Real-world insights into atezolizumab plus bevacizumab, carboplatin, and paclitaxel for advanced non-squamous non-small cell lung cancer

Introduction

For decades, platinum-doublet chemotherapy has been the cornerstone of first-line treatment for advanced non-small cell lung cancer (NSCLC) without driver oncogenes. However, the emergence of immune checkpoint inhibitors (ICIs), particularly those targeting programmed cell death-1 (PD-1) and its ligand PD-L1, has revolutionized the therapeutic approach to NSCLC (1-3). ICIs, either alone or combined with chemotherapy, are now widely adopted as first-line treatments, offering improved outcomes for patients without actionable mutations (4-12). Additionally, angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) also play a pivotal role in cancer therapy by inhibiting tumor growth through disruption of its blood supply (13). Beyond their antiangiogenic effects, these agents exhibit immunomodulatory properties, such as modulating inhibitory checkpoints on intratumoral CD8⁺ T cells, reversing VEGF-mediated immunosuppression, promoting dendritic cell maturation, and reducing the activity of immunosuppressive myeloid-derived suppressor cells (14-17). These synergistic mechanisms suggest that combining ICIs and angiogenesis inhibitors may enhance both angiogenesis regulation and antitumor immunity, offering a promising therapeutic strategy.

The pivotal phase 3 IMpower150 trial demonstrated that atezolizumab combined with bevacizumab, carboplatin, and paclitaxel (ABCP) therapy significantly improved overall survival (OS) and progression-free survival (PFS) compared to bevacizumab, carboplatin, and paclitaxel (BCP therapy) (6,18,19). Furthermore, this regimen achieved high objective response rates (ORRs), including 63.5% in patients without driver oncogenes and 50.3% in PD-L1-negative patients, highlighting its broad applicability.

Given these promising findings, it is crucial to assess the ABCP therapy in real-world clinical settings. Although randomized clinical trials provide high-quality evidence, real-world data offer valuable insights into the practical application of treatments, including their outcomes and safety profiles in broader, less-selective patient populations. However, real-world evidence on ABCP therapy remains limited. To address this gap, this retrospective study aims to assess the efficacy and safety of ABCP therapy in routine clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-393/rc).

Methods

Participants and study design

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the University of Occupational and Environmental Health, Japan (No. 22-056). Informed consent was not required for this retrospective observational study. However, patients were informed about the study, and they had the option to opt out if they did not wish to participate. We retrospectively analyzed 32 patients with non-squamous NSCLC who were treated with ABCP therapy from February 2019 to December 2021 at the University of Occupational and Environmental Health, Japan. Among them, 28 patients (87.5%) received ABCP as first-line treatment, and these patients were included in the primary efficacy and survival analyses. The remaining 4 patients (12.5%) who received ABCP as second- or later-line treatment were excluded from the primary analysis due to their heterogeneous backgrounds; however, their clinical characteristics and outcomes were descriptively summarized for reference.

Clinical data, including age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), smoking history, histological type, stage, PD-L1 status, presence of mutations, treatment line, and survival status were retrieved from the medical records. PD-L1 expression was evaluated using the PD-L1 IHC 22C3 pharmDx assay (Dako, Agilent Technologies, Santa Clara, CA, USA), and tumor proportion score (TPS) thresholds of ≥50%, 1–49%, and <1% were applied in accordance with the assay’s validated cutoff criteria. Clinical stages were classified according to the 8th edition of the Tumor, Node and Metastasis Classification of Malignant Tumors (20). Treatment response was assessed using the guideline for solid cancer response assessment (RECIST guideline: revised version 1.1) (21). The outcomes were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). ORR was the percentage of patients whose best overall response was CR or PR. Disease control rate (DCR) was the percentage of patients whose best overall response was CR, PR, or SD. Treatment-related adverse events (TRAEs) were assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) (22).

Induction treatment of atezolizumab, bevacizumab, carboplatin, and paclitaxel was administered every 21 days for 4 or 6 cycles. Atezolizumab was administered at a dose of 1,200 mg, bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 200 mg/m², and carboplatin at an area under the concentration−time curve of 6 mg/mL/min. After the induction phase, atezolizumab and bevacizumab were continued until disease progression or unmanageable toxicity.

Statistical analysis

Categorical variables were compared using Pearson’s chi-squared (χ²) test or Fisher’s exact test, as appropriate. Continuous variables were analyzed using Student’s t-test or Welch’s t-test for normally distributed data, and the Mann-Whitney U test for non-normally distributed data. OS was calculated from the date of the first administration of ABCP therapy until death or the last follow-up. PFS was calculated from the same starting point until disease progression, death, or the last follow-up. The Kaplan-Meier method was used to estimate OS and PFS, with 95% confidence intervals (CI). The log-rank test was used for survival comparisons. A P value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS (version 28.0, IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

The characteristics of patients with non-squamous NSCLC who received at least 1 course of ABCP therapy are summarized in Table 1. Among the 32 patients, 28 (87.5%) received ABCP therapy as first-line treatment, and these patients were included in the primary analysis.

The median age was 69.5 years [interquartile range (IQR), 60.5–72.3; range, 38–77], and 24 patients (85.7%) were males. Most patients (24, 85.7%) had ECOG PS scores of 0–1, and adenocarcinoma was predominant histology (27, 96.4%). The TNM stage distribution included stage IIIB in 2 patients (7.1%), stage IVA in 10 (35.7%), stage IVB in 6 (21.4%), and postoperative relapse in 10 (35.7%). PD-L1 TPS were ≥50% in 6 patients (21.4%), 1–49% in 10 (35.7%), <1% in 9 (32.1%), and not assessed (NA) in 3 (10.7%). Regarding molecular profiles, 2 patients (7.1%) had epidermal growth factor receptor (EGFR) mutations [exon 19 deletion in 1 (3.6%), exon 20 insertion in 1 (3.6%)]. Additionally, 4 patients (12.5%) harbored Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations [G12C in 3 (10.7%) and non-G12C in 1 (3.6%)].

Efficacy and survival outcomes

At the time of data cut-off (December 16, 2024), the median follow-up time was 27.1 months (IQR, 9.6–40.5; range, 1.4–69.1). Among the 28 patients, 2 (7.1%) achieved CR, 12 (42.9%) achieved PR, 12 (42.9%) had SD, 1 (3.6%) had PD, and 1 (3.6%) was NA. The ORR and DCR were 50.0% and 92.9%, respectively. Subgroup analysis based on PD-L1 status showed that ORR was 66.7%, 50.0%, and 33.3% for patients with TPS ≥50%, 1–49%, and <1%, respectively. DCR was 100%, 90.0%, and 88.9% for the respective PD-L1 groups.

Tumor progression was observed in 19 patients (67.9%). The most common sites of progression were lymph node (6 events), pleural dissemination or effusion (4 events), brain (4 events), primary tumor (4 events), and bone (4 events). Because some patients experienced progression at multiple anatomical sites, the total number of progression events exceeded the number of patients with progression.

The median OS was 27.3 months (95% CI: 9.1–45.5), with OS rates of 75.0% at 12 months and 56.3% at 24 months. The median PFS was 9.7 months (95% CI: 8.0–11.4), with PFS rates of 42.1% at 12 months and 15.3% at 24 months (Figure 1A,1B).

Figure 1 OS and PFS in patients treated with atezolizumab plus bevacizumab, carboplatin, and paclitaxel as first-line treatment (A,B), and subgroup analysis of OS and PFS stratified by PD-L1 status (C,D). MST, median survival time; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TPS, tumor population score.

Univariate survival analyses according to baseline characteristics and clinical factors are summarized in Table 2. Patients with high PD-L1 expression (TPS ≥50%) had significantly better OS compared with those with lower expression (TPS <50%) [not reached (NR) vs. 21.2 months, P=0.04] (Figure 1C). Although PFS demonstrated a favorable trend, the difference was not statistically significant (9.7 vs. 8.3 months, P=0.07) (Figure 1D).

Metastatic status (brain, bone, liver, or pleural dissemination/effusion) did not significantly affect survival. However, patients with brain metastases showed a non-significant trend toward improved outcomes (OS: 48.8 vs. 27.3 months, P=0.37; PFS: 17.1 vs. 9.7 months, P=0.29) (Figure 2A,2B). Patients with postoperative relapse also demonstrated trends toward better outcomes compared to those with stage IIIB–IVB disease (OS: 37.0 vs. 26.9 months, P=0.17; PFS: 10.0 vs. 9.4 months, P=0.23) (Figure 2C,2D).

Figure 2 Subgroup analysis of overall survival and progression-free survival in patients treated with atezolizumab plus bevacizumab, carboplatin, and paclitaxel as first-line treatment, stratified by brain metastasis (A,B) and treatment status (stage IIIB−IVB or postoperative relapse) (C,D).

Grade ≥3 TRAEs did not significantly affect survival outcomes (OS: 21.2 months with TRAEs vs. 32.1 months without TRAEs, P=0.52; PFS: 8.6 months with TRAEs vs. 10.0 months without TRAEs, P=0.98). Similarly, non-hematologic TRAEs did not influence survival (OS: 12.8 months with non-hematologic TRAEs vs. 33.1 months without non-hematologic TRAEs, P=0.43; PFS: 7.2 months with non-hematologic TRAEs vs. 10.0 months without non-hematologic TRAEs, P=0.89) (Figure 3A-3D).

Figure 3 Subgroup analysis of overall survival and progression-free survival in patients treated with atezolizumab plus bevacizumab, carboplatin, and paclitaxel as first-line treatment, stratified by Grade ≥3 TRAEs (A,B), and non-hematologic AEs (C,D). AE, adverse event; TRAEs, treatment-related adverse events.

In a descriptive analysis of the 4 patients who received ABCP as second- or later-line therapy, SD was observed in 3 (75.0%), and PD in 1 (25.0%), yielding ORR of 0% and DCR of 75.0%. Although these cases were not included in survival analyses due to their heterogeneity and small sample size, they demonstrated comparable or numerically favorable outcomes [The median OS was 54.0 months (95% CI: NA–NA), the median PFS was 14.5 months (95% CI: 3.0–26.0)] (Figure S1A,S1B).

Safety and tolerability

The safety profiles are summarized in Table 3. TRAEs of any grade were observed in 27 patients (96.4%), including hematologic TRAEs in 24 (85.7%) and non-hematologic TRAEs in 19 (67.9%). Grade 3–4 TRAEs were reported in 22 patients (78.6%), with hematologic TRAEs in 19 (67.9%) and non-hematologic TRAEs in 9 (32.1%). Grade 3–4 neutropenia or leukopenia occurred in 19 patients (67.9%). Among the 4 patients who received pegfilgrastim, none developed febrile neutropenia (FN), and only 1 patient (25.0%) experienced grade 3–4 neutropenia or leukopenia, compared with 9 (37.5%) and 18 (75.0%) of the 24 patients who did not receive pegfilgrastim. Pneumonitis was reported in only 1 patient (3.6%), and no treatment-related deaths occurred.

Induction therapy was discontinued in 1 patient (3.6%) due to a drug-related rash. Additionally, 9 patients (32.1%) transitioned to maintenance therapy without completing the planned 4 courses of induction therapy. During maintenance therapy, 2 patients discontinued treatment entirely (1 patient, nephritis; 1 patient, proteinuria). Bevacizumab was discontinued in 6 patients, while atezolizumab was discontinued in 3 patients.

Post-progression treatments

Among the 19 patients who experienced progression, subsequent treatments included cisplatin or carboplatin plus pemetrexed in 4 patients (21.1%), docetaxel and ramucirumab in 2 (10.5%), sotorasib in 2 (10.5%), and pemetrexed monotherapy in 1 (5.3%). Additionally, 4 patients (21.1%) continued treatment beyond progression, including 3 (15.8%) who received radiation therapy. Radiation therapy alone was administered to 1 patient (5.3%), and 1 (5.3%) was transferred for treatment another institution for further treatment. Best supportive care was provided to 4 patients (21.1%). Subsequent treatments administered after progression on the IMpower150 regimen appeared to contribute to favorable overall survival (37.0 months with subsequent treatments vs. 8.3 months without subsequent treatments, P=0.004) and post-progression survival (27.0 months with subsequent treatments vs. 4.2 months without subsequent treatments, P<0.001) (Figure S2A,S2B).

Discussion

This study retrospectively evaluated the real-world clinical outcomes of ABCP therapy in patients with advanced non-squamous NSCLC treated at our institution. These findings closely align with the existing clinical trial data and highlight the potential of ABCP therapy to improve patient outcomes. Given the limited availability of real-world data on ABCP therapy for advanced non-squamous NSCLC, this report provides valuable insights for clinicians and researchers seeking to optimize treatment strategies.

In terms of efficacy, ABCP therapy demonstrated substantial outcomes, even in a real-world cohort that included patients with poor performance status and older individuals. The median OS was 27.3 months (95% CI: 9.1–45.5) and the median PFS was 9.7 months (95% CI: 8.0–11.4) in our cohort, exceeding the results from the IMpower150 trial [OS: 19.8 months (95% CI: 17.4–24.2), PFS: 8.3 months (95% CI: 7.9–9.8)] (6,18). Although the ORR was slightly inferior to that reported in the Impower150 trial (ORR: 63.5%, DCR: 94.9%), this could be attributed to the high prevalence of patients with pleural dissemination or effusion, which can be difficult to evaluate using standard imaging criteria. Nonetheless, the robust tumor response observed in this regimen indicates its potential, likely due to the synergistic effect of angiogenesis inhibition.

Subgroup analysis revealed higher tumor response rates and improved survival among patients with high PD-L1 expression, particularly those with TPS ≥50%. OS was significantly better in these patients compared to those with TPS <50%, and while PFS demonstrated a favorable trend, the difference was not statistically significant. These findings align with the results of the IMpower150 trial and other immunotherapy combination regimens (4-6), supporting the role of PD-L1 expression as a potential predictive biomarker of the therapeutic efficacy with this regimen. Notably, even among patients with TPS <50%, both 1–49% and <1% subgroups also demonstrated high DCR, and survival outcomes outperforming prior immunotherapy combination regimens. These results highlight the broad applicability of ABCP therapy, regardless of PD-L1 status.

Patients with brain metastases also derived clinical benefits from ABCP therapy, consistent with the IMpower150 trial and other real-world studies (6,19,23,24). The IMpower150 trial reported a hazard ratio of 0.68 for time to new brain metastasis in the ABCP group compared to the BCP group, suggesting preventive effects against brain metastases. However, unlike the IMpower150 trial and other reports, our study did not observe significant clinical benefits in patients with liver metastasis or pleural dissemination/effusion (6,19,25).

Although not included in the primary analysis, 4 patients received ABCP therapy as second- or later-line treatment after EGFR-TKI failure. Their outcomes appeared comparable or slightly favorable. While interpretation is limited by the small sample size, these findings may indicate the potential of ABCP therapy in selected EGFR-mutated cases, consistent with prior reports of its efficacy in this setting (26-28).

Regarding safety, the incidence and severity of TRAEs in our study were generally consistent with those in previous reports (6,29). However, compared with the IMpower150 trial, in which grade 3–4 neutropenia and FN occurred in 13.2% and 3.4% of patients, respectively, our study showed a higher frequency of hematologic toxicity. Notably, Japanese real-world data have demonstrated even higher FN rates: 22.7% at 12 months in a nationwide claims analysis (29) and 17–46.7% in single-institution cohorts (24,25), suggesting an ethnicity-related vulnerability. In accordance with ASCO/EORTC guidelines—which recommend primary pegfilgrastim prophylaxis when the regimen carries ≥20% FN risk or 10–20% in older (≥65 years) or otherwise high-risk patients (30,31)—prophylactic pegfilgrastim may be appropriate for Japanese patients receiving ABCP therapy. Importantly, the addition of angiogenesis inhibitors did not appear to increase immune-related AEs relative to other chemoimmunotherapy regimens (4,9,10). However, complications such as gastrointestinal perforation, proteinuria, and bronchopleural fistula were observed, underscoring the importance of monitoring these complications and implementing risk mitigation strategies. While a previous study has suggested a potential association between TRAEs and favorable outcomes (32), our study did not observe a similar trend. Nevertheless, the comparable outcomes achieved despite treatment interruptions or dose reductions owing to TRAEs highlight the critical importance of managing these complications to improve prognosis.

Experimental study and clinical observation have shown that angiogenesis inhibitors play a role in mitigating ICIs-induced pneumonitis (33). The IMpower150 regimen reported a low incidence of ICI-induced pneumonitis (all grades: 2.8%; grade ≥3: 1.3%) (6). Furthermore, real-world data from the IMpower150 regimen showed significantly lower rates of pneumonitis (all grades: 3.3–6.9%) (23,24), aligning closely with the 3.6% observed in our cohort. In contrast, real-world data from the KEYNOTE-189 regimen, which lacks an angiogenesis inhibitor, showed rates of all-grade pneumonitis at 18.0% and grade ≥3 pneumonitis at 5.0% (34). This difference underscores the potential benefit of incorporating an angiogenesis inhibitor to reduce the incidence of pneumonitis. Given the established association between ICIs-induced pneumonitis and shorter OS and PFS (35), these findings highlight the IMpower150 regimen as a potential strategy to mitigate this complication and improve patient outcomes.

In the context of post-progression management, therapeutic interventions administered after progression may significantly influence long-term outcomes following ABCP therapy. Patients who received subsequent systemic treatments demonstrated markedly prolonged overall survival and post-progression survival compared to those who did not, highlighting the clinical importance of preserving treatment opportunities beyond initial disease progression.

This study has several limitations. First, its retrospective single-center design, small sample size, and heterogeneous patient population—including variations in disease stage, mutation status, and prior treatments—may have introduced selection bias and limited the generalizability of our findings. Second, the absence of a control arm precludes direct attribution of clinical outcomes or adverse events to the ABCP regimen. Third, survival analyses were conducted using univariate log-rank tests without multivariate adjustment for potential confounders such as age, ECOG performance status, or comorbidities. Additionally, multiple subgroup comparisons may have increased the risk of type I error. Given the exploratory nature of this study, these limitations should be considered when interpreting the results. Nevertheless, the diversity of the real-world cohort and the consistency of our findings with previously reported data underscore the potential utility of ABCP therapy in advanced non-squamous NSCLC.

Conclusions

This study provides exploratory real-world evidence on the efficacy and safety of ABCP therapy in patients with advanced non-squamous NSCLC. The regimen demonstrated favorable tumor control across PD-L1 subgroups and was associated with an acceptable safety profile, including low rates of pneumonitis. While these findings suggest that ABCP may be a promising and well-tolerated option in real-world clinical practice, they should be interpreted with caution given the retrospective design and limited sample size. Further prospective studies with larger cohorts and longer follow-up are warranted to validate these observations and optimize patient selection strategies.

Acknowledgments

The authors thank all the patients who participated in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-393/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-393/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-393/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-393/coif). M.T. receives a lecture fee from AstraZeneca. K.Y. receives a grant and honoraria for lectures or presentations from Chugai Pharmaceutical. F.T. receives research funds from Ono Pharmaceutical, Taiho Pharmaceutical, Eli Lilly Japan, and Chugai Pharmaceutical; consulting fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol Myers Squibb; and honoraria for lectures or presentations from MSD, Bristol Myers Squibb, Boehringer Ingelheim Japan, Ono Pharmaceutical, Johnson & Johnson, Covidien Japan, Taiho Pharmaceutical, Eli Lilly Japan, AstraZeneca, Chugai Pharmaceutical, Kyowa Kirin, Takeda Pharmaceutical, Pfizer, Olympus, Stryker, and Intuitive Japan. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the University of Occupational and Environmental Health (No. 22-056). Informed consent was not required for this retrospective observational study. However, patients were informed about the study, and they had the option to opt out if they did not wish to participate.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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