Benefit of Adjuvant Atezolizumab in PD-L1-Positive Early-Stage NSCLC
Around 30% of patients with non-small cell lung cancer (NSCLC) are diagnosed with early-stage disease and undergo surgery with curative intent. After complete resection, adjuvant platinum-based chemotherapy is recommended as the standard of care for patients who are at high risk of recurrence, including patients with stage II–IIIA and selected patients with stage IB disease. This is based on data showing approximately 5% improvement in survival with adjuvant chemotherapy at 5 years. Recently, adjuvant osimertinib substantially increased disease-free survival (DFS) for patients harboring EGFR activation mutations and has become the new adjuvant therapy standard for patients with this molecular subtype. However, for the majority of patients who are EGFR wild-type, there is a high unmet need for new adjuvant treatment strategies beyond chemotherapy to improve patient outcomes.
The global phase III IMpower010 trial was designed to evaluate the efficacy and safety of adjuvant atezolizumab versus best supportive care (BSC) after adjuvant chemotherapy in patients with completely resected stage IB–IIIA NSCLC. Primary results were presented at ASCO 2021 by Dr Heather Wakelee, MD (Stanford University School of Medicine/Stanford Cancer Institute, Stanford, California, US). Among enrolled patients, 1005 were randomly assigned to receive either adjuvant atezolizumab 1200 mg once every 3 weeks for 16 cycles, or BSC. The primary endpoint of investigator-assessed DFS was analyzed hierarchically: first in patients with resected stage II–IIIA NSCLC and PD-L1 expression ≥1% (SP623 assay), then in all-randomized patients with stage II–IIIA disease, and lastly in the intention-to-treat population (ITT), which included patients with stage IB–III disease. Overall, about 55% of patients had PD-L1 expression of at least 1%. The majority of patients had stage II disease, 40% had stage IIIA and 12% had stage IB. Median follow-up was between 32 and 33 months. In patients with stage II–IIIA NSCLC and PD-L1 expression ≥1%, adjuvant atezolizumab showed a statistically significant DFS benefit (median DFS not reached with atezolizumab versus 35.3 months with BSC [hazard ratio (HR), 0.66; P=0.004]). This translates into a 34% reduction in risk of death or disease recurrence. The benefit with atezolizumab was seen across all patient subgroups, except those who were active smokers at the time of enrollment and patients with ALK gene rearrangements. The degree of benefit with atezolizumab was also lower among patients with EGFR-mutant lung cancers. In all randomized stage II–IIIA NSCLC patients, DFS was also significantly improved with adjuvant atezolizumab (42.3 versus 35.3 months; HR, 0.79; P=0.02). However, in the subgroup of patients who had PD-L1 expression <1%, HR was 0.97, indicating no benefit. For the ITT population, which also included patients with stage IB disease, the significance boundary was not crossed. Of note, OS data (secondary endpoint) were immature at this interim analysis. The safety profile of atezolizumab was consistent with prior experience of monotherapy across indications and lines of therapy. Adverse events (AEs) of grade 3/4 occurred in 21.8% of patients in the atezolizumab arm versus 11.5% in the BSC arm. As expected, immune-related AEs (irAEs) were more frequent in the atezolizumab arm with grade 3/4 irAEs reported in 7.9% versus 0.6%, respectively; most were laboratory abnormalities for liver function tests, although <1% had a diagnosis of hepatitis. AEs leading to discontinuation of atezolizumab occurred in 18.2% of patients and there were four treatment-related deaths in the atezolizumab arm (0.8%).
In her conclusion, Dr Wakelee highlighted that the IMpower010 is the first phase III study of adjuvant immunotherapy in NSCLC, and the results support atezolizumab as a potential practice-changing adjuvant treatment option for patients with stage II–IIIA NSCLC and PD-L1 expression ≥1%. The abstract discussant, Dr Zosia Piotowska, MD, MHS (Center for Thoracic Cancer, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, US) acknowledged that, historically, OS has been considered as the gold-standard endpoint for adjuvant studies; however, in this trial, the DFS improvement seen with atezolizumab among patients with PD-L1-positive, stage II–IIIA disease is clinically meaningful. Furthermore, she highlighted that recent US Food and Drug Administration (FDA) approvals (e.g. adjuvant osimertinib for EGFR-mutated NSCLC and durvalumab in locally advanced NSCLC) have been based on DFS benefits. Nevertheless, Dr Piotowska emphasized that a full evaluation of the benefits of adjuvant atezolizumab will require longer follow-up, with OS results and quality-of-life assessments.
Wakelee H, et al, ASCO 2021; Abstract 8500.