April 2013 Biotech Focus: Tracking the Oncology Pipeline

FDA Breakthrough Therapies

The FDA’s Breakthrough Therapy Designation is intended to expedite the development of therapies that demonstrate improvement versus available treatments in at least one clinically significant endpoint.

•Palbociclib (formerly PD-0332991) has received breakthrough designation for the treatment of patients with breast cancer. The drug is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4/6 that prevents cellular DNA synthesis by blocking tumor cell progression. The FDA based its decision on phase II data showing that palbociclib plus letrozole significantly improved progression-free survival versus letrozole alone (26.1 vs 7.5 months) in postmenopausal women with ER-positive/ HER2-negative advanced breast cancer. Pfizer, which manufactures palbociclib, has initiated a phase III study in the setting. (Find out more>>>)

•Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has received an additional breakthrough designation for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma with deletion of the short arm of chromosome 17. Earlier this year, ibrutinib received breakthrough designation for Waldenström’s macroglobulinemia and previously treated relapsed/ refractory mantle cell lymphoma. The drug is being developed by Janssen Pharmaceutical Companies, which is part of Johnson & Johnson. (Find out more>>>)

•LDK378, an investigational, highly selective inhibitor of ALK, has received breakthrough designation status from the FDA for the treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC) who have already received crizotinib (Xalkori). In a phase I study of LDK378 presented at the 2012 ESMO Congress, investigators observed a response rate of 80% in ALK-positive NSCLC patients with progression on crizotinib (Shaw AT et al. Abstract 440). The compound’s manufacturer, Novartis, has launched two phase II trials and plans to start phase III research later this year. (Find out more >>>)

Research Advancements

Submissions

Setbacks

The Biotech Focus series provides updates on advances in the oncology treatment pipeline. In each entry, summaries of ongoing research, breaking news, and FDA decisions relating to a variety of cancers are presented.•Talimogene laherparepvec (TVEC) has become the first oncolytic virus to successfully complete a phase III trial in advanced melanoma, according to the drug’s developer, Amgen. TVEC is a genetically modified version of herpes simplex virus type 1. In the study, over 400 patients with unresected stage IIIB, IIIC, or IV melanoma were randomized 2:1 to either TVEC (intralesionally every 2 weeks) or subcutaneous granulocytemacrophage colony-stimulating factor (GMCSF; subcutaneously for the first 14 days of each 28 day-cycle). Treatment with TVEC significantly improved the primary endpoint of durable response rate (continuous complete or partial response for ≥6 months), at 16% compared with 2% in the GM-CSF. Overall survival (OS) data are not expected to mature until later this year; however, an interim analysis has shown an OS trend favoring TVEC. Disease progression, cellulitis, and pyrexia were among the most common serious adverse events. Amgen reported in a statement that additional data from the study will be submitted for presentation at the 2013 ASCO Annual Meeting. (Find out more>>>)•Seattle Genetics submitted a supplemental Biologics License Application to the FDA to expand its marketing approval for brentuximab vedotin (Adcetris) in patients with relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). Brentuximab, an antibody-drug conjugate, was approved in 2011 for patients with HL after failure of stem-cell transplant or failure of at least two multidrug chemotherapy regimens in patients ineligible for transplant. The drug was simultaneously approved in sALCL after failed treatment with at least one multidrug chemotherapy regimen. Seattle Genetics has now submitted new data with the hope of extending the agent’s approval for the retreatment of patients with HL and sALCL, as well as for administering patients more than 16 cycles of therapy. The submission includes updated data from a phase II study, the previous results of which were presented at the 2011 ASH Annual Meeting and the 2012 ASCO Annual Meeting. (Find out more>>>)•The FDA has identified a series of steps that AP Pharma must take before its drug APF530 can be approved to treat chemotherapy-induced nausea and vomiting (CINV), the company said. These measures include refining product quality analytical test methods, conducting a human errors validation study regarding the administration of the drug, and reanalyzing existing phase III clinical data.

John B. Whelan, president and CEO of AP Pharma, said in a statement that the company was “disappointed” about the notification, but that “we believe that the issues raised in the complete response letter are addressable, and we remain firmly committed to the successful development of APF530, which we believe will fulfill an important unmet need and improve the lives of patients suffering from CINV.”

APF530 is a subcutaneous injection containing the 5-HT3 antagonist granisetron and is designed to treat patients receiving either moderately or highly emetogenic chemotherapy. (Find out more>>>)

•A phase I study evaluating combination therapy with vemurafenib and ipilimumab in patients with advanced melanoma was closed to further accrual due to liver toxicities, according to a report in The New England Journal of Medicine. In the study, researchers examined two cohorts of 6 patients each; one group received full doses of both drugs, while the other received a modified dose of vemurafenib. Regardless of the dose levels, patients in both cohorts developed unacceptable hepatotoxicity. The BRAF inhibitor vemurafenib is manufactured by Genentech, and the CTLA-4— blocking antibody ipilimumab is developed by Bristol-Myers Squibb. (Find out more>>>)

•Palifosfamide, a bifunctional DNA alkylating agent, failed to meet the primary endpoint of improved progression-free survival in patients with metastatic soft tissue sarcoma in the phase III PICASSO 3 trial. The study randomized 447 patients to palifosfamide plus doxorubicin or doxorubicin alone. Ziopharm Oncology announced in a statement that it is halting development of the drug. (Find out more>>>)