Atezolizumab Plus Chemo Poised for EU Approval in Small Cell Lung Cancer

Sandra Horning, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of atezolizumab (Tecentriq) in combination with carboplatin and etoposide for the frontline treatment of patients with extensive-stage small cell lung cancer (SCLC).¹

UPDATE 9/6/2019: Atezolizumab Combo Approved in Europe for Small Cell Lung Cancer

The positive opinion is based on findings from the phase III IMpower133 trial, in which the combination regimen significantly improved progression-free and overall survival (OS) compared with chemotherapy alone in this patient population. In the intent-to-treat (ITT) population, the atezolizumab/chemotherapy combination led to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.91; P = .0069).^2,3 The median OS was 12.3 months and 10.3 months with atezolizumab/chemotherapy and chemotherapy alone, respectively.

The European Commission will now make a final decision on the approval. The FDA approved the atezolizumab/chemotherapy combination in this setting in March 2019.

“We are pleased to receive a positive opinion from the CHMP for our Tecentriq-based lung cancer combination for people living with extensive-stage small cell lung cancer,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, Roche, the manufacturer of atezolizumab. “The combination of Tecentriq and chemotherapy has the potential to address the high unmet need in this aggressive form of lung cancer where advances in survival have been very difficult to achieve.”

In the international, double-blind, randomized, placebo-controlled phase III IMpower133 study, investigators evaluated the efficacy and safety of frontline atezolizumab added to carboplatin/etoposide in 403 treatment-naïve patients with extensive-stage SCLC.

All patients received four 21-day cycles of carboplatin area under the curve 5 mg/mL/min intravenous (IV) on day 1 and 100 mg/m² etoposide IV on days 1 through 3. Patients were also randomized 1:1 to receive either concurrent atezolizumab at 1200 mg IV on day 1 (n = 201) or placebo (n = 202) during the induction phase. Treatment was followed by maintenance therapy with atezolizumab or placebo, according to the previous random assignment, every 3 weeks until progressive disease or loss of clinical benefit.

Investigator-assessed progression-free survival (PFS) and OS in the ITT population served as the primary endpoints; secondary endpoints included objective response rate (ORR), duration of response, and safety.

The median age was 64 years (range, 26-90) in both the atezolizumab and placebo groups, and the majority were male (64% vs 65%, respectively), white (81% vs 79%), and former smokers (58.7% vs 61.4%). The atezolizumab arm included 17 patients (8%) with brain metastases and 77 (38%) with liver metastases; while the placebo group consisted of 9% and 36%, respectively.

The median duration of treatment with atezolizumab was 4.7 months, with a median of 7 doses received. The investigators saw no major difference in ORR between arms (60.2% vs 64.4%, respectively) or in median duration of response (4.2 vs 3.9 months).

Results showed that OS events occurred in 51.7% of the atezolizumab arm and 66.3% of the control arm. Atezolizumab was associated with a higher 6-month PFS rate (30.9% vs. 22.4%), and a more than doubling 12-month PFS rate (12.6% vs 5.4%) compared with placebo.

The median PFS was 5.2 months and 4.3 months with atezolizumab/chemotherapy and chemotherapy alone, respectively (HR, 0.77; 95% CI, 0.62-0.96; P = .017).

Moreover, the PD-L1 inhibitor demonstrated superior 6-month (32.2% vs 17.1%) and 12-month (14.9% vs 6.2%) event-free rates. Eighteen patients treated with concurrent atezolizumab had ongoing responses versus 7 patients in the control group.

Regarding safety, the profile of the regimen was consistent with prior studies of the individual agents, with no new findings observed.

Serious adverse events (AEs) occurred in 56.6% of those who received atezolizumab/chemotherapy versus 56.1% of those on chemotherapy alone. The most common AEs (≥20%) in patients receiving the immunotherapy/chemotherapy combination were neutropenia (23%), anemia (14%), decreased neutrophil count (14%) and thrombocytopenia (10%).

Immune-related adverse events (irAEs) were more common with atezolizumab compared with placebo (39.9% vs 24.5%). The most common grade 1/2 irAEs among the atezolizumab and placebo arms included rash (16.7% vs 10.2%, respectively), hepatitis (5.6% vs 4.6%), infusion-related reactions (3.5% vs 4.6%), pneumonitis (1.5% vs 1.5%), and colitis (0.5% vs 0%).

References

1. CHMP recommends EU approval of Roche’s Tecentriq in combination with chemotherapy as an initial treatment of adults with extensive-stage small cell lung cancer. Roche. Published July 26, 2019. https://bit.ly/2K2A6bY. Accessed July 26, 2019.
2. Liu S, Mansfield A, Szczesna S, et al. IMpower 133: primary PFS, OS and safety in a ph1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.07.
3. Liu S, Mansfield A, Szczesna S, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;doi:10.1056/NEJMoa1809064.