Patritumab deruxtecan: advancing the treatment landscape for EGFR-resistant non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease encompassing several molecular subgroups (1). Somatic mutations of the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers in NSCLC, reported in 15% to 50% of patients with adenocarcinoma histology, according to ethnicity (2,3). The third-generation tyrosine kinase inhibitor (TKI) osimertinib is the current recommended upfront treatment as monotherapy (4) or in combination with platinum-based chemotherapy (PBC) (5). However, one of the most important issues with osimertinib is the acquired resistance mediated by on-target (e.g., other EGFR mutations like C797S) and off-target mechanisms (e.g., cMET and HER2 amplification), a combination of both, or the emergence of phenotype switching (e.g., transformation to small-cell or squamous-cell lung carcinoma) (6,7).

The epidermal growth factor receptor 3 (HER3) belongs to the human EGFR family. HER3 overexpression is involved in metastasis and resistance to anti-EGFR treatment (8).

Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of cytotoxic agents and are extensively studied in refractory NSCLC (9).

Patritumab deruxtecan (U3-1402, HER3-DXd) is a novel HER3-targeted ADC evaluated in patients with metastatic NSCLC. HER3-DXd is composed by an anti-HER3 IgG1 monoclonal antibody (moAb) covalently linked to an exatecan-derived topoisomerase I (topo I) inhibitor payload with a high drug-to-antibody ratio (DAR) of 8.

HER3-DXd safety and efficacy were assessed in heavily pretreated EGFR-mutated NSCLC in the phase I U31402-A-U102 study (ClinicalTrials.gov identifier: NCT03260491). This was an open-label, multiple dose, multicentric, dose expansion and dose escalation phase I trial of HER3-DXd (10,11). Key findings and translational insights of the study are reviewed and discussed here.

In this clinical trial, the recommended dose for the expansion (RDE) was established at 5.6 mg/kg intravenously every three weeks q3w during the dose escalation phase (n=12).

The dose expansion phase assessed safety and efficacy in two cohorts.

Cohort 1 included 45 EGFR-mutated patients with adenocarcinoma histology after progression (PD) on EGFR-TKIs and PBC, receiving HER3-DXd at 5.6 mg/kg.

Cohort 3 included 90 patients with any NSCLC histology randomized 1:1 to receive either HER3-DXd at 5.6 mg/kg (cohort 3a, n=45) or an up-titration regimen starting at 3.2 mg/kg (cohort 3b) (11).

Patients harbored various EGFR activating mutations (e.g., Ex19del, L858R, L861Q, G719A, Ex19ins) (11). The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoint included safety, disease control rate (DCR), duration of response (DOR), time to response, progression-free survival (PFS), and overall survival (OS).

The efficacy population had received prior PBC in addition to prior EGFR-TKI treatment. EGFR-TKI therapies include afatinib, dacomitinib, erlotinib, gefitinib, lazertinib, nazartinib, olmutinib, osimertinib and rociletinib (11).

The median age of the patients included in the efficacy analysis was 64 years (range, 40–80 years). The population was heavily pretreated, with a median of 4 prior lines of therapy.

In 97 efficacy-evaluable patients, ORR by BICR was 39.2% (95% CI: 29.4–49.6%). The median DOR (mDOR) was 9.6 months (95% CI: 6.9–15.4 months) and the median OS (mOS) was 15.8 months (95% CI: 10.8–21.5 months). In the subgroup of prior third-generation EGFR-TKI (n=78), ORR was 41.0% (95% CI: 30.0–52.7%), mDOR 11.2 months (95% CI: 7.0 to not evaluable) and mOS 16.2 months (95% CI: 11.2–21.9 months). In the brain metastases (BM) subgroup confirmed ORR (cORR) by BICR was 42.9% (95% CI: 27.7–59.0%) and mOS was 14.6 months (95% CI: 9.5–17.3 months).

HER3 was expressed in 80/97 tumors in the efficacy population and antitumor activity was observed across different levels of HER3 membrane expression. Efficacy was observed in patients with various mechanisms of EGFR-TKI resistance, including EGFR-dependent mechanisms (cORR =30%), EGFR-independent mechanisms (cORR =48%), or both (cORR =47%).

The trial’s safety population included 102 patients of whom 80 (78.4%) were on second-line treatment after EGFR-TKIs failure. Common grade 3 or higher treatment-emergent adverse events (TEAEs) included thrombocytopenia (26.5%), neutropenia (20.6%), and fatigue (9.8%). TEAEs associated with treatment discontinuation occurred in 12 patients (11.8%), and TEAEs associated with death were reported in 12 patients (11.8%).

TEAEs associated with dose reduction, grade ≥3 TEAEs (including thrombocytopenia) and serious adverse events (AEs) were more commonly reported among patients treated in fixed-dose regimen than up-titration regimen. However, efficacy results were in favor of the fixed-dose regimen (cORR 42.2% vs. 28.3%), and the discontinuation rate due to PD was superior in the uptitration regimen arm (82.6%) than in the fixed-dose arm (57.8%). Frequency of interstitial lung disease (ILD), which was previously identified in other studies of HER3-DXd, was assessed among secondary objectives. ILD was confirmed by an independent adjudication committee in nine (8.8%) patients. Adjudicated treatment-related ILD was reported in eight (7.8%) patients: two grade 1, grade 2, grade 3, and grade 5. Adjudicated therapy-related ILD emerged an average of 61 days (13–333 days) after starting HER3-DXd treatment (11). A recent study indicates that there is no clear association between RNA sequencing (RNA-seq) expression of targetable antigens and the incidence of ILD. Although the exact mechanism of ADCs damage still needs to be elucidated, some payloads (e.g., DXd) are more likely associated with increased risk of lung injury (12). A post-hoc analysis of trastuzumab deruxtecan trials in lung cancer found that previous thoracic radiation therapy may represent a potential risk factor for high-grade ILD, as radiation induced lung damage can exacerbate the toxic effect of the payload (13).

The study included exploratory objectives to evaluate the correlation between pretreatment HER3 membrane expression by immunohistochemistry (IHC) and clinical activity, to detect acquired genomic alterations as resistance mechanisms in patients treated with HER3-DXd for over 4 months and perform in vitro functional testing to characterize these alterations. The assessment of response rates across subgroups with different EGFR-TKI resistance-associated genomic alterations was also included.

Reduced HER3 surface expression and altered endocytosis can limit the efficacy of ADCs. In this study, HER3 membrane expression was quantified using an IHC-based H-score (0–300) and antitumor activity was observed across a broad range of HER3 expression levels. This aligns with findings in breast cancer therapy (14) and prior studies on HER3-DXd efficacy in EGFR-mutated NSCLC (15). Similar trends have been observed in the ASCENT trial (16). Novel generation ADCs, such as HER3-DXd, exhibit efficacy irrespective of target expression levels due to advancements in their pharmacological design, like potent cytotoxic payload, bystander killing effects and improved internalization properties. HER3 expression could serve as a predictive biomarker for patient selection and stratification in HER3-directed approaches. However, HER3 expression alone may not fully account for the treatment’s efficacy and its predictive value may be enhanced with other biomarkers (e.g., genomic alterations) or clinical features. Thus, techniques like IHC, tumor biopsy, circulating tumor DNA (ctDNA) analysis can help identifying HER3 overexpression, HER3-mediated resistance mechanisms, or associated oncogenic pathway. RNA-Seq enables detailed analysis of HER3 expression in tissue and its relationship with other oncogenic pathways associated with treatment resistance such as receptor tyrosine kinase fusion-mediated mechanisms.

HER3 is overexpressed in up to 40% of lung malignancies, including 80% of patients with NSCLC (17). HER3 has weak intrinsic kinase activity, limiting its potency as a standalone target. Effective HER3 inhibition may require simultaneous targeting of its dimerization partners (EGFR and HER2) (18). HER3-targeted ADCs show promise in EGFR-TKI-resistant NSCLC due to HER3’s role in activating bypass pathway (e.g., PI3K/Akt).

While HER3-targeted ADCs show potential, their efficacy in unselected NSCLC populations may be limited compared to widely expressed targets like TROP2. Companion diagnostics to measure HER3 expression in HER3-dependent signaling may optimize ADCs use in biologically driven, combinational treatment approaches.

Resistance to HER3-DXd may occur at different levels, involving on-target mutations that can decrease the target protein expression, ADC trafficking and internalization, and payload release. During progression, acquired mutations in HER3 (Y789fs, P489fs) and TOP1 (L721R) have emerged as potential mechanisms of resistance to HER3-DXd. The HER3 Y789fs mutation was functionally characterized and showed reduced protein expression compared with wild-type HER3, thus explaining the decrease in HER3-DXd internalization and abrogation in payload release.

The therapeutic landscape of NSCLC has advanced significantly with the development of ADCs which are effective across a broad range of tumor antigens in both oncogene- and non-oncogene-addicted cancers. HER3-DXd demonstrated meaningful clinical benefits and manageable safety profile in EGFR-mutated NSCLC, showing activity across different baseline characteristics, including various genomic alterations of EGFR-TKI resistance and intracranial disease. Central nervous system (CNS) efficacy was notable, addressing the high prevalence of BM in patients with EGFR-mutant NSCLC (19). Furthermore, the phase II HERTHENA-Lung01 results demonstrated HER3-DXd activity in pretreated EGFR-mutated locally advanced or metastatic NSCLC patients (ORR of 29.8%) (20). Significant and durable responses were reported in the subgroup with BM [ORR 33.3% (95% CI: 17.3–52.8%); CNS DOR 8.4 months (95% CI: 5.8–9.2)] highlighting the role HER3 targeted inhibition in refractory NSCLC. Presented results are of great clinical significance as an alternative therapeutic option is represented by docetaxel with a very limited activity (ORR of 12%).

HER3-DXd is currently being evaluated in the HERTHENA-Lung02 phase 3 trial (NCT05338970) comparing it to PBC after progression on third-generation EGFR-TKIs. A phase 1 trial is studying HER3-DXd in combination with osimertinib (NCT04676477).

HER3 remains a promising therapeutic target with investigational agents such as BL-B01D1 (21), SI-B001 (22), zenocutuzumab (23) or SHR-2009 (24) expanding the field.

In conclusion, this study underscores the potential of HER3-targeted ADCs in NSCLC care, particularly in EGFR-mutated and TKI-resistant populations, while highlighting the need for biomarkers-driven strategies. The role of HER3-DXd in treatment sequencing is evolving especially with effective first-line combinations like amivantamab + lazertinib (25) or osimertinib + PBC (5).

This article presents the first comprehensive analysis to characterize the acquired genomic alterations potentially associated with resistance to HER3-DXd treatment. Understanding HER3 expression dynamics and its role in resistance mechanisms is an active research focus. Comprehensive analyses are underway to further characterize genomic alterations associated with resistance to HER3-DXd.

Acknowledgments

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-24-206/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-206/coif). D.P. reports personal fees from AstraZeneca, Abbvie, Bristol Myers Squibb, Daiichi-Sankyo, Merck, Novartis, Janssen, Pfizer, Roche, and Sanofi-Aventis, institutional financial fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen. F.B. reports institutional fees from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis and Takeda. The other author has 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.

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