The FDA has granted an approval to the combination of atezolizumab (Tecentriq) with carboplatin and etoposide for the frontline treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).
The approval is based on findings from the phase III IMpower133 study, which demonstrated that the addition of atezolizumab to carboplatin and etoposide led to a significant improvement in overall survival (OS) in patients with ES-SCLC.
"Tecentriq is the first cancer immunotherapy approved for the initial treatment of extensive-stage small cell lung cancer, which is especially difficult to treat," said Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech (Roche), the manufacturer of the PD-L1 inhibitor. "Until now, there have been limited treatment advances for this disease, and we are excited to bring a potential new standard of care to patients that has been shown to improve survival compared to chemotherapy."
Data showed that after a median follow-up of 13.9 months, the median OS in IMpower133 was 12.3 months (95% CI, 10.8-15.9) in the atezolizumab arm compared with 10.3 months (95% CI, 9.3-11.3) in the carboplatin/etoposide and placebo arm, leading to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.91; P
Moreover, the median progression-free survival (PFS) was 5.2 months (95% CI, 4.4-5.6) in the atezolizumab arm compared with 4.3 months (95% CI, 4.2-4.5) in the placebo group (HR, 0.77; 95% CI, 0.62-0.96; P
The international, double-blind, randomized, placebo-controlled phase III IMpower133 trial evaluated the efficacy and safety of frontline atezolizumab added to the standard of care, combination carboplatin and etoposide, in 403 treatment-naïve patients with ES-SCLC.
All patients received four 21-day cycles of carboplatin AUC 5 mg/mL/min 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 PFS and OS in the intention-to-treat population served as the primary endpoints. Secondary endpoints included objective response rate (ORR), duration of response, and safety.
Age, demographics, and smoking status were representative of the disease: 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 from the study were presented at the 19th World Conference on Lung Cancer.2
The results were simultaneously published in the New England Journal of Medicine
Additional data 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 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 compared with only 7 patients in the control arm.
Regarding safety, the profile of the regimen was consistent with prior studies of the individual agents, with no new findings observed. The most common all-grade adverse events (AEs; ≥20%) in those who received atezolizumab/chemotherapy were fatigue/asthenia (39%), nausea (38%), alopecia (37%), decreased appetite (27%), constipation (26%) and vomiting (20%).
Additionally, the most common grade 1/2 treatment-related AEs among the atezolizumab and placebo arms included neutropenia (13.1% vs 10.2%, respectively), anemia (24.7% vs 20.9%), decreased neutrophil count (3.5% vs 6.1%), thrombocytopenia (6.1% vs 7.1%), and leukopenia (7.6% vs 5.1%). Serious AEs occurred in 37% of patients who received atezolizumab plus chemotherapy compared with 35% of those on chemotherapy alone.
Immune-related adverse events (irAEs) were more common with atezolizumab compared with placebo (39.9% vs 24.5%). The most common grade 1 or 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%).
"Extensive-stage small cell lung cancer is a highly aggressive form of lung cancer, which until now, has seen limited treatment advances over the last 20 years," said Andrea Ferris, president and CEO of LUNGevity Foundation. "Today's approval of Tecentriq is an important step forward in ensuring that people across the spectrum of lung cancer types have effective new therapies."
- FDA Approves Genentech’s Tecentriq in Combination With Chemotherapy for the Initial Treatment of Adults With Extensive-Stage Small Cell Lung Cancer. Genentech (Roche). Published March 18, 2019. https://bit.ly/2Y5jVkw. Accessed March 19, 2019.
- 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.
- 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.