A study comparing Opdivo to dacarbazine chemotherapy in treatment naïve advanced melanoma patients marks first PD-1 immune checkpoint inhibitor to demonstrate a survival benefit in a phase III trial.
The trial, CheckMate-066, met its primary endpoint of overall survival, with median OS not reached in the Opdivo (nivolumab) arm, compared to 10.8 months in patients receiving dacarbazine chemotherapy.
The one-year survival rate was 73 percent for Opdivo vs. 42 percent for DTIC, and there was a 58 percent decrease in the risk of death for patients treated with Opdivo (HR: 0.42, p<0.0001).
The trial enrolled 418 patients with treatment naïve BRAF wild-type advanced melanoma, and the survival benefit was observed in both PD-L1 positive and PD-L1 negative patients treated with Opdivo.
The rate of objective response was significantly higher for Opdivo than dacarbazine, at 40 percent and 14 percent, respectively—and it included a higher percentage of complete responses, at 7.6 percent compared to 1 percent.
The data was published in The New England Journal of Medicine and presented during an oral session at the Society for Melanoma Research 2014 International Congress in Zurich, Switzerland.
The trial enrolled 418 patients who were randomized to receive either Opdivo 3 mg/kg every two weeks (n=210) or DTIC 1000 mg/m2 every three weeks (n=208). Treatment continued until there was disease progression or an unacceptable level of toxicity. Thirty-eight percent of patients in the DTIC arm received Yervoy (ipilimumab) after stopping study treatment.
All randomized patients were followed for up to 16.7 months at the time of database lock. Secondary endpoints included progression free survival, objective response rate by RECIST v1.1 criteria and PD-L1 expression as a predictive biomarker of OS. PD-L1 positivity was defined as at least 5 percent of tumor cells showing cell-surface PD-L1 staining.
The study, sponsored by Bristol-Myers Squibb, was designed in consultation with the Committee for Medicinal Products for Human Use, was primarily conducted in countries where DTIC is a commonly-used treatment in the first-line setting, including Canada, Europe and Australia, but not at U.S. trial sites.
Opdivo is a fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells.
Opdivo is being studied in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials in non-small cell lung cancer, melanoma, renal cell carcinoma, head and neck cancer, glioblastoma and non-Hodgkin lymphoma.
In 2012, the FDA granted Fast Track designation for Opdivo in NSCLC, melanoma and RCC, and a Breakthrough Therapy designation in May 2014 for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab.
Study: Keytruda Improves PFS in Ipilimumab-Refactory Disease
A pre-specified analysis of a pivotal phase II study showed that Keytruda substantially improved the primary endpoint of progression-free survival compared to chemotherapy in patients with ipilimumab-refractory advanced melanoma.
At six months, the PFS rates for Keytruda (pembrolizumab) were 34 percent at the 2 mg/kg dose (95% CI, 27-41) (n=180) and 38 percent at the 10 mg/kg dose (95% CI, 31-45) (n=181), compared to 16 percent for chemotherapy (95% CI, 10-22) (n=179). The median duration of follow-up at the interim analysis was 10 months.
The study, named KEYNOTE-002, was presented at the Society of Melanoma Research 2014 International Congress in Zurich, Switzerland.
For the pre-specified analysis of PFS, no significant differences were observed between Keytruda doses (HR 0.91, range 0.71-1.16) (P<0.44). An assessment of PFS by investigator review was shown to be consistent with the central review findings. In addition, the PFS effect in favor of Keytruda was consistent across all pre-specified sub-groups.
The objective of the pre-specified analysis was to evaluate the superiority of either dose of Keytruda over chemotherapy for PFS (conducted after ≥ 270 PFS events at a 0.25% significance level) (one-sided) (estimated HR, 0.66). The study was designed with co-primary endpoints of PFS and overall survival. An evaluation of overall survival is planned at the pre-specified final analysis in 2015.
Overall response rates (confirmed) for Keytruda were five to six times higher compared to chemotherapy. For Keytruda, ORR was 21 percent at 2 mg/kg dose (95% CI, 15-28) and 25 percent at 10 mg/kg dose (95% CI, 19-32), compared to 4 percent for chemotherapy (95% CI, 2-9) (P<0.0001 for both comparisons).
At the time of pre-specified analysis, the median duration of response for Keytruda was not reached, and confirmed responses were ongoing in 92 percent of patients receiving 2 mg/kg dose (range 6+ to 50+) and 87 percent receiving 10 mg/kg dose (range 5+ to 48+), respectively.
The median duration of response was 37 weeks for chemotherapy arm and 63 percent of responses were ongoing (range 7+ to 41). There was no significant difference in ORR or duration of response between the doses of Keytruda (P=0.21).
Keytruda, sponsored by Merck, is indicated in the U.S. at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
The indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
Addition of Immune Stimulant to Yervoy Therapy Increases Overall Survival, Study Says
Patients with metastatic melanoma who were treated with Yervoy survived 50 percent longer if they simultaneously received an immune stimulant, according to a study.
Patients in the phase II trial who received the combined therapies demonstrated a median overall survival of 17.5 months compared to 12.7 months with Yervoy (ipilimumab) alone, and also had fewer adverse side effects. The study was published in the Journal of the American Medical Association.
The group treated with both Yervoy and the immune stimulant sargramostim, had a one-year survival rate of 68.9 percent compared to 52.9 percent in the Yervoy -only arm. The median progression-free survival in both groups was 3.1 months.
Sargramostim is a form of granulocyte-macrophage colony-stimulating factor, which spurs the growth of white blood cells. It is used, among other things, to restore white blood cells following a stem cell transplant for cancer.
The randomized clinical trial was conducted by the Eastern Cooperative Oncology Group, enrolling 245 patients with stage 3 or stage 4 metastatic melanoma who had been treated with other drugs. The patients were followed for a median of 13.3 months.
The advantage in overall survival of nearly five months in the group receiving sargramostim was significant, as was the lower toxicity in that group. Why the drug combination did not prolong the time before the disease progress – as might be expected, because it did extend overall survival – is not clear, the researchers said.
“It could be that the treatment is causing inflammation that that looked like early disease progression, but we won’t know without further studies,” said F. Stephen Hodi, first author on the clinical trial report, and director of the Melanoma Treatment Center and Center for Immuno-Oncology at Dana-Farber Cancer Institute.
