Recent advances and updates in oncology and cancer drug development.
The NCCN Annual Conference took place this recently in Hollywood, Florida. In addition to a number of interesting presentations on the state of treatment across several types of cancer, there were also sessions on guideline updates and biosimilars.
Articles and videos from the presenters can be found at http://www.onclive.com/conference-coverage/NCCN-2016
The FDA has approved defibrotide sodium as a treatment for severe hepatic veno-occlusive disease with associated kidney or lung abnormalities following hematopoietic stem cell transplantation, based on data from the collection of 3 studies. Across the single-arm trials, two of which were prospective and one that was an expanded access study, 38% to 45% of patients were alive at 100 days following HSCT.
The current 100-day survival rates with best supportive care following HSCT for patients with severe hepatic VOD are 21% to 31%, according to the FDA. Severe hepatic VOD occurs in approximately 2% of patients treated with HSCT and has an 84% mortality rate. The approval for defibrotide followed a priority review by the FDA that was granted after a rolling submission that was allowed under a fast track designation.
Prior to the FDA approval, defibrotide received an orphan drug designation to prevent VOD in May 2003. Additionally, in October 2013, defibrotide was approved by the European Medicines Agency under exceptional circumstances for severe hepatic VOD. In the United States, the therapy is expected to cost $156,000, which left many hematologists on Twitter speechless. Miguel Perales, MD, from MSK, called the price a "big mistake" and said that the cost would likely restrict the use of the potentially life-saving medication. Others questioned whether insurance would reimburse, leaving the importance of the approval in the air.
A new drug application has been submitted to the FDA for telotristat etiprate as a treatment for carcinoid syndrome in patients with metastatic neuroendocrine tumors, according to a statement from the drug's developer, Lexicon Pharmaceuticals. The application was based on data from two phase III trials, both of which demonstrated significant reductions in the frequency of daily bowel movements with telotristat etiprate versus placebo.
In the first study, TELESTAR, telotristat etiprate reduced daily bowel movements by up to 35%. In the second study, TELECAST, there was also a significant reduction in bowel movements (P ≤.004), although the exact data were not yet released. The FDA will review the NDA within 60 days of submission, at which point the agency will assign a review deadline under the Prescription Drug User Fee Act. Lexicon requested a priority review for the NDA, which would provide a 6-month deadline if the designation is granted.
Adding daratumumab to standard bortezomib and dexamethasone improved progression-free survival in patients with relapsed/refractory multiple myeloma enrolled in the phase III CASTOR (MMY3004) trial. Up to this point, all of the data available for daratumumab has been from phase II studies. The significant delay in disease progression (P <.0001) met the study’s primary endpoint, as measured by an independent data monitoring panel at a preplanned interim analysis.
Following the panel’s recommendation, the study has been halted and patients randomized to bortezomib and dexamethasone alone can cross over at progression to receive daratumumab. Full results from the study are being prepared for a peer-reviewed publication and presentation at an upcoming scientific meeting. Janssen also plans to communicate with the FDA about the potential to file for regulatory approval for a new or broader indication for daratumumab based on the data.
The FDA approved Daratumumab in November 2015 as a monotherapy for patients with multiple myeloma following at least 3 prior therapies, based on data from 2 open-label clinical trials. The indication for daratumumab is specifically for patients following progression on a proteasome inhibitor and an immunomodulatory agent, or for those who are double refractory to a proteasome inhibitor and IMiD.
Adding plitidepsin to dexamethasone reduced the risk of disease progression by 35% versus dexamethasone alone in patients with relapsed/refractory multiple myeloma enrolled in the phase III ADMYRE trial. The progression-free survival benefit observed with the plitidepsin combination met the trial’s primary endpoint of a statistically significant improvement in progression-free survival (P = .0054).
Complete data from the trial will be presented at an upcoming medical meeting. In a previously published phase II trial that evaluated both single-agent and combination plitidepsin therapy in multiple myeloma, the overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin monotherapy and 22% in the group of patients who added dexamethasone (n = 19, 18 evaluable). Both Single-agent plitidepsin and the combination regimen were well tolerated. Prior to this announcement, plitidepsin has received an orphan drug designation from the FDA and the European Medicines Agency.
The Committee for Medicinal Products for Human Use gave a positive opinion to single-agent daratumumab for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an immunomodulatory agent. The opinion, which was part of the EMA's accelerated assessment program, was primarily based on data from the phase II SIRIUS MMY2002 study, which also led to FDA approval last year.
The CHMP also granted a positive assessment to the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) for advanced melanoma. The positive opinion was based on the collection of data from the CheckMate-069 and -067 studies and a phase Ib trial. In the studies, the combination significantly improved ORR and progression-free survival versus monotherapy with ipilimumab for patients with advanced melanoma. In the CHMP opinion, the combination also improved PFS versus single-agent nivolumab, but only in patients with low tumor expression of PD-L1.
The EMA validated an application for use of nivolumab for previously treated patients with classical Hodgkin lymphoma, which officially begins the centralized review process. The EMA will be evaluating nivolumab primarily based on data from the phase II CheckMate-205 trial, which is evaluating nivolumab in both newly diagnosed and previously treated patients with cHL. Results from the study will likely be presented at a scientific meeting later this year.
The MEK inhibitor binimetinib failed to improve progression-free survival compared with physician's choice of chemotherapy for patients with low-grade serous ovarian cancer, according to early findings from the phase III MILO study that were released by the drug's developer, Array BioPharma. Results from MILO were not anticipated until 2017; however, a planned interim analysis revealed that the hazard ratio for PFS had crossed a predefined futility boundary.
The study has now been discontinued, which will allow patients in the binimetinib arm to cross over to receive chemotherapy. In the study, patients had recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. Physician's choice of chemotherapy included liposomal doxorubicin, paclitaxel, and topotecan. The primary endpoint was PFS. The study had not yet fully accrued participants at the time of its discontinuation.
Treatment with gefitinib failed to show noninferiority compared with erlotinib for patients with pretreated non—small cell lung cancer, according to findings from a phase III study. In patients with EGFR-mutant advanced lung adenocarcinoma (n = 401), the median progression-free survival with gefitinib was 8.3 versus 10.0 months with erlotinib (HR, 1.093; P = .424). In those with EGFR alterations, median OS was 26.5 months with gefitinib versus 31.4 months with erlotinib (HR, 1.189; P = .221).
The ORR was 58.9% versus 55% for gefitinib and erlotinib, respectively. Grade 3 rash was more common with erlotinib versus gefitinib (18.1% vs 2.2%) and liver enzymes were more frequently elevated with gefitinib versus erlotinib. These data add to a phase IIb analysis that compared afatinib (Gilotrif) with gefitinib for patients with untreated EGFR-mutant NSCLC, which was labeled LUX-Lung 7. In this trial, the median PFS was 11.0 versus 10.9 months, for afatinib and gefitinib, respectively (HR, 0.73; P = .0165). The ORR was 70% compared with 56% for afatinib and gefitinib, respectively (P = .0083).