirolimus (Torisel, Wyeth Pharmaceuticals) in PFS and overall response rate.

“BTK inhibitors, which are now FDA-approved for several kinds of leukemia and lymphoma, have been a revolution in the way we treat these patients,” he said.

Brody said that although the community already suspected the therapy would benefit this population, the results by Simon Rule, MD, Derriford Hospital, Plymouth, United Kingdom and colleagues are meaningful.

“it wasn’t a huge surprise,” he said. “But these findings are important — even after the FDA approved them – to give a high-level of evidence.”

New frontiers

Some additional small molecule inhibitors now entering the armamentarium surfaced at ASH, but Park emphasized “longer follow up is needed to determine what kind of roles the new agents will play.”

He touched on the BCL-2 inhibitor venetoclax (ABT-199, Genentech and AbbVie) — granted FDA breakthrough therapy designation for relapsed or refractory CLL with 17p deletion and more recently priority review for patients after one prior therapy — as well as PI3 kinase inhibitor idelalisib (Zydelig, Gilead) that is already FDA-approved for patients with relapsed follicular lymphoma after two prior therapies.

Brody pointed to research by Bonnie K. Harrington, DVM, at The Ohio State University in Columbus, Ohio, and colleagues in which the second-generation BTK inhibitor ACP-196 (Acerta Pharma) “appears to be as effective as ibrutinib in the first early studies, and might even have some reasons why it has the potential to be safer than ibrutinib.”

“Kinase inhibitors are part of this big sea change of moving away from standard chemotherapy toward things that are more specifically targeted …  and give our patients both high remission rates with a little less toxicity,” Brody said. – by Allegra Tiver

References:

Fowler N, et al. Abstract 470. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Rule S, et al. Abstract 469. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Harrington BK, et al. Abstract 2908. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: Brody reports receiving research funding and honoraria from Acerta Pharmaceuticals, Celldex Therapeutics, Gilead Sciences and Janssen Pharmaceutica, Merck & Co., and Pharmacyclics. Park reports receiving research funding from Seattle Genetics and Teva.