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Atezolizumab as First-Line Treatment for Specific Type of Metastatic Lung Cancer

The FDA has accepted the supplemental Biologics License Application (sBLA) and granted Priority Review for atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin for first-line treatment of people with metastatic non-squamous non-small cell lung cancer (NSCLC).

FDA. FDA... - Click to enlarge in new windowFDA. FDA

The FDA is expected to make a decision on approval by Sept. 5, 2018. A Priority Review designation is granted to medicines the FDA has determined to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.


This sBLA is based on results from the IMpower150 study, which met its co-primary endpoints of overall survival (OS) and progression-free survival (PFS) in the initial treatment of people with advanced non-squamous NSCLC. The safety profile of the combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified.


IMpower150 is a multicenter, open-label, randomized, controlled phase III study evaluating the efficacy and safety of atezolizumab in combination with carboplatin and paclitaxel with or without bevacizumab in people with stage IV non-squamous NSCLC who had not been treated with chemotherapy for their advanced disease. It enrolled 1,202 people, of which those with ALK and EGFR mutations were excluded from the primary intention-to-treat (ITT) analysis. People were randomized (1:1:1) to receive:


* atezolizumab plus carboplatin and paclitaxel (Arm A), or


* atezolizumab and bevacizumab plus carboplatin and paclitaxel (Arm B), or


* bevacizumab plus carboplatin and paclitaxel (Arm C, control arm).



The co-primary endpoints were OS and PFS, as determined by the investigator using RECIST v1.1. The primary analysis of the co-primary PFS endpoint in IMpower150 was assessed in two populations: all randomized people without an ALK or EGFR genetic mutation (ITT wild-type) and in a subgroup of people who had a specific biomarker (T-effector "Teff" gene signature expression). The co-primary OS endpoint was assessed in all randomized people without an ALK or EGFR genetic mutation (ITT wild-type). Key secondary endpoints included investigator-assessed PFS and OS, as well as safety in the ITT population and in EGFR and ALK mutation subgroups.


Atezolizumab is currently approved by the FDA to treat people with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA-approved targeted therapy if their tumor has ALK or EGFR gene abnormalities.


Dabrafenib Plus Trametinib for Adjuvant Treatment of BRAF V600-Mutant Melanoma

The FDA has approved dabrafenib in combination with trametinib for the adjuvant treatment of patients who have melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. The FDA granted the combination Breakthrough Therapy Designation for this indication in October 2017 and Priority Review in December 2017.


The melanoma approval is based on results from COMBI-AD, a phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection (N Engl J Med 2017;377:1813-1823). Patients received the dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n=438) or matching placebos (n=432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met.


Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53 percent as compared to placebo (HR: 0.47 [95% CI: 0.39-0.58]; p<0.0001; median not reached with combination therapy vs. 16.6 months with placebo). The RFS benefit among the combination arm was observed across all patient subgroups, including disease sub-stage. Improvements were also observed in key secondary endpoints, including overall survival, distant metastasis-free survival, and freedom from relapse.


Adverse events (AEs) were consistent with other dabrafenib + trametinib studies, and no new safety signals were reported. Of patients treated with the combination, 97 percent experienced an AE, 41 percent had grade 3/4 AEs, and 26 percent had AEs leading to treatment discontinuation (vs. 88%, 14%, and 3%, respectively, with placebo).


"The purpose of adjuvant therapy is to improve recurrence-free and overall survival in our patients with melanoma. Adjuvant therapy options are crucial today because more than half of patients have a recurrence after surgery," said John M. Kirkwood, MD, Usher Professor of Medicine and Director of Melanoma and Skin Cancer at the University of Pittsburgh. "We developed the first adjuvant therapy approved by the FDA 22 years ago, and now we have the first effective oral targeted therapy combination that prevents relapse among patients with BRAF-mutated melanoma that has spread to lymph nodes."


"Prevention and early detection are important safeguards from melanoma, but that's only half the picture. Melanoma is an aggressive cancer that can recur, particularly when it shows certain warning signs like increased depth, ulceration, or spread to the lymph nodes," noted Sancy Leachman, MD, PhD, Chair of the Department of Dermatology at OHSU School of Medicine. "With proven treatment options for these patients, it is important for dermatologists to assure that appropriate patients are offered adjuvant treatment options-a 'watch and wait' approach is no longer the standard of care. Collaborating with a multidisciplinary care team of surgeons, pathologists, and oncologists, and determining the right treatment based on the patient's individual circumstances and mutational status are crucial to our patients' care plans."


Alert Issued Regarding Pembrolizumab or Atezolizumab for Urothelial Cancer

The FDA recently alerted health care professionals, oncology clinical investigators, and the public about decreased survival associated with the use of pembrolizumab or atezolizumab monotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of PD-L1.


In two ongoing clinical trials (KEYNOTE-361 and IMVIGOR-130), early reviews from the Data Monitoring Committees (DMC) found patients in the monotherapy arms of both trials with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy. There was no change in the adverse event profile of pembrolizumab or atezolizumab. Enrollment of patients whose tumors have PD-L1 low status to the pembrolizumab or atezolizumab monotherapy arms have stopped per the DMC recommendations.


The clinical trials compare platinum-based chemotherapy combined with pembrolizumab or atezolizumab to platinum-based chemotherapy alone. Both trials enrolled a third arm of monotherapy with pembrolizumab or atezolizumab to compare to platinum-based chemotherapy alone. The monotherapy arms remain open only to patients whose tumors have PD-L1 high status. The combination arms and the chemotherapy arms of both studies also remain open. The FDA is reviewing the findings of the ongoing clinical trials and will communicate new information as necessary.


Both pembrolizumab and atezolizumab are currently approved under accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma patients who are not eligible for cisplatin-containing chemotherapy, irrespective of PD-L1 status. Patients taking pembrolizumab or atezolizumab for other approved uses should continue to take their medication as directed by their health care professional.