Biotech Focus: Tracking the Oncology Pipeline

2012 ASH Annual Meeting

Several investigational treatments were highlighted at the 2012 American Society of Hematology Annual Meeting, which took place from December 8-11 in Atlanta, Georgia. View our complete coverage of the meeting.

• Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, demonstrated dramatic activity in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). In a 116-patient phase Ib/II study of patients with relapsed/refractory (RR) or treatment-naïve (aged ≥65 years) CLL or SLL, ibrutinib monotherapy was associated with estimated progression-free survival rates of 96% and 76% in the treatment-naïve and RR groups, respectively. The maximum follow-up was 26 months. In a second study, researchers sought to accelerate response to ibrutinib by pairing the drug with rituximab in 40 patients with CLL/SLL (median age, 65 years) considered high risk. In all, 38 of 40 patients continued on therapy without disease progression. The overall response rate (ORR) was 83%. A third trial demonstrated that singleagent ibrutinib had an “unprecedented” ORR of 66.1% in 109 evaluable patients with relapsed or refractory MCL (median age, 68 years). The ongoing phase II study included both bortezomib-naïve and bortezomib-exposed patients. Ibrutinib is being developed under the FDA’s Fast Track program for patients with CLL/SLL who have relapsed or refractory disease after at least one prior therapy, according to Pharmacyclics, Inc, which is developing ibrutinib in collaboration with Janssen Biotech, Inc.
• Pomalidomide, an immunomodulatory agent, combined with low-dose dexamethasone nearly doubled median progression-free survival versus high-dose dexamethasone (15.7 weeks vs 8.0 weeks; P < .001) in a phase III trial of patients with multiple myeloma who had exhausted prior therapies. Median overall survival was 34 weeks in the control arm and had not yet been reached in the pomalidomide arm. The FDA is reviewing a New Drug Application for pomalidomide in combination with dexamethasone, with a decision expected by February 10, 2013, according to Celgene Corporation, which is developing the drug.
• Quizartinib (AC220), a tyrosine kinase inhibitor, showed promise in patients with treatment-resistant acute myeloid leukemia (AML) who are carriers of the FLT3-ITD mutation, which is associated with poor outcomes. In a phase II study of singleagent quizartinib that included 137 AML patients, 44% (44/99) of patients with an FLT3-ITD mutation experienced some level of complete remission. Additionally, over onethird of patients overall (47/137) were able to receive a potentially curative transplant following a response to quizartinib. Ambit Biosciences, which manufactures the targeted agent, is planning phase III studies that will accrue AML patients with the FLT3- ITD mutation.

Other Developments

• Radium-223, an alpha-emitting radiopharmaceutical, has been submitted for FDA approval by Bayer HealthCare to treat patients with castration-resistant prostate cancer that has metastasized to the bone. The New Drug Application is based on results from the phase III ALSYMPCA study that were presented at the 2012 ASCO Annual Meeting. In the trial, radium-223 significantly improved median overall survival by 3.6 months versus placebo, translating into a 30.5% reduction in the risk of death.
• Sorafenib (Nexavar), a multi-tyrosine kinase inhibitor, significantly improved progression-free survival versus placebo in patients with advanced, radioactive iodine-refractory, differentiated thyroid cancer, according to data from the phase III DECISION trial. Based on the results, Bayer HealthCare and Onyx Pharmaceuticals, Inc, who co-develop sorafenib, plan to seek regulatory approval to market the drug to treat patients with thyroid cancer. The drug already has FDA-approved indications in liver and kidney cancer.
• Reolysin, a formulation of the reovirus, showed promise as a second-line treatment in combination with carboplatin and paclitaxel in patients with platinum-refractory head and neck cancers with no prior taxane treatment. At the initial 6-week endpoint of a doubleblind, randomized phase III study, 86% of patients with evaluable metastatic tumors who received the Reolysin combination had tumor stabilization or shrinkage, as compared with 67% of patients who received carboplatin and paclitaxel alone (P = .025). Reolysin is being developed by Oncolytics Biotech Inc.
• Selumetinib, a small-molecule inhibitor, extended progression-free survival when administered in combination with docetaxel versus docetaxel alone in patients with KRAS-mutated non—small cell lung cancer (5.3 months vs 2.1 months; P = .014), according to a phase II study. The combination also improved overall survival (9.4 months vs 5.2 months), however, the results were not considered statistically significant (P = .21). No targeted therapies are currently FDAapproved for KRAS-mutated non—small cell lung cancer. Selumetinib is being developed through a collaboration between Array BioPharma Inc and AstraZeneca.
• CDX-011, a monoclonal antibody drug conjugate, improved survival versus investigator’s choice of single-agent chemotherapy in a subset of heavily pretreated patients with glycoprotein NMB (GPNMB)—expressing triple-negative breast cancer, according to the final results of the randomized phase IIb EMERGE trial. In the triple-negative subgroup, CDX-011 treatment led to a statistically significant 4.3-month improvement in overall survival (P = .018) and 1.2-month improvement in progression-free survival, as well as a higher overall response rate (32% vs 13%). Celldex Therapeutics, which manufactures CDX-011, is now developing a pivotal study to support regulatory approval.
• Belinostat, a pan-HDAC inhibitor, had an objective response rate of greater than 20% in patients with relapsed/ refractory peripheral T-cell lymphoma in the phase II BELIEF registrational trial. The result exceeded the study’s primary endpoint, which was established through an agreement between Spectrum Pharmaceuticals Inc and the FDA. The company anticipates that it will file with the FDA for marketing approval for belinostat by mid-2013.
• L-BLP25 (formerly Stimuvax), an investigational cancer immunotherapy, failed to improve overall survival in patients with advanced non—small cell lung cancer, according to results from the phase III START trial. However, Merck KGaA, which licensed the drug from Oncothyreon, reported that the drug did show promising results in certain subgroups of patients and further analysis is planned.