ASH 2015 Preview: Novel Agents and Combinations Progress in Hematologic Malignancies

Novel Agentsin Hematologic Malignancies

Gary Schiller, MD

In the last 5 years, the treatment paradigm for patients with hematologic malignancies has seen vast changes. These alterations continue their progress in the field with groundbreaking data and new ideas presented at the 2015 American Society of Hematology (ASH) Annual Meeting from December 5 through 8.

"We have witnessed a tremendous growth of therapeutic options in a number of hematologic malignancies," said Gary Schiller, MD, hematology and oncology in the Department of Medicine, Hematology and Oncology, Ronald Reagan UCLA Medical Center. "There have been so many changes in this last decade that I think hold promise for the future for most hematologic malignancies. They will not only be much easier to control and induce long-term survival, but there will be far fewer off-target therapies."

Novel therapies for patients with multiple myeloma and chronic lymphocytic leukemia (CLL) reign on the agenda of upcoming presentations at ASH. In an interview withTargeted Oncology, Schiller, ASH spokesperson, highlighted some of the top findings being presented at this year's meeting.

In treatment for acute myeloid leukemia (AML), Schiller highlighted data for the multikinase inhibitor midostaurin (PKC412). This novel agent was shown to prolong survival, compared with placebo, when combined with daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and as maintenance therapy in newly diagnosed patients withFLT3-mutated AML.

In the large phase III international study, 717 patients with untreated AML received midostaurin or placebo. According to the study's abstract, patients who received midostaurin had a median overall survival (OS) of 74.7 months compared with 26.0 months in the placebo arm.

"That is a positive trial with a survival advantage in the treatment group. That is a potential game-changer. Part of that is because we have had so little progress," Schiller said. "Here, you have a huge study upfront that shows survival advantages. Therefore, I think it will force the FDA to consider approving midostaurin, and that will have a big impact both within that indication for upfront management and maybe forFLT3-mutated patients in other settings."

Novel agent Venetoclax (ABT-199/GDC-0199) also has new, promising data ready for presentation at ASH that could be instrumental in FDA approval, according to Schiller. This agent demonstrated deep remissions in a phase II study for ultra-high risk patients with relapsed/refractory CLL with 17p deletion. In the abstract for its study, the objective response rate (ORR) with venetoclax monotherapy was 79.4% by independent review. Complete responses (CR) or CRs with incomplete hematologic recovery were experienced by 7.5% of patients.

"Venetoclax has shown a lot of single agent activity in CLL; it is a very interesting drug. CLL is a very common disease, for which there have not been a lot of therapeutic advancements in the last year," Schiller said. "Here, we have another drug that has a lot of single-agent activity. It stands to reason that more combinations might be studied in the future."

A number of reports will also focus on already approved treatments under exploration for new indications. These studies are looking at a host of treatments, including rituximab (Rituxan), idelalisib (Zydelig), ibrutinib (Imbruvica), ixazomib (Ninlaro), elotuzumab (Empliciti), and daratumumab (Darzalex).

Schiller noted that data would be presented from the phase II RESONATE-2 trial, which examined the efficacy of ibrutinib versus chlorambucil in elderly patients with treatment-naïve CLL or small lymphocytic leukemia. The drug is already approved in relapsed/refractory disease as well as in 17p deletion CLL. Treatment with single-agent ibrutinib was shown to be superior to chlorambucil across all measurements of efficacy.

Overall, ibrutinib reduced the risk of death by 84% compared with chlorambucil, according to the abstract. Updated data from this study will be presented during a late breaking abstract session.

"It is the newly diagnosed patients with CLL who need treatment. I think the abstract that will be presented could be a potential game changer that could influence our prescribing behavior right away," Schiller said.

Regarding future treatments of CLL, use of bendamustine and rituximab (BR) could evolve, as shown in results of a phase III study where idelalisib plus BR was superior to BR alone. On November 16, 2015, Gilead Sciences, the manufacturer of idelalisib announced that it had stopped this trial early following a positive interim analysis. These data add to the prior HELIOS trial, which explored ibrutinib plus BR in CLL.

"Bendamustine and rituximab is a tolerable regimen for frail, older people or patients with comorbidities. It is easy to deliver, has a high response rate, and generally has a short duration. However, what is nice about it is it is given in a very time-limited fashion," said Schiller. "The addition of a supplemental agent that does not add the toxicity but deepens the prolonged response would definitely be adopted in the potential frontline treatment for older people. The question will be: "how will it compare to novel combinations?"

Other important findings will be presented, including data from the pivotal phase III TOURMALINE-MM1 study, which examined ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. These data were pivotal in the recent FDA approval for ixazomib, an oral proteasome inhibitor. The decision followed a priority review and arrived 4 months ahead of schedule.

"We already know that it is an effective drug; it is already FDA approved," Schiller said. "Patients with myeloma have had more of an open door FDA policy regarding approvals on the basis of response. However, for this to be an oral proteasome inhibitor, that is a big deal for us."

Findings for other recently approved therapies for multiple myeloma will also be presented throughout the congress, specifically an update of the pivotal ELOQUENT-2 trial for elotuzumab and new findings for daratumumab in combination with lenalidomide and dexamethasone.

"These studies are very helpful, because people want to know where they will use daratumumab, for example," Schiller said. "In that trial, the addition of daratumumab in the relapse setting, it had an impact on response and progression-free survival, so that will teach us how to use the drug. It is more of a question regarding where to position the drug."

In the phase I/II GEN503 study, the combination of daratumumab, lenalidomide, and dexamethasone showed an ORR of 88% for patients with relapsed or relapsed/refractory multiple myeloma. At the meeting, updated data will be presented on the safety and efficacy of the combination for patients who received 12 months therapy.

"We have a lot of drugs that are effective in combination therapy in relapsed myeloma and positioning them in the various lines of therapy is a big question," said Schiller. "I wish that we had that kind of portfolio of management options [for ALL], but we don't. We have them exclusively for myeloma. However, it's a good paradigm that maybe the regulatory agencies could take a look at."

Even though the regulatory pipeline is not quite as full for ALL as myeloma, a number of findings will be presented at the meeting. In data from the phase III GRAALL-R 2005 study, the addition of rituximab to a multidrug chemotherapy regimen improved event-free survival (EFS) and prolonged OS in a select group of adult patients with newly diagnosed CD20-positive Ph-negative B-cell precursor ALL.

"It's not a perfect phase III randomized trial, but there was a survival benefit in patients who received rituximab in addition to conventional chemotherapy for ALL," Schiller said. "The problem with the trial is that the rituximab arm had more patients going on allogeneic transplant."

According to the abstract, after censoring the data for patients who received an allogeneic stem cell transplant while experiencing their first complete response, the 2-year EFS rate was 66% with rituximab versus 53% without. In this same group, the 2-year OS rate was 74% versus 63%, with and without rituximab, respectively.

The data will clinically impact practice, Schiller explained. "We have already started incorporating rituximab into the management of adult ALL," he added. "Because rituximab is available, whether it gets the label or not, it is pretty easy for us to incorporate it into management. That is a game changer that could be put to use tomorrow."