From Amivantamab to Next-Generation Therapies: The Evolving Bispecific Antibody Landscape in NSCLC

Bispecific antibodies (BsAbs) have become a pivotal innovation in the treatment of advanced non–small cell lung cancer (NSCLC). By simultaneously targeting 2 distinct antigens or pathways, these agents aim to improve antitumor efficacy, overcome resistance mechanisms, and reduce tumor heterogeneity compared with conventional monoclonal antibodies. At the 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, Myung-Ju Ahn, MD, professor in the department of hematology and oncology at the Samsung Medical Center at Sungkyunkwan University in Seoul, South Korea, presented updated findings on approved and investigational BsAbs, highlighting their mechanisms of action, clinical trial outcomes, toxicity profiles, and future therapeutic potential.¹

Mechanisms of Action of BsAbs

BsAbs provide a dual binding capacity that allows blockade of parallel oncogenic pathways or immune checkpoints, receptor–antibody internalization and degradation, and activation of innate immune mechanisms such as macrophage-mediated trogocytosis and antibody-dependent cell-mediated cytotoxicity (ADCC) through Fc gamma receptor engagement.¹

“Altogether, these mechanisms enhance efficacy and help overcome heterogeneity or resistance,” Ahn said during the WCLC session.¹

For example, amivantamab (Rybrevant; Janssen Biotech), a bispecific targeting EGFR and MET, exemplifies the diverse actions of this class, Ahn explained. Amivantamab blocks ligand binding, promotes receptor internalization and degradation by endocytosis, and induces macrophage-mediated trogocytosis and ADCC by NK cells. This multifaceted action is especially relevant in NSCLC, where resistance frequently emerges through bypass signaling or pathway redundancy.¹

Currently Approved BsAbs in NSCLC

Microscopic view of non small cell lung cancer cells. Image Credit: © Keopaserth - stock.adobe.com

There are 2 BsAbs currently approved by the FDA for NSCLC: amivantamab and zenocutuzumab (Bizengri; Merus). Amivantamab has been studied extensively across EGFR-mutated disease subsets. Its approvals encompass several clinical scenarios, including monotherapy in the second line for EGFR exon 20 insertion mutations, combination with chemotherapy in the first line, and use with lazertinib (Lazcluze; Johnson & Johnson) in the first line for EGFR exon 19 deletion or L858R mutations following osimertinib (Tagrisso; AstraZeneca). Amivantamab was approved on September 19, 2024, based on the results from MARIPOSA-2 (NCT04988295). In this trial, amivantamab demonstrated significant benefit when added to chemotherapy with or without lazertinib in patients with progression on third-generation EGFR tyrosine kinase inhibitors (TKIs).^1,2,4

Zenocutuzumab represents another important addition, as it was granted accelerated approval on December 4, 2024, for tumors harboring NRG1 fusions in the salvage setting.^1,3 Although rare, NRG1 fusions are enriched in invasive mucinous adenocarcinoma of the lung and other malignancies such as pancreatic cancer. By targeting HER2/HER3 heterodimerization, zenocutuzumab blocks constitutive downstream signaling driven by the chimeric ligand domain of NRG1 fusions. Its tissue-agnostic activity underscores the versatility of bispecific design, according to Ahn.¹

Clinical Trial Evidence: Amivantamab

The clinical trial program for amivantamab helped to establish it as the most extensively validated bispecific antibody in NSCLC. In the phase 1 CHRYSALIS trial (NCT02609776),⁵ amivantamab monotherapy demonstrated an overall response rate (ORR) of approximately 40% with a median progression-free survival (PFS) of 8.3 months. Notably, responses were observed across mutation subtypes, confirming activity irrespective of specific exon 20 insertion variants, Ahn explained.¹

The phase 3 PAPILLON study (NCT04538664) expanded on these findings, comparing amivantamab plus chemotherapy against chemotherapy alone in untreated EGFR exon 20 insertion NSCLC.^1,6 The combination achieved a significant PFS and overall survival (OS) advantage, with an HR of 0.67. This provided the basis for first-line regulatory approval in March 2024.¹

In the MARIPOSA trial (NCT04487080),⁷ amivantamab plus lazertinib was compared with osimertinib in patients with EGFR exon 19 deletion or L858R mutations. Median PFS was significantly prolonged at 23.7 months vs 16.6 months (HR 0.70), and updated OS analyses showed a favorable HR of 0.75, suggesting a survival advantage. MARIPOSA-2 extended these observations to patients progressing after osimertinib, where amivantamab plus chemotherapy or amivantamab plus lazertinib and chemotherapy both significantly improved PFS compared with chemotherapy alone (6.3 vs 4.2 months, HR 0.40).¹

Together, these studies establish amivantamab as a versatile therapy across multiple EGFR-driven NSCLC contexts, with demonstrated survival benefit in several phase 3 trials.¹

Toxicities and Management Strategies

Although efficacious, amivantamab presents a distinct toxicity profile reflecting both its EGFR and MET binding. Common EGFR-related adverse events (AEs) include acneiform dermatitis (31%), rash (54%), paronychia (56%), diarrhea (21%), and stomatitis (25%). MET-related toxicities include peripheral edema (30%) and hypoalbuminemia (41%). Infusion-related reactions occur in approximately 42% of patients, typically during the first administration.¹

Serious but less frequent toxicities include venous thromboembolism and challenges termed “time toxicity” due to the demands of weekly intravenous administration. Financial toxicity has also been recognized, underscoring the need for mitigation strategies.¹

To address dermatologic AEs, the PALOMA trial incorporated proactive dermatologic management alongside amivantamab plus lazertinib. This approach reduced grade II or higher skin events by half (76% vs 38%) and lowered discontinuation rates from 19% to 11%. Another strategy of subcutaneous administration has proven particularly promising, according to Ahn. In PALOMA, subcutaneous delivery reduced infusion-related reactions from 66% to 13% while preserving efficacy, reflected by an HR of 0.62 for PFS.¹

Zenocutuzumab and NRG1 Fusions

Zenocutuzumab addresses the unmet need of patients with NRG1 fusion–positive tumors. Although rare in NSCLC (approximately 1%), NRG1 fusions drive constitutive HER2/HER3 signaling that is poorly addressed by other targeted therapies. By blocking HER2–HER3 interaction, zenocutuzumab disrupts this oncogenic signaling axis.¹

In a phase 1/2 tissue-agnosticeNRGy trial,⁸ zenocutuzumab demonstrated durable responses across multiple tumor types, including NSCLC, leading to accelerated approval in December 2024. Its development highlights the potential for BsAbs to address rare molecular subsets, complementing more broadly targeted agents such as amivantamab, Ahn explained.¹

BsAbs Targeting VEGF and PD-1

Beyond oncogene-directed therapy, bispecifics are advancing into immunotherapy by combining checkpoint inhibition with angiogenesis blockade. VEGF is a critical modulator of the tumor microenvironment, impairing dendritic cell maturation and T-cell trafficking while fostering immunosuppression. Traditional strategies combining VEGF inhibitors with immune checkpoint inhibitors (ICIs) have shown variable OS benefit in NSCLC, according to Ahn.¹

Ivonescimab (SMT112; Summit Therapeutics), a tetravalent PD-1/VEGF bispecific antibody, has shown promise by uniting dual checkpoint and angiogenic inhibition within a single agent. In early-phase studies, ivonescimab monotherapy achieved an ORR of 52% in PD-1–positive NSCLC, with a favorable safety profile compared with bevacizumab (Avastin; Genentech). Hypertension and proteinuria were the most common AEs, but grade III or higher events and discontinuations were rare (<1%).¹

Phase 2 studies combining ivonescimab with chemotherapy reported ORRs of 52% to 67% and median PFS of 15 to 18 months, with outcomes considered highly encouraging, according to Ahn. The HARMONi trial program has provided pivotal confirmatory evidence. In HARMONi-A (NCT05184712),⁹ conducted in EGFR-mutant NSCLC after TKI failure, ivonescimab plus chemotherapy achieved a PFS benefit over chemotherapy alone (7.1 vs 4.8 months) with an ORR of 50% vs 35%.¹ HARMONi-2 (NCT05499390) compared ivonescimab with pembrolizumab (Keytruda;Merck) monotherapy in PD-1–positive NSCLC, demonstrating a significant PFS advantage (HR 0.5) with consistent benefit across PD-L1 subgroups and histologies, including squamous NSCLC.^1,10 Importantly, hemorrhagic complications—a known limitation of bevacizumab—were absent. OS data remain pending. Ongoing trials such as HARMONi-3 (NCT05899608) and HARMONi-7 (NCT06767514) are evaluating global and biomarker-selected populations, respectively.^1,11,12

Dual Immune Checkpoint Bispecifics

A third major avenue for BsAb development involves dual immune checkpoint inhibition, Ahn explained. By simultaneously targeting inhibitory receptors such as PD-1 and CTLA-4, LAG-3, or TIGIT, bispecifics may enhance immune activation beyond what is achieved with single-agent ICIs or even combination regimens of separate monoclonal antibodies.¹

Several early-phase trials in NSCLC have investigated these constructs. Cadonilimab (Akeso), which targets PD-1/CTLA-4, demonstrated modest activity, with an ORR of 10% in ICI-naïve second-line patients and no responses in resistant populations. Median OS varied from 4.9 to 19.6 months across subgroups, whereas grade III or higher treatment-related AEs (TRAEs) occurred in approximately 11%. KN046 (Alphamab Oncology), another PD-1/CTLA-4 BsAb, showed higher response rates when combined with chemotherapy, with ORRs near 46% and median OS exceeding 2 years, though with higher rates of grade III or higher TRAEs.¹

PD-1/CTLA-4 therapy colrustomig (AstraZeneca) and PD-1/TIGIT therapy rilvegostomig (AstraZeneca) have also been evaluated. Volrustomig plus chemotherapy demonstrated an ORR of 50% and median PFS of 15.1 months in the first-line metastatic setting, whereas rilvegostomig produced ORRs of 29% to 62% depending on PD-L1 status in previously treated NSCLC. These outcomes are early but support continued exploration.¹

Other checkpoint bispecifics, such as FS118 (F-star Therapeutics) and tebotelimab (MacroGenics), and LY3415244 (Eli Lilly), remain in early clinical development, with limited but emerging data.¹

Future Directions

BsAbs represent a transformative advance in the treatment landscape of advanced NSCLC, offering the potential to address both common and rare molecular subsets as well as immune-mediated pathways. Agents such as amivantamab and zenocutuzumab have already demonstrated durable efficacy and received regulatory approval, whereas next-generation constructs targeting VEGF, PD-1, CTLA-4, TIGIT, as well as other immune checkpoints, continue to expand the therapeutic horizon.

Importantly, clinical trial data suggest that BsAbs can deliver meaningful improvements in survival and response rates across a spectrum of patient populations, including those with limited treatment options after progression on standard therapies. However, challenges remain, including management of unique toxicity profiles, optimization of administration strategies, and mitigation of financial and logistical burdens associated with these therapies. As research advances, BsAbs are poised to play a central role in shaping precision medicine for NSCLC, with the promise of more durable disease control, greater personalization of therapy, and improved patient outcomes.

REFERENCES

1. Ahn MJ, Patel S, Mountzios G, Piotrowska Z. A new era of targeted therapy for advanced NSCLC. World Conference on Lung Cancer 2025; Barcelona, Spain; September 6-9, 2025.
2. A Study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure (MARIPOSA-2). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 6, 2025. https://clinicaltrials.gov/study/NCT04988295
3. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. December 4, 2024. Accessed September 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic
4. FDA approves amivantamab-vmjw with carboplatin and pemetrexed for non-small cell lung cancer with EGFR exon 19 deletions or L858R mutations. FDA. September 19, 2024. Accessed September 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-carboplatin-and-pemetrexed-non-small-cell-lung-cancer-egfr-exon-19
5. Study of amivantamab, a human bispecific EGFR and cMet antibody, in participants with advanced non-small cell lung cancer (CHRYSALIS). Clinicaltrials.gov. Updated July 18, 2025. Accessed September 6, 2025. https://clinicaltrials.gov/study/NCT02609776
6. A study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in participants with advanced or metastatic non-small cell lung cancer characterized by epidermal growth factor receptor (EGFR) exon 20 insertions (PAPILLON). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT04538664
7. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 6, 2025. https://clinicaltrials.gov/study/NCT04487080
8. Kim DW, Schram AM, Hollebecque A, et al. The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions. Future Oncol. 2024;20(16):1057-1067. doi:10.2217/fon-2023-0824
9. Phase 3 clinical study of AK112 for NSCLC patients. Clinicaltrials.gov. Updated June 28, 2025. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT05184712
10. AK112 in advanced non-small cell lung cancer. Clinicaltrials.gov. Updated March 5, 2025. Accessed September 6, 2025. https://clinicaltrials.gov/study/NCT05499390
11. Clinical study of ivonescimab for first-line treatment of metastatic NSCLC patients. Clinicaltrials.gov. Updated June 3, 2025. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT05899608
12. Clinical study of ivonescimab for first-line treatment of metastatic NSCLC patients with high PD-L1 (HARMONi-7). Clinicaltrials.gov. Updated April 29, 2025. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT06767514