New Blood Cancer Landscape Taking Shape

The innovation that helped produce a dramatic leap forward in survival outcomes among patients across the spectrum of hematologic malignancies during the past decade has been continuing at a rapid pace, with the emergence of novel agents and therapeutic strategies with the potential to change treatment paradigms anew.

Thus far, the adoption of new therapies has been most pronounced in the chronic lymphocytic leukemia (CLL) field, where recently approved agents have been quickly integrated into treatment guidelines and clinical practice. The drug discovery pipeline is brimming with additional novel candidates for the treatment of patients with blood cancers, including new targeted drugs identified through the unfolding molecular characterization of these tumors.

Chronic Lymphocytic Leukemia

The Pharmaceutical Research and Manufacturers of America reported that approximately 28% of 836 oncology drugs and vaccines in all stages of development are being evaluated in leukemias, multiple myeloma, and lymphomas. In recent weeks, OncLive has interviewed leading researchers in those three categories about some of the promising therapies under development. While there are too many drugs under study to offer a complete picture, here is an overview of the experts’ outlook in certain subtypes of these malignancies.The PI3K inhibitor idelalisib (Zydelig) and the BTK inhibitor ibrutinib (Imbruvica) made a dramatic impact on the CLL field when they were approved in 2013 and 2014, respectively. Since then, several next-generation PI3K and BTK inhibitors, including duvelisib (IPI- 145), TGR-1202, ONO-4059, and ACP-196, have demonstrated promising data in early trials, suggesting that the newer agents may build on the success of the targeted therapies introduced in the past two years.

In addition, the novel Bcl-2 inhibitor, venetoclax (ABT-199), which received a breakthrough therapy designation from the FDA for patients with 17p deletion CLL in May 2015, has also shown potential.

In a phase II study for patients with relapsed or refractory CLL harboring the 17p deletion, venetoclax met its primary endpoint for overall response rate (ORR). Full study results have not been presented; however, previous studies have shown an ORR of 79% with venetoclax in CLL, with 26% of patients experiencing a complete response, and 53% of patients experiencing a partial response.

Venetoclax is likely to be the next inhibitor approved in CLL, according to Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and an associate professor of Medicine at Harvard Medical School.

“This drug is in very advanced clinical development and has shown excellent response rates in the order of 80% to 90% in relapsed refractory CLL,” said Brown. “Complete remission rates from 25% to 40% were observed in the combination study with rituximab. It is somewhat unique in its ability to induce complete remissions compared to other Bcl-2 inhibitors. It is in a number of registration trials, as well as combination therapy trials.

“I am very excited about ABT-199 as a novel class of inhibitors that affects Bcl-2, particularly because some of its mode of action suggests that it may be synergistic with and work well in combination with ibrutinib,” Brown added. “This could perhaps form the backbone for a potential combination therapy that is free of chemotherapy.”

In the PI3K inhibitor category, duvelisib is the most advanced in terms of clinical development. Duvelisib inhibits the delta isoforms of PI3K, as does idelalisib, and it also targets the gamma isoform. “The data with duvelisib look quite good so far,” Brown said. “In the follow-up of the phase I story, approximately 66% were still in remission at 2-years PFS [progression-free survival]. That drug is in registration trials that are ongoing.”

Another PI3K inhibitor exhibiting potential is TGR-1202, which is a delta-specific agent. “That is a next-generation molecule with a different structure, which we hope might reduce some of the hepatotoxicity that is seen with other PI3K inhibitors,” said Brown. “Efficacy data are still early and relatively immature, but the response rates with that drug in CLL look promising.”

In the realm of new BTK inhibitors, Brown points to two agents, ONO-4059 and ACP-196. “ONO-4059 had very promising phase I data a couple of years ago, and we are now awaiting additional trials,” said Brown.

“Unfortunately, no clinical data have been reported on [ACP-196]. However, [ACP-196] has a very extensive trial portfolio, including two phase III studies designed for potential registration that have been initiated. Notably, they are doing a head-to-head trial of ACP-196 versus ibrutinib in patients with relapsed CLL. It will be very interesting to see how these registration trials for these additional inhibitors develop over the next few years.”

Meanwhile, development continues for the two agents that launched the targeted therapy era in CLL. A supplemental new drug application has been submitted for ibrutinib as a therapy for treatment-naïve patients with CLL who are over the age of 65, according to a statement from the company developing the BTK inhibitor, AbbVie. The application was based on findings from the phase III RESONATE-2 trial, which demonstrated superior outcomes with ibrutinib compared with chlorambucil in untreated patients with CLL. At presstime, specific data were yet released, but AbbVie has announced that ibrutinib had improved PFS, overall survival, and ORR compared with chlorambucil in the study.

Ibrutinib was approved in February 2014 as a treatment for patients with CLL who had received at least one prior therapy; it later gained an indication as a frontline therapy for individuals with CLL that harbors a 17p deletion. The oral small molecule also is indicated in mantle cell lymphoma (MCL) and Waldenström macroglobulinemia.

Multiple Myeloma

Ibrutinib, as a single agent or in combinations, is the subject of extensive clinical studies across a number of settings, including 13 phase III trials. Within the next year, AbbVie anticipates new indications for ibrutinib in the first-line setting for patients with MCL and CLL. Additionally, within the next 3 to 5 years, indications are anticipated in diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. Efforts also are under way to develop idelalisib in frontline and relapsed/refractory settings for both CLL and indolent non-Hodgkin lymphoma. The oral agent currently is approved in combination with rituximab in relapse settings in CLL, follicular B-cell non-Hodgkin lymphoma, and small lymphocytic leukemia.Five years from now, multiple myeloma will have a therapeutic backbone consisting entirely of combinations of novel agents, Sagar Lonial, MD, chief medical officer at Winship Cancer Institute of Emory University, said in a presentation at the 2015 Society of Hematologic Oncology Annual Meeting, held in Houston, Texas, in September.

Key Statistics for Hematologic Malignancies

^aMore deaths than cases may reflect lack of specific cause of death information or undercount in the number of cases.

^bStandard error is between 5 and 10 percentage points. ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia.

Source

American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.

The combinations will involve immunomodulatory agents (IMiDs), proteasome inhibitors, and monoclonal antibodies. Stem-cell transplantation will retain a role in treatment of myeloma, but its role in the era of monoclonal antibodies will likely be a topic of multiple clinical trials. Lonial is a leading investigator into two of those novel antibodies: elotuzumab, which targets signaling lymphocytic activation molecule F7 (SLAMF7), and daratumumab, which is aimed at CD38.

Both drugs have applications pending under the FDA’s priority review program. Elotuzumab is being evaluated in combination with lenalidomide and dexamethasone for patients who have relapsed after one or more prior therapies. Daratumumab is under review as monotherapy for patients who have failed at least three lines of prior therapy or who are double refractory to a proteasome inhibitor and an IMiD. The phase III ELOQUENT-2 trial showed that more patients with relapsed/refractory multiple myeloma responded to lenalidomide and dexamethasone combined with the monoclonal antibody elotuzumab (79%) compared with lenalidomide and dexamethasone alone (66%). In addition, the triplet combination resulted in a PFS benefit of almost 5 months, as well as an approximately 30% reduction in the risk of progression.

In a phase II trial of patients who were heavily pretreated, daratumumab monotherapy resulted in a PFS of 3.7 months, with nearly 30% of patients responding and a duration of response of 7.4 months.

Lonial said during an OncLive Peer Exchange program that some of the responses seen in this trial were stringent complete responses, which he found “quite striking” considering that the participants had received a median of five prior lines of therapy, including carfilzomib and pomalidomide as well as other drugs.

Clinical trial data also are helping to delineate the optimal use of currently approved agents such as carfilzomib (Kyprolis), a proteasome inhibitor, and panobinostat (Farydak), a histone deacetylase inhibitor (HDAC). Panobinostat is the first HDAC inhibitor approved in multiple myeloma. In the ENDEAVOR trial, patients with one to three prior lines of therapy had significantly higher PFS rates with carfilzomib and dexamethasone treatment (18.7 months) than with bortezomib and dexamethasone treatment (9.4 months). Importantly, all patient subgroups benefited from carfilzomib, including those with prior bortezomib exposure.

Panibinostat, which is indicated in combination with bortezomib and dexamethasone for patients who have received at least two standard lines of therapy, demonstrated its efficacy in the PANORAMA-1 trial. The addition of panobinostat to bortezomib and dexamethasone led to a higher overall ORR (58.5%) compared with placebo (41.4%) in patients who had received both prior bortezomib and either lenalidomide or thalidomide. The PFS was also 4.8 months longer with panobinostat than with placebo.

Beyond the new agents and combinations under study, advances in genomic tumor profiling will drive change in treatment strategies, Lonial indicated.

Current therapeutic approaches based on diagnostic tissue specimens may help guide treatment over the short term but may not reveal that clone that will be present at relapse, Lonial said. Recent studies have shown that myeloma is a disease consisting of both normal and malignant- cell biology, and treatment should target both types of biology.

In the not-too-distant future, RNA sequencing will become standard diagnostic testing at the initial evaluation of a patient with myeloma, replacing both fluorescence in situ hybridization and gene expression profiling. RNA sequencing at presentation may not be reflective of myeloma genetics at relapse, so reassessment would be required when the disease burden has decreased and would be helpful in guiding maintenance therapy, said Lonial.

Hodgkin Lymphoma

“We will sequence patient samples after two to four cycles of therapy in order to understand the specifics of the remaining clone and how to target it,” Lonial predicted. “This will guide maintenance therapy. Once patients become MRD [minimal residual disease]—negative, they will be randomized to continue or stop therapy based on their genetics at presentation.”The prospect of combining PD-1 inhibitors with existing therapies, particularly brentuximab vedotin (Adcetris), is emerging as the most exciting new development in advancing the treatment of patients with Hodgkin lymphoma, according to Anas Younes, MD, a medical oncologist who is chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York City. Younes said that nivolumab (Opdivo) and pembrolizumab (Keytruda), which are monoclonal antibodies targeting the PD-1 immune checkpoint, have demonstrated promise in early clinical trials among patients with Hodgkin lymphoma who have had multiple relapses. Both nivolumab and pembrolizumab are approved in melanoma and non—small cell lung cancer.

“Both showed very good tolerance but also remarkable activity exceeding 60% or 70% response rates,” said Younes. “Some of these responses are really durable. This has generated tremendous excitement about further developing these agents and about the potential of combining them with other nonchemotherapeutic agents.”

In May 2014, the FDA designated nivolumab as a breakthrough therapy in Hodgkin lymphoma. A registrational trial, CheckMate205, is continuing into nivolumab monotherapy in classical Hodgkin lymphoma after transplant failure. The study seeks to enroll 240 patients.

When it comes to identifying partners for these immunotherapies, a regimen that would pair a PD-1 inhibitor with brentuximab “is the most exciting combination” to explore, said Younes. A phase I/II trial is scheduled to be launched combining brentuximab with nivolumab in an estimated 60 patients with relapsed or refractory Hodgkin lymphoma after failure of frontline therapy.

“There is interest now in combining brentuximab vedotin with checkpoint inhibitors—two active agents,” he said. “Whether this will be sufficient by itself or would still need to be combined with chemotherapy would be the next step in drug development with Hodgkin lymphoma.” He said new combinations initially would be evaluated in the relapse setting and then tested in earlier lines of treatment. “It makes a lot of sense to combine them since each one has high single-agent activity,” Younes added. “We need to learn about the safety and efficacy of this combination.”

Younes said the focus of research into Hodgkin lymphoma is “basically pushing the cure rate of an already highly curable disease.” “This is almost unheard of in cancer therapy,” said Younes. “Everybody is focusing on the highly unmet need patient population and rightly so—we need to bring up the cure rate of cancer that has a very low survival and that’s where most drug development is focusing. We are in an unusual and fortunate situation where we can push the cure rate even higher. Hopefully, at one point we can cure everybody.”

He said that if clinicians are able to introduce safe and effective new agents earlier in the treatment paradigm, patients might be able to forgo transplants or be treated with less intensive chemotherapy or radiation therapy regimens. “It is possible to replace, defer, or delay the need for transplant if these new combinations prove to be effective in the relapsed setting,” said Younes. “Or, if we improve the cure rate by introducing [new therapies] in the frontline setting, the need for second-line therapy including transplant will become less and less important.”

This article is based on reporting by OncLive staff members Anita T. Shaffer, Laura Panjwani, and Silas Inman.