Is atezolizumab plus bevacizumab with chemotherapy effective for non-small cell lung cancer with EGFR- or ALK-alteration?

Previous phase III studies on immune checkpoint inhibitors (ICIs), including programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors, with or without cytotoxic chemotherapy have improved the overall survival (OS) of patients with non-small cell lung cancer (NSCLC). Therefore, ICI with or without chemotherapy have become the standard of care for patients with NSCLC (1-3). However, the efficacy of ICIs in patients with epidermal growth factor receptor (EGFR) mutations or anaplastic leukaemia kinase (ALK) translocations remains to be established. A phase II study of pembrolizumab for patients with EGFR-mutated NSCLC and positive PD-L1 expression was conducted; an interim analysis of this study showed a 0% objective response rate (ORR) in 10 patients, resulting in early discontinuation owing to absence of efficacy (4). In a combined analysis of phase II/III trials comparing ICIs (nivolumab, pembrolizumab and atezolizumab) with docetaxel in the second-line treatment of NSCLC, the hazard ratio (HR) for OS of ICIs compared with that of docetaxel in patients with EGFR-mutated NSCLC was 1.11 (95% CI: 0.80–1.53, P=0.54), indicating no clinical benefit of ICI monotherapy for EGFR-mutated NSCLC (5). Further, insufficient evidence is available for recommending the use of combination therapy of ICI with cytotoxic chemotherapy in EGFR-mutated NSCLC. Several clinical trials on drug therapies, including ICIs, for NSCLC with driver mutations have been reported (Table 1). Two phase III studies have investigated the efficacy of an additional ICI in chemotherapy for NSCLC with EGFR mutation. Nivolumab + chemotherapy did not show improvement of progression-free survival (PFS) in the CheckMate 722 study (6). Addition of pembrolizumab to chemotherapy also failed to demonstrate significant PFS and OS benefits in the KEYNOTE 789 study (7). According to these results, the efficacy of simply adding an ICI to chemotherapy was considered insufficient for EGFR mutant NSCLC. However, the efficacy of adding both an ICI and an anti-angiogenic agent to a cytotoxic chemotherapy remains unclear.

Park et al. recently reported the results of a phase III, multi-centre, open-label, randomised trial comparing the clinical efficacy of ABCP (atezolizumab plus bevacizumab, carboplatin, and paclitaxel) followed by maintenance therapy with atezolizumab + bevacizumab (BEV) and pemetrexed (PEM) + carboplatin (CBDCA) or cisplatin (CDDP), followed by PEM maintenance (PC arm) in patients with EGFR-mutated or ALK translocation-positive NSCLC who had progressed on prior tyrosine kinase inhibitor (TKI) treatment (ATTLAS/KCSG LU19-04 study) (16). In total, 228 patients with activating EGFR mutation (n=215) or ALK translocation (n=13) were randomly assigned to either the ABCP or PC arm in a 2:1 ratio. The primary endpoint was investigator-assessed PFS. The median follow-up duration was 26.1 months. The median PFS was significantly longer in the ABCP group (8.48 vs. 5.62 months, HR 0.62, 95% CI: 0.45–0.86, P=0.004). The 1-year PFS rates were 36% and 23%, and the 2-year PFS rates were 13% and 9% for the ABCP and PC arm, respectively. Subgroup analysis showed that PFS was particularly better in the ABCP arm for patients with brain metastases, those with the L858R mutation, and those without the acquired T790M mutation. The ORR was 69.5% in the ABCP group and 41.9% in the PC group, which was significantly higher in the ABCP group (P<0.001). The median maximum change in the target lesion size was −43.8% in the ABCP group and −26.0% in the PC group, showing a deeper response in the ABCP group. The number of patients receiving the second-line treatment was 94 in the ABCP group and 46 in the PC group, with cytotoxic anticancer drugs used in approximately half of the patients, other TKIs in 20%, and antibody-drug conjugates in 6–10%. OS was similar in the ABCP and PC groups, with a median OS of 20.63 months in the ABCP group and 20.27 months in the PC group (HR 1.01, 95% CI: 0.69–1.46, P=0.98).

Anti-angiogenic agents appear to be promising options for treating NSCLC with EGFR mutation. Indeed, addition of BEV or ramucirumab to erlotinib has successfully prolonged PFS compared with erlotinib alone (18-20). In terms of mechanism of action, vascular endothelial growth factor (VEGF) is suggested to contribute to the development of an immunosuppressive TME by activating regulatory T cells and myeloid-derived suppressor cells, inducing CD8⁺ T cells exhaustion, and inhibiting dendritic cells (21). Thus, VEGF inhibition may improve the immunosuppressive microenvironment in patients with NSCLC carrying EGFR mutations and enhance the antitumour effects of ICIs. In the EGFR mutant subset of IMpower 150 study comparing atezolizumab + BEV + CBDCA + paclitaxel (PTX) (ABCP) with CBDCA + PTX + BEV (BCP) in non-squamous NSCLC as the first-line treatment, the mPFS of ABCP and BCP was 10.2 and 6.9 months, respectively (HR 0.61, 95% CI: 0.36–1.03). Further, an updated analysis of OS in patients after EGFR-TKI treatment for active EGFR mutations alone (exon 19 deletion and L858R mutation) showed a trend towards a better OS HR of 0.74 (95% CI: 0.38–1.46, median: 29.4 vs. 18.1 months) (8,9), indicating the benefit of adding an anti-VEGF inhibitor in addition to chemotherapy + ICI. A similar trend was observed in the APPLE study (WJOG11218L), a phase III trial that compared CBDCA + PEM + BEV + atezolizumab with CBDCA + PEM + atezolizumab (10). In the analysis of the driver alteration subset, most of which were EGFR mutations, additional administration of BEV resulted in longer mPFS (9.7 vs. 5.8 months, HR 0.67; 95% CI: 0.46–0.98). IMpower 151 was a phase III study that compared CBDCA + PEM or PTX + BEV + atezolizumab with CBDCA + PEM or PTX + BEV + placebo in patients with non-squamous NSCLC, most of whom received PEM (97.4%). In the subgroup of patients with EGFR/ALK-positive disease, the atezolizumab arm did not show significantly prolonged PFS (mPFS was 8.5 months with atezolizumab vs. 8.3 months with the placebo, HR 0.86, 95% CI: 0.61–1.21) (11). However, these results were obtained from subgroup analysis.

Recently, several prospective clinical trials have investigated the efficacy of platinum doublet + anti-VEGF inhibitor + ICI in NSCLC with EGFR mutation or ALK alteration. Two single-arm phase II studies investigating the efficacy of CBDCA + PEM + BEV + atezolizumab and CBDCA + PTX + BEV + atezolizumab for EGFR-mutant NSCLC after EGFR-TKI failure showed clinically meaningful PFS, respectively (9.4 months, 95% CI: 7.6–12.1, 7.4 months, 95% CI: 5.7–8.2) (12,13). Further, a phase III study of CDDP + PEM + sintilimab (anti-PD-1 antibody) + IBI305 (bevacizumab biosimilar) versus CDDP + PEM + sintilimab versus chemotherapy alone for EGFR-mutated NSCLC (ORIENT-31) was recently reported (14,15). The four-drug combination demonstrated significant improvement of PFS compared to that with chemotherapy alone (median 7.2 vs. 4.3 months, HR 0.51, 95% CI: 0.39–0.67, P<0.0001). Interestingly, even CDDP + PEM + sintilimab significantly prolonged PFS compared to that with chemotherapy alone (median 5.5 vs. 4.3 months, HR 0.72, 95% CI: 0.55–0.94, P=0.02), indicating that this was the first prospective phase III trial to show the benefit of adding anti-PD-1 antibody to chemotherapy in patients with EGFR-mutated NSCLC. In contrast, the ATTLAS study first showed a significant clinical benefit of anti-PD-L1 antibody in combination with chemotherapy + BEV in patients with EGFR- or ALK-alteration-positive NSCLC who progressed on the relevant targeted therapy (16).

Prolonged PFS did not translate into prolonged OS in either the ORIENT-31 study or the ATTLAS study. There are several possible explanations for this observation. First, according to previous reports, the efficacy of anti-angiogenic agents in prolonging survival is modest in non-squamous NSCLC. Although a phase III study (ECOG4599) evaluating the efficacy of adding BEV to CBDCA + PTX showed an increased ORR, significantly longer PFS, and significantly longer OS in the BEV combination arm (median 12.3 vs. 10.3 months, HR 0.79, 95% CI: 0.67–0.92, P=0.003), a phase III study (AVAiL study) in which BEV was added to CDDP + GEM and a randomized phase II trial (JO19907) adding BEV to CBDCA + PTX both showed an increased ORR and prolonged PFS, but no significant prolongation of OS (22-24). It should be noted that a similar trend was replicated in the ATTLAS study, and that the addition of ICIs and anti-angiogenic agents to cytotoxic chemotherapy has not been shown to lead to prolonged OS in NSCLC with EGFR mutation or ALK alteration.

Second, survival could be affected more by prior or subsequent therapies, especially targeted therapies, rather than by ICI or anti-angiogenic agents, owing to the nature of NSCLC with driver mutations. Therefore, detailed analyses of pre- and post-ICI treatment regimens are needed.

Finally, biomarkers for ICI and anti-angiogenic agents, including the regimens for NSCLC with EGFR mutation or ALK alteration, remain to be established, indicating that these trials may include a mix of populations that benefit greatly and those that benefit little from ICI or anti-angiogenic agents. Exploratory biomarker analysis in the ATTLAS study showed that the PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively (16). Further, the benefit of prolonged PFS seems to be greater in L858R than in del19 based on subgroup analysis in both the ORIENT-31 and ATTLAS studies (15,16). However, these are not absolute predictors of ICI and anti-angiogenic agents. The ATTLAS study also showed that for patients with a high inflammation score calculated by the distribution of tumour-infiltrating lymphocytes, the ABCP arm showed a significantly prolonged PFS compared to that of the control arm. Recently, another biomarker analysis using peripheral blood mononuclear cells (PBMCs) from a single-arm phase II study of ABCP for NSCLC with EGFR mutation after TKI failure (NEJ043) was reported (25). Patients with a higher percentage of CD11b⁺DR^lowCD3⁻CD14⁺ myeloid-derived suppressor cells before ABCP or patients with increased CD62L^lowCD8⁺ cells and PD-1⁺CCR7⁻CD45RA⁻CD8⁺ cells after two cycles of ABCP had significantly longer PFS. However, these analyses were exploratory and further investigation and validation of predictive or monitoring markers for these agents in independent cohorts are warranted.

The ATTLAS study showed that the incidence of grade 3 or higher treatment-related adverse events (TRAEs) was 35.1% and 14.9% in the ABCP and PC groups, respectively. The most common TRAEs n the ABCP arm were peripheral neuropathy, alopecia, and myalgia. In the ABCP arm, immune-related adverse events of grade 3 were observed in 6.6% and grade 4 in 1.3%. No new safety issues were identified. However, it should be noted that there were three treatment-related deaths (2%) owing to pneumonia (n=2) and cerebral embolic infarction (n=1). Data from other clinical trials also show that the frequency of adverse events increases when ICIs or anti-angiogenic agents are added to cytotoxic drugs (Table 1). Therefore, it is important that the choice of high-intensity treatment regimen is based on a balance between the benefit of therapeutic efficacy and safety.

The ATTLAS study had several limitations. First, the experimental arm was ABCP, whereas the control arm was CBDCA + PEM alone. In other words, the necessity of ICI to achieve the primary endpoint was not conclusive because the control arm did not include BEV. Second, patients were recruited from a single country, Korea; i.e., all patients were of Asian ethnicity. This was similar to the ORIENT-31 study conducted in China. Currently, a randomised, phase II, multi-centre, open-label trial to assess CBDCA + PEM + BEV with or without atezolizumab, including 117 subjects with non-squamous NSCLC who had EGFR mutation or had never smoked is ongoing across the U.S. (NCT03786692) (17). The results of the study may provide insights into the effects on patients of other ethnicities.

In conclusion, the addition of ICI and anti-angiogenic agents to chemotherapy appears to be a promising strategy against NSCLC with EGFR mutation after TKI failure. Although the frequency of adverse events was found to be generally higher in the combination arm than in the control arm in all the clinical trials mentioned above, the safety profile was comparable to that reported previously. However, further exploration of biomarkers is required to identify patients who will benefit from this treatment.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-12/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-12/coif). Y.S. has received honoraria for speakers bureaus from Chugai, AstraZeneca, Lilly and ONO. S.W. has received grants from Boehringer Ingelheim and Nippon Kayaku; and received honoraria for speakers bureaus from Lilly, Novartis Pharma, Chugai Pharma Bristol-Myers, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, Merck, Takeda Pharmaceutical, Celltrion and AstraZeneca. T.K. has received grants from Nobelpharma, Boehringer Ingelheim, Taiho Pharmaceutical, KYORIN Pharmaceutical, Shionogi, Chugai Pharma, Asahi Kasei, Daiichi Sankyo, Nippon Kayaku, TEIJIN PHARMA; and received honoraria for speakers bureaus from Viatris, Astellas Pharma, Insmed, Boehringer Ingelheim, Terumo, Eli Lilly, AstraZeneca, Daiichi Sankyo, KYORIN Pharmaceutical, Novartis, Merck, Bristol-Myers, NIPRO, Eisai, Ono Pharmaceutical, Chugai Pharma, GSK, Sumitomo Pharma, Kyowa Kirin, MSD, Sanofi, Shionogi, Meiji Seika Pharm0 and Taiho Pharmaceutical; and participated in the advisory board of Janssen Pharmaceutical, and received drugs from Nobelpharma. The authors have no other 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.

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/.

References

1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92. [Crossref] [PubMed]
2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. [Crossref] [PubMed]
3. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2019;381:2020-31. [Crossref] [PubMed]
4. Lisberg A, Cummings A, Goldman JW, et al. A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC. J Thorac Oncol 2018;13:1138-45. [Crossref] [PubMed]
5. Lee CK, Man J, Lord S, et al. Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis. JAMA Oncol 2018;4:210-6. [Crossref] [PubMed]
6. Mok TSK, Nakagawa K, Park K, et al. LBA8 Nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) with disease progression after EGFR tyrosine kinase inhibitors (TKIs) in CheckMate 722. Ann Oncol 2022;33:S1561-S1562. [Crossref]
7. Yang JCH, Lee DH, Lee JS, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. J Clin Oncol 2023;41:LBA9000. [Crossref]
8. Nogami N, Barlesi F, Socinski MA, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol 2022;17:309-23. [Crossref] [PubMed]
9. 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 liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 2019;7:387-401. [Crossref] [PubMed]
10. Shiraishi Y, Kishimoto J, Sugawara S, et al. Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol 2024;10:315-24. [Crossref] [PubMed]
11. Zhou C, Dong X, Chen G, et al. OA09.06 IMpower151: Phase III Study of Atezolizumab + Bevacizumab + Chemotherapy in 1L Metastatic Nonsquamous NSCLC. J Thorac Oncol 2023;18:S64-S5. [Crossref]
12. Lam TC, Tsang KC, Choi HC, et al. Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure. Lung Cancer 2021;159:18-26. [Crossref] [PubMed]
13. Watanabe S, Furuya N, Nakamura A, et al. A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study). Eur J Cancer 2024;197:113469. [Crossref] [PubMed]
14. Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2022;23:1167-79. [Crossref] [PubMed]
15. Lu S, Wu L, Jian H, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med 2023;11:624-36. [Crossref] [PubMed]
16. Park S, Kim TM, Han JY, et al. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol 2024;42:1241-51. [Crossref] [PubMed]
17. Bodor JN, Patel JD, Wakelee HA, et al. Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked. Clin Lung Cancer 2023;24:e242-6. [Crossref] [PubMed]
18. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 2014;15:1236-44. [Crossref] [PubMed]
19. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625-35. [Crossref] [PubMed]
20. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:1655-69. [Crossref] [PubMed]
21. Lapeyre-Prost A, Terme M, Pernot S, et al. Immunomodulatory Activity of VEGF in Cancer. Int Rev Cell Mol Biol 2017;330:295-342. [Crossref] [PubMed]
22. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. [Crossref] [PubMed]
23. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804-9. [Crossref] [PubMed]
24. Niho S, Kunitoh H, Nokihara H, et al. Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer 2012;76:362-7. [Crossref] [PubMed]
25. Watanabe S, Furuya N, Nakamura A, et al. A biomarker study of atezolizumab (atezo) + bevacizumab (bev) + carboplatin (carbo) + paclitaxel (pac) (ABCP) for patients with NSCLC harboring EGFR mutations (EGFRm) after failure of TKI therapy: NEJ043. J Clin Oncol 2023;41:9079. [Crossref]