Optimal sequencing of kinase inhibitors may yield durable responses in CLL treatment

Toxicity serves as the most common reason for kinase inhibitor discontinuation when treating chronic lymphocytic leukemia, according to results of a multicenter, retrospective analysis.

However, patients who discontinue treatment due to toxicity may achieve durable responses with alternate kinase inhibitors as second-line therapy, results showed.

After the FDA approval of ibrutinib (Imbruvica, Janssen) and idelalisib (Zydelig, Gilead) to treat patients with CLL, physicians have increasingly adopted them into their prescribing practices.

However, data on optimal sequencing of kinase inhibitors, as well as on outcomes of patients who discontinue use or are subsequently treated with another kinase inhibitor, had been lacking.

“In the absence of clear guidelines and randomized data, the unique toxicity profile for each agent and clinicians’ preference with either compound likely guide which agent is used first,” Anthony R. Mato, MD, assistant professor of medicine at Hospital of the University of Pennsylvania and Abramson Cancer Center, and colleagues wrote. “Furthermore, whether patients who discontinue one of these two agents derive any therapeutic benefit, if the alternate kinase is prescribed, has not been adequately studied. Data from landmark clinical trials suggest a discontinuation rate for ibrutinib or idelalisib as high as 35%. However, patients’ characteristics and treatment approaches following discontinuation have not been reported.”

Mato and colleagues evaluated patient responses, toxicity, postkinase inhibitor therapies and OS in patients who had discontinued kinase inhibitors. Researchers identified 178 patients with CLL treated at 10 U.S. academic cancer centers who discontinued treatment with ibrutinib (n = 143) or idelalisib (n = 35) from 2013 to 2015.

Researchers noted patients had high-risk features — such as deletion of 17p (35%), deletion of 11q (33%), p53 mutation (27%) and complex karyotype (29%) — and had received a median of three prior therapies.

Patients in the ibrutinib cohort were treated with a median starting dose of 420 mg daily for a median of 5 months. Eighteen percent of these patients required dose modification and 43% required dose interruption.

Patients in the idelalisib cohort received a median starting dose of 150 mg twice daily for a median of 5.5 months. Thirty-five percent of patients required dose modification and 64% required dose interruption.

ORR to first kinase inhibitor treatment was 58% in the ibrutinib cohort and 76% in the idelalisib cohort. Thus, ORR to first kinase inhibitor was 62% (complete response rate, 14%).

“Outcomes did not appear to differ whether ibrutinib or idelalisib was selected as the first or second kinase inhibitor, suggesting that either sequence is appropriate,” Mato and colleagues wrote.

The most common reasons for kinase inhibitor discontinuation included toxicity (ibrutinib, 51%; idelalisib, 52%), CLL progression (ibrutinib, 28%; idelalisib, 31%) and Richter’s transformation (ibrutinib, 8%; idelalisib, 6%).

Overall, the entire cohort demonstrated a median PFS of 10.5 months and median OS of 20 months over a median follow-up of 14 months.

After stratification for PFS or OS by reason of discontinuation, initial kinase inhibitor choice did not impact disease progression or survival. However, patients who developed Richter’s transformation experienced inferior OS compared with patients who discontinued due to toxicity and CLL progression (P = .001).

The most common choice for treatment after following kinase inhibitor discontinuation was an alternate kinase inhibitor (39%).

In addition, 114 patients received subsequent salvage therapy following kinase inhibitor discontinuation (64%). ORR to subsequent KI was 50% and median PFS was 11.9 months.

Median PFS in kinase inhibitor–intolerant patients treated with an alternate kinase inhibitor was not reached (range, .57-20 months). However, patients with CLL progression on the first kinase inhibitor and who were subsequently treated with an alternate kinase inhibitor experienced a median PFS of 7 months (range, .76-12 months).

“Because the number of patients who discontinue kinase inhibitor [treatment] due to toxicity or disease progression within the first 1 to 2 years of initiating therapy is not trivial, understanding the extent of kinase inhibitor toxicity or disease progression, and how these patients can be subsequently treated, is a critical area of research,” the researchers concluded. – by Kristie L. Kahl

Disclosure: Mato reports a consulting role with and/or research funding from AbbVie, Acerta, Celgene, Gilead, Janssen, Pharmacyclics, Pronai Therapeutics and TG Therapeutics. Please see the full study for a list of all other researchers’ relevant disclosures.