December 2016 Vol 9, Special Issue: Payers’ Perspectives In Oncology: AVBCC 2016 Highlights - Emerging Therapies
David Knight

Washington, DC—The oncology pipeline is bustling and shows no sign of slowing down anytime soon, said Anita Dopkosky, RPh, MS, Director, National Accounts, Walgreens, Pittsburgh, PA, at the Sixth Annual Conference of the Association for Value-Based Cancer Care. She provided an overview of key drugs in the oncology pipeline.

Cancer Types




Breast Cancer

Abemaciclib is an oral CDK4/6 inhibitor with attributes distinct from palbociclib that contribute to its discrete therapeutic effects, in particular, its single-agent activity.

One advantage abemaciclib has over palbociclib is its greater selectivity for CDK4, which may explain why it does not affect white blood cell count as severely as palbociclib, allowing abemaciclib to be taken on a continuous schedule without treatment holidays.

The MONARCH 3 clinical trial is evaluating the combination of abemaciclib and a nonsteroidal aromatase inhibitor in patients with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. Abemaciclib is expected to launch in 2017.

Buparlisib is being studied in combination with fulvestrant for the treatment of patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer.

The phase 3 BELLE-2 clinical trial of buparlisib met its primary end point, demonstrating a modest improvement in progression-free survival (PFS) with buparlisib plus fulvestrant.

“The primary outcome was quite dramatic in patients whose tumors had mutant PIK3CA,” said Ms Dopkosky. Buparlisib is expected to launch in 2017 or 2018.

Entinostat, a histone deacetylase inhibitor, is being studied in combination with exemestane for the treatment of postmenopausal women with recurrent or metastatic estrogen-receptor–positive breast cancer that progressed after nonsteroidal aromatase inhibitor therapy. Entinostat’s long half-life allows for continuous exposure, potentially resulting in positive immunomodulatory effects without the corresponding cytotoxic effects. Entinostat is anticipated to launch in 2018.

Glembatumumab vedotin is an intravenous antibody-drug conjugate in phase 2 clinical trials for the treatment of patients with triple-negative breast cancers that overexpress glycoprotein nonmetastatic B.

Neratinib is a tyrosine kinase inhibitor (TKI) in phase 3 clinical trial development for extended treatment after adjuvant treatment with trastuzumab in women with early-stage HER2-­positive breast cancer. Neratinib differs from other TKIs in that it irreversibly binds not only to HER1 and HER2 but also to HER4. Neratinib’s Prescription Drug User Fee Act (PDUFA) date is July 21, 2017.

Ribociclib is a CDK4/6 inhibitor with breakthrough therapy designation, in combination with letrozole, for the treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer. An independent data monitoring committee recommended to prematurely stop the MONALEESA-2 clinical trial, because results of a preplanned interim analysis showed that ribociclib plus letrozole met the primary end point of clinically meaningful improvement in PFS compared with letrozole monotherapy. Ribociclib is expected to launch in 2017.

Talazoparib is an oral PARP inhibitor in phase 3 clinical trials for the treatment of patients with advanced or metastatic breast cancer plus BRCA mutation.

“In our research, we’re finding that this particular product is considered to be one of the most potent PARP inhibitors reported, but it has the strongest tumor killing ability, and it has the highest efficiency for PARP 1 and PARP 2, so this is being touted as being one of the best in class,” said Ms Dopkosky. Talazoparib is expected to launch in 2017.

Veliparib is another oral PARP inhibitor in phase 3 clinical trials for the treatment of patients with BRCA mutation–positive, HER2-negative metastatic or locally advanced breast cancer, or newly diagnosed triple-negative breast cancer. Adding veliparib plus carboplatin to standard treatment met the predictive success criteria in a clinical trial of patients with triple-negative breast cancer. Veliparib is expected to be reviewed by the FDA in 2018.

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Lung Cancer

Alunbrig is an ALK inhibitor that has received an orphan drug status and a breakthrough therapy designation for the treatment of patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) that was treated with crizotinib.

“The search for new drugs or strategies to overcome TKI resistance is of great need right now, and that’s the place that alunbrig will play,” Ms Dopkosky said. “It will be joining alectinib and ceritinib, which are also on the market for NSCLC that has become resistant to crizotinib.” Alunbrig’s PDUFA date is August 30, 2017.

Durvalumab is a PD-L1 human monoclonal antibody in phase 3 clinical trial development for the treatment of patients with NSCLC, for which it has received breakthrough therapy designation. It is also being investigated for the treatment of patients with bladder cancer (see bladder cancer).

Epacadostat is a first-in-class, oral, selective inhibitor of the indoleamine 2,3-dioxygenase 1 enzyme that reverses tumor-associated immune suppression and restores effective antitumor immune responses.

Olmutinib is an oral, once-daily, third-generation, EGFR TKI that received breakthrough therapy designation for the treatment of patients with advanced or metastatic NSCLC with EGFR T790M–mediated resistance to initial EGFR TKI treatment. Olmutinib is in accelerated development, and is being studied in the fully recruited, pivotal, phase 2 ELUXA 1 clinical trial, with 2 phase 3 clinical trials starting soon. Olmutinib is expected to launch in 2018.

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Ovarian Cancer

Niraparib is an oral, once-daily, PARP inhibitor for the treatment of patients with high-grade serous, platinum-sensitive, relapsed ovarian cancer. Niraparib received orphan drug status and a fast track designation; the drug manufacturer initiated a rolling new drug application submission for niraparib.

In explaining the need for new therapies for this indication, Ms Dopkosky said, “Despite several advances in treatment of ovarian cancer, most patients ultimately relapse, and subsequent responses to additional treatment are often limited in duration.”

In a phase 3 clinical trial involving patients with germline BRCA mutation–positive ovarian cancer that responded to platinum-based chemotherapy, niraparib improved the median PFS by 15.5 months versus placebo. Patients with nongermline BRCA mutation–positive tumors with homologous recombination deficiency had a 9.1-month PFS advantage with nirapa­rib over placebo.

Rucaparib is another oral PARP inhibitor, but it is administered twice daily. Rucaparib is being developed for the treatment of patients with ovarian cancer, specifically in patients with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity. Rucaparib’s PDUFA date is February 3, 2017.

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Hematologic Malignancies

Midostaurin, an oral signal transduction inhibitor, received an orphan drug status and a breakthrough therapy designation for the treatment of patients with acute myeloid leukemia (AML) and FLT-3 mutation, which has the lowest survival rate of all adult leukemias. Midostaurin is expected to launch in 2017.

Volasertib, an intravenous inhibitor of Polo-like kinase, is being investigated in combination with low-dose cytarabine for the treatment of patients aged ≥65 years with previously untreated AML who are ineligible for intensive remission induction therapy. Volasertib received an orphan drug status and a breakthrough therapy designation. However, the phase 3 POLO-AML-2 clinical trial that investigated volasertib plus low-dose cytarabine did not meet the primary end point of objective response rate in elderly patients with AML.

Inotuzumab ozogamicin, an antibody-drug conjugate, is being investigated for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia. Inotuzumab ozogamicin received an orphan drug status and a breakthrough therapy designation. In the phase 3 INO-VATE ALL clinical trial, inotuzumab ozogamicin demonstrated improvement over chemotherapy on several measures, including complete hematologic remission and PFS. Inotuzumab ozogamicin is scheduled for FDA review in 2017.

Duvelisib is an oral dual inhibitor PI3K-delta and PI3K-gamma. It is in clinical trials for the treatment of patients with refractory indolent non-­Hodgkin lymphoma, relapsed or refractory chronic lymphocytic leukemia, or small lymphocytic lymphoma. Duvelisib received an orphan drug status and a fast track designation. Duvelisib is expected to be reviewed by the FDA in 2017.

Momelotinib, an oral Janus kinase inhibitor, is being investigated for the treatment of patients with myelofibrosis. Momelotinib received an orphan drug status and a breakthrough therapy designation. The international phase 3 clinical trial SIMPLIFY 1 is comparing the efficacy and safety of momelotinib with that of ruxolitinib for the treatment of patients with myelofibrosis. Momelotinib is anticipated to launch in 2018.

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Bladder Cancer

Durvalumab received a breakthrough therapy designation for the treatment of patients with bladder cancer, on the basis of early clinical data from a phase 1 clinical trial in patients with advanced metastatic urothelial bladder cancer that progressed during or after 1 standard platinum-based regimen. Durvalumab is expected to be reviewed by the FDA in 2017.

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Melanoma

Binimetinib, a mitogen-activated protein kinase inhibitor, is a targeted treatment for NRAS mutation–positive melanoma. Binimetinib has a PDUFA date of June 30, 2017.

NRAS mutations are found in approximately 15% of metastatic melanomas, noted Ms Dopkosky.

Encorafenib is a selective RAF kinase inhibitor that binds to the BRAF V600E mutation. Two phase 3 clinical trials of encorafenib are ongoing, including the COLUMBUS clinical trial (encorafenib in combination with binimetinib for melanoma with BRAF mutation) and the BEACON clinical trial (encorafenib, binimetinib, and cetuximab [Erbitux] for colorectal cancer with BRAF mutation). The top-line results from the COLUMBUS clinical trial are expected in the second half of 2016. Encorafenib is expected to launch in 2018.

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Other Cancers

Telotristat etiprate, a tryptophan hydroxylase inhibitor, received an orphan drug status and a fast track designation for the treatment of patients with carcinoid syndrome. A new drug application was filed on March 30, 2016. If approved, telotristat etiprate would be the only approved therapy for patients who can no longer control their carcinoid syndrome with the current standard-of-care therapy.

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