FDA Delays Decision on Frontline Atezolizumab Plus Carboplatin/Nab-Paclitaxel in Nonsquamous NSCLC

The FDA has extended the review period for a supplemental biologics license application (sBLA) for atezolizumab (Tecentriq) for use in combination with carboplatin and nab-paclitaxel (Abraxane) as a first-line treatment for patients with metastatic nonsquamous non—small cell lung cancer (NSCLC) who do not have EGFR or ALK aberrations.

Roche (Genentech), the manufacturer of the PD-L1 inhibitor atezolizumab, reported in a press release that the extension will allow ample time for the FDA to review additional information it requested for the application. The new action date for the sBLA is December 2, 2019.

In the multicenter, open-label, randomized IMpower130 study, patients were randomized 2:1 to receive the atezolizumab triplet as induction therapy followed by maintenance atezolizumab, or chemotherapy alone followed by best supportive care or pemetrexed every 3 weeks as maintenance. Atezolizumab was administered until investigator-assessed loss of clinical benefit or toxicity, while chemotherapy was given until progressive disease or toxicity. Stratification factors included gender, baseline liver metastases, and PD-L1 expression.

The co-primary endpoints were progression-free survival (PFS) as assessed by investigator using RECIST v1.1 in patients with EGFR or ALK mutations in the intent-to-treat wild-type (ITT-WT) population, and OS in the ITT-WT population.

Findings of the interim analysis, which were presented at the 2018 ESMO Congress, showed that the atezolizumab arm was superior in OS in the ITT-WT population. The median OS was 18.6 months (95% CI, 16.0-21.2) versus 13.9 months (95% CI, 12.0-18.7) with carboplatin/nab-paclitaxel alone (HR, 0.79; 95% CI, 0.64-0.98; P = .033). The 1- and 2-year OS rates with atezolizumab were 63.1% and 39.6% versus 55.5% and 30.0% in the carboplatin/nab-paclitaxel arm.

Additionally, there was also an improvement in PFS with the atezolizumab combination; the median PFS was 7.0 months (95% CI, 6.2-7.3) and 5.5 months (95% CI, 4.4-5.9) for carboplatin/nab-paclitaxel alone (HR, 0.64; 95% CI, 0.54-0.77; P<.0001). The 6- and 12-month PFS rates also favored the atezolizumab arm at 56.1% and 29.1% versus 42.5% and 14.1% with chemotherapy.

Overall response rate (ORR) and median duration of response was 49.2% and 8.4 months (6.9-11.8) with the atezolizumab regimen versus 31.9% and 6.1 months (5.5-7.9) with chemotherapy (P = .0004). In the atezolizumab arm, the ORR consisted of a 2.5% complete response rate, 46.8% partial response rate, 30.4% stable disease rate, and 11% progressive disease rate. Responses were ongoing in 36.8% of patients on atezolizumab and 19.4% on chemotherapy.

The PFS benefit was observed across all prespecified subgroups, except for those with liver metastases (HR, 0.93; 95% CI, 0.59-1.47); this group also did not experience an OS benefit (HR, 1.04; 95% CI, 0.63-1.72).

Investigator-assessed PFS and OSS in the ITT population were similar to the ITT-WT population, with a median PFS of 7.0 months for atezolizumab and 5.6 months for carboplatin/nab-paclitaxel (HR, 0.65; 95% CI, 0.54-0.77; P <.0001). The 6- and 12-month PFS rates were 56.4% and 28.9% with atezolizumab and 42.9% and 14.2% for chemotherapy.

The median OS for the ITT group for atezolizumab and chemotherapy was 18.1 months and 13.9 months, respectively (HR, 0.80; 95% CI, 0.65-0.99; P = .039). Additionally, the 1- and 2-year OS rates in this group were 62.7% and 39.3% on the atezolizumab arm and 55.1% and 29.9% with carboplatin/nab-paclitaxel.

The PFS and OS benefits varied in the EGFR/ALK-positive subgroups; the median PFS was 7.0 months and 6.0 months with atezolizumab and carboplatin/nab-paclitaxel alone (HR, 0.75; 95% CI 0.36-1.54), respectively; median OS was 14.4 months and 10.0 months (HR, 0.98; 95% CI, 0.41-2.31).

PFS data were also reported by levels of high, low, and negative PD-L1 expression: high (6.4 vs 4.6 months; HR, 0.51; 95% CI, 0.34-0.77), low (8.3 vs 6.0 months; HR, 0.61; 95% CI, 0.43-0.85), and negative (6.2 vs 4.7 months; HR, 0.72; 0.56-0.91). For OS, the benefit was similar: high (17.3 vs 16.9 months; HR, 0.84; 95% CI, 0.51-1.39), low (23.7 vs 15.9 months; HR, 0.70; 95% CI, 0.45-1.08) and negative (15.2 vs 12.0 months; HR, 0.81; 95% CI, 0.61-1.08).

Regarding safety, the atezolizumab/chemotherapy regimen appeared consistent with the known safety profiles of each agent alone, and no new safety signals were observed with the combination. Grade 3/4 treatment-related adverse events (AEs) were reported in 73.2% of patients who received the atezolizumab regimen compared with 60.3% of those who received chemotherapy alone. Ones of special interest include colitis (n = 5), hypothyroidism (n = 3), hepatitis (n = 2), and diabetes mellitus (n = 2). Serious grade 3/4 TRAEs were doubled in the atezolizumab arm at 23.7% versus 12.9%, and AEs leading to dose interruptions occurred in 85.0% and 80.2% of patients.

In December 2018, the FDA approved atezolizumab in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for the frontline treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations.

Cappuzzo F, McCleod M, Hussein M, et al. IMpower130: progression-free survival (PFS) and safety analysis from a randomised phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA53.

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In January 2019, Roche reported that the FDA had granted a priority review to the sBLA based on findings from the phase III IMpower130 trial. The study demonstrated a statistically significant improvement in both progression-free and overall survival (OS) with the atezolizumab triplet compared with chemotherapy alone in patients with stage IV nonsquamous NSCLC.