Top news of the week in cancer drug development and research.
FDA Expands Nivolumab Melanoma Approval
During the blizzard on Saturday, the FDA expanded the frontline melanoma indications for nivolumab as a single agent and in combination with ipilimumab to include patients with BRAF V600 mutations, based on data from the phase III CheckMate-067 trial. In the three-arm CheckMate-067 study, the combination of nivolumab and ipilimumab reduced the risk of progression by 58% compared with ipilimumab alone (HR, 0.42; P <.0001) in patients with advanced melanoma.
Single-agent nivolumab reduced the risk of progression by 43% versus ipilimumab (HR, 0.57; P <.0001). Outcomes were similar regardless of BRAF mutation status. For those with BRAF mutations treated with single-agent nivolumab (n = 98), the median PFS was 5.6 months compared with 4.0 months with single-agent ipilimumab (n = 100; HR, 0.77). In those with wild-type BRAF melanoma treated with nivolumab (n = 218), the median PFS was 7.9 months versus 2.8 months with ipilimumab (HR, 0.50).
Nivolumab was previously approved in advanced melanoma as a monotherapy and in combination with ipilimumab for BRAF V600 wild-type patients, as well as for patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor. The new indications for patients with BRAF mutations are both accelerated approvals that are contingent on results from confirmatory trials.
Carfilzomib Combo Approved for Myeloma
The FDA has approved carfilzomib in combination with dexamethasone or with lenalidomide plus dexamethasone for patients with relapsed/refractory multiple myeloma following prior treatment with 1 to 3 lines of therapy, based on findings from the phase III ENDEAVOR trial.
In the study, carfilzomib and dexamethasone reduced the risk of progression by 47% compared with bortezomib and dexamethasone. The median progression-free survival with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR, 0.53; P <.0001). The advantage in PFS seen with carfilzomib was consistent across subgroups. The median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib arm (HR, 0.79; P = .066).
The ORR was 77% with carfilzomib versus 63% with bortezomib. In addition to the combination approvals, this decision also converts carfilzomib’s single-agent accelerated approval in this setting to a full approval. Carfilzomib is now approved as a monotherapy for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy.
Venetoclax Combination Granted Breakthrough Designation for CLL
The FDA has granted a breakthrough therapy designation to venetoclax in combination with rituximab as a potential treatment for patients with relapsed/refractory chronic lymphocytic leukemia. The designation, which will expedite the development and review of the combination in CLL, is based on data from the phase Ib M13-365 study.
In the trial, the venetoclax/rituximab combination had an overall response rate of 86%, with deep and durable responses in patients with relapsed/refractory CLL. MRD-negative status was achieved in 53% of patients, including 75% of those who reached CR/CRi (n = 20). The median progression-free survival has not been reached. At a median follow-up of 17.5 months, the 12- and 24-month PFS rates were 87% and 84%, respectively. Ninety-four percent of patients were alive at 12 months.
The median overall survival has not been reached. The venetoclax/rituximab combination is being compared head-to-head with bendamustine plus rituximab in patients with relapsed/refractory CLL in the phase III MURANO trial.
FDA Approves Maintenance Ofatumumab in CLL
The FDA has approved ofatumumab for the extended treatment of patients with recurrent or progressive chronic lymphocytic leukemia who are in complete or partial response following at least two lines of therapy, based on a near doubling in progression-free survival seen with the treatment compared with observation in the phase III PROLONG trial.
In the open-label study, maintenance ofatumumab demonstrated a median PFS of 29.4 versus 15.2 months with observation, representing a 50% reduction in the risk of progression (HR, 0.50; P <.0001). Additionally, the time to next therapy was 6.9 months longer with ofatumumab compared with observation.
Data from the PROLONG trial were also submitted to the European Medicines Agency in early July 2015 by Novartis, which acquired ofatumumab from GlaxoSmithKline as part of a multi-billion-dollar product exchange. The European decision is still pending.
GI Cancers Symposium
Immuno-Oncology Arrives in Gastric Cancer
A number of studies presented at the 2016 GI Cancers Symposium demonstrated promising early results for PD-1 and PD-L1 inhibitors as treatments for patients with gastric cancer. In the first study, nivolumab showed an overall response rate of 14% with an acceptable safety profile in patients with gastric or gastroesophageal junction cancer.
Patients with PD-L1 expression >1% had an ORR of 27% compared with 12% in patients with PD-L1 expression <1%. When using a 5% threshold, the rates were 33% versus 15% in patients with PD-L1 expression >5% versus <5%, respectively.
As a maintenance therapy following frontline chemotherapy, the PD-L1 inhibitor avelumab showed an ORR of 7.3% for patients with gastric/GEJ cancer. In the second-line setting, avelumab demonstrated an ORR of 15%. Stable disease rates were 35% in the second-line setting and 47.3% in the maintenance cohort.
In patients with PD-L1 expression on ≥5% of cells, the ORR in the second-line setting was 50% (1 out of 2). In the maintenance setting (n = 7), there was 1 response, for an ORR of 14.3%. The median PFS was not reached for those in the second-line group and was 18.0 weeks in the maintenance group.
PD-1 Inhibitors Effective in Esophageal Cancer
Nivolumab and pembrolizumab both demonstrated promising early signs of activity in separate early phase trials for patients with advanced esophageal carcinoma. In the first study, after a median follow-up duration of 7.1 months, the objective response rate with pembrolizumab was 30% in patients with PD-L1-expressing disease.
Nine percent of patients had stable disease and more than half of patients treated with pembrolizumab demonstrated some degree of tumor shrinkage. A decrease in target lesion burden, defined as any amount of tumor shrinkage from baseline, was experienced by 52.2% of patients treated with pembrolizumab.
In the second study, nivolumab showed an ORR of 17.2% in patients with esophageal cancer. Overall, 16 patients had stable disease (25%). Responses had a median duration of 92 days and a maximum of 205 days. The median OS was 10.78 months and the median PFS was 1.51 months.
Second-Line MM-398 OS Data Updated
Adding liposomal irinotecan (nal-IRI; MM-398) to 5-fluorouracil and leucovorin reduced the risk of death by 25% for patients with metastatic pancreatic cancer following progression on a gemcitabine-based regimen, according to updated data from the phase III NAPOLI-1.
In the updated analysis that was conducted after 91% of events, median overall survival with liposomal irinotecan, 5-FU, and leucovorin was 6.2 months compared with 4.2 months for 5-FU and leucovorin alone (unstratified HR, 0.75; P = .0417). After 12 months, 26% of patients treated with the liposomal irinotecan combination remained alive compared with 16% with 5-FU plus leucovorin alone.
At approximately 20 months, survival was similar between the two groups. In the primary analysis that was conducted after 83% events, median OS was 6.1 months with the liposomal irinotecan triplet compared with 4.2 months with 5-FU and leucovorin alone (unstratified HR, 0.67; P = .012). The median progression-free survival was 3.1 months for the combination compared with 1.5 months with the control (HR, 0.56; 95% CI, 0.41-0.75; P = .0001).
Panitumumab Improves OS in Refractory mCRC
Adding panitumumab to best supportive care reduced the risk of death by 30% for patients with RAS wild-type chemorefractory metastatic colorectal cancer, according to findings from a phase III study. In those with RAS wild-type mCRC, median overall survival was 10.0 months with panitumumab versus 6.9 months with best supportive care alone for those with RAS wild-type mCRC (HR, 0.70; P = .0135).
Median PFS was 5.2 months with panitumumab versus 1.7 months with supportive care (HR, 0.46; P <.0001). The ORR with panitumumab was 31% compared with 2.3% with supportive care (odds ratio, 20.0; P <.0001). In those with wild-type KRAS mCRC, median OS was 10.0 months in the panitumumab arm compared with 7.4 months with best supportive care alone (HR, 0.73; P = .0096). Median PFS was 3.6 versus 1.7 months with and without panitumumab, respectively (HR, 0.51; P <.0001).
The ORR was 27% with panitumumab versus 1.6% with supportive care (odds ratio, 24.9; P <.0001). This was the first phase III study to prospectively assess efficacy in both RAS and KRAS wild-type mCRC, and further solidifies a continued shift toward an expanded testing strategy.