Multiple Myeloma Accelerated Approval Highlights Week in Oncology News

FDA Approves Daratumumab for Multiple Myeloma

Acting 4 months ahead of schedule, the FDA granted an accelerated approval to the CD38-targeted monoclonal antibody daratumumab (Darzalex) as a monotherapy for patients with multiple myeloma following at least 3 prior therapies, based on data from two open-label clinical trials.

In the phase II MMY2002 study, daratumumab demonstrated a 65% one-year overall survival rate and a 29.2% objective response rate. The median duration of response was 7.4 months. After a median follow-up of 9.4 months, 45.2% of patients remained on therapy.

The median progression-free survival was 3.7 months. In the phase I/II GEN501 study, the ORR was 36%, median progression-free survival was 5.6 months, and the one-year OS rate was 77%.

The FDA's decision makes daratumumab the first monoclonal antibody approved for patients with multiple myeloma. The decision follows a breakthrough therapy designation and a priority review, allowing for an approval based on ORR as a surrogate endpoint. A full indication for daratumumab is contingent on confirmatory studies, which are currently ongoing.

See more at: http://www.onclive.com/web-exclusives/fda-approves-daratumumab-for-pretreated-multiple-myeloma

FDA Osimertinib for T790M-Positive NSCLC

The FDA granted an accelerated approval to osimertinib (Tagrisso, AZD9291) for patients with advanced EGFR T790M mutation-positive non—small cell lung cancer following progression on a prior EGFR TKI, based on data from 411 patients in two single-arm studies.

Osimertinib's approval, which arrived 3 months ahead of schedule, is the first for a treatment following a rebiopsy and molecular testing, marking a significant milestone in the move toward precision medicine. In data provided by the FDA for the first pivotal study, labeled AURA, the objective response rate with osimertinib was 61% for those with EGFR T790M-mutant NSCLC.

In the second trial, known as AURA2, the ORR was 57%. Along with osimertinib, the FDA also approved the cobas EGFR Mutation Test v2 as a companion diagnostic. The time from the start of clinical trials to FDA approval for osimertinib was just two and a half years.

Given this rapid development and approval under the FDA’s accelerated program, a full indication for osimertinib is contingent on findings from confirmatory studies, which is already fully accrued and anticipating results in December 2017.

See more at: http://www.onclive.com/web-exclusives/fda-approves-osimertinib-for-egfr-t790m-positive-nsclc

FDA Approves Cobimetinib/Vemurafenib for BRAF-Mutant Melanoma

The FDA approved the combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) as a treatment for patients with BRAF-positive metastatic or unresectable melanoma, based on an extension in progression-free survival in the phase III coBRIM study.

In the data submitted to the FDA, the median PFS with the combination was 12.3 versus 7.2 months for vemurafenib alone (HR, 0.56; P <.001). At a 17-month analysis, 65% of patients receiving the combination remained alive versus 50% for vemurafenib.

There was a 37% reduction in the risk of death with the combination of vemurafenib and cobimetinib compared with vemurafenib alone (HR, 0.63; P = .0019). Updated OS data will be presented later this month at the 2015 Society for Melanoma Research Congress.

The objective response rate with the combination was 69.6% compared with 50% for vemurafenib alone. The complete response rate in the combination arm was 15.8% versus 10.5% with vemurafenib and placebo (P <.001). The median duration of response was 12.98 months versus 9.23 months, with cobimetinib and placebo, respectively.

See more at: http://www.onclive.com/web-exclusives/fda-approves-vemurafenib-cobimetinib-combo-for-melanoma

Nivolumab Granted Priority Review for RCC

The FDA assigned a priority review designation to the PD-1 inhibitor nivolumab (Opdivo) as a treatment for patients with advanced renal cell carcinoma following prior antiangiogenic therapy, based on an extension in overall survival in the CheckMate-025 trial.

In the pivotal phase III study, nivolumab reduced the risk of death by 27% versus everolimus (Afinitor), representing a 5.4-month improvement in median OS. At a minimum follow-up of 14 months, the median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; P = .002).

Median progression-free survival was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03; P = .11). Grade 3/4 adverse events were also lower with the PD-1 inhibitor compared with everolimus.

The rate of grade 3/4 toxicities was lower with nivolumab (19%) versus everolimus (37%). The priority review follows a breakthrough therapy designation for nivolumab, which was granted by the FDA in September 2015. A final approval decision for the supplemental biologics license application will be made by March 16, 2016.

See more at: http://www.onclive.com/web-exclusives/fda-grants-priority-review-to-nivolumab-for-renal-cell-carcinoma

FDA Requests Updated Rociletinib Data

The FDA has requested additional clinical trial data to support a new drug application for rociletinib as a potential therapy for pretreated patients with EGFR T790M mutation-positive non—small cell lung cancer. The NDA for rociletinib was based on data from the ongoing phase I/II TIGER-X trial.

In an initial analysis of the data submitted to the FDA, patients with T790M-mutant NSCLC who received rociletinib at the 500 mg dose (n = 48) had an objective response rate of 60%. However, at a preplanned 90-day meeting with the FDA, Clovis noted that response rates had changed, initiating the call for a more thorough review.

According to the updated numbers, evaluable patients treated with the 500 mg dose of rociletinib (n = 79) experienced a confirmed response rate of just 28%. In 170 patients treated with the 625 mg dose, the confirmed response rate was 34%.

The company noted that a majority of responses could not be confirmed at subsequent scans due to progression, which frequently manifested as brain metastases. Additionally, scans did not continue to show tumor shrinkage of >30%.

The announcement closely follows the approval of osimertinib, which is rociletinib's main competitor. In data supporting this approval, the ORR with osimertinib was near 60%. The request for additional data will likely delay a regulatory decision on the medication by 90 days.

Prior to this development, the FDA had granted rociletinib a priority review and an action date of March 30, 2016. Following the announcement, shares for Clovis dropped by 70%.

See more at: http://www.onclive.com/web-exclusives/fda-requests-additional-data-for-rociletinib-in-egfr-t790m-mutant-nsclc

Application Submitted for Ibrutinib Plus Bendamustine/Rituximab in CLL

A supplemental new drug application has been submitted for ibrutinib (Imbruvica) for use in combination with bendamustine and rituximab to treat patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The application is based on findings from the phase III HELIOS study.

At a median follow-up of 17.2 months, progression-free survival with ibrutinib was not yet reached, as compared with 13.3 months for patients receiving BR alone (HR, 0.203; P <.0001). The PFS benefit held up across subgroups of high-risk patients. The objective response rate was 82.7% in the ibrutinib arm versus 67.8% in the control group (P <.0001).

Complete response rates (including CR with incomplete blood count recovery) were 10.4% versus 2.8% with ibrutinib versus placebo, respectively. The overall survival analysis showed a nonsignificant 37% reduction in the risk of death (P = .0598). Crossover to the ibrutinib arm that was allowed when the trial was unblinded may have confounded the OS data.

See more at: http://www.onclive.com/web-exclusives/fda-approval-sought-for-ibrutinib-regimen-in-cll

Positive Analysis Stops Phase III Idelalisib Study

A phase III study exploring idelalisib (Zydelig) in combination with bendamustine and rituximab for patients with previously treated chronic lymphocytic leukemia has been stopped early following a positive interim analysis, according to a statement from Gilead Sciences, the company developing the PI3K delta inhibitor.

Following a recommendation from an independent data monitoring committee, the trial, labeled Study 115, was unblinded, allowing patients in the control arm to receive idelalisib. The recommendation to halt the study was based on a statistically significant extension in progression-free survival and overall survival experienced by patients receiving idelalisib plus BR compared with BR alone.

According to data being presented at ASH in December, the median PFS with idelalisib was 23 months compared with 11 months for BR alone (HR, 0.33; P <.0001). There was a 45% reduction in the risk of death with the addition of idelalisib to BR, although the median OS had not yet been reached in either arm (HR, 0.55; P = .008).

Findings from the study will be submitted to the FDA and European Medicines Agency early next year.

See more at: http://www.onclive.com/web-exclusives/positive-interim-analysis-halts-phase-iii-idelalisib-cll-study