IMpower151 fails to meet its primary endpoint of investigator-assessed progression-free survival
The phase III IMpower151 study was conducted in China to evaluate the efficacy and safety of atezolizumab, bevacizumab and carboplatin, plus paclitaxel or pemetrexed (ABCP) vs. BCP, as first-line treatment for patients with metastatic non-squamous non-small cell lung cancer. Unfortunately, IMpower151 did not meet its primary endpoint of investigator-assessed progression-free survival (PFS) and only demonstrated numerical improvements in PFS and overall survival for ABCP vs. BCP.
Previously, the phase III IMpower150 trial demonstrated significant progression-free survival (PFS) and overall survival (OS) improvements with atezolizumab vs. placebo in combination with bevacizumab, carboplatin and paclitaxel in patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR/ALK genomic alterations. In 2020, to address regional differences in patient genomic composition (e.g. EGFR mutation prevalence rates) and clinical practice (e.g., pemetrexed use), the phase III IMpower151 study was conducted in China to evaluate the efficacy and safety of atezolizumab + bevacizumab + carboplatin + pemetrexed or paclitaxel (ABCP) vs. BCP, as first-line treatment for metastatic nonsquamous NSCLC regardless of sensitizing EGFR/ALK genomic alterations.
Study design
Patients with chemotherapy-naive metastatic nonsquamous NSCLC were randomised (1:1) to receive atezolizumab/placebo (1200 mg) plus bevacizumab (15 mg/kg), carboplatin (AUC 6) and paclitaxel (175 mg/m2) or pemetrexed (500 mg/m2) IV Q3W for 4 cycles, followed by atezolizumab/placebo maintenance treatment until unacceptable toxicity or loss of clinical benefit, and bevacizumab and pemetrexed (if given during induction) until progression (RECIST 1.1). Stratification factors were EGFR/ALK genotype (alterations vs. wild-type, capped at 50% wild-type) and PD-L1 expression (tumour cell <50% vs. ≥50% by SP263). The primary endpoint was investigator-assessed (INV)-PFS in the intention-to-treat (ITT) population. Secondary endpoints included INV-PFS in the EGFR/ALK+ population, INV-PFS in PD-L1 subgroups, independent review facility (IRF)-PFS, overall survival, objective response rate and duration of response.
Results
Out of the 305 patients that were randomised, almost all patients (97.4%) received pemetrexed and more than half of the population (53%) had EGFR/ALK+ nonsquamous NSCLC. After a median follow-up of 14.0 months (minimum follow-up 10.5 months), median INV-PFS was 9.5 months for patients receiving ABCP and 7.1 months for patients receiving BCP (HR[95%CI]: 0.84[0.65-1.09], p= 0.18). ABCP showed numerical PFS improvements in wildtype subgroups compared with BCP (mPFS 10.4 vs. 7.0 months, HR[95%CI]: 0.81[0.55-1.19]). In the EGFR/ALK+ subgroup, an incremental PFS benefit of atezolizumab in addition to BCP was not observed (mPFS 8.5 vs. 8.3 months, HR[95%CI]: 0.86[0.61-1.21]). No PD-L1 dependent INV-PFS differences were observed. Similar ORR were observed in both arms (48.0% vs. 49.7%) but the duration of response was longer with ABCP than with BCP (11.3 vs. 8.3 months). There were no clinically meaningful OS improvements for ABCP vs. BCP in the ITT population (median OS 20.7 vs. 18.7 months, HR[95%CI]: 0.93[0.67-1.28]).
All-cause adverse events (AEs) occurred in 99.3% (ABCP; Grade 3/4, 66.4%) and 100% (BCP; Grade 3/4, 61.4%) of patients and led to discontinuation of any treatment in 23.0% and 15.0%, respectively. All-cause Grade 5 AEs occurred in 7.9% (ABCP; treatment-related, 5.9%) and 7.8% (BCP; treatment-related, 6.5%) of patients.
Conclusion
IMpower151 did not meet its primary endpoint of INV-PFS in the ITT population, although numerical improvements were observed in PFS for ABCP vs. BCP. In addition, there was no clinically meaningful improvement in OS for ABCP vs. BCP in the ITT population. However, ABCP was generally well tolerated and no new safety signals were identified. These results are thus inconsistent with the positive and clinically meaningful PFS and OS improvements that were seen with ABCP in the IMpower150 trial.
Reference
Zhou C, et al. IMpower151: Phase III study of atezolizumab + bevacizumab + chemotherapy in first line metastatic nonsquamous NSCLC. Presented at WCLC 2023; Abstract OA09.06.
