For most patients with resected non-small cell lung cancer (NSCLC), the standard of care has not changed in over fifteen years and still consists of adjuvant platinum-based chemotherapy. IMpower010 is a randomised phase III open-label trial of atezolizumab vs. best supportive care (BSC) after surgery and adjuvant chemotherapy in patients with early-stage (IB-IIIA) NSCLC. Primary results of this trial, presented at ASCO 2021 demonstrate that, adjuvant atezolizumab significantly improves the disease-free survival after surgical resection and adjuvant chemotherapy for patients with stage II-IIIA NSCLC.
The IMpower010 study
IMpower010 enrolled 1,280 patients, of whom 1,269 received up to four 21-day cycles of adjuvant chemotherapy (cisplatin, partnered with either pemetrexed, docetaxel, gemcitabine or vinorelbine). In total, 1,005 of these patients were subsequently randomised (1:1) to sixteen cycles of atezolizumab (1,200 mg Q3W) or BSC. All eligible patients had completely resected (4-12 weeks prior to enrolment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and had an ECOG performance status of 0-1. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 tumour cell (TC) ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomised patients with Stage II-IIIA disease, and finally DFS in the ITT population (Stage IB-IIIA). Only if the latter analysis was positive, the OS could be tested in the ITT population. Baseline patient characteristics were well balanced between all treatment arms. The median age of the patients was 62 years and 67% of patients were male. Most patients had non-squamous histology (65.6%) and 12.2% of patients had stage IB disease. In total, 54.6% of patients had PD-L1 TC expression levels ≥1%.
Significant disease-free survival benefit with adjuvant atezolizumab vs. BSC
After a median follow-up of 32.8 months, adjuvant atezolizumab demonstrated a statistically significant DFS benefit over BSC in the PD-L1 TC ≥1% Stage II-IIIA population (median DFS not evaluable vs. 35.3 months, HR[95%CI]: 0.66[0.50-0.88], p= 0.004). This benefit was observed in all subgroups, except for active smokers at the time of enrolment and in patients with an ALK rearrangement (both small subgroups of N= 75 and N= 23, respectively). Furthermore, atezolizumab also reduced the risk of disease recurrence or death by 21% in the all-randomised population of patients with stage II-IIIA NSCLC, with a median DFS of 42.3 months vs. 35.3 months with BSC (HR[95%CI]: 0.79[0.64-0.96], p= 0.02). Interestingly, PD-L1 expression levels do seem to be of clinical relevance in this trial, with a strong benefit for patients with tumour cell expression levels of at least 50% (HR[95%CI]:0.43[0.27-0.66]) and no benefit for patients without PD-L1 expression (HR[95%CI]:0.97[0.72-1.31]). In the ITT population (stage IB-IIIA NSCLC), the statistical significance boundary for DFS was not crossed for atezolizumab versus BSC. For these patients the median DFS was not estimable in the atezolizumab arm as compared to 37.2 months with BSC (HR[95%CI]: 0.81[0.67-0.99], p= 0.04). OS data were still immature and not formally tested at this interim analysis. However, a trend towards OS improvement with atezolizumab was observed in the PD-L1 TC ≥1% stage II-IIIA population (HR[95%CI]: 0.77[0.51-1.17]). Follow-up is ongoing for DFS and OS analyses in the ITT population.
Any-grade adverse events (AEs) occurred in 92.7% and 70.7% of patients in the atezolizumab and BSC groups, respectively. AEs were grade 3/4 in severity in 21.8% and 11.5% of patients, respectively. Grade 5 treatment-related AEs were rare and occurred in only 0.8% of patients in the atezolizumab arm. AEs leading to atezolizumab discontinuation were reported in 18.2% of atezolizumab-treated patients. Immune-mediated AEs mostly occurred in a small proportion of patients (<1%). However, grade 3/4 laboratory abnormalities for liver function were detected in 20 patients (4%), of which only four were diagnosed with hepatitis.
IMpower010 is the first phase III study demonstrating a DFS improvement with adjuvant immunotherapy in NSCLC patients following platinum-based chemotherapy. The safety profile of atezolizumab was consistent with prior experience of atezolizumab monotherapy across indications and lines of therapy. Based on these findings, the authors conclude that atezolizumab should be considered a practice-changing adjuvant treatment option for patients with PD-L1 TC ≥1% Stage II-IIIA NSCLC.
Wakelee HA, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Presented at ASCO 2021; abstract 8500.