Notable Gains in Survival Achieved With Atezolizumab in Non–Small Cell Lung Cancer

FDA Approves Drug in Second-Line Setting


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Atezolizumab offers a new second-line therapeutic strategy for patients with advanced NSCLC, regardless of the PD-L1 status of the tumor.
— Fabrice Barlesi, MD, PhD

The programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq) significantly improved overall survival, compared to docetaxel, in previously treated, advanced non–small cell lung cancer (NSCLC), according to preliminary results of the phase III OAK study. The findings are the first phase III data ever to be reported for an anti–PD-L1 agent. The presentation was made at the 2016 European Society for Medical Oncology (ESMO) Congress by Fabrice Barlesi, MD, PhD, Professor of Medicine at Aix-Marseille University and Head of Multidisciplinary Oncology and Therapeutic Innovations at the Public Assistance Hospital in Marseilles, France.1

Median overall survival was 13.8 months with atezolizumab vs 9.6 months with docetaxel in the overall population of NSCLC patients unselected for the expression of PD-L1. The absolute difference increased to 5 months in the subgroup of patients with ≥ 1% PD-L1 expression, Dr. Barlesi reported.

“When you look at the comparators, a median overall survival in this unselected population of 13.8 months is an unprecedented benefit,” he noted at a press briefing. “The benefit was seen regardless of PD-L1 expression levels and was consistent across all subgroups, including squamous and nonsquamous disease, smoking status, or presence of brain mets at baseline. Atezolizumab offers a new second-line therapeutic strategy for patients with advanced NSCLC, regardless of the PD-L1 status of the tumor.”

In a subgroup analysis of OAK, survival time was correlated with magnitude of PD-L1 expression among patients assigned to atezolizumab. The subgroup with the highest levels of PD-L1 expression lived more than twice as long when treated with atezolizumab as compared with chemotherapy. But even patients who were PD-L1–negative showed a benefit from this agent, Dr. Barlesi said.

Atezolizumab received approval from the U.S. Food and Drug Administration (FDA) on October 18, 2016, for the treatment of people with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy and whose disease has progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities.

Phase III OAK Trial

The multicenter phase III OAK trial involved 1,225 patients with locally advanced or metastatic NSCLC who had received 1 or 2 prior lines of chemotherapy. Patients with any PD-L1 expression status (positive or negative) were randomly assigned to atezolizumab (1,200 mg every 3 weeks) or docetaxel (75 mg/m2 every 3 weeks).

Second-Line Atezolizumab in NSCLC

  • The OAK trial is the first phase III study of an anti–PD-L1 antibody.
  • Atezolizumab significantly improved overall survival vs docetaxel in the second-line setting of advanced non–small cell lung cancer.
  • Patients benefited regardless of the magnitude of PD-L1 expression. Mortality was reduced in the highest PD-L1 stratum (≥ 50%) by 59%; among those with PD-L1–negative (< 1%) expression, it was reduced by 25%.
  • Patients with squamous and nonsquamous histologies derived benefit, as did patients who were never-smokers.

The two coprimary endpoints were overall survival in the intent-to-treat population and overall survival in the subgroup of patients with PD-L1 expression ≥ 1%. The primary endpoint analysis included the first 850 patients enrolled, who had been followed for at least 19 months.

In the intent-to-treat analysis, median overall survival was 13.8 months with atezolizumab vs 9.6 months with docetaxel (hazard ratio [HR] = 0.73, P = .0003). At 12 months, overall survival was 14% higher in the atezolizumab arm (55% vs 41%), and at 18 months, overall survival was 13% higher (40% vs 27%), he reported.

The investigators also examined outcomes in all subsets of PD-L1 expression, showing the benefit of atezolizumab vs docetaxel, as follows:

  • PD-L1 ≥ 50%: median overall survival of 20.5 vs 8.9 months (HR = 0.41, P < .0001).
  • PD-L1 expression ≥ 1%: median overall survival of 15.7 vs 10.3 months (HR = 0.74, P = .0102).
  • PD-L1 < 1%: median overall survival of 12.6 vs 8.9 months (HR = 0.75, P = .0205).

Patients with both major NSCLC histologic subtypes benefited from atezolizumab. Overall survival in patients with nonsquamous cell tumors was 15.6 vs 11.2 months (HR = 0.73, P= .0015), and in those with squamous cell cancer was 8.9 vs 7.7 months, respectively (HR = 0.73, P =.0383). In subgroup analyses, only 1 group fared better on docetaxel—the 10% of patients with epidermal growth factor receptor (EGFR)-mutant tumors, whose median survival was 16.2 vs 10.5 months for atezolizumab (HR = 1.24).

When asked if, compared to anti–programmed cell death protein 1 (PD-1) antibodies, the PD-L1 inhibitors as a class may be more active in a broader population of patients, Dr. Barlesi responded, “I think atezolizumab could be a drug that acts a little differently and may provide additional benefit, because the interaction is not exactly the same as with the PD-1 inhibitors…. With atezolizumab, you are also inhibiting B7-1 (also known as CD80). We are priming the immune system differently and activating the T cell differently. This may lead to differences in activity and also in the safety profile.”

Other Outcomes

Interestingly, median progression-free survival did not differ significantly, being 2.8 months with atezolizumab and 4.0 months with docetaxel (HR = 0.95, P = .4928). The objective response rates were also similar—14% and 13%, respectively. However, response rates with atezolizumab increased as PD-L1 expression rose, reaching an absolute difference of 20% (31% vs 11%) among patients with the highest levels of PD-L1 expression. Response duration was also longer with atezolizumab—16.3 vs 6.2 months with docetaxel.

Atezolizumab was well tolerated, with a favorable safety profile. No new safety signals were identified, and the rate of immune-mediated adverse events was low. Treatment-related adverse events occurred more often with docetaxel (86% vs 64%), as did the incidence of grade 3/4 treatment-related adverse events (15% vs 43%). ■

Disclosure: Dr. Barlesi is on the advisory boards of AstraZeneca, Bristol-Myers Squibb, Boehringer–Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, and Pfizer.

Reference

1. Barlesi F, Park K, Ciardello F, et al: Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in advanced NSCLC. 2016 ESMO Congress. Abstract LBA_44. Presented October 9, 2016.


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