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Combination Trials Signal Next Wave of Treatment for CLL

Angelica Welch
Published: Tuesday, Oct 09, 2018

Shagun Arora, MD

Shagun Arora, MD

Within the last decade, the FDA has approved 8 new agents for the treatment of patients with chronic lymphocytic leukemia (CLL). This began in 2010 with rituximab (Rituxan), followed by obinutuzumab (Gazyva), ibrutinib (Imbruvica), idelalisib (Zydelig), ofatumumab (Arzerra), venetoclax (Venclexta), and most recently, duvelisib (Copiktra). Additionally, there are multiple agents targeting the CLL cell in clinical trials, including acalabrutinib (Calquence) and umbralisib.

According to Shagun Arora, MD, much effort is being put into determining optimal combinations and sequences with these available agents. Trials have investigated ibrutinib in treatment-naïve and relapsed/refractory patients, venetoclax after ibrutinib or idelalisib, venetoclax plus rituximab, ibrutinib plus venetoclax in treatment-naïve and relapsed/refractory patients, and immunotherapy with chimeric antigen receptor (CAR) T-cell therapy.

In a presentation during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Arora, assistant clinical professor of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed new agents and combination studies beyond chemoimmunotherapy for patients with CLL.

In a 5-year update of single-agent ibrutinib in treatment-naïve and relapsed/refractory patients with CLL, it was concluded that long-term use of the BTK inhibitor was well tolerated.1 Additionally, there were minimal adverse events (AEs) observed, with the most common AE at 5 years being hypertension.

"The median progression-free survival (PFS) is double what was seen with fludarabine-cyclophosphamide-rituximab (FCR) in relapsed/refractory CLL—and this is with just a single agent," explained Arora. "In deletion 17p [del(17p)], the median overall survival (OS) was 57 months with a 5-year OS of 32%."

However, most of the responses with single-agent ibrutinib were partial responses. Arora added that high-risk cytogenetics and number of prior therapies predicted inferior survival, and more work must be done for patients with del(17p). This is an area of particular need, as chemoimmunotherapy is not effective in patients with del(17p).

Ibrutinib was approved by the FDA in 2016 for the frontline treatment of patients with CLL based on data from the RESONATE-2 trial, which showed that ibrutinib improved PFS by 84% versus chlorambucil in previously untreated patients.2 Arora noted that this population was aged 65 years or older, and patients with del(17p) were not included.

In a National Institutes of Health study, which included patents with del(17p) and TP53 mutations, the 24-month PFS for treatment-naïve patients was 90%, Arora said.3 The MURANO trial investigated venetoclax plus rituximab versus bendamustine plus rituximab in patents with relapsed/refractory CLL. At a 23-month median follow-up, the median PFS was not reached with venetoclax plus rituximab versus 18.1 months (95% CI, 15.8-22.3) with bendamustine plus rituximab (HR, 0.19; 95% CI, 0.13-0.28; P <.0001).4 The overall response rate was 92% for the venetoclax arm and 72% for the bendamustine arm. These data led to a full FDA approval in June 2018 for venetoclax in CLL regardless of del(17p).

Currently, there are 3 main trials investigating the combination of ibrutinib and venetoclax: CLARITY (ISCRTN13751862), CAPTIVATE (NCT02910583), and a phase II single-center trial at The University of Texas MD Anderson Cancer Center (NCT02756897). "A combination that is being looked at in the world of CLL is ibrutinib with venetoclax—2 oral agents,” said Arora. “There are some preclinical data saying that there may be synergy, and as we know, they work a little different with ibrutinib being a BTK inhibitor and venetoclax working on BCL-2.”

The doses in these trials are the same that are being evaluated in different settings. CLARITY is looking at relapsed/refractory CLL, while CAPTIVATE is enrolling treatment-naïve patents. Arora says that these 2 trials are stopping treatment based on minimal residual disease (MRD) status. In CAPTIVATE, if the patients are MRD-negative after 12 cycles, they are being randomized to placebo versus single-agent ibrutinib. In CLARITY, they are stopping therapy all together once MRD negativity is reached.

Arora honed in on the third trial, which is being conducted by Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center. This study is investigating the combination of venetoclax and ibrutinib in patients with high-risk and relapsed/refractory CLL. Of the patients enrolled, 37 are relapsed/refractory, 40 are treatment-naïve with high-risk disease, del(17p), del(11q), or are IGVH-unmutated, reported Arora. These patients received venetoclax for 2 years and ibrutinib until progressive disease. Jain is looking at MRD, said Arora; however, the drug is not being stopped based on the results.

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