The European Commission has approved and granted marketing authorization to the frontline combination of atezolizumab, bevacizumab, paclitaxel, and carboplatin for the first-line treatment of patients with metastatic, nonsquamous non–small cell lung cancer.
Sandra Horning, MD
The European Commission has approved and granted marketing authorization to the frontline combination of atezolizumab (Tecentriq), bevacizumab (Avastin), paclitaxel, and carboplatin for the first-line treatment of patients with metastatic, nonsquamous non—small cell lung cancer (NSCLC).1
For patients with EGFR or ALK molecular abnormalities, the 4-drug regimen should be indicated only after progression on appropriate targeted therapies.
The approval is based on data from the phase III IMpower150 study, which showed that the combination of atezolizumab, bevacizumab, and chemotherapy improved overall survival (OS) versus bevacizumab plus chemotherapy alone.2,3 The median OS was 19.8 months with the atezolizumab regimen versus 14.9 months with bevacizumab/carboplatin/paclitaxel (HR, 0.76; 95% CI, 0.63-0.96; P = .006) in the intent-to-treat population. Regarding safety, the profile of the atezolizumab combination was consistent with what has been reported in prior studies.
“Today’s announcement makes the combination of Tecentriq, Avastin and chemotherapy available to people in Europe with advanced, nonsquamous non—small cell lung cancer,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech (Roche), said in a press release. “This approval includes EGFR-mutant or ALK-positive non—small cell lung cancer after failure of a targeted therapy marking a first for this subgroup of patients, in which there is a significant need for alternative treatment options.”
The decision follows a positive opinion granted by the European Medicine’s Agency Committee for Medicinal Products for the frontline regimen in February 2019. The FDA approved the frontline regimen of atezolizumab, bevacizumab, carboplatin, and paclitaxel for this patient population in December 2018.
In the multicenter, open-label, controlled, randomized IMpower150 trial, researchers evaluated the efficacy and safety of atezolizumab in combination with carboplatin and paclitaxel with or without bevacizumab in 1202 patients with stage IV or recurrent metastatic nonsquamous NSCLC who were not previously treated with chemotherapy for their advanced disease.
Patients were randomized evenly to receive atezolizumab, carboplatin, and paclitaxel ([ACP] arm A; n = 402), atezolizumab, bevacizumab, and chemotherapy ([ABCP] arm B; n = 400), or bevacizumab and chemotherapy ([BCP] arm C; n = 400).
In the investigational arms, atezolizumab was administered at 1200 mg intravenously every 3 weeks and bevacizumab was given at 15 mg/kg. In each arm, carboplatin and paclitaxel were given on day 1 of each cycle for 4 to 6 cycles. In arm A, maintenance therapy was given with atezolizumab alone and in arm B patients received maintenance therapy with the combination of bevacizumab and atezolizumab. In arm C, maintenance was given with bevacizumab alone.
The trial was designed to exclude data for patients with EGFR/ALK-mutated NSCLC from the co-primary endpoints of OS and progression-free survival (PFS). Approximately 13% of the trials' patients were EGFR or ALK-positive. Prior to study entry, these patients had received at least 1 prior EGFR tyrosine kinase inhibitor.
Additional results showed that ABCP reduced the risk of disease progression or death by 41% compared with BCP (HR, 0.59; 95% CI, 0.50-0.69; P <.0001) in the overall ITT population. Moreover, the overall response rate (ORR) was 56.4% (95% CI, 51.4-61.4) with ABCP versus 40.2% (95% CI, 35.3-45.2) for those on BCP. The responses on the ABCP arm consisted of a 2.8% complete response (CR) rate and a 53.7% partial response rate. The median duration of response (DOR) was 11.5 months (95% CI, 8.9-15.7) for ABCP and 6.0 months (95% CI, 5.5-6.9) for BCP.
Additionally, in patients with liver metastases, there was a 46% reduction in the risk of death with ABCP compared with BCP (HR, 0.54; 95% CI, 0.33-0.88) and a 46% reduction in the risk of death for patients with EGFR/ALK-mutated NSCLC (HR, 0.54; 95% CI, 0.29-1.03).
In the wild-type intent-to-treat population, the 18-month PFS rate was 27% with ABCP and 8% for BCP. The 18-month OS rate was 53% with ABCP compared with 41% for BCP. The ORR with ABCP was 55% compared with 42% for BCP, with CRs rates of 4% and 1%, respectively. The DOR was 10.8 months with ABCP, 6.5 months with BCP, and 9.5 months with ACP.
In patients with liver metastases in the wild-type analysis, the median OS with ABCP was 13.2 month compared with 9.1 months with BCP (HR, 0.54). Patients without liver metastases had a median OS of 19.8 versus 16.7 months for ABCP and BCP, respectively (HR, 0.83). The median OS in patients with EGFR/ALK mutations only was not evaluable with ABCP versus 17.5 months for BCP (HR, 0.54).
Favorable efficacy was seen with the ABCP combination compared with BCP across PD-L1 expression levels. In those with PD-L1 high expression (tumor cells [TC] 3 or immune cells [IC] 3; n = 136), the median OS was 25.2 months with ABCP compared with 15.0 months for BCP (HR, 0.70; 95% CI, 0.43-1.13). The ORR in this group was 69% with ABCP compared with 62% with ACP and 49% with BCP. The DOR with ABCP in this group was 22.1 months compared with 12.2 months with ACP and 7.0 months for BCP.
In the PD-L1—low group (TC1/2 or IC1/2; n = 226), the median OS was 20.3 versus 16.4 months for ABCP and BCP, respectively (HR, 0.80; 95% CI, 0.55-1.15). In the PD-L1–negative group (TC0/IC0; n = 339), the median OS was 17.1 versus 14.1 months for ABCP and BCP, respectively (HR, 0.82; 95% CI, 0.62-1.08).
Regarding safety, the most common adverse events occurring in ≥20% of patients receiving ABCP were asthenia (50%), alopecia (48%), nausea (39%), diarrhea (32%), constipation (30%), decreased appetite (29%), arthralgia (26%), hypertension (25%), and peripheral neuropathy (24%).
The FDA approved the frontline regimen of atezolizumab, bevacizumab, carboplatin, and paclitaxel for this patient population in December 2018.