This week is turning out to be a busy and exciting week in readouts from Phase 3 clinical trials, including results from the CheckMate 227 trial in first-line advanced non-small cell lung cancer; the IMmotion 151 trial in unresectable locally advanced or metastatic renal cell carcinoma; and the COLUMBUS trial in melanoma.
Progression-free survival in NSCLC
First up, Bristol-Myers Squibb (BMS) announced yesterday significant results for its ongoing Phase 3 CheckMate 227 study. The study met its co-primary endpoint of progression-free survival (PFS) with an Opdivo (nivolumab; BMS) plus Yervoy (ipilimumab; BMS) combination arm versus chemotherapy in first-line advanced non-small cell lung cancer (NSCLC) patients whose tumors have high (≥10 mutations/megabase, mut/mb) tumor mutation burden (TMB), regardless of PD-L1 expression.
“For the first time, this Phase 3 study shows superior PFS with first-line combination immunotherapy in a predefined population of NSCLC patients with high TMB,” said Matthew D. Hellmann, MD, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center.
Using Foundation Medicine’s FoundationOne CDx validated assay, CheckMate 227 is an open-label Phase 3 trial that randomized more than 2,500 non-squamous and squamous histologies to an Opdivo-based treatment arm or to platinum-doublet chemotherapy. The study is being carried out in three parts, and yesterday’s announcement is the result of Part 1.
Critics are pointing out the modification of only assessing patients with tumors with high TMB (≥10 mutations/megabase) — BMS enacted a change on the trial design that could have affected whether PFS was significant. Other critics point out that the threshold BMS used for high TMB is far lower than the established FoundationOne threshold of >20 mut/mb found in only about 13% of patients.
Hellmann said, “TMB has emerged as an important biomarker for the activity of immunotherapy.” Hellmann is correct in that statement, but TMB was not a prospectively identified biomarker, and its threshold here does not align with a consensus of TMB threshold. Subset analyses and the overall survival (OS) readout should provide a much clearer picture on the best candidates for and the efficacy of the Opdivo plus Yervoy combination in advanced NSCLC.
Lung cancer expert Jack West, MD, is an editor on the OBR editorial board. He provided OBR with a full analysis of these results. To see his comments please click here.
Results from IMmotion 151 in renal cell carcinoma
Continuing in immunotherapy, Roche announced results from its Phase 3 trial, IMmotion 151, of Tecentriq (atezolizumab; Genentech) plus Avastin (bevacizumab; Genentech) versus standard-of-care Sutent (sunitinib; Pfizer) in patients with unresectable locally advanced or metastatic renal cell carcinoma (RCC).
Treatment-naive patients of any prognostic risk category (N=915) were randomly assigned to an atezolizumab plus bevacizumab treatment arm or to a sunitinib arm; and were stratified by PD-L1 status.
IMmotion 151 met one of its two endpoints, with significantly improved PFS in patients with tumors expressing PD-L1. Median PFS was 11.2 months in the atezolizumab plus bevacizumab treatment arm versus 7.7 months in the sunitinib arm (hazard ratio, 0.74; [95% CI, 0.57–0.96]; P=.02). However, that association was not clearly supported using independent, blinded reviewer-assessed PFS, cautioned lead investigator Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, New York City.
The combination of atezolizumab plus bevacizumab is gaining momentum: In December 2017, Roche announced that this combination with chemotherapy in front-line NSCLC improved 12-month PFS in the Phase 3 IMpower150 study.
Results from the COLUMBUS study in melanoma
In melanoma, Array Biopharma’s binimetinib—a MEK inhibitor—in combination with encorafenib—a BRAF inhibitor—in patients with BRAF-mutant melanoma reduced the risk of death compared with vemurafenib (Zelboraf; Genentech) in the Phase 3 trial (hazard ratio 0.61, [95% CI 0.47, 0.79]; P<0.001).
The combination arm almost doubled median OS compared with vemurafenib: 33.6 months vs 16.9 months, respectively.
"This data suggest that the combination of encorafenib and binimetinib may have the potential to become a meaningful new therapy for patients with advanced BRAF-mutant melanoma," said Keith T. Flaherty, M., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School.
These results come as a major win for Array, which in March 2017 pulled its New Drug Application (NDA) for binimetinib monotherapy in NRAS-mutant melanoma after results from the Phase 3 NEMO trial showed no difference in median OS when compared to standard-of-care chemotherapy.
Binimetinib monotherapy and binimetinib plus encorafenib remain under review for BRAF-mutant advanced, unresectable, or metastatic melanoma, with an FDA decision expected by June 30, 2018.
Lastly, in non-metastatic, castration-resistance prostate cancer
Finally, Janssen’s next-generation androgen inhibitor, apalutamide, showed a 72% reduced risk for metastasis or death compared with placebo among men with non-metastatic castration-resistant prostate cancer at high risk for developing metastatic disease.
In yesterday’s ASCO pre-GU Symposium press cast, Eric J. Small, MD, FASCO, professor of medicine at University of California, San Francisco, said, “To date there has been no therapy approved for this disease state, and the aim of this study was to see if the development of metastases in the transition from non-metastatic to metastatic could be slowed.”
In the Phase 3, SPARTAN trial, patients (N=1207) were randomized 2:1 to daily apalutamide or placebo, in addition to continuous androgen deprivation therapy (ADT). The primary endpoint was metastasis-free survival (MFS). The trial ended early when the interim analysis showed the primary endpoint had been met.
Median MFS in the apalutamide treatment arm was 40.5 months versus 16.2 months in the placebo arm, representing a 72% reduction in the hazard for metastatic progression or death.
Even though apalutamide was associated with a reduced risk of death, according to Dr. Small, “that was not significant at this early interim analysis and will continue to be followed. The trend was certainly encouraging," he said.
The FDA granted priority review to apalutamide, with an estimated PDUFA date by April 11, 2018.
The apalutamide program is also being assessed in the Phase 3 TITAN trial, comparing apalutamide combined with ADT to ADT alone in metastatic, hormone-sensitive prostate cancer.
By Megan Garlapow