2014 Oncology Pipeline Looks Impressive
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 (MK-3475; formerly lambrolizumab) in phase 1 and 2 studies of patients with non–small-cell lung cancer, 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.
CO-1686 is a selective, oral tyrosine kinase inhibitor (TKI) that specifically targets EGFR mutations in patients with NSCLC. The efficacy of other EGFR inhibitors has been limited by acquired resistance, most frequently a second T790M mutation. The proposed solution to this challenge is to create drugs that can inhibit these newly mutated targets. At ASCO 2014, investigators reported early data on 3 drugs that successfully target T790M.
In a phase 1/2 dose-finding trial of CO-1686, responses were achieved by 58% of 72 heavily pretreated patients with T790M mutations; in a phase 2 extension study of 40 patients, median progression-free survival (PFS) was not reached and was estimated to exceed 12 months. Activity against metastases in the central nervous system was observed. The most common toxicity was elevated glucose, which was well-managed with oral hypoglycemic and/or dose reduction.
In a phase 1 trial of AZD9291 in 199 heavily pretreated patients with EGFR mutation, the objective response rate (ORR) was 51%, rising to 64% among the 89 patients with a T790M mutation. Among T790M-negative patients, the response rate was 23%. Nearly all patients were still responding at the data cutoff, with the longest response lasting more than 8 months. AZD9291 is also associated with less skin toxicity than other EGFR inhibitors. Because greater efficacy is seen in patients with the T790M mutation, future studies of this drug will be limited to this subgroup.
Although they are still in clinical testing, AZD9291 and CO-1686 have already received breakthrough therapy designation from the FDA. Both drugs are in phase 3 clinical trials.
The oral CDK 4/6 inhibitor abemaciclib (LY2835219), given twice daily, showed evidence of single-agent activity in heavily pretreated patients with NSCLC in a phase 1 study. The study enrolled 57 patients whose disease progressed or relapsed after a median of 4 previous treatments. KRAS mutations were present in 29 of the patients. The disease control rate was 49%, including 2 partial responses and 26 patients with stable disease. The disease control rate was higher for patients with KRAS mutation (55%) compared with the wild-type KRAS (38%).
The human anti-EGFR monoclonal antibody necitimumab improved median OS by approximately 2 months when added to standard chemotherapy in a phase 3 trial of patients with stage IV NSCLC of squamous histology.
In the international phase 3 PANORAMA 1 trial in multiple myeloma (MM), 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 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 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.
Anti-CD38 Monoclonal Antibodies
Impressive data from small earlyphase studies were presented for 2 monoclonal antibodies that target the CD38 protein—SAR650984 and daratumumab. In a phase 1b study, the combination of SAR650984 and lenalidomide plus dexamethasone in 31 patients with refractory disease who had received 6 previous treatments for MM showed strong antitumor activity and good tolerability.
The ORR was 58% but rose to 63% among patients receiving the highest dose (10 mg/kg given every other week), with 25% of patients achieving a very good partial response.
Antitumor activity for the second monoclonal antibody, daratumumab, as a single agent was shown in a phase 2 study of 50 heavily pretreated patients with relapsed/refractory MM. The ORRs for the single agent were 35% with the 16-mg/kg dose and 10% with the 8-mg/kg dose. The median PFS times were 23 weeks in the 16-mg/kg group and 15 weeks in the 8-mg/kg cohort, although the investigators noted that the PFS analysis is still immature.
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.
For the treatment of metastatic differentiated radioiodine-refractory thyroid cancer, treatment with the multi-TKI lenvatinib reduced disease progression by 79% versus placebo in the phase 3 SELECT trial. The median PFS (the primary end point) was improved by 14.7 months. Patients receiving lenvatinib had a median PFS of 18.3 months, whereas in patients receiving placebo the PFS was only 3.6 months (P <.001). Toxicity could be challenging, and 6 treatment-related deaths were reported. Disease progression at 2 years was reported in 41% of patients in the lenvatinib arm versus 86% of patients in the placebo arm.
The ORR was 65% with lenvatinib versus 2% with placebo (P <.001). The median OS has not been reached in either arm; because of the expected crossover on disease progression, this end point may be hard to interpret. Receipt of previous anti–vascular endothelial growth factor therapy did not adversely affect outcomes.
The poly (ADP-ribose) polymerase inhibitor veliparib demonstrated activity in a phase 2 trial of 41 patients with metastatic breast cancer and BRCA1 or BRCA2 mutation. At enrollment, the patients received a median of 3 previous chemotherapy regimens. The partial remission rate in patients receiving at least 4 cycles of follow-up was 17% (2 of 12 patients) with BRCA1 mutations and 23% (3 of 13 patients) with BRCA2 mutations. The time to failure while receiving veliparib was 2 months and 5.1 months, respectively. In all, 20 patients are still alive from the group receiving veliparib; 10 patients proceeded to postprogression therapy with veliparib and carboplatin, with 1 partial response in a patient with a BRCA1 mutation.