Finding the right HARMONi-A

Epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) have significantly advanced the treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC), improving objective response rate (ORR), progression-free survival (PFS), and ultimately, overall survival (OS). However, resistance to TKIs inevitably develops, making metastatic EGFR-mutant NSCLC an incurable disease in most cases.

The emergence of immune checkpoint inhibitors (ICIs), particularly anti-programmed death 1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibodies, has revolutionized cancer therapy, moving these agents from the metastatic setting to the forefront of perioperative treatment. ICIs harness the adaptive immune system to potentially eradicate cancer, even in advanced disease. Yet, in EGFR-mutant NSCLC, ICIs have been largely ineffective due to several factors, including low tumor mutational burden, an immunosuppressive tumor microenvironment, limited cytotoxic T-cell infiltration, and low PD-L1 expression. For instance, Lisberg et al. found no response to ICIs in 10 metastatic EGFR-mutant NSCLC, despite seven of them having high PD-L1 expression [tumor proportion score (TPS) ≥50%] (1). Recent trials combining ICIs with chemotherapy also failed to improve PFS or OS in this population (2,3).

Conversely, the interplay between the EGFR and vascular endothelial growth factor (VEGF) pathways is critical. EGFR activation drives hypoxia-independent HIF1α activation, leading to constitutive VEGF-A (VEGFA) expression. Resistance to EGFR inhibition is associated with increased VEGFA levels and activation of the VEGF receptor (VEGFR) pathway. VEGFA also suppresses adaptive immunity by impairing lymphocyte trafficking, inhibiting dendritic cell maturation, and recruiting immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) (4,5). Multiple studies have shown that dual inhibition of EGFR and VEGF/VEGFR enhances ORR and PFS in NSCLC (6,7).

A subanalysis of the IMpower150 trial demonstrated improved PFS in EGFR-mutant patients who received chemotherapy, atezolizumab (an ICI), and bevacizumab (an anti-VEGFA antibody) after TKI failure, suggesting that VEGF blockade may potentiate ICI efficacy in this setting (8,9). A recent network meta-analysis by Zhao et al., which included 17 single-arm and 15 randomized trials, confirmed that the combination of chemotherapy, ICI, and anti-angiogenics yielded the best PFS outcomes in metastatic EGFR-mutant NSCLC compared to other regimens (10).

Ivonescimab, a novel bispecific antibody targeting PD-1 and VEGFA, has shown promising results in metastatic EGFR-mutant NSCLC post-TKI failure. Its cooperative binding mechanism significantly enhances affinity for PD-1 when ligated to VEGF, creating a synergistic effect (11,12).

The HARMONi-A trial, published in JAMA, compared ivonescimab plus chemotherapy (carboplatin and pemetrexed) to placebo plus chemotherapy in patients with advanced EGFR-mutant NSCLC (unresectable stage IIIB–IIIC or stage IV) who had progressed on TKIs (13). This well-designed, double-blind phase III trial evaluated PFS as the primary endpoint, assessed by blinded independent central review (BICR), and was conducted entirely in China. Notably, 20% of patients had brain metastases, and 85% had received third-generation TKIs. After a median follow-up of 7.9 months, the study demonstrated a significant reduction in the risk of disease progression [hazard ratio (HR) =0.46; P<0.001], with twice as many patients in the ivonescimab arm remaining progression-free at nine months (37.9% vs. 18.3%). Ivonescimab also showed activity in the central nervous system, likely due to the anti-edema effects of VEGF blockade. Interestingly, the incidence of immune-related adverse events (irAEs) and serious adverse events (SAEs) related to VEGF inhibition was lower than in previous trials combining ICIs, VEGF blockade, and chemotherapy (13).

The recently published phase 3 trial MARIPOSA-2 has established a new standard of care for EGFR-mutant NSCLC patients who progress after osimertinib. The study demonstrated the superiority of the combination of chemotherapy (carboplatin and pemetrexed) plus amivantamab, with or without lazertinib, over chemotherapy alone. Amivantamab, in combination with chemotherapy (with or without lazertinib), significantly extended PFS compared to chemotherapy alone (HR =0.48 and =0.44, respectively) and 6-month PFS rates (51% and 59%). The results of the HARMONi-A trial, which demonstrated a HR of 0.46 and a 6-month PFS rate of 55.4%, are comparable to those of MARIPOSA-2 (14).

The crucial question remains: does the simultaneous blockade of PD-1 and VEGF create an actual synergistic effect, or are we witnessing a merely additive impact of VEGF inhibition, which has improved PFS in previous studies without extending OS? Ivonescimab’s promising results in other settings—such as PD-L1 high-expressing NSCLC and the perioperative setting, as reported at the World Conference on Lung Cancer (WCLC) 2024—suggest this drug class could significantly alter the treatment landscape for EGFR-mutant NSCLC (15,16).

Ivonescimab may harmonize therapeutic pathways for patients progressing on third-generation EGFR-TKI therapy, offering much-needed effective and tolerable treatment options, but, unfortunately, it has not yet provided us the so-desired final opus, the cure of patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-864/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-864/coif). V.C.C.d.L. received a consulting fee from Roche; received honoraria for lectures, presentations, manuscript writing, and educational events from Roche Brasil, Amgen, MSD Brasil, BMS Brasil, Jassen, Daichii-Sankyo, Pfizer, and Astra Zeneca; and received financial support to attend scientific meetings and travels from Astra Zeneca, Roche, and Janssen. He also participated in advisory boards from Roche Brasil, Amgen, MSD Brasil, BMS Brasil, Jassen, Daichii-Sankyo, Pfizer, Astra-Zeneca, and Pfizer. H.C.F. has received payment or honoraria for lectures, presentations, speaker bureaus, or educational from MSD, Roche, Lilly, Pfizer, Takeda, BMS, Amgen, AstraZeneca, and Merck. Support for attending meetings or travel has been provided by BMS, MSD, Pfizer, Roche, AZ, Takeda, and Sanofi. He also participates in advisory boards for MSD, Pfizer, Lilly, Takeda, Roche, BMS, and Amgen. Additionally, his spouse works in the clinical research department at AstraZeneca. 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. 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]
2. Yang JC, Lee DH, Lee JS, et al. Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer. J Clin Oncol 2024;42:4029-39. [Crossref] [PubMed]
3. Mok T, Nakagawa K, Park K, et al. Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722. J Clin Oncol 2024;42:1252-64. [Crossref] [PubMed]
4. Larsen AK, Ouaret D, El Ouadrani K, et al. Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 2011;131:80-90. [Crossref] [PubMed]
5. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity 2013;39:61-73. [Crossref] [PubMed]
6. Le X, Nilsson M, Goldman J, et al. Dual EGFR-VEGF Pathway Inhibition: A Promising Strategy for Patients With EGFR-Mutant NSCLC. J Thorac Oncol 2021;16:205-15. [Crossref] [PubMed]
7. 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]
8. 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]
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. Zhao Y, He Y, Cai Q, et al. Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis. Lancet Oncol 2024;25:1347-56. [Crossref] [PubMed]
11. Zhong T, Huang Z, Pang X, et al. Abstract B123: Mechanism of action of ivonescimab (AK112/SMT112): a first-in-class tetravalent Fc-silent bispecific antibody with dual blockade of PD-1 and VEGF that promotes cooperative biological effects. Mol Cancer Ther 2023;22:B123. [Crossref]
12. Wang L, Luo Y, Ren S, et al. A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC. J Thorac Oncol 2024;19:465-75.
13. HARMONi-A Study Investigators. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA 2024;332:561-70. [Crossref] [PubMed]
14. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024;35:77-90. [Crossref] [PubMed]
15. Zhou C, Chen J, Wu L, et al. PL02. 04 Phase 3 Study of Ivonescimab (AK112) vs. Pembrolizumab as First-line Treatment for PD-L1-positive Advanced NSCLC: Primary Analysis of HARMONi-2. J Thorac Oncol 2024;19:S1.
16. Wang C, Zhao X, Zhang L, et al. OA01. 06 A Phase II Study of Perioperative Ivonescimab Alone or Combined with Chemotherapy in Resectable Non-Small Cell Lung Cancer. J Thorac Oncol 2024;19:S10.