Atezolizumab Combo Confirmed as Frontline Standard in Advanced Small Cell Lung Cancer

Martin Reck, MD, PhD

With follow-up of nearly 2 years, the addition of atezolizumab to first-line carboplatin plus etoposide (CP/ET) for the treatment of extensive stage small cell lung cancer (ES-SCLC) continues to demonstrate improved overall survival (OS) compared with placebo plus CP/ET, according to updated results from the phase III IMpower133 trial.

At a median follow-up of 22.9 months, median OS remained 12.3 months in patients randomized to atezolizumab and 10.3 months in the placebo group (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).¹ The long-term follow-up was presented by Martin Reck, MD, PhD, at the 2019 ESMO Congress.

IMpower133 is the first trial to demonstrate a significant improvement in survival as first-line treatment for patients with SCLC since the introduction of platinum-based chemotherapy in the 1990s. Other trials of immunotherapy in SCLC in the first-line setting had shown less promising results.

“Exploratory biomarker analyses that included both PD-L1 immunohistochemistry and blood-based tumor mutational burden suggest that patients derive treatment benefit from the addition of atezolizumab regardless of biomarker status,” said Reck, head, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany.

He added, “Overall, these results confirm the role of the combination of atezolizumab and platinum-based chemotherapy as an attractive new therapeutic opportunity for patients with advanced SCLC.”

Better first-line treatment of ES-SCLC is an unmet need. The IMpower133 study demonstrated a significant improvement in efficacy and a tolerable safety profile by adding atezolizumab to CP/ET, with a statistically significant improvement in median OS and median progression-free survival (PFS) compared with chemotherapy alone.

In the primary analysis, at a median follow-up of 13.9 months, the primary endpoint of median OS was 12.3 months in the atezolizumab plus CP/ET arm compared with 10.3 months in the placebo plus CP/ET arm (HR, 0.7;  P = .007).² The median PFS, a coprimary endpoint, was 5.2 versus 4.3 months, respectively (HR, 0.77;  P = .02). The survival benefit was observed across all subgroups.

Based on the primary data, atezolizumab was approved as first-line treatment for ES-SCLC by both the FDA (March 2019) and the European Medicines Agency (September 2019).

IMpower133 was an international, randomized, placebo-controlled, double-blind, phase III trial that involved 403 treatment-naïve patients with ES-SCLC. Patients were randomized to CP/ET with either the PD-L1 inhibitor atezolizumab or placebo for four 21-day cycles followed by maintenance therapy with atezolizumab or placebo, according to the prior randomization. Treatment continued until progressive disease or loss of clinical benefit. Patients with treated asymptomatic brain metastases were eligible.

At 18 months, 34% of patients were alive in the atezolizumab-CP/ET arm compared with 21% in the placebo-CP/ET arm. Response rates remained comparable between arms, with 60.2% and 64.4%, having complete or partial responses in the atezolizumab and chemotherapy-alone arms, respectively. Median duration of response was also similar between the 2 arms, at 4.2 and 3.9 months, respectively. “At the time of this analysis, 9.1% of patients in the atezolizumab combination arm had an ongoing response compared to 2.3% in the chemotherapy arm,” Reck said.

A consistent benefit with the addition of atezolizumab was observed across subgroups “with a slight difference with regard to age, which needs further exploration,” he said. Patients aged ≥65 years seemed to have a more pronounced survival benefit with the addition of atezolizumab compared with patients aged <65 years.

There was no correlation between efficacy of the atezolizumab combination and blood tumor mutational burden level, whether the cutoff was 10 or 16 mut/Mb.

A posthoc exploratory analysis was conducted for OS by PD-L1 expression in 34% (n = 137) of the intent-to-treat (ITT) population in whom PD-L1 expression status was measured using the Ventana SP263 assay. “Interestingly, PD-L1 expression was seen mostly on the immune cells, with only limited expression on the tumor cells,” said Reck.

Tumor cells were negative for PD-L1 expression in 94.2% of the biomarker evaluable population, compared with 49.6% of immune cells. In contrast, PD-L1 positivity on tumor cells was observed in only 5.8% of the patients, compared with 50.4% on immune cells. Only 1.5% and 20.4% of patients had high (≥5%) PD-L1 expression on immune cells and tumor cells, respectively.

The efficacy of atezolizumab on OS was comparable between the biomarker evaluable population and non-biomarker evaluable population. “There was no correlation between the PD-L1 expression status and the efficacy of the combination with atezolizumab,” he said. There was a numerical advantage favoring atezolizumab plus CP/ET in the patients with PD-L1 expression ≥5% compared with the ITT population, but only 29 patients had high PD-L1 expression.

Subsequent therapy was received by 54.7% of patients randomized to the atezolizumab combination and 61.9% of those assigned to placebo plus chemotherapy. The most frequently used subsequent class of therapy was nonanthracycline chemotherapy.

There was no change in tolerability in the updated analysis. About two-thirds of patients in each arm had grade 3/4 adverse events (AEs) and 35.2% (placebo plus CP/ET) and 38.9% (atezolizumab plus CP/ET) had serious AEs.

As expected, the incidence of immune-related AEs was higher in the atezolizumab arm compared with the chemotherapy-only arm (41.4% vs 24.5%). The most frequent immune-related AEs in the atezolizumab arm were rash (20.2%), hepatitis (7.6%), changes in thyroid function (18.2%), and infusion-related reactions (5.5%). There were no grade 5 immune-related AEs.

References

1. Reck M, Liu SV, Mansfield AS, et al. IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract 1736O.
2. Horn L, Mansfield AS, Szcesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220-2229.

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