Idelalisib Use Expands With New CLL Indication Pending

Jeffrey A. Jones, MD, MPH

The utilization of idelalisib (Zydelig) increased substantially between the first and second quarters of 2015, representing promising growth in a highly competitive setting, according to Gilead Sciences, the developer of the drug.

Sales for the PI3K delta inhibitor rose from $26 million in the first quarter of 2015 to $30 million in the second, representing an 15% increase. At the time of the second quarter analysis, idelalisib had been on the market for nearly one year, having gained approval chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma in July 2014. Sales immediately following the approval totaled $6 million and $17 million, in the third and fourth quarters of 2014, respectively.

Building on this success, Gilead has filed an application with the FDA to expand the indication of idelalisib to include use in combination with ofatumumab for patients with relapsed CLL. This new application is based on findings from a phase III trial known as Study 119, which showed an improvement in objective response rates (ORR), progression-free survival (PFS), and lymph node response (LNR) with the combination of idelalisib and ofatumumab compared with the CD20 inhibitor alone in patients with previously treated CLL.¹

"It has been fascinating the rate of innovation we have seen in the blood cancer space, and it has gotten extremely crowded, leaving fewer opportunities for new products," John F. Milligan, PhD, president and chief operating officer of Gilead, said during a webcast. "It's clear that we're going to be active, and we're open to opportunities that can better our portfolio."

Study 119 randomized 261 patients with CLL who progressed within 24 months from their last therapy to idelalisib plus ofatumumab (n = 174) or single-agent ofatumumab (n = 87). Patients were stratified based on relapsed versus refractory status, 17p deletion (del17p) and/or TP53 mutation status, and whether they harbored an IGHV mutation.

The combination reduced the risk of disease progression by 73% versus single-agent ofatumumab, with a medium PFS of 16.3 versus 8.0 months, respectively (HR = 0.27; P <.0001). In patients with del17p or TP53 mutations, the median PFS was 13.7 versus 5.8 months, respectively (HR = 0.33; P <.0001).

The overall response rate was 75.3% in the combination arm versus 18.4% in the ofatumumab alone arm (odds ratio [OR] = 15.9; P <.0001). In the ofatumumab arm, the LNR rate was 93.3% versus 4.9% in the ofatumumab arm (OR = 487; P <.0001).

However, at the time of the analysis, improvements in ORR, PFS, and LNR had not yet translated into extensions in overall survival (OS), with data still maturing. Medium OS was 20.9 months in the idelalisib/ofatumumab arm compared with 19.4 months in the ofatumumab arm (HR = 0.74; P = .27).

“The data reported reinforce prior results showing that idelalisib, here in combination with the anti-CD20 monoclonal antibody ofatumumab, not only significantly improved overall and lymph node response rates, but more importantly progression-free survival in patients with previously treated CLL,” lead investigator Jeffrey A. Jones, MD, MPH, Associate Professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, said in a statement. “Importantly, these improvements were also observed in patients with genetic features typically associated with poor prognosis.”

The initial CLL approval for idelalisib was based on early data from the phase III Study 116 trial that randomized 220 patients in a 1:1 ratio to receive oral idelalisib plus rituximab (n = 110) or rituximab and placebo (n = 110). Patients had received a median of 3 prior therapies, 44% had del17p or TP53 mutations, and 84% were IGHV-unmutated.

In data from a second interim analysis presented at the 2014 ASH Annual Meeting,² the ORR with idelalisib plus rituximab was 77% versus 15% with rituximab and placebo (Odds ratio = 19.6; 95% CI, 9.6-39.9). The median OS was not reached in either arm, with an early 72% increase seen with idelalisib (HR = 0.28; 95% CI, 0.11-0.69).

Median PFS was 5.5 months with placebo and rituximab and was not yet reached with idelalisib, representing a 82% improvement (HR = 0.18; 95% CI, 0.10-0.32). This benefit was consistent across subgroups. The 12-month PFS rates were 66% versus 13% for idelalisib and placebo, respectively.

“Zydelig has now demonstrated strong efficacy in two randomized phase III studies among previously treated CLL patients,” Norbert Bischofberger, PhD, executive vice president of Research and Development and chief scientific officer at Gilead, said in a statement. “We continue to explore the clinical profile of Zydelig in combination with both standard and novel treatment regimens, including seven ongoing or completed phase III clinical trials for B-cell malignancies.”

In addition to combination strategies, idelalisib has been explored as a monotherapy in treatment-naïve patients ≥65 years with CLL or SLL.³ In a 38-patient phase II study, single-agent idelalisib showed an ORR of 87%. The 9-month PFS rate was 83% and the median had not been reached.

Outside of CLL, idelalisib was also granted an accelerated approval as a treatment for patients with SLL or follicular lymphoma. In the pivotal phase II trial for this indication, treatment with single-agent idelalisib demonstrated an ORR of 54% for patients with follicular lymphoma and 61% for patients with SLL, with complete remission rates of 14% and 4%, respectively.⁴

The approval for idelalisib includes a Boxed Warning regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation. To address concerns with these side effects, idelalisib is also being approved along with a Risk Evaluation and Mitigation Strategy (REMS).

Ongoing studies continue to assess idelalisib in hematological malignancies, with results anticipated from a phase III study looking at the agent in combination with bendamustine and rituximab for previously treated patients with indolent non-Hodgkin lymphomas (NCT01732926). Additionally, a phase III study exploring idelalisib plus rituximab is currently enrolling participants with previously treated indolent non-Hodgkin lymphomas (NCT01732913).

References

1. Sharman JP, Coutre SE, Furman RR, et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 330.
2. Jones JA, Wach M, Robak T, et al. Results of a phase III randomized, controlled study evaluating the efficacy and safety of idelalisib (IDELA) in combination with ofatumumab (OFA) for previously treated chronic lymphocytic leukemia (CLL). J Clin Oncol. 2015;33 (suppl; abstr 7023).
3. Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase II study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 1986.
4. Gopal AK, Kahl BS, de Vos S, et al. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 1708.