By Linda Zhao, Ph.D., Director, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Two important drugs obtained approval from the Food and Drug Administration (FDA) last year for use in relapsed/refractory chronic lymphocytic leukemia (CLL): Imbruvica® (ibrutinib, Pharmacyclics/Janssen) as a single agent in February 2014 and Zydelig® (idelalisib, Gilead) in combination with Rituxan® (rituximab, Genentech/Roche) in July 2014. Still, better treatment options with greater therapeutic outcomes are strongly needed in CLL treatment to prolong survival in these patients.
Imbruvica is a covalent inhibitor of Bruton’s tyrosine kinase (BTK), which is involved in the maturation and activation of B-cells and is implicated as a driver of B-cell related lymphomas and leukemias. Pharmacyclics and Janssen are aggressively developing Imbruvica in CLL across multiple lines of therapy and are looking beyond its recent approval as monotherapy and hoping that combining Imbruvica with the standard-of-care chemotherapy backbone in second-line – Rituxan plus Treanda (bendamustine, Teva/MundiPharma/Eisai), the BR regimen – will yield stronger clinical benefits over R-Treanda alone in the relapsed/refractory setting.
In September 2012, Janssen initiated the Phase III placebo-controlled HELIOS trial (NCT01611090) to evaluate the safety and efficacy of BR (up to six cycles) with or without Imbruvica (given until disease progression) in relapsed or refractory CLL or small lymphocytic lymphoma (SLL) patients; patients with del17p (> 20% of cells) were excluded. The trial completed enrollment of 578 patients in February 2014. The primary endpoint of the study is progression-free survival (PFS), and secondary endpoints include objective response rate (ORR), overall survival (OS), rate of minimal residual disease (MRD)-negative remissions, quality of life, and adverse events. In March 2015, Janssen announced that the independent data monitoring committee (IDMC) unanimously recommended unblinding the HELIOS trial, citing that the study met its primary endpoint by demonstrating a significant improvement in PFS in favor of the Imbruvica arm. Today, the much anticipated results from this trial were reported in Chicago at the American Society for Clinical Oncology (ASCO) annual meeting by Dr. Asher Alban Akmal Chanan-Khan as a Late Breakthrough Abstract oral presentation.1
The pre-planned interim analysis reported today confirmed the positive news as stated in the company’s news release. Enrolled patients had received a median of two prior lines of therapy and had a median age was 64 years old, and 38% of patients were Rai Stage III/IV. At a median follow-up of 17.2 months, the IDMC-assessed median PFS in the Imbruvica + BR arm was significantly longer than the control arm (not reached in the Imbruvica + BR arm vs. 13.3 months in the BR arm, HR: 0.203p< 0.0001). The PFS results were consistent across all subgroups analyzed. The ORR and complete remission (CR/CRi) rates were also significantly improved in the Imbruvica arm: 82.7% versus 67.8% and 10.4% versus 2.8%, respectively. Even though the median OS were not reached in either arm at the time of interim analysis, the survival curves suggest a benefit in favor of the Imbruvica + BR arm (HR 0.628, p=0.0598). This trend to OS benefit is all the more encouraging considering that patients with confirmed progressive disease in the BR + placebo arm were allowed per protocol to cross over to receive Imbruvica (a fact that may ultimately confound the ability to reach statistical significance).
Most adverse events (AEs) were similar between the two arms. The most common all-grade AEs were neutropenia (58.2% in the Imbruvica + BR arm vs. 54.7% in the placebo + BR arm) and nausea (36.9% in vs. 35.2%); the most common Grade 3/4 AEs were neutropenia, also similar in the two arms (53.7% vs. 50.5%), and thrombocytopenia (15.0% each arm). Rates of Grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhages occurred in 2.1% and 1.7% of patients, respectively.
The BR regimen is commonly used in second-line CLL (among patients who don’t receive single-agent Imbruvica) and is the most commonly used regimen used in the first-line setting. The addition of Imbruvica to this standard backbone regimen reduced the risk of progression or death by 80%, with few additional AEs (although with a slight increase in Grade 3/4 atrial fibrillation). The results reported here strongly confirm Imbruvica as an important treatment option for patients with previously treated CLL/SLL and pave the way to significantly expanded use of Imbruvica in relapsed/refractory disease and may even support the use of the Imbruvica + BR regimen in front-line. The excitement driven by the efficacy benefit seen in HELIOS is heightened by the fact that the safety profile with Imbruvica + BR is not worse than the safety profiles from Imbruvica or BR alone; this could alleviate physician concern regarding exacerbated side effects usually seen when two drugs are combined. Overall, the success of the HELIOS trial will significantly expand the commercial opportunity for Imbruvica in CLL, and it’s just the beginning: HELIOS is just one of the six pivotal trials of Imbruvica ongoing for CLL treatments. Ultimately it will maximize the commercial opportunities for Imbruvica if its use in combination with the BR regimens will displace the use of traditional chemotherapy in the second-line setting or expand its use into front-line.
The question raised by the discussant, Professor Lloyd Damon from the University of California San Francisco, was whether the HELIOS trial has asked the best question for CLL treatment. Dr. Damon compared the results of HELIOS with several other single-arm studies: an earlier Phase II trial of Imbruvica + BR2 and a combined analysis of several single-agent Imbruvica studies,3 citing the similarities between patient baseline features, prior regimens, ORR, CR, as well as the median PFS between these three studies. Dr. Damon suggested that the implication of the HELIOS trial may lie in whether chemotherapy can be omitted as first treatment for CLL/SLL. This issue is being explored in the ongoing Phase III ECOG E1912 study (which compares R-Imbruvica versus the historical R-FC (fludarabine and cyclophosphamide) regimen in previously treated patients) and the ALLIANCE A041202 trial (which compares Imbruvica versus R-Imbruvica versus BR alone in previously untreated elderly patients). Success in these trials could lead to a revolutionary change in CLL treatment. Of course, Gilead is also seeking to expand the role of Zydelig in CLL and has several ongoing randomized studies that will keep it in direct competition with Imbruvica across all lines of therapy.
With the recent introductions of Imbruvica, Zydelig, and Gazyva® (obinutuzumab, Genentech/Roche), the CLL treatment landscape has already changed drastically from just 15 months ago. The results from HELIOS today will support even further change, and with the number of ongoing Phase III trials for these agents as well as several other promising new drugs, outcomes for patients with CLL are beginning to look very bright.
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