IMpower151 Misses Primary PFS End Point With Frontline Atezolizumab Plus Bevacizumab/Chemo in NSCLC

Caicun Zhou, PhD, MD

The addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), carboplatin, and pemetrexed or paclitaxel (ABCP; BCP) did not result in a statistically significant improvement in progression-free survival (PFS) vs BCP for patients with metastatic nonsquamous non–small cell lung cancer in the first line, missing the primary end point of the phase 3 IMpower151 study (NCT04194203). ¹

Data from the trial, which were presented at the 2023 IASLC World Conference on Lung Cancer, demonstrated that at a median follow-up of 14.0 months, the atezolizumab combination (n = 152) led to a median investigator-assessed PFS of 9.5 months (95% CI, 7.6-10.6) compared with 7.1 months (95% CI, 6.9-9.5) with the control regimen (n = 153; HR 0.84; 95% CI, 0.65-1.09; P = .18). The 6-month PFS rates were 69.6% vs 64.5%, respectively, and the 12-month PFS rates were 36.9% vs 27.7%, respectively.

Patients with EGFR/ALK wild-type disease (n = 142) experienced a numerical increase in PFS from 7.0 months (95% CI, 6.2-9.5) with BCP to 10.4 months (95% CI, 7.6-13.3) with ABCP (HR, 0.81; 95% CI, 0.55-1.19). An incremental PFS benefit was observed with ABCP in the subgroup of patients with EGFR/ALK-positive disease (n = 163). The median PFS was 8.5 months (95% CI, 6.9-10.3) with ABCP vs 8.3 months (95% CI, 6.9-10.1) with the BCP (unstratified HR, 0.86; 95% CI, 0.55-1.19). PD-L1–dependent differences in investigator-assessed PFS were not observed.

“These results are inconsistent with the positive and clinically meaningful PFS and overall survival [OS] improvements seen with ABCPac in [the phase 3] IMpower150 [(NCT02366143) study],” lead study author Caicun Zhou, PhD, MD, in the Department of Oncology at Shanghai Pulmonary Hospital and Tongji University School of Medicine in Shanghai, PR China, and colleagues, noted in a presentation of the data.¹

Previously reported data from the randomized, 3-armed IMpower150 trial demonstrated that atezolizumab plus bevacizumab, carboplatin, and paclitaxel produced superior PFS and OS vs placebo plus bevacizumab and chemotherapy in patients with metastatic nonsquamous NSCLC without EGFR/ALK genomic alterations.² The median OS with the atezolizumab combination was 19.2 months (95% CI, 17.0-23.8) vs 14.7 months (95% CI, 13.3-16.9) with the placebo regimen (HR 0.78; 95% CI, 0.64-0.96; P = .01). The median PFS was 8.3 months (95% CI, 7.7-9.8) in the experimental arm and 6.8 months (95% CI, 6.0-7.1) in the control arm (HR 0.62; 95% CI, 0.52-0.74; P <.001).² Notably, a PFS benefit was also observed in the 11% of patients with sensitizing EGFR/ALK genomic alterations who progressed on a prior TKI.³

Findings from IMpower150 supported the FDA approval of the regimen in 2018 for the first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK aberrations.⁴

After identifying a need to address regional differences in the prevalence of genomic alterations and the real-world use of antiangiogenic biosimilars in clinical practice, researchers in China designed the IMpower151 study. The data cutoff date for the current analysis was February 2, 2023.¹

The double-blinded study enrolled patients who were diagnosed with stage IV nonsquamous NSCLC who were naïve to chemotherapy. Patients were allowed to have sensitizing EGFR or ALK alterations, provided they had experienced disease progressed after 1 or more prior TKIs. Notably, no more than 50% of the overall trial population could have wild-type NSCLC.

Patients were randomly assigned 1:1 to ABCP (arm A) or BCP (arm B). In the induction phase, all patients received 15 mg/kg of bevacizumab, and either 500 mg/m² of pemetrexed or 175 mg/m² of paclitaxel. Those in arm A were also intravenously (IV) administered 1200 mg of atezolizumab, and patients in arm B received 1200 mg of IV placebo. After 4 cycles of induction therapy, patients in both arms entered the maintenance phase, where they continued treatment with the same doses of atezolizumab, bevacizumab, and pemetrexed (arm A) or placebo, bevacizumab, and pemetrexed (arm B). Patients were stratified by EGFR/ALK mutational status (alterations vs wild-type) and PD-L1 expression (<50% vs ≥50%).

Treatment with atezolizumab or placebo was continued until unacceptable toxicity or loss of clinical benefit. In arm B, bevacizumab and pemetrexed continued until patients experienced disease progression per RECIST v1.1 criteria.

The study’s primary end point was investigator-assessed PFS in the intention-to-treat (ITT) population. Key secondary end points included PFS in the ITT population as assessed by independent review facility, PFS according to genomic alteration and PD-L1 status, OS in the ITT population, overall response rate (ORR), and duration of response (DOR). Other key end points included safety and biomarker analyses.

A total of 305 patients were enrolled onto the study. The median age was 61 across both groups (range, 30-76). Most patients were male (arm A, 59.2%; arm B, 59.5%), younger than 65 years of age (65.8%; 64.1%), had an ECOG performance status of 1 (82.2%; 79.7%) and had previously received pemetrexed (98% vs 96.7%). Regarding tobacco use, 53.9% and 49% of patients in the experimental and control arms, respectively, were never smokers; 7.2% and 3.3%, respectively, were current smokers.

In arm A, 11.2% of patients had liver metastasis, 8.6% had brain metastasis, and 48.7% had bone metastasis; these percentages were 11.1%, 13.1%, and 51%, respectively, in arm B. High PD-L1 expression (using a ≥50% cutoff on tumor cells) was seen in 69.7% of those treated with ABCP and 69.9% of those receiving BCP; 30.3% and 30.1% of patients, respectively, had a PD-L1 expression of less than 50% on tumor cells.

There were 142 EGFR/ALK wild-type patients split evenly amongst the investigative and control arms, and 163 patients with EGFR/ALK-mutated disease. Of these, the majority had an EGFR mutation (52%; 51.6%) vs an ALK rearrangement(1.3%; 2%).

Seventy-nine and 83 patients in arms A and B had previously received a TKI; of these patients, 53.2% and 47%, respectively, had prior exposure to 2 or more of these agents. Most patients had received a TKI in the first or second line followed by a subsequent third-line TKI (53.8% vs 48.1%).

Further efficacy analysis revealed similar ORRs in both treatment arms. In arm A, the ORR was 48%, and consisted entirely of partial responses (PRs). Stable disease (SD) was achieved by 39.5% of patients, and 6.6% experienced progressive disease (PD). The ORR in arm B was 49.7%, with 0.7% having a complete response, 39.9% of patients achieving SD, and 5.9% experiencing PD. The median DOR was longer in arm A vs arm B, at 11.3 months (95% CI, 7.4-13.6) vs 8.3 months (95% CI, 5.7-9.9), respectively.

Moreover, at a median follow-up of 14 months, the median OS in the ITT population was 20.7 months (95% CI, 15.4-25.6) with ABCP vs 18.7 months (95% CI, 14.6-25.2) with BCP (stratified HR, 0.93; 95% CI, 0.67-1.28). The improvement was not considered to be clinically meaningful. The 6-month OS rates were 92.7% vs 87.5%, respectively; at 12 months, these rates were 72.6% vs 68.3%, respectively.

Safety analysis revealed that ABCP was safe and well tolerated, with no new safety signals observed. Any-grade adverse effects (AEs) were experienced by 99.3% of patients in arm A and 100% of those in arm B; these effects were grade 3 or 4 in 66.4% vs 61.4% of patients, respectively, and grade 5 in 7.9% vs 7.8% of patients, respectively.

Treatment-related AEs (TRAEs) occurred in 98.7% and 100% of patients in arms A and B, respectively. Of these effects, 67.1% vs 62.1% were grade 3 or 4 and 5.9% vs 6.5% were grade 5. In arms A and B, serious AEs were reported in 42.1% vs 34% of patients, respectively; these effects were treatment related in 36.8% vs 32% of patients, respectively.

In the ABCP arm, AEs led 23% of patients to withdraw from the study. Of these patients, 7.2% withdrew due to atezolizumab-related AEs and 14.5% withdrew due to bevacizumab-related toxicities. Fifteen percent of patients treated in the BCP arm withdrew from the study due to AEs; 5.2% and 14.5% of these effects were associated with atezolizumab or bevacizumab, respectively.

Atezolizumab-related AEs of special interest (AESI) were seen in 67.8% and 71.2% of patients in arms A and B, respectively. In arm A, 11.2% of patients experienced a grade 3/4 AESI, 1.3% reported a grade 5 AESI, and 18.4% had AESIs requiring the use of a systemic corticosteroid; in arm B, these percentages were 7.2%, 0.7%, and 9.8%, respectively. Lastly, COVID-19 was confirmed or suspected in 13.2% and 9.8% of patients in these respective arms.

References

1. Zhou C, Dong X, Chen g, et al. IMpower151: Phase III study of atezolizumab + bevacizumab + chemotherapy in first-line metastatic nonsquamous NSCLC. Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA09.06.
2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa176948
3. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline lever metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7(5):387-401. doi:10.1016/S2213-2600(19)30084-0
4. FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. News release. FDA. December 6, 2018. Accessed September 11, 2023. https://www.fda.gov/drugs/fda-approves-atezolizumab-chemotherapy