Frontline Atezolizumab Regimen Improves PFS in NSCLC

Martin Reck, MD, PhD

Treatment with the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel delayed progression or death by 38% compared with bevacizumab and chemotherapy alone for patients with advanced non-squamous non—small cell lung cancer (NSCLC), according to findings from the phase III IMpower150 trial presented at the ESMO Immuno Oncology Congress.

UPDATE 3/26/2018: Frontline Atezolizumab Regimen Improves Survival in NSCLC

In the study, the atezolizumab regimen demonstrated a median progression-free survival (PFS) of 8.3 months compared with 6.8 months with bevacizumab and chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.74; P <.0001). The 12-month PFS rate was 37% with the atezolizumab-containing regimen and 18% with the bevacizumab/chemotherapy regimen.

In a preliminary examination of overall survival (OS), there was a 22.5% reduction in the risk of death with the atezolizumab combination compared with bevacizumab and chemotherapy alone. After a minimum follow-up of 9.5 months, the median OS was 14.4 (95% CI, 12.8-17.1) versus 19.2 months (95% CI, 16.8-26.1), in favor of the atezolizumab group (HR, 0.775; 95% CI, 0.619-0.970; P = .0262). The next OS analysis will take place in the first half of 2018.

“This is the first phase III trial to report on the combination of chemotherapy, antiangiogenic treatment and immunotherapy as first line treatment for advanced non-squamous NSCLC,” said lead author Martin Reck, MD, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany. “The trial met its co-primary endpoint of PFS and the preliminary results of the co-primary endpoint of overall survival, although immature, look encouraging.”

The IMpower150 study enrolled 1202 patients with stage IV non-squamous NSCLC. Patients were randomized evenly to receive atezolizumab plus carboplatin and paclitaxel (arm A), atezolizumab with bevacizumab plus carboplatin and paclitaxel (arm B), or bevacizumab plus carboplatin and paclitaxel (arm C). Those with known EGFR or ALK alterations were excluded from the study. Patients were also tested for a tumor T-effector gene expression signature.

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 median age of patients in the trial was 63 years and 60% were previous smokers. Overall, most patients were male and the ECOG performance status was 0 for 39% of patients in arm B and for 43% in arm C. The minimum follow-up at the time of the analysis was 9.5 months. For the interim analysis, the study was only designed to compare arms B and C.

The objective response rate (ORR) in the atezolizumab arm was 64% compared with 48% in the bevacizumab/chemotherapy alone group. PD-L1 expression on immune and tumor cells did not appear to impact efficacy, as those testing negative for the marker still experienced an improvement in PFS with atezolizumab (HR, 0.77; 95% CI, 0.61-0.99). However, there was a 50% reduction in the risk of progression or death with atezolizumab in those testing positive for PD-L1 on immune and tumor cells (IHC1/2/3; HR, 0.50; 95% CI, 0.39-0.64).

“There was a significant and clinically relevant improvement in progression-free survival favoring the addition of atezolizumab to bevacizumab and chemotherapy," said Reck. "The results show that there is a way to improve the efficacy of platinum-based chemotherapy in patients with advanced non-squamous NSCLC."

Each of the agents showed similar toxicity profiles as in previous trials. Serious treatment-related adverse events were observed in 25.4% of patients treated with the atezolizumab regimen compared with 19.3% of those in the control arm. "There were no new safety signals or toxicity issues with this combination so it appears to be a feasible approach for this group of patients," Reck noted.

Preliminary findings were also presented for the comparison of arm A (atezolizumab plus chemotherapy without bevacizumab) with the control arm of bevacizumab plus chemotherapy (arm C). In this analysis, there was not a benefit seen in PFS for atezolizumab (HR, 0.936; 95% CI, 0.787-1.112). Additionally, ORR was similar between the two groups (49% vs 48%). Data for this comparison continue to mature for OS.

“This Tecentriq study is the first positive Phase III combination trial that showed a cancer immunotherapy reduced the risk of the disease getting worse when used as an initial treatment in a broad group of people with advanced non-squamous NSCLC,” Sandra Horning, MD, chief medical officer and Head of Global Product Development at Roche, the company developing the drugs. “The IMpower150 study represents an important advance in lung cancer treatment, and we will submit these results to regulatory authorities around the world to potentially bring a new standard of care to people living with this disease as soon as possible.”

Atezolizumab is currently approved as a treatment for patients with metastatic NSCLC following progression on a platinum-containing regimen. For lung cancer, bevacizumab is approved for patients with non-squamous NSCLC in combination with carboplatin and paclitaxel.

Several studies continue to assess atezolizumab as a treatment for patients with lung cancer as part of various combinations or as monotherapy. The PD-L1 inhibitor is being looked at with nab-paclitaxel (Abraxane) and in combinations with pemetrexed and other chemotherapy agents. The combination of atezolizumab and bevacizumab is being assessed in several solid tumors, with promising findings presented in renal cell carcinoma. Trial looking at this combination are currently ongoing.

Reck M. Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Annals of Oncology, 2017;28(11). Abstract LBA1_PR.

In the T-effector signature wild-type population, the addition of atezolizumab reduced the risk of progression or death by 49%. The median PFS was 11.3 months with the PD-L1 inhibitor versus 6.8 months with bevacizumab/chemotherapy alone (HR, 0.51; 95% CI, 0.38-0.68; P <.0001). The ORR in this group was 69% with atezolizumab compared with 54% without the PD-L1 inhibitor. The 12-month PFS rate was 18% with bevacizumab/chemotherapy and 46% with the addition of atezolizumab.