Atezolizumab Plus Chemo Extends PFS in Frontline Squamous NSCLC

The addition of atezolizumab (Tecentriq) to frontline carboplatin and nab-paclitaxel (Abraxane) delayed the risk of progression or death by 29% compared with chemotherapy alone for patients with advanced squamous NSCLC.

Robert Jotte, MD, PhD

The addition of atezolizumab (Tecentriq) to frontline carboplatin and nab-paclitaxel (Abraxane) delayed the risk of progression or death by 29% compared with chemotherapy alone for patients with advanced squamous non—small cell lung cancer (NSCLC), according to findings from the phase III IMpower131 trial presented at the 2018 ASCO Annual Meeting.

At a median follow-up of 17.1 months, the median progression-free survival (PFS) was 6.3 months (95% CI, 5.7-7.1) with the addition of atezolizumab versus 5.6 months (95% CI, 5.6-5.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.85; P = 0.0001). The 12-month PFS rates were 24.7% versus 12.0%, respectively.

“IMpower131 data show that patients with advanced squamous NSCLC benefit more from initial treatment with atezolizumab plus chemotherapy than from chemotherapy alone. This PFS benefit was observed across all-comers—all PD-L1—expressing subgroups—and was enriched in subgroups with higher PD-L1 expression,” said lead author Robert Jotte, MD, PhD, medical director and cochair, USON Thoracic Committee, Rocky Mountain Cancer Centers.

The multicenter, open-label phase III IMpower131 study randomized 1021 chemotherapy-naïve patients with stage IV squamous NSCLC to upfront treatment with atezolizumab, carboplatin, and paclitaxel (arm A); atezolizumab, carboplatin, and nab-paclitaxel (arm B); or the control arm of carboplatin and nab-paclitaxel (arm C).

For arm A (n = 338), the induction phase comprised 4 or 6 cycles of atezolizumab (1200 mg) plus carboplatin (AUC 6) and paclitaxel (200 mg/m2), administered on day 1 of each 21-day cycle. Patients then received maintenance atezolizumab every 3 weeks as long as a clinical benefit continued to occur and there was no disease progression.

The induction phase for arm B (n = 343) involved 4 to 6 cycles of atezolizumab (1200 mg), carboplatin (AUC 6), and nab-paclitaxel (100 mg/m2). Patients received atezolizumab and carboplatin on day 1 of each 21-day cycle. This was followed by the same maintenance atezolizumab regimen as in arm A.

For arm C (n = 340), induction comprised 4 or 6 cycles of carboplatin and nab-paclitaxel (100 mg/m2). Patients received carboplatin on day 1 of each 21-day cycle, and nab-paclitaxel was administered on days 1, 8, and 15 of each 21-day cycle. The maintenance phase consisted of best supportive care.

The coprimary endpoints for the IMpower131 study were PFS and overall survival (OS). The current analysis was only a comparison of arm B versus arm C. The study design stipulated that the nab-paclitaxel arm (B) must first demonstrate a statistically significant OS benefit versus the control arm (C) before the paclitaxel arm (A) can be compared with the control arm for PFS and OS.

The PFS benefit was observed across PD-L1 subgroups. The median PFS was 10.1 versus 5.5 months (HR, 0.44; 95% CI 0.27-0.71) and 6.0 versus 5.6 months (HR, 0.70; 95% CI, 0.53-0.92), with atezolizumab versus chemotherapy alone in the PD-L1—high (TC3 or IC3) and PD-L1–low (TC1/2 or IC1/2) subgroups. Among PD-L1–negative patients (TC0 and IC0), the median PFS was 5.7 versus 5.6 months, respectively (HR, 0.81; 95% CI, 0.64-1.03).

In the overall intent to treat population, the overall response rate (ORR) was 49% (2% complete response [CR]; 48% partial response [PR] among patients receiving atezolizumab (n = 169) compared with 41% (1% CR, 40% PR) in the control arm (n = 140). The median duration of response was 7.2 months (range, 1.7-28.1) in the atezolizumab arm, with 54 patients having ongoing responses.

Among PD-L1—high patients, the ORR was 60% (all PR) among patients receiving atezolizumab (n = 32) compared with 33% (2% CR, 31% PR) in the control arm (n = 16). The median duration of response was 18.7 months (range, 1.7-26.0) in the atezolizumab arm, with 17 patients having ongoing responses.

In those patients classified as PD-L1 low, the ORR was 52% (2% CR, 50% PR) among patients receiving atezolizumab (n = 67) compared with 44% (2% CR, 42% PR) in the control arm (n = 53). The median duration of response was 6.9 months (range, 2.6-22.4) in the atezolizumab arm, with 17 patients having ongoing responses.

At the first interim OS analysis, the median OS was 14.0 months (95% CI, 12.0-17.0) with the atezolizumab triplet compared with 13.9 months (95% CI, 12.3-16.4) with chemotherapy alone (HR, 0.96; 95% CI, 0.78-1.18; P = 0.6931). The 12- and 24-month OS rates were 55.6% versus 56.9% and 31.9% versus 24.1%, respectively. The OS follow-up is continuing, with another analysis anticipated later this year.

“The overall survival results are immature. We hope that the results seen with progression-free survival translate to improved overall survival. If, and when, that’s shown, I think we’ll clearly have a new standard of care for the frontline treatment of squamous cell non—small cell lung cancer,” ASCO Expert David Graham, MD, FASCO, said at an ASCO press briefing.

Regarding safety, Jotte said, “Atezolizumab and chemotherapy has a manageable safety profile consistent with known safety risks of the individual therapies. No new safety signals were identified,”

Treatment-related adverse events (TRAEs) of any grade occurred in 94.6% of the atezolizumab arm compared with 90.7% of the control arm. Grade 3/4 and serious TRAEs occurred in 68.0% versus 56.9% and 20.4% versus 10.5% of the 2 arms, respectively.

Genentech (Roche), the manufacturer of the PD-L1 inhibitor recently reported in a press release that adding atezolizumab to nab-paclitaxel and carboplatin in the frontline setting significantly improved OS in patients with advanced nonsquamous NSCLC, according to findings from the phase III IMpower130 study.

The FDA is currently reviewing a separate atezolizumab regimen for approval in the frontline nonsquamous NSCLC setting. Specifically, the supplemental biologics license application (sBLA) is for atezolizumab for use in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for the first-line treatment of patients with metastatic nonsquamous NSCLC. The FDA is scheduled to make its decision on the sBLA by September 5, 2018.

Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. 2018;36 (suppl; abstr LBA9000).

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Among the PD-L1—negative cohort, the ORR was 44% (2% CR, 42% PR) among patients receiving atezolizumab (n = 70) compared with 42% (1% CR, 41% PR) in the control arm (n = 71). The median duration of response was 6.9 months (range, 1.9-28.1) in the atezolizumab arm, with 20 patients having ongoing responses.