Idelalisib Trial Stopped Because of 'Overwhelming Efficacy'

Roxanne Nelson, BSN, RN

December 09, 2015

ORLANDO, Florida — Another phase 3 trial has shown efficacy for idelalisib (Zydelig, Gilead Sciences, Inc) in relapsed or refractory chronic lymphocytic leukemia (CLL).

The novel drug was approved last year for use with rituximab (Rituxin, Genentech/Roche) in this setting. In the new trial, it was used in combination with rituximab and also chemotherapy with bendamustine (multiple brands). The manufacturer intends to file the new data for a supplementary approval.

However, an independent CLL expert who was not involved in the study questioned whether adding bendamustine yielded much benefit beyond that already seen with idelalisib and rituximab, although it would increase toxicity.

The new trial, known as study 115, showed that the three-drug regimen of idelalisib, rituximab, and bendamustine was superior to the combination of rituximab and bendamustine, increasing both progression-free survival (PFS) and overall survival (OS). In fact, the trial was stopped early owing to "overwhelming efficacy," the trialists said here at the American Society of Hematology (ASH) 57th Annual Meeting.

"There was a 67% reduction of the risk of progression or death, and 45% reduction in death from relapsed/refractory CLL," said lead author Andrew D. Zelenetz, MD, PhD, vice chair of medical informatics in the Department of Medicine and attending physician with the Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York City. The results were also consistent in patients with or without high-risk features, such as del(17p)/TP53, unmutated IGHV, and refractory disease, he told attendees.

The safety profile was consistent with previously reported studies. "These new findings add to the role of idelalisib-containing regimens for the treatment of relapsed CLL," Dr Zelenetz commented in a statement.

Caused a Stir

Idelalisib is a first-in-class targeted PI3k delta inhibitor that received FDA approval last year for use in combination with rituximab in patients with relapsed CLL and as first-line treatment in cases involving 17p deletion or TP53 mutation in patients for whom chemo-immunotherapy was unsuitable.

Gilead has said that it will submit the results from the latest study for supplemental approval in both Europe and the United States.

As previously reported by Medscape Medical News, idelalisib caused quite a stir when early clinical results showing that the drug produced rapid and long-lasting tumor shrinkage in half of patients with relapsed or treatment-resistant CLL were presented at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The Missing Third Arm

Approached for comment, Tait Shanafelt, MD, professor of medicine at the Mayo Clinic, Rochester, Minnesota, wondered whether the three-drug combination was really more effective than idelalisib and rituximab alone.

Bendamustine and rituximab are frequently used in the relapsed setting, but with new agents being approved, one question is how best to use them. "Are they best applied individually or, in idelalisib's case, with rituximab? Or are they best combined with standard chemotherapy to maximize or enhance the benefit?" he questioned.

In the current study, adding idelalisib to the standard therapy improved outcomes, so it was clear that the new drug provided a benefit. "So while it's clear that the new medication adds something beyond the old, what is not clear is if the three-drug combination is better than idelalisib with rituximab alone," Dr Shanafelt said in an interview. "What we don't know is if the benefit that we're seeing is due to the fact that it was the only arm that received idelalisib and that the novel agent is more effective in relapsed patients than traditional therapies.

"We know that combining it with chemotherapy is going to enhance the side effects, so we have to wonder what would be the results if there had been a third arm in this trial ― idelasisib together with rituximab ― and then we could see if the three-drug combination was really any better," he said.

Study Details: Improved Outcomes, Higher Toxicity

The study was conducted in 416 patients with relapsed/refractory CLL. Patients were randomly assigned to receive bendamustine/rituximab for 6 cycles Q 28 days (B = 70 mg/m2 D1, D2 of each cycle; R = 375 mg/m2 C1 and 500 mg/m2 C2 - C6) and idelalisib 150 mg BID or placebo (administered continuously).

Treatment was administered until disease progression, death, intolerable toxicity, or withdrawal of consent.

After 12 months of follow-up, the median PFS with idelalisib was 23.1 months compared with 11.1 months for bendamustine/rituximab alone (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.24 - 0.45; P < .0001), which was highly statistically significant.

"The 11.1 months was very consistent with what we'd expect for bendamustine and rituximab, so this represents a substantial increase in progression-free survival," said Dr Zelenetz.

The median OS has not yet been reached in either arm (HR, 0.55; 95% CI, 0.36 - 0.86; P = .008), although to date, there have been 34 (16.4%) deaths in the idelalisib arm vs 51 (24.4%) in the double-therapy arm.

Adding idelalisib to the treatment regimen, however, increased the rate of toxicities. Although adverse events of any grade were experienced by virtually all study participants, grade ≥3 adverse events were reported by 93% of patients in the idelalisib arm vs 76% of those who received bundamustine/rituximab alone.

Serious events were observed in 66% of patients treated with idelalisib vs 44% of those in the control arm, and almost double the number of patients discontinued treatment in the idelalisib arm because of toxicity (n = 54 [26%] vs n = 28 [13%]).

The most common grade ≥3 toxicities seen in the investigational arm were neutropenia (59.9%), ALT abnormality (21.3%), febrile neutropenia (20.3%), and AST abnormality (15.5%). For benamustine/rituximab alone, they were neutropenia (45.9%) and anemia (12%). Grade ≥3 ALT and AST abnormalities were seen in 2.9% and 3.3% of patients in the placebo arm, respectively.

The study was funded by Gilead, manufacturer of idelalisib. Dr Zelenetz has received research funding from Gilead. Several coauthors report relationships with industry, including Gilead, as noted in the abstract.

57th Annual American Society of Hematology (ASH) Meeting and Exposition. Abstract LBA-5. Presented December 7, 2015.

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