Atezolizumab Significantly Extends Survival in NSCLC

Fabrice Barlesi, MD

Atezolizumab (Tecentriq) reduced the risk of death by 27% compared with docetaxel in patients with advanced non—small cell lung cancer (NSCLC) following the failure of platinum-based chemotherapy, according to findings from the phase III OAK trial presented at the 2016 ESMO Congress.

The median overall survival (OS) was improved by 4.2 months with the PD-L1 inhibitor versus chemotherapy. The survival benefit with atezolizumab was observed regardless of PD-L1 status or histology.

“This is the first phase III study of atezolizumab, a PD-L1 inhibitor, and it confirms the efficacy seen in the POPLAR phase II study, along with the results of PD-1 inhibitors,” lead study investigator Fabrice Barlesi, MD, PhD, head of the Multidisciplinary Oncology and Therapeutic Innovations Department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France, said in a statement.

“Atezolizumab offers a new second-line therapeutic strategy for patients with non¬—small cell lung cancer, regardless of the PD-L1 status of the tumor,” added Barlesi.

The international, open-label randomized phase III OAK trial included 1225 patients with locally advanced or metastatic NSCLC—regardless of histology or PD-L1 status—who progressed during or after platinum-containing chemotherapy. Patients were randomized in a 1:1 ratio to 75 mg/m² of intravenous docetaxel or 1200 mg of intravenous atezolizumab every 3 weeks.

Patient demographics were well balanced between the 2 arms at baseline. The median patients age was 64 years, 61% of patients were male, 18% had never smoked, and 25% had received 2 prior lines of therapy. Patients had an ECOG performance status of 0 (37%) or 1 (63%). Among patients randomized to docetaxel, 17% received immunotherapy as their next treatment.

The coprimary endpoints of the trial were OS in the entire study population and in a PD-L1—defined subgroup. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR). The primary efficacy assessment included only the initial 850 randomized patients, and the secondary efficacy analysis will include data from all 1225 randomized patients.

In the intent to treat population (N = 850), the median OS was 13.8 months in the atezolizumab arm (n = 425) versus 9.6 months in the docetaxel arm (n = 425; HR, 0.73; 95% CI, 0.62-0.87; P = .0003). The PFS was 2.8 months versus 4 months (HR, 0.95), respectively. The ORR and DoR were 13.6% versus 13.4%, and 16.3 versus 6.2 months, respectively.

In nonsquamous patients, the median OS was 15.6 months in the atezolizumab group (n = 313) compared with 11.2 months in the control group (n = 315; HR, 0.73; 95% CI, 0.60-0.89). Among patients with squamous histology, the median OS was 8.9 months in the atezolizumab cohort (n = 112) versus 7.7 months on the docetaxel arm (n = 110; HR, 0.73; 95% CI, 0.54-0.98).

Regarding PD-L1 status, PD-L1—positive patients (TC1/2/3 or IC1/2/3) had expression on at least 1% of their tumor cells (TC) or tumor-infiltrating immune cells (IC). PD-L1 negative patients (TC0 or IC0) had less than 1% expression on their TC and IC.

Among the PD-L1¬—positive group, the median OS was 15.7 months in the atezolizumab arm (n = 241) compared with 10.3 months in the control arm (n = 222; HR, 0.74; 95% CI, 0.58-0.93; P = .0102). Among PD-L1—negative patients, the median OS was 12.6 months in the atezolizumab cohort (n = 180) versus 8.9 months in the docetaxel group (n = 199; HR, 0.75; 95% CI 0.59-0.96; P = .0205).

“Interestingly, the study also showed an improvement in overall survival, even in patients with no PD-L1 expression, which means we have a problem with using PD-L1 negativity as an exclusion factor for treatment,” Martin Reck, MD, PhD, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, said in a statement.

“My suggestion would be that PD-L1 is perhaps one imperfect surrogate marker to describe the activity; it’s a good enrichment factor but we need additional markers for the characterization of patients who might not benefit from this treatment or who might really benefit,” added Reck.

The safety profile with atezolizumab in the OAK trial was consistent with adverse event (AE) outcomes observed in previous studies of the PD-L1 inhibitor. AEs occurring more frequently in the atezolizumab arm included musculoskeletal pain (11% vs 4% with docetaxel) and pruritus (8% vs 3%).

The rate of grade 3/4 AEs was lower in the atezolizumab arm versus the control arm at 15% versus 43%, respectively. No treatment-related deaths occurred in the atezolizumab cohort compared with 1 in the docetaxel arm.

Commenting in a statement on the OAK data, Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, the manufacturer of atezolizumab, said, “Tecentriq is the first and only anti—PD-L1 cancer immunotherapy to help people with metastatic NSCLC live significantly longer than chemotherapy regardless of their PD-L1 expression level or their disease histology. Even people whose disease had low or no observed PD-L1 expression still showed a significant benefit from the medicine.”

In April 2016, the FDA granted a priority review to atezolizumab for the treatment of patients with locally advanced or metastatic NSCLC who express PD-L1 and have progressed after a platinum-containing regimen.

The application for atezolizumab was based on data from multiple clinical trials, including the phase II BIRCH and POPLAR trials. The FDA will issue a final decision on approval by October 19, 2016.

Atezolizumab is currently approved by the FDA as a treatment for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA44.