September 2014, Part 3
2014 Oncology Pipeline Looks ImpressiveEmerging Therapies
The cancer drug pipeline continues to boast many new therapies, reinforcing the recent trends of new and improved monoclonal antibodies and other classes of targeted therapies for different types of tumors. At ASCO 2014, researchers presented findings for many of these drugs, with immunotherapies leading the way in current drug development in oncology.
The future looks particularly bright for the anti–programmed death (PD)-1 monoclonal antibodies, which are being evaluated in several solid tumors. Strong results were reported for both nivolumab and pembrolizumab (already approved for melanoma, see page 7) in phase 1 and 2 studies of patients with non–small-cell lung cancer (NSCLC), melanoma, and renal-cell carcinoma. The durability of responses to these agents is perhaps more impressive than the response rates themselves. The majority of responders continue to demonstrate responses at the time of the study analyses.
The monoclonal antibody ramucirumab, which is already approved for the treatment of advanced gastric cancer, is being investigated in NSCLC. Ramucirumab improved overall survival (OS) when added to docetaxel versus chemotherapy alone in a phase 3 trial of 1253 patients with stage IV NSCLC, although the median OS was prolonged by only 1.4 months.
In the international phase 3 PANORAMA 1 trial in multiple myeloma, the addition of the oral pan-histone deacetylase (HDAC) inhibitor panobinostat to a bortezomib-containing regimen led to a statistically and clinically significant 4-month increase in median progression-free survival (PFS), meeting the study’s primary end point. The study enrolled 768 patients who had received 1 to 3 previous lines of treatment but their disease was not refractory to bortezomib.
The overall response rates (ORRs) were similar between the arms–60.7% with panobinostat and 54.6% with placebo (P = .087)–but the active combination was associated with almost a doubling in the rate of complete responses (CRs) and near CRs–27.6% versus 15.7%, respectively (P = .006). The median PFS was significantly improved, from 8.1 months with placebo to 12 months with panobinostat (P<.001), a 37% reduction in risk. After 28 months of follow-up, the median OS remained comparable at 33.6 months in the panobinostat arm and 30.4 months in the placebo arm (P = .87).
In May 2014, the FDA granted priority review status to panobinostat. Other panobinostat-containing combinations and additional HDAC inhibitors are currently in clinical trials.
Favorable findings from the STARLYTE phase 2 trial were reported for coltuximab ravtansine (SAR3419), a CD19-targeting antibody drug conjugate, in diffuse large B-cell lymphoma. Study investigators reported achievement of proof of concept, with a 43.9% ORR in 55 patients with relapsed and/or refractory disease who received the single agent, including responses among patients whose disease had not responded to previous therapy. There were few treatment-related grade 3/4 adverse events. This was a “Best of ASCO” abstract.
Blinatumomab is an investigational bispecific T-cell–engaging antibody developed using bispecific T-cell engager technology designed to bring the T-cells into closer contact with the tumor cells, thereby promoting T-cell–mediated lysis of tumor cells.
A large phase 2 study presented at the meeting confirmed the antileukemic activity of single-agent blinatumomab in a difficult-to-treat population of 189 patients with relapsed and/or refractory acute lymphocytic leukemia. Treatment with blinatumomab resulted in a 43% CR/complete hematologic response rate during the first 2 cycles. The median relapse-free survival was 5.9 months, and the median OS was 6.1 months.
ABT-199 (GDC-0199), an investigational B-cell lymphoma 2–selective inhibitor, in combination with rituximab produced an ORR of 84% in an open-label phase 1b study of 45 patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). In a separate phase 1 study of ABT-199/GDC-0199 as monotherapy in patients with relapsed and/or refractory CLL, the ORR was 77% in 78 evaluable patients, with 23% of the patients achieving a CR.
The ORRs for the 19 patients with 17p deletion and the 41 patients with fludarabine-refractory CLL were 79% and 76%, respectively. The median duration of response has not been reached. This same monotherapy trial enrolled 124 patients with various subtypes of non-Hodgkin lymphoma, where the ORR was 48% in the 59 patients who were evaluable for efficacy.
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