Role of Novel Bispecific Antibodies and Immunotherapy in Non–Small Cell Lung Cancer With Common Epidermal Growth Factor Receptor Mutations

Epidermal growth factor receptor (EGFR) mutations are major oncogenic drivers in non–small cell lung cancer (NSCLC). Approximately 85% are common activating mutations, exon 19 deletions and exon 21 L858R mutations, responsive to EGFR tyrosine kinase inhibitors (TKIs). The remaining 15% comprise uncommon EGFR mutations, representing a heterogeneous group, including both sensitizing and resistant variants¹; among this group, exon 20 insertions may be targetable with amivantamab.¹ In this review, we focus exclusively on common EGFR mutations.

Although third-generation EGFR-TKIs, such as osimertinib, have received US Food and Drug Administration (FDA) approval for their efficacy in both the first-line setting in common EGFR mutations and the second-line setting in the presence of a T790M mutation, disease progression remains inevitable. Overcoming primary and acquired resistance to osimertinib remains a significant challenge¹ (Fig 1A).

FIG 1.

(A) Timeline of approved therapeutic strategies and landmark clinical trials for patients with EGFR-mutant NSCLC. (B) Comparison of clinical trials using chemotherapy in combination with PD-1/PD-L1 and VEGF-targeting agents. (C) Representative ongoing clinical trials with novel immunotherapy including bispecific antibodies and T/NK cell engaged therapies which potentially applied on EGFR-mutant NSCLC. (D) Proposed treatment algorithm for patients with EGFR-mutant NSCLC. ^aTreatment arm; ^bversus bevacizumab plus chemotherapy (C/T); ^cversus chemotherapy (C/T) alone; ^d52% of data maturity; ^econjugated with actinium-225, a radio-isotope. AGA, actional genomic alteration; CAR-T, chimeric antigen receptor T cells; CCRT, concurrent chemoradiotherapy; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma; HR, hazard ratio; MET, mesenchymal-epithelial transition; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; TRAE, treatment-related adverse events.

The introduction of immune checkpoint inhibitors (ICIs) has enhanced the overall survival (OS) of patients with metastatic NSCLC; however, several limitations persist when administering these treatments to patients harboring oncogenic driver mutations. A meta-analysis of three phase III clinical trials—KEYNOTE-010, CheckMate-057, and POPLAR—demonstrated that patients with EGFR mutations do not derive clinical benefit from ICIs.² Similarly, the retrospective IMMUNOTARGET study highlighted that the ICI monotherapy response rate among patients with oncogenic driver mutations is exceedingly low, particularly in those with EGFR mutations (12%) or ALK rearrangements (0%).³ The combination of EGFR-TKI and immunotherapy has also been evaluated previously, but the results raised the concern of increased toxicity and limited efficacy. The phase Ib TATTON study investigated the treatment efficacy of an osimertinib-durvalumab combination either postresistance to first-line EGFR-TKI or as a first-line treatment.⁴ Despite an objective response rate of 43% (95% CI, 23 to 66) and a median duration of response of 20.4 months among patients with acquired resistance to first-line EGFR-TKI, enrollment into the first-line treatment cohort was prematurely terminated because of an increased incidence of interstitial lung disease-related adverse events.⁴ In the phase I/II KEYNOTE-021 study, the combination of pembrolizumab and gefitinib was not feasible because of high rates of severe hepatotoxicity.⁵

Subsequent studies have begun to focus on the combination of chemotherapy and immunotherapy in EGFR TKI-resistant NSCLC. In the phase III CheckMate-722 study, patients treated with a combination of nivolumab and chemotherapy exhibited median progression-free survival (PFS) and OS of 5.6 and 19.4 months, respectively; these figures are comparable with those in patients receiving chemotherapy alone (PFS of 5.4 months and OS of 15.9 months).⁶ Although subgroups with sensitizing EGFR mutations or only one prior line of EGFR-TKI therapy showed improved PFS outcomes with the nivolumab-chemotherapy combination, these parameters were not stratification factors in the study.⁶ Additionally, they showed that adding pembrolizumab to chemotherapy failed to improve PFS (5.6 v 5.5 months) or OS (15.9 v 14.7 months) in EGFR-TKI-resistant NSCLC, even with PD-L1 ≥1%.⁷ This suggests limited efficacy of ICIs, alone or with chemotherapy, in EGFR-mutant NSCLC post-TKI resistance.

The ineffectiveness of ICIs was also noted in early-stage EGFR-mutant NSCLC. Although durvalumab improves PFS and OS in locally advanced NSCLC after concurrent chemoradiotherapy (CCRT), no benefit was observed in EGFR-mutant subgroups.⁸ Retrospective data further indicated poor outcomes with durvalumab in EGFR/HER2-mutant stage III cases after CCRT.⁹ Notably, EGFR-mutant patients had similar survival with or without durvalumab post-CCRT but had significant benefit from consolidative EGFR-TKI therapy.¹⁰ Subsequently, the LAURA study demonstrated that consolidative osimertinib significantly improved PFS compared with the placebo group.¹¹ Additionally, for patients with early-stage resectable NSCLC, the implementation of atezolizumab demonstrated benefits in DFS and OS.¹² However, subgroup analysis on patients with EGFR mutations showed no DFS or OS benefit.¹² Conversely, the phase III ADAURA study demonstrated significant benefits in DFS and OS when administering osimertinib to this group of patients.¹³ The ongoing phase III NeoADAURA study is investigating the treatment efficacy of combining osimertinib and chemotherapy in the neoadjuvant setting (ClinicalTrials.gov identifier: NCT04351555). Taken together, these studies indicate that immunotherapy monotherapy does not work effectively for patients with early-stage EGFR-mutant NSCLC; targeted therapy is a better choice. Furthermore, comprehensive genomic profiling will play an important role in managing patients with early-stage NSCLC.

To overcome acquired resistance to first-line EGFR-TKIs, including osimertinib and others, the integration of antiangiogenic therapy with chemoimmunotherapy has been extensively investigated in patients with EGFR-mutant NSCLC. An initial positive signal emerged from an ad hoc analysis of the IMpower150 study, wherein a subgroup of patients with EGFR mutations exhibited numerically superior PFS (10.2 v 6.9 months) and OS (26.1 v 20.3 months) when treated with a combination of atezolizumab, bevacizumab, and platinum-doublet chemotherapy compared with those receiving chemotherapy combined with bevacizumab alone.¹⁴ Notably, there was no discernible difference between the group receiving platinum-doublet chemotherapy with atezolizumab and the group receiving platinum-doublet chemotherapy with bevacizumab in patients with EGFR mutations.¹⁴ Further subgroup analysis revealed a more pronounced OS benefit in patients with sensitizing EGFR mutations who had undergone prior EGFR-TKI therapy (27.8 v 18.1 months); however, the limited number of patients precluded statistical significance.¹⁴

Subsequently, the ORIENT-31 study, focusing solely on patients with EGFR mutations who had undergone prior EGFR-TKI therapy, demonstrated a significantly extended PFS for those receiving sintilimab (an anti–PD-1 inhibitor), IBI305 (a bevacizumab biosimilar), and platinum-doublet chemotherapy compared with chemotherapy alone (7.2 v 4.3 months); no significant OS difference was observed.¹⁵ A similar pattern was noted in the ATTLAS study, where patients treated with the combination of atezolizumab, bevacizumab, and platinum-doublet chemotherapy showed significantly improved PFS (8.5 v 5.6 months) compared with those receiving chemotherapy alone.¹⁶ In the exploratory analysis of the ATTLAS study, patients with a PD-L1 expression >1%, an inflamed score exceeding 20%, or the presence of brain metastasis demonstrated greater benefit from combination therapy, although these parameters were not stratified.¹⁶ By contrast, there is only numerical improvement in PFS in the IMPower151 study.¹⁷ The reason for the inconsistent result may be associated with the percentage of patients who received multiple lines of EGFR-TKI. In two studies that demonstrated PFS benefit from combination therapy, ATTLAS and ORIENT-31, the percentages of multiple EGFR-TKI use before enrollment were 34.7% and 28%, respectively, whereas the percentage of multiple EGFR-TKI use before enrollment in the IMPower151 study was 53.2%, which is higher than the other two studies. The difference might be associated with poor response to immunotherapy, as shown in the CheckMate-722 study,⁶ but further studies are needed to identify the underlying mechanism. Figure 1B summarizes the treatment efficacy of combination therapy across different trials.

The various combinations of chemoimmunotherapy with antiangiogenic therapy show encouraging but inconsistent efficacy. Novel bispecific antibodies can potentially enhance antitumor efficacy compared with two separate compounds with different targets. Bispecific antibodies targeting PD-1 and VEGF enhance antitumor efficacy by forming soluble immune complexes on VEGF engagement, enabling cooperative PD-1 binding. This dual targeting synergistically inhibits both PD-1/PD-L1 and VEGF/VEGFR pathways, offering more efficient immune modulation and vascular normalization than separate agents via spatial-temporal cotargeting in the tumor microenvironment.¹⁸ Ivonescimab, a bispecific PD-1 and VEGF antibody, has shown promising efficacy in NSCLC.¹⁹ In the phase III HARMONi-A clinical trial, patients with metastatic EGFR-mutant NSCLC who experienced disease progression after treatment with EGFR-TKIs were randomly assigned to receive chemotherapy with or without ivonescimab. Stratification criteria included the presence of brain metastases and prior exposure to third-generation EGFR-TKIs.¹⁹ Notably, approximately 30% of the participants had received first-line osimertinib before entering the trial.¹⁹ The PFS was significantly extended in patients receiving the combination therapy compared with those receiving chemotherapy alone (7.1 v 4.8 months; hazard ratio [HR], 0.46; P < .001), and the survival benefit was observed in subgroups with and without brain metastases.¹⁹ With approximately 30% data maturity, OS was 17.1 versus 14.5 months (HR, 0.72 [95% CI, 0.48 to 1.09]). Continued follow-up is warranted to fully assess the survival benefit.¹⁹ The incidence of grade 3 or higher adverse events was under 10%. Interestingly, the clinical benefit could also be observed in patients regardless of whether they had received single or multiple lines of prior EGFR-TKIs. These results support the efficacy of combining chemotherapy with PD-1/PD-L1 and VEGF-targeting agents.¹⁹ Several additional bispecific antibodies cotargeting PD-1/PD-L1 and VEGF pathways are currently under investigation in ongoing studies (Fig 1C).

Furthermore, another novel bispecific antibody, amivantamab, which targets both EGFR and MET, provides an alternative therapeutic strategy for patients with EGFR-mutant NSCLC. In the phase III MARIPOSA-2 study, patients were randomly assigned to receive the combination of lazertinib, amivantamab, and chemotherapy; the combination of amivantamab and chemotherapy; or chemotherapy alone.²⁰ Both combination arms demonstrated a PFS benefit compared with chemotherapy alone. Notably, the study also reported significant intracranial PFS benefits in these two combination therapies, persisting even in subgroup patients with a history of brain metastasis who had not undergone prior brain irradiation.²⁰ Moreover, the clinical benefit was observed among both patients who received single-line EGFR-TKI and those received two or more lines of EGFR-TKIs. However, the incidence of grade 3 adverse events was 92% among patients receiving the triple combination, with 10% of participants discontinuing treatment because of adverse events.²⁰ Subcutaneous administration of amivantamab is currently being reviewed by the FDA, which could be considered in the future to reduce the incidence of adverse events, on the basis of recent clinical trial results.²¹ The combination of lazertinib and amivantamab was recently FDA-approved in the first-line setting based on the phase III MARIPOSA trial, which showed its superior efficacy compared with osimertinib monotherapy.²² The combination of amivantamab and anti–PD-1/PD-L1 inhibitors is also being investigated. Preclinical studies have demonstrated that lung tumors with high EGFR and MET expression exhibit enriched immunosuppressive lactate signatures, which in turn suppress the infiltration of cytotoxic immune cells.²³ Inhibition of EGFR and MET with amivantamab was shown to modulate the tumor immune microenvironment and enhance tumor regression when combined with pembrolizumab.²³ A ongoing phase I/II clinical trial, PolyDamas, is evaluating the combination of amivantamab and cetrelimab, an anti–PD-1 antibody, in patients with NSCLC. Emerging bispecific antibodies targeting both EGFR and MET are currently under investigation (ClinicalTrials.gov identifier: NCT05908734). Notably, one of these agents is conjugated to a radioisotope and has demonstrated promising signal in preclinical models (Fig 1C).

In addition to EGFR, several alternative pathways have emerged as relevant therapeutic targets in EGFR-mutant NSCLC. HER3 is often upregulated after EGFR inhibition by activating PI3K/AKT signaling.²⁴ Mucin1 (MUC1), which is frequently overexpressed in EGFR-mutant tumors, forms complexes with EGFR to enhance PI3K/AKT and MAPK signaling, contributing to resistance to EGFR TKIs.²⁵ Novel bispecific antibodies cotargeting EGFR and these pathways are now in clinical trials (Fig 1C).

Emerging immunotherapy modalities—including tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) T-cell therapy, and bispecific immune cell engagers—have been investigated as potential strategies for patients with EGFR-mutant NSCLC. A phase I clinical trial investigating the therapeutic efficacy of TILs demonstrated a partial response in a patient with NSCLC harboring an EGFR L861Q mutation.²⁶ Further larger-scale clinical trials are warranted to validate these findings. Additionally, in a phase I trial investigating of EGFR-targeted CAR T cells in patients with NSCLC, 2 of 11 patients achieved a partial response and 4 of 11 patients had stable disease, with tolerable adverse events.²⁷ Another phase I trial, STRIvE-01, using EGFR-targeted second-generation CAR T-cell therapy, also revealed an acceptable toxicity profile, with response evaluation ongoing (ClinicalTrials.gov identifier: NCT03618381). Multiple EGFR-targeted T-cell engagers (EGFR x CD3), such as TAK186 (ClinicalTrials.gov identifier: NCT04844073), are under investigation with promising activity and tolerability (Fig 1C). Alternative strategies cotarget EGFR with T-cell costimulatory receptors like CD28 and 4-1BB (CD137), which enhance T-cell activation, survival, cytokine production, and persistence.²⁴ Bispecific antibodies simultaneously targeting EGFR and either CD28 or 4-1BB are being evaluated in ongoing clinical trials (Fig 1C). EGFR-targeted innate immune engagers, such as AFM24 cotargeting EGFR and CD16A, aim to activate NK cells and have also shown antitumor activity with manageable safety in phase I trials (ClinicalTrials.gov identifier: NCT04259450). Additional studies are needed to assess their efficacy in EGFR-overexpressing and mutant tumors. Furthermore, it remains to be elucidated whether EGFR-targeted CAR T-cell therapy and immune cell engagers can be effectively applied to both EGFR-overexpressing and EGFR-mutant tumors.

Patients with actionable EGFR mutations will inevitably develop resistance to osimertinib and other TKIs. Overcoming primary and acquired resistance continues to be a significant challenge. Previous studies evaluating the combination of ICIs, antiangiogenic therapy, and chemotherapy have inconsistent results, which might be associated with various lines of previous EGFR-TKI therapy. The emerging bispecific antibodies, including EGFR- and MET-targeting amivantamab and PD-1- and VEGF-targeting ivonescimab, both yielded significant clinical benefits regardless of the previous lines of EGFR-TKI use. The treatment algorithm in NSCLC with common EGFR mutation is rapidly evolving and physician's discretion is needed (Fig 1D). Future clinical trials are needed to compare head-to-head the treatment efficacy of this regimen with that of amivantamab and chemotherapy, as well as with the combination of ivonescimab and chemotherapy. With FDA approval of osimertinib plus chemotherapy and lazertinib plus amivantamab as first-line treatments, managing postresistance therapy becomes increasingly complex, highlighting the need for trials to define optimal second-line strategies. Emerging options including bispecific antibodies, adoptive cell therapy, and immune-cell engagers hold potential as promising future treatment options.

AUTHOR CONTRIBUTIONS

Conception and design: Po-Lan Su, Chien-Chung Lin, Kai He

Administrative support: Christian Rolfo, David P. Carbone

Collection and assembly of data: Po-Lan Su, Peiran Xu, David P. Carbone

Data analysis and interpretation: Peiran Xu, Christian Rolfo, David P. Carbone

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

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