The Era of Antibody Drug Conjugates in Lung Cancer: Trick or Threat?

Article information

Cancer Res Treat. 2025;57(2):293-311

Publication date (electronic) : 2024 November 28

doi : https://doi.org/10.4143/crt.2024.714

Mariona Riudavets ¹

, David Planchard^,²

¹Department of Pneumology, Hôpital Cochin APHP Centre, Paris, France

²Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France

Correspondence: David Planchard, Department of Cancer Medicine, Gustave Roussy Cancer Campus, 114 Edouard Vaillant Street, F-94800, Villejuif, France Tel: 33-1-4211-4564 E-mail: David.PLANCHARD@gustaveroussy.fr

Received 2024 July 26; Accepted 2024 November 27.

Abstract

Antibody drug conjugates (ADCs) are a novel class of therapeutics that structurally are composed by an antibody directed to a tumor epitope connected via a linker to a cytotoxic payload, and that have shown significant antitumor activity across a range of malignancies including lung cancer. In this article we review the pharmacology and design of ADCs, as well as we describe the results of different studies evaluating ADCs in lung cancer directed to several targets including HER2, HER3, TROP2, MET, CEACAM5 and DLL3.

Keywords: Lung neoplasms; ADCs; HER2; HER3; TROP2; MET; CEACAM5; DLL3

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide. Non–small cell lung cancer (NSCLC), the main histologic subtype accounts for 85% of lung cancer cases and is a heterogeneous disease driven by a wide spectrum of molecular alterations [1,2]. Additional treatment options after failure of chemotherapy and immunotherapy combinations, and following development of acquired resistance to targeted therapies in oncogenic-driven subtypes are needed.

Antibody drug conjugates (ADCs) are an emerging class of antitumor agents that selectively target tumor cells and deliver concentrated cytotoxic payloads through an antibody-mediated process, effectively sparing normal tissue. Moreover, ADCs can also stimulate the immune-cell effector function and disrupt receptors dimerization [3]. Modern ADCs have been developed to maintain their pharmacodynamic stability, preferentially blinded to a target antigen expressed on cancer cells leading to accumulation within the tumor compartment, followed by internalization by target cells and releasing cytotoxic levels of the chemotherapy payload. This precise delivery mechanism may at last lead to an increased therapeutic index of the corresponding payload cytotoxic compound, limiting secondary effects at equivalent systemic doses.

These agents have demonstrated an advantage in terms of outcomes in both multiple solid and hematologic malignancies, with recent advances in the treatment of oncogene-driven and wild-type NSCLC [4,5].

Here, we provide a concise overview of the pharmacology and design of ADCs and we particularly review advances in ADCs directed against HER2 (human epidermal growth factor receptor 2), HER3, TROP2 (trophoblast cell-surface antigen 2), MET (mesenchymal-epithelial transition receptor) and CEACAM5 (carcinoembryonic antigen–related cell adhesion molecular 5) in NSCLC.

Design

Antibody-drug conjugates are composed of three main parts: the antibody, the linker and the payload. Each of them has undergone significant refinement in recent decades, culminating in better efficacy and tolerability.

1. Antibody and antigen target

The antibody component of ADCs is predominantly humanized, being the IgG 1 class the predominant antibody backbone [6], given its extended serum half-life and Fcγreceptor (FcγR)–binding affinity associated with complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity [7].

An ideal target protein is that on with a high expression on the surface of tumors cells compared to its limited expression in normal cells [8]. The variability in expression patterns between cancer and non-cancer cells may in part explain some of the on-target toxicities noted with these agents.

Another essential factor to be considered is the rate of antigen turnover or cycling on tumor cell surface, since high turnover rates of ADC targets may increase internalization and delivery of cytotoxic payload intracellularly increasing their cytotoxic killing effect [9].

2. Linker

The linker is a biochemical component assembling the antibody to the cytotoxic payload. Since it maintains the ADCs stability within the bloodstream, in plays a double role in both the toxicity and the activity profile of ADCs. Linker instability in this setting can lead to inappropriate or premature release of the cytotoxic payload and, in consequence, considerable toxicity. Conversely, an effective linker must also successfully release the cytotoxic payload once the ADC is internalized by the targeted cell; instead, the clinical activity of the ADC can be rather diminished [10].

Linkers are categorized into cleavable or non-cleavable according to their mechanism of payload release [11]: cleavable linkers degrade and release the cytotoxic payload on the basis of certain intracellular factors, such as acidity, glutathione reduction or the presence of lysosomal proteases leading to peptide cleavage [12,13]; on the other side, non-cleavable linkers are formed by non-reducible bonds with the antibody amino-acid residues, leading to higher stability within the systemic circulation, and they release the payload through lysosomal-dependent degradation of the entire antibody-linker complex [14].

3. Payload

The payload compound of the ADC potentiates cytotoxic effects on the target cell after internalization and release by the linker. They consist of higher-potency chemotherapy agents with IC50s (half maximal inhibitory concentration) in the nanomolar and picomolar range [15]. General categories of these cytotoxic payloads include anti-microtubule agents (i.e., DM1) and agents that exert DNA damage such as topoisomerase I inhibitors (i.e., SN-38, deruxtecan) [16].

Pharmacology

A crucial factor in the pharmacologic profile and clinical activity of ADCs depends on the drug-antibody ratio (DAR), defined as the average number of payload moieties attached to each monoclonal antibody. Food and Drug Administration (FDA)–approved ADCs present DARs ranging from 2 to 8 [17].

Although ADCs with higher DARs have expectedly greater in vitro potency, preclinical studies suggest that they may be subject to more rapid hepatic clearing and a less favorable safety profile, eventually lowering their therapeutic index [18].

The variability in ADCs design may render differences in their pharmacokinetics (PK) and pharmacodynamics (PD). The major compound of the ADC is the antibody portion, with the PKs and PDs thereby significantly influenced by the properties of the antibody backbone: target-specific binding, Fc receptor–dependent recycling and Fc effector functions [19]. In addition, the other elements carry their own PK considerations; for example, the site of conjugation of the linker can affect the PK of the ADCs through effects on stability while the ADC is within circulation or after internalization and more unstable linkers may lead to a faster decline in antibody concentrations [20]; besides, the cytotoxic payload mechanism of action can affect the therapeutic index, which is important when investigating and determining appropriate dosing regimens [21].

Main characteristics of principal ADCs in NSCLC are summarized in Table 1.

Table 1.

Characteristics of principal antibody-drug conjugates for NSCLC

ADC in Non–Small Cell Lung Cancer

Here, we review the current ADCs targets in NSCLC and the efficacy and toxicity profile of these agents. Tables 2-4 summarize data about ADCs in NSCLC.

Table 2.

Antibody-drug conjugates in NSCLC with HER2 molecular alterations

Table 3.

Antibody-drug conjugates anti-TROP2 in NSCLC

Table 4.

Other antibody-drug conjugates in NSCLC

1. ADC against HER2

HER2 gene, also known as ErbB2, is a known proto-oncogene that is located on the long arm of chromosome 17 (17q21), and the HER2 protein product is a member of the Her/ErbB family of tyrosine kinases receptors. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%), and protein overexpression (2%-30%), with different prognostic and predictive outcomes.

1) Trastuzumab emtansine

Trastuzumab emtansine (T-DM1) is an anti-HER2 ADC composed of trastuzumab and the cytotoxic microtubule agent emtansine (DM1) linked via a non-cleavable linker, a maytansine derivative [22].

A small phase II trial reported limited efficacy of T-DM1 monotherapy in 15 relapsed HER2-altered NSCLC patients with an objective response rate (ORR) of 6.7% and median progression-free survival (PFS) and overall survival (OS) of 2 (95% confidence interval [CI], 1.4 to 4) and 10.9 months (95% CI, 4.4 to 12), respectively. No responses were obtained in the HER2-amplified/overexpressing subgroup, and only one of seven patients in the HER2-mutant cohort responded (ORR 14.3%) [23].

Analyses from a phase II basket trial highlighted the potential role of T-DM1 in HER2-mutant NSCLC patients, administered at the dose of 3.6 mg/kg intravenously every 3 weeks (Q3W). Eight of 18 patients presented a partial response, with a median duration of response (DoR) of 4 months (range, 2 to 9) and a median PFS of 5 months (95% CI, 3 to 9) [24]. Updated data including 28 patients with HER2-mutant refractory NSCLC showed an ORR of 50% (95% CI, 31 to 69) [24-26].

T-DM1 was also administered to 11 patients with HER2-amplified NSCLC included in the former basket trial and achieved an ORR of 55% (95% CI, 23 to 83) [24-26] and Peters et al. [27] studied the efficacy of T-DM1 in HER2-overexpressing NSCLC, with no responses in the immunohistochemistry (IHC) 2+ subgroup and an ORR of 20% (95% CI, 5.7 to 43.7) in the IHC 3+ subgroup despite comparable median PFS (2.6 vs. 2.7 months) and OS (12.2 vs. 5.3 months). Besides, when HER2 overexpression patterns were further analyzed, 3 of 4 responders had HER2 amplification and two patients had a concomitant HER2 mutation. In conclusion, this study showed that the HER2 positivity status determined solely by IHC cannot be a predictive biomarker for T-DM1 activity [27].

T-DM1–related adverse events (AEs) were mainly of grades 1 or 2, including increased liver transaminases (63%), thrombocytopenia (31%), and nausea (29%). No dose reductions or treatment discontinuation due to toxicity were needed in the HER2-mutant cohort [24].

2) Trastuzumab deruxtecan

Trastuzumab deruxtecan (T-DXd or DS-8201a) is an ADC composed of trastuzumab, a tetrapeptide-based cleavable linker and a topoisomerase I inhibitor payload called MAAA-1181. Its mechanism of action differs from other ADCs: it binds to topoisomerase I-DNA complexes and stabilizes them which in turn induces DNA double-strand breaks and apoptosis [28]. T-DXd’s stable and homogeneous design, despite its higher DAR compared to other available ADCs (8 vs. 2 to 4), allows for a steady delivery of the topoisomerase I inhibitor in HER2-low expressing conditions [29,30].

The expansion cohort of the first-in-human phase I trial evaluating T-DXd in non-breast and non-gastric/gastrooesophageal tumors enrolled patients with relapsed NSCLC harboring HER2 alterations. T-DXd demonstrated promising antitumor activity with an acceptable safety profile; the maximum tolerated dose (MTD) was 6.4 mg/kg Q3W [31]. Updated data including 11 patients with HER2-mutant refractory NSCLC, showed an ORR of 72.7%, a median DoR of 9.9 months (95% CI, 6.9 to 11.5) and a median PFS of 11.3 months (95% CI, 8.1 to 14.3) [32].

DESTINY-Lung01, a phase II trial evaluating the efficacy of T-DXd in pre-treated NSCLC harboring HER2 molecular alterations includes two cohorts of patients: The HER2-mutant cohort included 91 patients, showing an ORR of 55%, a median DoR of 9.3 months (95% CI, 5.7 to 14.7) and medians PFS and OS of 8.2 (95% CI, 6.0 to 11.9) and 17.8 months (95% CI, 13.8 to 22.1), respectively [4,33,34].

Results from the 49 patients included in the HER2-overexpressing NSCLC were promising albeit less spectacular in comparison with the latter, with an ORR of 26.5% (95% CI, 15.0 to 41.1), a median DoR of 5.8 months (95% CI, 4.3 to not reached [NR]) and a median PFS of 5.7 months (95% CI, 2.8 to 7.2). Responses did not differ according to HER2 IHC expression levels (ORR, 20.0% vs. 25.6% in IHC3+ and IHC2+ patients, respectively) [34,35].

The phase II study DESTINY-Lung02 included 152 patients with refractory HER2-mutant NSCLC randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg Q3W. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median DoR was 16.8 (95% CI, 6.4 to not estimable) and NR (95% CI, 8.3 to NR) with 5.4 and 6.4 mg/kg, respectively [36]. Median PFS were 9.9 (95% CI, 7.4 to NR) and 15.4 months (95% CI, 8.3 to NR), and median OS 19.5 (95% CI, 13.6 to NR) and NR (95% CI, 12.1 to NR) in the 5.4 and 6.4 mg/kg arms, respectively [36].

Exploratory pooled brain metastases analyses from DESTINY-Lung01 and DESTINY-Lung02 presented at European Society for Medical Oncology (ESMO) 2023, demonstrated intracranial (IC) efficacy of T-DXd, with IC-ORR of 50% and 30% and median IC-DoR of 9.5 months and 4.4 months, for 5.4 mg/kg and 6.4 mg/kg Q3W schedules, respectively. T-DXd IC efficacy was similar in treated and untreated brain metastases. Limitations of this post hoc analysis include the small number of patients and the lack of a comparator arm.

Regarding T-DXd toxicity, gastrointestinal and hematological events were the most common AEs of any grade, with neutropenia being the most common AE of grade ≥ 3. In the phase II study, up to 46%-53% of AEs were of grade 3 or higher and 16%-25% led to treatment discontinuation [4,33-35]. Importantly, five cases of T-DXd–related interstitial lung disease (ILD) were reported in the phase I basket trial [32]. In the phase II DESTINY-Lung01 trial, 4 patients in the HER2-mutant cohort presented with grade 3 drug-related ILD and two patients with a grade 5 [4]. In the HER2-overexpressing cohort, drug-related ILD occurred in 20% of patients (3 patients with grade 5, 5 with grade 2, and 2 with grade 1) [33,35]. All patients with grade 5 ILD had received prior immune-checkpoint inhibitors (ICIs) [33,35].

In DESTINY-Lung02 trial, grade ≥ 3 AEs occurred in 38.6% and 58% of patients with 5.4 and 6.4 mg/kg, respectively; similarly, ILD was reported in 12.9% and 28% of cases, respectively [36].

Based on these two trials, DESTINY-Lung01 and DESTINY-Lung02, T-DXd 5.4 mg/kg was approved by the FDA and the European Medicines Agency (EMA) for patients with previously treated HER2-mutant metastatic NSCLC marking the first approval of an ADC for lung cancer.

DESTINY-Lung04 is an ongoing randomized phase 3 study evaluating T-DXd as first-line treatment in patients with metastatic NSCLC harbouring HER2 exon 19 or 20 mutations.

Table 2 summarizes data about ADCs in HER2-altered NSCLC.

2. ADCs against TROP2

TROP2 is a glycoprotein transmembrane calcium signal transducer upregulated in more than 50% of lung adenocarcinoma and squamous cell carcinoma of the lung and participates in several oncogenic signaling pathways, but exhibits limited expression in normal human tissues, which makes it an attractive therapeutic blank in cancer treatment. TROP2 is associated with poor survival [37-39].

1) Datopotamab deruxtecan

Datopotamab deruxtecan (Dato-DXd) is an anti-TROP2 ADC linked to topoisomerase I inhibitor deruxtecan via a cleavable linker.

Dato-DXd showed encouraging antitumor activity in phase I TROPION-PanTumor01 dose-escalation and dose-expansion study evaluating Dato-DXd in solid tumors, in which patients were not selected based on TROP2 expression [40,41].

In the NSCLC expansion cohort, a total of 180 previously treated patients received Dato-DXd 4, 6, and 8 mg/kg Q3W. The recommended dose for further development was 6 mg/kg Q3W. The ORR was 26%, median DoR was 10.5 months and median PFS and OS were 6.9 months (95% CI, 2.7 to 8.8) and 11.4 months (95% CI, 7.1 to 20.6), respectively. Responses occurred regardless of TROP2 expression [42]. In the same study, Dato-DXd also achieved and ORR of 35% and DoR of 9.5 months in 34 NSCLC previously treated patients with actionable genomic alterations, including anaplastic lymphoma kinase (ALK) (n=3), epidermal growth factor receptor (EGFR) (n=29), ROS (n=1), and RET (n=1) [43].

The first report of TROPION-Lung01 study, a phase III trial comparing Dato-DXd 6 mg/kg Q3W vs. docetaxel in pre-treated advanced NSCLC with or without actionable genomic alterations, has been presented in the ESMO congress 2023. A total of 604 patients were included in the full analysis set; 43.1% had received ≥ 2 prior lines of systemic therapy. PFS was significantly improved with Dato-DXd: 4.4 vs. 3.7 months (hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.91; p=0.004); and ORRs were 26.4% vs. 12.8%, with a median DoR of 7.1 and 5.6 months, respectively. Longer median PFS was observed in the prespecified non-squamous histology subgroup (5.6 vs. 3.7 months) [44].

TROPION-Lung05 phase II trial has evaluated Dato-DXd in 137 patients with oncogenic addition NSCLC (including EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14, and RET) progressing to ≥ 1 targeted therapy and platinum-doublet chemotherapy. A total of 71.5% of patients had received ≥ 3 prior lines of therapy and 56.9% had EGFR mutations. The ORR was 35.8%, disease control rate (DCR) 78.8%, and median DoR 7.0 months; similar response was seen in pts with EGFR mutations [45].

The most common AEs with Dato-DXd are stomatitis (49.2%) and nausea (37%). Grade 3 occurs in 24.6% of patients. In TROPION-Lung01 study, ILD of grade ≥ 3 occurred in 3.4% of patients in the Dato-DXd arm [44].

The phase Ib TROPION-Lung02 trial is a dose-escalation and -expansion study evaluating Dato-DXd (4 or 6 mg/kg) combined with pembrolizumab (doublet) with or without platinum agents (triplet therapy) in both previously untreated and pre-treated patients with metastatic NSCLC without actionable genomic alterations. In 62 evaluable first-line patients, the ORR was 60% (12/20) and 55% with doublet and triplet therapy, respectively. Responses were observed in all programmed death-ligand 1 (PD-L1) expression level subgroups. Although immature, median PFS was 10.8 (95% CI, 8.3 to 15.2) and 7.8 months (5.5 to NR) with doublet and triplet therapy, respectively. The most frequent AEs included stomatitis and nausea (both 45%). Grade 3 AEs occurred in 61% of patients, most frequently neutropenia (8%) and amylase increased (8%). Drug-related ILD occurred in 12 cases (10%; with three grade 3 and no grade 4-5) [46].

Dato-DXd is also being evaluated as first-line therapy for patients with advanced/metastatic NSCLC with PD-L1 expression ≥ 50% in the phase III TROPION-Lung08 trial comparing Dato-DXd in combination with pembrolizumab vs. pembrolizumab monotherapy (NCT05215340).

ICARUS-Lung01 is a multicentre, single-arm, phase II trial evaluating Dato-DXd in refractory NSCLC (including patients with an actionable genomic alteration) and progressing to at least one line of immunotherapy and platinum-doublet regimen.

Planchard et al. [47] presented latest results at American Society of Clinical Oncology (ASCO) 2024, with Dato-DXd showing similar efficacy and safety data to that reported in TROPION-Lung01. Patients with TROP2 expression ≥ 100 (H-score) on fresh tissue biopsy with non-squamous histology derived the greatest benefit.

Although the small number of simple size (n=15), no genomic alterations at baseline or at progression seem to be associated with Dato-DXd response. Activation of DNA repair and suppression of immune-related pathways could be associated to treatment resistance. Multiple genomic analyses on sequential biopsies are in progress.

2) Sacituzumab govitecan

Sacituzumab govitecan (SG) is an anti-TROP2 antibody linked to the topoisomerase I inhibitor SN-38 by a hydrolyzable cleavable linker.

The phase I/II IMMU-132-01 basket trial included 495 patients with refractory solid tumors regardless of TROP2 expression evaluating SG at 8, 10, 12, and 18 mg/kg on days 1 and 8 of 21-day cycles. The dose of 10 mg/kg was selected for further development [48].

The IMMU-132-01 study included a single-arm expansion cohort of 54 patients with previously treated NSCLC achieving an ORR of 16.7%, median DoR of 6 months, a median PFS of 4.4 months (95% CI, 2.5 to 5.4) and median OS of 7.3 months (95% CI, 5.6 to 14.6). More than 90% of the 26 assessable archival tumor specimens were positive for TROP2 by IHC [48,49].

Most common AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Grade ≥ 3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively; with dose reductions required in 32% of patients. Interestingly, the presence of homozygosity of the UGT1A1 *28 allele (*28/*28; 9.3% of patients) was associated with an almost two-fold increase in incidence of neutropenia [48].

The phase III EVOKE-01 trial, evaluating SG vs. docetaxel in refractory EGFR and ALK wild-type NSCLC patients, has not met the statistical significance for the primary endpoint of OS: 11.1 vs. 9.8 months (HR, 0.84; p=0.053), respectively [50]. A prespecified subgroup analysis showed meaningful improvement in OS of 3.5 months (HR, 0.75) with SG in NSCLC that was non-responsive to last anti-PD-(L)1-containing regimen. Furthermore, patients reported an improvement in cancer-related symptoms, reflective of a better tolerability and disease control with SG.

SG is being evaluated in combination with immunotherapy in the first-line setting (EVOKE-02, NCT05186974).

3) Sacituzumab tirumotecan

Sacituzumab tirumotecan (Sac-TMT/SKB264) is an anti–TROP2 ADC developed with pyrimidine-thiol linker conjugated to a novel topoisomerase I inhibitor (belotecan derivative). Its proprieties lead to realize the payload both in the tumor microenvironment and inside cancer cells.

Sac-TMT showed encouraging early clinical activity in 43 heavily pre-treated patients with EGFR wild-type NSCLC, with an ORR of 26.3% and a DoR of 9.6 months [51].

At ASCO 2024, Fang et al. [50] have recently presented the results of the phase II non-randomized OptiTROP-Lung01 study, evaluating the combination of Sac-TMT with KL-A167, an anti–PD-L1 inhibitor, as first-line treatment for advanced NSCLC. A total of 103 patients were included, 40 in cohort 1A (Sac-TMT 5 mg/kg+KL-A167 1,200 mg Q3W) and 63 in cohort 1b (Sac-TMT 5 mg/kg+KL-A167 900 mg every 2 weeks [Q2W]).

Median ORR were 48.6% vs. 77.6%, and median PFS of 15.4 months (95% CI, 6.7 to NR) vs. NR (95% CI, 8.4 to NR) in cohort 1A and 1B, respectively.

In cohort 1B, efficacy was greater according to PD-L1 expression: 63.2% (PD-L1 < 1%) vs. 81.3% (PD-L1 1%-49%) vs. 87% (PD-L1 ≥ 50%). The Q2W dosing regimen was chosen for further investigation.

Most common AEs were anemia, neutropenia and alopecia. Most common immune-related AEs were rash and aspartate aminotransferase/alanine transaminase increase. Grade ≥ 3 AEs were more frequently observed with the Q2W than with the Q3W regimen (54% vs. 42.5%). ILD occurred in one patient in the cohort 1b (grade 2), with no grade ≥ 3 reported.

Three phase 3 studies of sac-TMT in combination with pembrolizumab in NSCLC are ongoing (NCT06170788, NCT06422143, NCT06312137).

Table 3 summarizes data about anti-TROP2 in NSCLC.

3. ADCs against HER3

HER3 is also a member of the Her/ErbB family. Its heterodimerization with other tyrosine-kinase receptors and MET leads to activation of oncogenic pathways. HER3 is universally expressed in primary NSCLC tumors, and has gained attention as an important contributor to EGFR/HER2-targeted therapy resistance [52-56].

1) Patritumab deruxtecan

Patritumab deruxtecan (HER3-DXd) is a HER3-targeted ADC consisting of fully human anti-HER3 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker.

A phase I trial included patients with metastatic EGFR-mutated NSCLC with previous EGFR tyrosine kinase inhibitor (TKI) therapy. Among the 57 patients receiving HER3-DXd 5.6 mg/kg Q3W, the ORR was 39% and median PFS 8.2 months (95% CI, 4.4 to 8.3). Interestingly, responses were observed across various mechanisms of EGFR-TKI resistance (including EGFR C797S, MET or HER2 amplification, and BRAF fusions) across a multiple range of HER3 expression [57]. In a sub-cohort of 47 patients with previously treated advanced NSCLC without EGFR mutations, ORR was 28.6% and median PFS was 10.8 months (95% CI, 2.8 to 16.0) in the group with driver genomic alterations other than EGFR (n=21); among patients without identified driver genomic alterations, HER3-DXd was associated with an ORR of 26.9% [58].

HERTHENA-Lung01 is a phase II study analyzing HER3-DXd in metastatic EGFR-mutant NSCLC previously treated with EGFR-TKI and platinum-based chemotherapy. A total of 225 patients received HER3-DXd 5.6 mg/kg Q3W. The ORR was 29.8%, and median PFS and OS were 5.5 months (95% CI, 5.1 to 5.9) and 11.9 months (95% CI, 11.2 to 13.1), respectively. The subgroup of patients with previous osimertinib and chemotherapy had similar outcomes. Tumor reduction was seen across different mechanisms of EGFR-TKI resistance: ORR of 32.4% in EGFR-dependent and 36.2% in EGFR-independent resistance pathways. In patients with non-irradiated brain metastases at baseline (n=30), the confirmed central nervous system (CNS) ORR was 33.3% (95% CI, 17.3 to 52.8) [59].

HERTHENA-Lung02, a phase III trial in EGFR-mutated NSCLC after progression on a third-generation EGFR-TKI is ongoing (NCT05338970).

Regarding HER3-DXd toxicity, the most common grade ≥ 3 AEs were hematologic toxicities: thrombocytopenia (20.9%) and neutropenia (19.1%). Interstitial lung disease was identified in 12 patients (5.3%): nine grade 1-2, two grade 3, and one grade 5. Median time to onset of ILD was 53 (range, 9 to 230) days. The rate of ILD was lower in patients nonexposed to previous immunotherapy (4% vs. 8%) [59].

Preclinical studies suggest that although EGFR-TKI resistance mechanisms do not lead to alterations in HER3, EGFR inhibition leads to feedback the HER3 membrane expression. Therefore, targeting HER3 might increase the efficacy of EGFR-TKI [60]. In this context, a phase I study of HER3-DXd and osimertinib combination in the first-line setting of EGFR-mutated NSCLC is also ongoing (NCT04676477).

2) BL-B01D1

BL-B01D1 is a first-in-class bispecific ADC against EGFR and HER3-targeted bounded to a novel topoisomerase I inhibitor payload via a cleavable linker.

The phase I study BL-B01D1-101 included patients with progressive NSCLC or other solid tumors. In the dose-escalation phase, Q3W schemas were selected (d1, d8 2.5 mg/kg and d1 4.5 mg/kg) as recommended doses of BL-B01D1.

The updated results from this first-in-human trial were presented at ESMO 2023 by Zhang et al. [61] including preliminary efficacy data in the NSCLC cohort receiving Q3W regimens. A total of 102 NSCLC patients were included, 51% had received three or more prior therapy lines and 31% presented baseline CNS metastasis. Overall efficacy data showed an ORR of 51%, with a median DoR of 8.5 months and a median PFS of 5.6 months (95% CI, 4.1 to 6.8). Differences in efficacy were observed depending on the presence of baseline CNS involvement: ORR 52% vs. 48.1% and PFS of 6.8 months (95% CI, 4.3 to NR) vs. 4.1 months (95% CI, 3.1 to 5.6) in case of treated/no CNS metastasis and untreated CNS metastasis, respectively.

In the EGFR-mutant NSCLC cohort (n=40), overall ORR was 67.5%, DoR was 8.5 months, and PFS 5.6 months (95% CI, 3.9 to 9.7); DoR was 12.3 months and median PFS 15 months (95% CI, 4.3 to NR) in patients without CNS metastasis.

In the safety part, a total of 369 patients with solid tumors and Q3W regimens were analyzed. Most frequent AEs were anemia (64%), neutropenia (59%), thrombocytopenia (55%), nausea (36%), and asthenia (31%), being more common with the 4.5 mg/kg d1 Q3W regimen. Only one grade 2 ILD was observed.

3) SHR-A2009

SHR-A2009 is a novel ADC composed of a fully human anti-HER3IgG1 mAb, covalently linked to a DNA topoisomerase I inhibitor via a cleavable peptide linker (DAR, 4). Its activity is being evaluated in a phase I first-in-human trial (NCT05114759).

At ESMO 2023, Zhou et al. [62] presented results across different solid tumors subtypes, including 36 NSCLC patients with 94% having an EGFR mutation. All were resistant to EGFR-TKI, with 85% previously treated with a third-generation EGFR-TKI. ORR in NSCLC was 30% (95% CI, 14.7 to 49.4) and DoR was 7 months. Most common AEs were anaemia (50%), neutropenia (48%), nausea and vomiting (48%), decreased appetite (38%), and alopecia (36%). More recently, in ESMO 2024, results of the expansion dose of 9 mg/kg in the EGFR-mutant NSCLC cohort have been presented, with a total of 103 patients included. The ORR was 47% and median PFS 9.6 months (95% CI, 5.7 to 12.4). Overall, grade ≥ 3 AEs were reported in 56.3% of cases, 8.7% leading to drug discontinuation and ILD occurring in 8.7% of patients [63].

4. ADC against MET

The c-MET is a tyrosine-kinase receptor kinase is the cell surface receptor for hepatocyte growth factor encoded by the MET proto-oncogene. While in NSCLC c-MET overexpression is more common than MET amplification, occurring in 25% vs. 1%-5%, respectively, ~90% of MET amplification tumors are c-Met overexpressed [64-66].

1) Telisotuzumab vedotin

Telisotuzumab vedotin (Teliso-V, ABBV-399) is an ADC composed of a c-MET-binding antibody conjugated to the microtubule inhibitor cytotoxin monomethyl auristatin E (MMAE) via a cleavable valine-citrulline linker.

In a phase I trial, of 16 patients with c-MET–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, ORR was 18.8% and PFS was 5.7 months (95% CI, 1.2 to 15.4); the recommended phase II dose was established at 2.7 mg/kg Q3W [67].

The LUNGMAP sub-study S1400K included 28 previously treated patients with squamous histology and c-MET–positive tumors. ILD was an unanticipated toxicity (two grade 5 events), and the 9% ORR failed to meet the prespecified response, leading to trial discontinuation [68].

The phase II LUMINOSITY trial aimed to identify the population best suited to receive Teliso-V. Patients with NSCLC progressing to ≤ 2 prior lines of systemic therapy and c-MET overexpression by IHC (Ventana), defined for the non-squamous cohort as ≥ 25% 3+ [high, ≥ 50% 3+; intermediate, 25 to < 50% 3+] and for the squamous cohort as ≥ 75% 1+ by IHC) were included. A total of 136 patients were treated with Teliso-V, dosed at 1.9 mg/kg Q2W. In patients with non-squamous EGFR wild-type tumors a promising 36.5% ORR was achieved, while results in the EGFR-mutant and squamous cohorts met stopping criteria (11.6% and 11.1%, respectively) [69]. Updated date of the first cohort has been presented at ASCO 2024 [70], with a total of 161 evaluable patients. Global ORR was 28.6%, showing a biomarker enrichment in patient with c-MET high overexpressing tumors, with and ORR of 34.6% (vs. 22.9% in intermediate) and DoR of 9 months (vs. 7.2 months). Median PFS and OS were 5.7 (95% CI, 4.6 to 69) and 14.5 months (95% CI, 9.9 to 16.6), respectively, with no differences between high and intermediate c-MET overexpressing groups.

A phase III randomized trial is currently comparing Teliso-V vs. docetaxel in previously treated c-MET overexpressing, EGFR wild-type non-squamous NSCLC (TeliMET NSCLC-01, NCT04928846).

A retrospective analysis of LUMINOSITY, including 10 patients with MET amplification by fluorescence in situ hybridization and c-MET overexpression by central IHC, showed promising efficacy results with an ORR of 80% (95% CI, 44.4 to 97.5), a median DoR of 6.9 months and a median PFS of 8.0 months (95% CI, 1.3 to NR) [71]. These preliminary data support the ongoing phase II trial of Teliso-V in patients with previously untreated MET amplification NSCLC (TeliMET NSCLC-02; NCT05513703), which is currently enrolling.

The most common AEs with Teliso-V include late-onset peripheral sensory neuropathy (25%), nausea (22.1%), and hypoalbuminemia (20.6%) [69]. Corneal epitheliopathy occurred in 18.6% patients in the LUMINOSITY trial, been vision blurred (9.2%, 1.2% grade ≥ 3) followed by keratitis (5.8%, no grade ≥ 3) the most common subtypes. Drug-related ILD was observed in 9.9%, with 5.2% grade ≥ 3 and 1.7 grade 5.

Besides, Teliso-V in combination with osimertinib has also been studied in 38 patients with MET-positive EGFR-mutant advanced NSCLC progressing to osimertinib, showing a tolerable safety profile and an encouraging efficacy, regardless of MET amplification status and number of prior lines, with and ORR of 53%, a DoR of 8 months and a median PFS of 6.8 months (95% CI, 5.3 to 9.2) [72].

2) ABBV-400

ABBV-400 is another anti-MET ADC, and its preliminary efficacy has been tested in a phase I basket trial including 271 refractory solid tumors. Results of the dose expansion NSCLC cohort (n=48) have been recently presented at ESMO 2024 by De Miguel et al. [73], showing an ORR of 47.9% in the entire cohort and 77.8% in the MET high-expressor subgroup (IHC ≥ 50% 3+).

5. ADC against CEACAM5

CEACAM5 is a glycoprotein member of the carcinoembryonic antigen (CEA) gene family and seems to promote cell proliferation and migration [74,75]. High levels of CEACAM5 expression have been observed in several epithelial tumors [76-80]. In lung cancer, Zhang et al. [75] found that CEACAM5 expression was correlated with T category, lymph nodes invasion, and histological grade.

1) Tusamitamab ravtansine

Tusamitamab ravtansine (TUSA, SAR408701) is a CEACAM5 monoclonal antibody linked to the maytansinoid derivative payload (DM4) that inhibits microtubule assembly, via a cleavable disulfide linker.

In a phase I trial, 31 patients with metastatic solid tumors were included in the dose-escalation part, and the MTD of 100 mg/m² Q2W was selected for further investigation [81]. The NSCLC dose-expansion cohort included 92 pre-treated patients who were divided into two categories according to CEACAM5 expression by IHC: 28 moderate (≥ 2+ intensity between ≥ 1% to < 50%) and 64 high expressors (≥ 50% of the tumor cell population). The ORR was greater in the high-expressor cohort (20.3% vs. 7.1%); in the first group, the median DoR was 5.6 months [82]. An exploratory analysis of patients with long-term treatment exposure has revealed that responses to TUSA may be durable and could not be related to CEACAM5 expression [83].

The phase III CARMEN study comparing docetaxel vs. TUSA in previously treated patients with metastatic non-squamous NSCLC and CEACAM5 high expression by IHC (NCT04154956) has been discontinued by the sponsor since did not meet its primary endpoint of improving PFS: 5.4 vs. 5.9 months (HR, 1.14; p=0.8204).

Most frequent AEs were asthenia (38.0%), keratopathy/keratitis (38.0%), neuropathy (26.1%), dyspnea (23.9%), and diarrhea (22.8%); grade ≥ 3 AEs occurred in 15.2% of cases [82].

6. ADC against integrin beta-6

Integrin beta-6 (Iβ6) is highly expressed in NSCLC (> 90% of cases) and other solid tumors, implicated in their pathogenesis and invasiveness [84-86].

1) Sigvotatug vedotin

Sigvotatug vedotin (SV) consists of an anti-Iβ6 humanized antibody linked to a MMAE payload via a protease-cleavable linker.

The phase 1 SGN-B6A-001 trial is evaluating SV monotherapy in refractory NSCLC, with a dose escalation and a dose expansion disease-specific cohort, the last one still ongoing. It includes a total of 117 patients, with a median of prior systemic therapies lines of 3 (1-10), most of them had received a platinum-based regimen and ICIs [87].

In the dose escalation cohort, which also includes other advanced solid tumors, the recommended dose of SV was 1.8 mg/kg Q2W. SV shows a manageable and tolerable safety profile, with most common AEs being fatigue (51.6%), peripheral sensory neuropathy (48.4%), decreased appetite (35.5%), diarrhea (32.3%), dyspnea (32.3%), nausea (29%) and alopecia (29%). Grade ≥ 3 AEs were seen in 87.1% of cases, with no reported grade 5 AEs.

Preliminary antitumoral activity has been presented at ASCO 2024, with an ORR of 19% and a median DoR of 11.3 months in all NSCLC subtypes (n=116) and 31% and 11.6 months, respectively, in non-squamous taxane-naïve NSCLC (n=42). Promising OS and PFS data have been shown, especially in non-squamous taxane-naïve NSCLC (n=42), with a median PFS of 6.4 months (95% CI, 4.5 to 10.5) and median OS of 16.3 months (95% CI, 11.5 to NR), compared to 3.5 months (95% CI, 2.7 to 5.3) and 11.2 months (95% CI, 8.3 to 13.7), respectively, in all NSCLC subtypes [87].

Results from this evolving phase I data warrant further investigation in NSCLC. A phase III trial is currently ongoing, Be6A Lung-01 study, comparing SV and docetaxel in refractory non-squamous NSCLC not previously treated with antimicrotubule agents (NCT06012435).

Table 4 includes a summary of ADCs anti-HER3, anti-MET, anti-CEACAM5, and anti-Iβ6 in NSCLC.

Fig. 1 summarizes all ADCs and their targets in NSCLC.

Fig. 1.

Targets for antibody drug conjugates approved or in development in non–small cell lung cancer (NSCLC). Percentages represent protein expression in lung cancer cells. ^a)Approved in the USA and the EU for the treatment of HER2-mutated NSCLC. CEACAM5, carcinoembryonic antigen–related cell adhesion molecular 5; DM1, emtansine; DM4, ravtansine; DXd, deruxtecan; HER2, human epidermal growth factor 2 receptor; ITGB6, integrin subunit beta 6; MMAE, monomethyl auristatin E; T1 inh, topoisomerase 1 inhibitor; TROP2, trophoblast cell-surface antigen.

ADCs in Small-Cell Lung Cancer

The treatment landscape of ADCs in small-cell lung cancer (SCLC) is also evolving. Molecules such as delta-like protein 3 (DLL3), CD56 and even TROP2 have been evaluated as targets for ADCs development [88].

Rovalpituzumab tesirine (Rova-T), a DLL-3-targeting ADC, failed to improve efficacy outcomes compared with topotecan or as maintenance after first-line therapy in the TAHOE and MERU phase III trials [89,90].

Lorvotuzumab mertansine is an ADC targeting CD56 with a maytansinoid payload. Its combination with first-line platinum-based chemotherapy was evaluated in a phase I/II trial. Safety was a concern, with peripheral neuropathy being reported in 29% of patients and a greater incidence of serious infections with fatal outcomes [91].

SG has also been analyzed in 62 patients with refractory SCLC included in the IMMU-132-01 phase I-II trial, showing an ORR of 17.7%, a median PFS of 3.7 months and a median OS of 7.1 months [48,92]. TROPiCS-03 (NCT03964727) is a phase II basket trial evaluating SG in patents with metastatic or locally advanced solid tumors. The extended-SCLC cohort included 26 patients that progressed after no more than 1 prior line of platinum-based chemotherapy and ICIs, and who received SG 10 mg/kg on days 1 and 8 of a 21-day cycle. In the efficacy analysis (n=14), ORR was 29% (4/14) and DCR 92% (13/14). No AEs leading to discontinuation of study treatment were reported [93].

Ifinatamab deruxtecan (DS-7300a, I-DXd), a B7-H3-targeting ADC with a potent DNA topoisomerase I inhibitor, showed promising results in 19 patients with heavily pretreated SCLC, achieving an ORR of 58%. The most common treatment-emergent adverse events were nausea, anemia, and infusion-related reactions [94]. I-DXd is currently being evaluated in a phase II clinical trial of patients with previously treated SCLC (NCT05280470).

New ADC data in SCLC has also been presented at ASCO 2024 by Shun et al. [95] MHB088C is a novel B7-H3 antibody with a SuperToPoi payload, which is 5-10 times more potent that DXd. A total of 31 patients with included in the efficacy data, with an encouraging ORR of 61.3%. Antitumor activity was specially observed with 1.6 mg/kg Q2W and 2.0 mg/kg Q3W, with a remarkably lower proportion of AEs. Toxicities were mostly hematologic (neutropenia and thrombopenia). No cases of ILD were described.

Fig. 2 summarizes ADCs and their targets in SCLC.

Fig. 2.

Targets for antibody drug conjugates approved or in development in small cell lung cancer. Percentages represent protein expression in lung cancer cells. DLL3, delta-like protein 3; DXd, deruxtecan; MMAE, monomethyl auristatin E; PBD, pyrrolobenzodiazepine; TROP2, trophoblast cell-surface antigen.

Conclusion

Advances in the fields of chemistry, pharmacology, and immunology have led to the development of ADCs that now demonstrate clinically meaningful activity in different subsets of patients with lung cancer.

In HER2-altered advanced NSCLC, ADC-based therapies seem to offer the highest response rates and the best survival outcomes. ADCs directed against additional targets, including TROP2, HER3 and MET have shown promising results, reinforcing the need to make further molecular testing a systematic reflex upon diagnosis of advanced NSCLC.

As we begin to understand the nuances in ADC and tumor interactions, further refine in the design and chemistry of ADCs, development of strategies for patient selection, understanding of mechanisms of resistance and toxicity management are needed. Besides all the advances, a few phase III studies comparing ADCs to docetaxel in NSCLC are reinforcing the need to identify biomarkers predictive of response. Indeed, with the exception of patients with HER2-mutant NSCLC, current response rates preclude ADCs evaluation as first-line monotherapy, suggesting that enrichment of the population and/or a combination of approaches will be necessary.

Notes

Author Contributions

Conceived and designed the analysis: Riudavets M, Planchard D.

Collected the data: Riudavets M, Planchard D.

Contributed data or analysis tools: Riudavets M, Planchard D.

Performed the analysis: Riudavets M, Planchard D.

Wrote the paper: Riudavets M, Planchard D.

Conflict of Interest

DP declared consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; clinical trials research from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; and travel, accommodations, expenses from AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. MR declared no conflicts of interest.

Acknowledgements

To patients and their families. To all researchers that make possible progress in lung cancer therapeutics and prognosis.

References

1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144:1941–53.

2. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, et al. NCCN clinical practice guidelines in oncology (NCCN Guidelines) for non-small cell lung cancer (version 2.2021) National Comprehensive Cancer Network; 2021.

3. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther 2022;7:93.

4. Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazieres J, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 2022;386:241–51.

5. Levy B, Paz-Ares L, Rixe O, Su WC, Yang TY, Tolcher A, et al. MA13.07 TROPION-Lung02: initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. J Thorac Oncol 2022;17(9 Suppl):S91.

6. Tiller KE, Tessier PM. Advances in antibody design. Annu Rev Biomed Eng 2015;17:191–216.

7. Yu J, Song Y, Tian W. How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J Hematol Oncol 2020;13:45.

8. Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol 2021;18:327–44.

9. de Goeij BE, Satijn D, Freitag CM, Wubbolts R, Bleeker WK, Khasanov A, et al. High turnover of tissue factor enables efficient intracellular delivery of antibody-drug conjugates. Mol Cancer Ther 2015;14:1130–40.

10. Jain N, Smith SW, Ghone S, Tomczuk B. Current ADC linker chemistry. Pharm Res 2015;32:3526–40.

11. Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell 2018;9:33–46.

12. Bargh JD, Isidro-Llobet A, Parker JS, Spring DR. Cleavable linkers in antibody-drug conjugates. Chem Soc Rev 2019;48:4361–74.

13. Nolting B. Linker technologies for antibody-drug conjugates. In : Ducry L, ed. Antibody-drug conjugates. Methods in Molecular Biology, Vol. 1045 Humana Press; 2013. p. 71–100.

14. Tang H, Liu Y, Yu Z, Sun M, Lin L, Liu W, et al. The analysis of key factors related to ADCs structural design. Front Pharmacol 2019;10:373.

15. Zhao P, Zhang Y, Li W, Jeanty C, Xiang G, Dong Y. Recent advances of antibody drug conjugates for clinical applications. Acta Pharm Sin B 2020;10:1589–600.

16. Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J Natl Cancer Inst 2019;111:538–49.

17. Nagayama A, Ellisen LW, Chabner B, Bardia A. Antibody-drug conjugates for the treatment of solid tumors: clinical experience and latest developments. Target Oncol 2017;12:719–39.

18. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 2004;10:7063–70.

19. Hedrich WD, Fandy TE, Ashour HM, Wang H, Hassan HE. Antibody-drug conjugates: pharmacokinetic/pharmacodynamic modeling, preclinical characterization, clinical studies, and lessons learned. Clin Pharmacokinet 2018;57:687–703.

20. McCombs JR, Owen SC. Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J 2015;17:339–51.

21. Kamath AV, Iyer S. Preclinical pharmacokinetic considerations for the development of antibody drug conjugates. Pharm Res 2015;32:3470–9.

22. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008;68:9280–90.

23. Hotta K, Aoe K, Kozuki T, Ohashi K, Ninomiya K, Ichihara E, et al. A phase II study of trastuzumab emtansine in HER2-positive non-small cell lung cancer. J Thorac Oncol 2018;13:273–9.

24. Li BT, Shen R, Buonocore D, Olah ZT, Ni A, Ginsberg MS, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol 2018;36:2532–7.

25. Li BT, Makker V, Buonocore DJ, Offin MD, Olah ZT, Panora E, et al. A multi-histology basket trial of ado-trastuzumab emtansine in patients with HER2 amplified cancers. J Clin Oncol 2018;36(15 Suppl):2502.

26. Li BT, Michelini F, Misale S, Cocco E, Baldino L, Cai Y, et al. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov 2020;10:674–87.

27. Peters S, Stahel R, Bubendorf L, Bonomi P, Villegas A, Kowalski DM, et al. Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers. Clin Cancer Res 2019;25:64–72.

28. Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 2006;6:789–802.

29. Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res 2016;22:5097–108.

30. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci 2016;107:1039–46.

31. Tsurutani J, Park H, Doi T, Modi S, Takahashi S, Nakagawa K, et al. OA02.07 Updated results of phase 1 study of DS-8201a in HER2-expressing or –mutated advanced non-small-cell lung cancer. J Thorac Oncol 2018;13(10 Suppl):S324.

32. Tsurutani J, Iwata H, Krop I, Janne PA, Doi T, Takahashi S, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov 2020;10:688–701.

33. Smit EF, Nakagawa K, Nagasaka M, Felip E, Goto Y, Li BT, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol 2020;38(15 Suppl):9504.

34. Nakagawa K, Nagasaka M, Felip E, Pacheco J, Baik C, Goto Y, et al. OA04.05 Trastuzumab deruxtecan in HER2-overexpressing metastatic non–small cell lung cancer: interim results of DESTINY-Lung01. J Thorac Oncol 2021;16(3 Suppl):S109–10.

35. Smit EF, Felip E, Uprety D, Nagasaka M, Nakagawa K, PazAres Rodriguez L, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol 2024;25:439–54.

36. Goto K, Goto Y, Kubo T, Ninomiya K, Kim SW, Planchard D, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol 2023;41:4852–63.

37. Trerotola M, Cantanelli P, Guerra E, Tripaldi R, Aloisi AL, Bonasera V, et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 2013;32:222–33.

38. Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Subat S, et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget 2017;8:28725–35.

39. Zeng P, Chen MB, Zhou LN, Tang M, Liu CY, Lu PH. Impact of TROP2 expression on prognosis in solid tumors: a systematic review and meta-analysis. Sci Rep 2016;6:33658.

40. Spira A, Lisberg A, Sands J, Greenberg J, Phillips P, Guevara F, et al. OA03.03 Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: updated results of TROPION-PanTumor01 phase 1 study. J Thorac Oncol 2021;16(3 Suppl):S106–7.

41. Garon E, Johnson M, Lisberg A, Spira A, Yamamoto N, Heist R, et al. MA03.02 TROPION-PanTumor01: updated results from the NSCLC cohort of the phase 1 study of datopotamab deruxtecan in solid tumors. J Thorac Oncol 2021;16(10 Suppl):S892–3.

42. Shimizu T, Sands J, Yoh K, Spira A, Garon EB, Kitazono S, et al. First-in-human, phase I dose-escalation and dose-expansion study of trophoblast cell-surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan in non-small-cell lung cancer: TROPION-PanTumor01. J Clin Oncol 2023;41:4678–87.

43. Garon EB, Johnson ML, Lisberg AE, Spira A, Yamamoto N, Heist RS, et al. LBA49 Efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs): preliminary results from the phase I TROPION-PanTumor01 study. Ann Oncol 2021;32(Suppl 5):S1326–7.

44. Ahn MJ, Lisberg A, Paz-Ares L, Cornelissen R, Girard N, Pons-Tostivint E, et al. LBA12 Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01. Ann Oncol 2023;34(Suppl 2):S1305–6.

45. Paz-Ares L, Ahn MJ, Lisberg AE, Kitazono S, Cho BC, Blumenschein G, et al. 1314MO TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs). Ann Oncol 2023;34(Suppl 2):S755–6.

46. Goto Y, Su WC, Levy BP, Rixe O, Yang TY, Tolcher AW, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC). J Clin Oncol 2023;41(16 Suppl):9004.

47. Planchard D, Cozic N, Wislez M, Chouaid C, Curcio H, Cousin S, et al. ICARUS-LUNG01: a phase 2 study of datopotomab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small cell lung cancer (NSCLC), with sequential tissue biopsies and biomarkers analysis to predict treatment outcome. J Clin Oncol 2024;42(16 Suppl):8501.

48. Bardia A, Messersmith WA, Kio EA, Berlin JD, Vahdat L, Masters GA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol 2021;32:746–56.

49. Heist RS, Guarino MJ, Masters G, Purcell WT, Starodub AN, Horn L, et al. Therapy of advanced non-small-cell lung cancer with an SN-38-Anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 2017;35:2790–7.

50. Paz-Ares LG, Juan-Vidal O, Mountzios GS, Felip E, Reinmuth N, de Marinis F, et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III EVOKE-01 study. J Clin Oncol 2024;42:2860–72.

51. Fang W, Cheng Y, Chen Z, Wang W, Li Y, Yin Y, et al. Abstract CT247: updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in phase 2 study. Cancer Res 2024;84(7 Suppl):CT247.

52. Scharpenseel H, Hanssen A, Loges S, Mohme M, Bernreuther C, Peine S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep 2019;9:7406.

53. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039–43.

54. Kawakami H, Yonesaka K. HER3 and its ligand, heregulin, as targets for cancer therapy. Recent Pat Anticancer Drug Discov 2016;11:267–74.

55. Li Q, Zhang R, Yan H, Zhao P, Wu L, Wang H, et al. Prognostic significance of HER3 in patients with malignant solid tumors. Oncotarget 2017;8:67140–51.

56. Lyu H, Han A, Polsdofer E, Liu S, Liu B. Understanding the biology of HER3 receptor as a therapeutic target in human cancer. Acta Pharm Sin B 2018;8:503–10.

57. Janne PA, Baik C, Su WC, Johnson ML, Hayashi H, Nishio M, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov 2022;12:74–89.

58. Johnson ML, Steuer CE, Hayashi H, Su WC, Nishio M, Kim DW, et al. PP01.48 Efficacy and safety of patritumab deruxtecan (HER3-DXd) in locally advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. J Thorac Oncol 2023;18(3 Suppl):E30–1.

59. Yu HA, Goto Y, Hayashi H, Felip E, Chih-Hsin Yang J, Reck M, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol 2023;41:5363–75.

60. Haikala HM, Lopez T, Kohler J, Eser PO, Xu M, Zeng Q, et al. EGFR inhibition enhances the cellular uptake and antitumor-activity of the HER3 antibody-drug conjugate HER3-DXd. Cancer Res 2022;82:130–41.

61. Zhang L, Ma Y, Zhao Y, Fang WF, Zhao H, Huang Y, et al. 1316MO BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with non-small cell lung cancer: updated results from first-in-human phase I study. Ann Oncol 2023;34(Suppl 2):S758.

62. Zhou Q, Wu YL, Li J, Liu A, Cui J, Kuboki Y, et al. 658MO Phase I study of SHR-A2009, a HER3-targeted ADC, in advanced solid tumors. Ann Oncol 2023;34(Suppl 2):S463.

63. Zhou Q, Wu YL, Wu L, Zhang Y, Ni S, Liu A, et al. 642P Phase I study of SHR-A2009, a HER3-targeted ADC, in pretreated EGFR-mutated NSCLC. Ann Oncol 2024;35(Suppl 2):S509.

64. Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol 2016;34:721–30.

65. Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 2008;47:1025–37.

66. Schildhaus HU, Schultheis AM, Ruschoff J, Binot E, Merkelbach-Bruse S, Fassunke J, et al. MET amplification status in therapy-naive adeno- and squamous cell carcinomas of the lung. Clin Cancer Res 2015;21:907–15.

67. Strickler JH, Weekes CD, Nemunaitis J, Ramanathan RK, Heist RS, Morgensztern D, et al. First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, in patients with advanced solid tumors. J Clin Oncol 2018;36:3298–306.

68. Waqar SN, Redman MW, Arnold SM, Hirsch FR, Mack PC, Schwartz LH, et al. A phase II study of telisotuzumab vedotin in patients with c-MET-positive stage IV or recurrent squamous cell lung cancer (LUNG-MAP Sub-study S1400K, NCT03574753). Clin Lung Cancer 2021;22:170–7.

69. Camidge DR, Bar J, Horinouchi H, Goldman JW, Moiseenko FV, Filippova E, et al. Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2022;40(16 Suppl):9016.

70. Camidge DR, Bar J, Horinouchi H, Goldman JW, Moiseenko FV, Filippova E, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: primary analysis of the LUMINOSITY trial. J Clin Oncol 2024;42(16 Suppl):103.

71. Camidge DR, Goldman J, Vasilopoulos A, Ansell P, Xia S, Bolotin E, et al. Abstract CT214: Preliminary efficacy of telisotuzumab vedotin (Teliso-V) treatment in the 2L/3L setting in MET gene amplified (MET Amp), c-Met protein overexpressing (c-Met OE), non-squamous, non-small cell lung cancer (NSQ NSCLC): retrospective analysis of LUMINOSITY. Cancer Res 2023;83(8 Suppl):CT214.

72. Horinouchi H, Cho BC, Camidge DR, Goto K, Tomasini P, Li Y, et al. 515MO Phase Ib study of telisotuzumab vedotin (Teliso-V) and osimertinib in patients (Pts) with advanced EGFR-mutated (Mut), c-Met overexpressing (OE) non-small cell lung cancer (NSCLC): final efficacy and safety updates. Ann Oncol 2023;34(Suppl 4):S1670.

73. De Miguel M, Yamamoto N, Raimbourg J, Cho BC, Gottfried M, Stemmer SM, et al. 1257MO ABBV-400, a c-Met protein-targeting antibody-drug conjugate (ADC), in patients (Pts) with advanced EGFR wildtype (WT) non-squamous (NSQ) non-small cell lung cancer (NSCLC): results from a phase I study. Ann Oncol 2024;35(Suppl 2):S805–6.

74. Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 2013;32:643–71.

75. Zhang X, Han X, Zuo P, Zhang X, Xu H. CEACAM5 stimulates the progression of non-small-cell lung cancer by promoting cell proliferation and migration. J Int Med Res 2020;48:300060520959478.

76. Minton JP, Hoehn JL, Gerber DM, Horsley JS, Connolly DP, Salwan F, et al. Results of a 400-patient carcinoembryonic antigen second-look colorectal cancer study. Cancer 1985;55:1284–90.

77. Thompson JA, Grunert F, Zimmermann W. Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J Clin Lab Anal 1991;5:344–66.

78. Zhou J, Fan X, Chen N, Zhou F, Dong J, Nie Y, et al. Identification of CEACAM5 as a biomarker for prewarning and prognosis in gastric cancer. J Histochem Cytochem 2015;63:922–30.

79. Powell E, Shao J, Picon HM, Bristow C, Ge Z, Peoples M, et al. A functional genomic screen in vivo identifies CEACAM5 as a clinically relevant driver of breast cancer metastasis. NPJ Breast Cancer 2018;4:9.

80. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 1999;9:67–81.

81. Gazzah A, Bedard PL, Hierro C, Kang YK, Abdul Razak A, Ryu MH, et al. Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study. Ann Oncol 2022;33:416–25.

82. Gazzah A, Cousin S, Boni V, Ricordel C, Kim TM, Kim JS, et al. First-in-human phase 1 study of the antibody-drug conjugate (ADC) SAR408701 in advanced solid tumors: dose-expansion cohort of patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC). J Clin Oncol 2019;37(15 Suppl):9072.

83. Ricordel C, Barlesi F, Cousin S, Cho BC, Calvo E, Kim TM, et al. Safety and efficacy of tusamitamab ravtansine (SAR408701) in long-term treated patients with nonsquamous non–small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). J Clin Oncol 2022;40(16 Suppl):9039.

84. Li F, Shang Y, Shi F, Zhang L, Yan J, Sun Q, et al. Expression of integrin beta6 and HAX-1 correlates with aggressive features and poor prognosis in esophageal squamous cell carcinoma. Cancer Manag Res 2020;12:9599–608.

85. Elayadi AN, Samli KN, Prudkin L, Liu YH, Bian A, Xie XJ, et al. A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for non-small cell lung cancer. Cancer Res 2007;67:5889–95.

86. Lyon RP, Jonas M, Frantz C, Trueblood ES, Yumul R, Westendorf L, et al. SGN-B6A: a new vedotin antibody-drug conjugate directed to integrin beta-6 for multiple carcinoma indications. Mol Cancer Ther 2023;22:1444–53.

87. Peters S, Hollebecque A, Sehgal K, Lopez JS, Calvo E, Dowlati A, et al. Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: updated phase 1 results (SGNB6A-001). J Clin Oncol 2024;42(16 Suppl):8521.

88. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 2015;7:302ra136.

89. Blackhall F, Jao K, Greillier L, Cho BC, Penkov K, Reguart N, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: results from the phase 3 TAHOE study. J Thorac Oncol 2021;16:1547–58.

90. Johnson ML, Zvirbule Z, Laktionov K, Helland A, Cho BC, Gutierrez V, et al. Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: results from the phase 3 MERU study. J Thorac Oncol 2021;16:1570–81.

91. Socinski MA, Kaye FJ, Spigel DR, Kudrik FJ, Ponce S, Ellis PM, et al. Phase 1/2 study of the CD56-targeting antibody-drug conjugate lorvotuzumab mertansine (IMGN901) in combination with carboplatin/etoposide in small-cell lung cancer patients with extensive-stage disease. Clin Lung Cancer 2017;18:68–76.

92. Gray JE, Heist RS, Starodub AN, Camidge DR, Kio EA, Masters GA, et al. Therapy of small cell lung cancer (SCLC) with a topoisomerase-I-inhibiting antibody-drug conjugate (ADC) targeting Trop-2, sacituzumab govitecan. Clin Cancer Res 2017;23:5711–9.

93. Dowlati A, Cervantes A, Babu S, Hamilton EP, Wong SF, Tazbirkova A, et al. 1990MO Sacituzumab govitecan (SG) as second-line (2L) treatment for extensive stage small cell lung cancer (ES-SCLC): preliminary results from the phase II TROPiCS-03 basket trial. Ann Oncol 2023;34(Suppl 2):S1061–2.

94. Doi T, Patel M, Falchook GS, Koyama T, Friedman CF, PihaPaul S, et al. 453O DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: extended follow-up of a phase I/II study. Ann Oncol 2022;33(Suppl 7):S744–5.

95. Shen L, Zhou C, Meng X, Sun Y, Ji Y, Yang H, et al. Results of a phase 1/2 study of MHB088C: a novel B7H3 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in recurrent or metastatic solid tumors. J Clin Oncol 2024;42(16 Suppl):3012.

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Agent/Study	Sample size (n)	Population	HER2 alteration type	Efficacy data				Safety and treatment modification			Reference
Agent/Study	Sample size (n)	Population	HER2 alteration type	ORR n (%)	DCR n (%)	Median PFS (95% CI, mo)	Median OS (95% CI, mo)	All grade AEs (%)	Grade 3-5 (%)	Dose reduction/Discontinuation	Reference
Trastuzumab-emtansine
PhII Single arm	7/15	Median number of prior lines 4 (1-7)	HER2 mutation (5A775_G776ins YVMA)	1/7 (4.3)	5/7 (71.4)	2.0 (1.2-4)	10.9 (4.4-12)	Interstitial pneumonia (7%)	Thrombocytopenia (40%), hepatotoxicity (20%), acute renal failure (7%)	-	Hotta et al. [23]
	8/15		HER2 amplification/overexpression (IHC3+ or IHC2 confirmed by FISH)	0/8 (0)	3/8 (37.5)
PhII Single arm	49	98% ≥ 1 Prior ChT line	HER2 overexpression (IHC2-3+)	IHC2+: 0/29 (0)	IHC2+: 8/29 (28)	IHC2+: 2.6 (1.4-2.8)	IHC2+: 12.2 (3.8-23.3)	Infusion reaction (14%), peripheral neuropathy (14%), hemorrhage (14%)	Infusion reaction (2%), thrombocytopenia (2%)	4% Discontinuation	Peters et al. [27]
PhII Single arm	49	98% ≥ 1 Prior ChT line	HER2 overexpression (IHC2-3+)	IHC3+: 4/20 (20)	HC3+: 8/20 (40)	HC3+: 2.7 (1.4-8.3)	IHC3+: 15.3 (4.1-NR)		Infusion reaction (2%), thrombocytopenia (2%)	4% Discontinuation	Peters et al. [27]
PhII Basket trial^a) (NCT02675829)	28/49	Median line of therapy for T-DM1 2 (1-7)	HER2 mutation (subtypes not specified)	14/28 (50)	-	5 (3.5-5.9)	-	Hepatotoxicity (63%), thrombocytopenia (31), nausea (29%), fatigue (16%)	Thrombocytopenia (2%), anemia (2%)	None	Li et al. [24,26]
	11/49		HER2 amplification (NGS, FISH)	6/11	-
Trastuzumab-deruxtecan
Ph I (NCT02564900)	11/60^b)	Median number of prior lines 4 (1-10)	HER2 mutations (44.4% exon 20 insertions)	8/11 (72.7)	10/11 (90.9)	11.3 (8.1-14.3)	17.3 (17.3-NR)	Nausea (74.6%), vomiting (52.6%), anemia (39%), thrombocytopenia (37.4%)	Anemia (25.4%), neutropenia (20.3%), thrombocytopenia (15.3%), pneumonitis (1.7%)	23.7% Dose reduction	Tsurutani et al. [32]
Ph I (NCT02564900)	11/60^b)	Median number of prior lines 4 (1-10)	HER2 mutations (44.4% exon 20 insertions)	8/11 (72.7)	10/11 (90.9)	11.3 (8.1-14.3)	17.3 (17.3-NR)			8.5% Discontinuation	Tsurutani et al. [32]
PhII Two-cohort and two-arm^c) DESTINY-Lung01	91	Median number of prior lines 2 (1-7)	HER2 mutations (85 mutations in the kinase; subtype not specified)	50/91 (55)	84/91 (92)	8.2 (6.0-11.9)	17.8 (13.8-22.1)	ILD (26%)	Neutropenia (19%), anemia (10%) 2.2% ILD (2 grade 5)	34% Dose reduction	Li et al. [4], Smit et al. [35]
PhII Two-cohort and two-arm^c) DESTINY-Lung01	91	Median number of prior lines 2 (1-7)		50/91 (55)	84/91 (92)	8.2 (6.0-11.9)	17.8 (13.8-22.1)	ILD (26%)	Neutropenia (19%), anemia (10%) 2.2% ILD (2 grade 5)	25% Discontinuation	Li et al. [4], Smit et al. [35]
	49	Median number of prior lines 3 (2-4)	HER2 overexpression (IHC2-3+)	13/49 (26.5)	34/49 (69.4)	5.7 (2.8-7.2)	12.4 (7.8-17.2)	ILD (10%)	Neutropenia (24%), pneumonia (12%), fatigue (12%) 6% ILD (3 grade 5)	35% Dose reduction
	49	Median number of prior lines 3 (2-4)	HER2 overexpression (IHC2-3+)	13/49 (26.5)	34/49 (69.4)	5.7 (2.8-7.2)	12.4 (7.8-17.2)	ILD (10%)		16% Discontinuation
PhII DESTINY-Lung02	102 (5.4 mg/kg)	Median number of prior lines 2 (1-12)	HER2 mutations	50/102 (49)	95/102 (93.1)	9.9 (7.4-NR)	19.5 (13.6-NR)	ILD (12.9%)	Neutropenia (18.8%), anemia (10.9%)	16.8% Dose reduction	Goto et al. [36]
PhII DESTINY-Lung02	102 (5.4 mg/kg)	Median number of prior lines 2 (1-12)	HER2 mutations	50/102 (49)	95/102 (93.1)	9.9 (7.4-NR)	19.5 (13.6-NR)	ILD (12.9%)	Neutropenia (18.8%), anemia (10.9%)	13.9% Discontinuation	Goto et al. [36]
	50 (6.4 mg/kg)	Median number of prior lines 2 (1-7)	HER2 mutations	28/50 (28)	46/50 (92)	15.4 (8.3-NR)	NR (12.1-NR)	ILD (28%)	Neutropenia (36%), anemia (16%), leucopenia (16%), trombocitopenia (10%)	32% Dose reduction
	50 (6.4 mg/kg)	Median number of prior lines 2 (1-7)	HER2 mutations	28/50 (28)	46/50 (92)	15.4 (8.3-NR)	NR (12.1-NR)	ILD (28%)		20% Discontinuation

Agent/Study	Sample size (n)	Population	Efficacy data				Safety and treatment modification			Reference
Agent/Study	Sample size (n)	Population	ORR n (%)	DCR n (%)	Median PFS (95% CI, mo)	Median OS (95% CI, mo)	All grade Aes	Grade 3-5	Dose reduction/Discontinuation	Reference
Datopotamab deruxtecan
PhI dose-expansion (TROPION-PanTumor01)	180^a)	54%-64% ≥ 3 prior lines	13/50 (26)	35/50 (70)	6.9 (2.7-8.8)	11.4 (7.1-20.6)	Nausea (64%), stomatitis (60%), alopecia (42%)	Pneumonia (16.8%), anemia (13%), lymphopenia (11.8%)	-	Shimizu et al. [42]
PhI dose-expansion (TROPION-PanTumor01)	180^a)	54%-64% ≥ 3 prior lines	13/50 (26)	35/50 (70)	6.9 (2.7-8.8)	11.4 (7.1-20.6)	ILD 29.8%	ILD 3%	-	Shimizu et al. [42]
PhIII (TROPION-Lung01)	299/604	43.1% ≥ 2 lines	26.4	-	4.4 (4.2-5.6)	-	Stomatitis (49.2%), nausea (37%)	Neutropenia (8%), amylase increased (8%)	19.5% Dose reduction	Ahn et al. [44]
PhIII (TROPION-Lung01)	299/604	43.1% ≥ 2 lines	26.4	-	4.4 (4.2-5.6)	-	Stomatitis (49.2%), nausea (37%)	ILD 3.4%	7.7% Discontinuation	Ahn et al. [44]
Sacituzumab govitecan
Ph I/II basket trial (IMMU-132-01)	54/495^b)	92% ≥ 2 prior lines	9/54 (16.7)	31/54 (57.4)	4.4 (2.5-5.4)	7.3 (5.6-14.3)	Nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), neutropenia (57.8%)	Neutropenia (42.4%), febrile neutropenia (5.3%)	32.3% Dose reduction	Bardia et al. [48]
Ph I/II basket trial (IMMU-132-01)	54/495^b)	92% ≥ 2 prior lines	9/54 (16.7)	31/54 (57.4)	4.4 (2.5-5.4)	7.3 (5.6-14.3)		Neutropenia (42.4%), febrile neutropenia (5.3%)	8.3% Discontinuation	Heist et al. [49]
PhIII (EVOKE-01)	299/603	44.1% ≥ 2 prior lines	41/299 (13.7)	202/299 (67.6)	4.1 (3-4.4)	11.1 (9.4-12.3)	Fatigue (56.8%), diarrhea (52.7%), alopecia (43.2%), nausea (41.6%), anemia (40.2), neutropenia (37.5%)	Neutropenia (24.7%), fatigue (12.5%), diarrhea (10.5%)	29.4% Dose reduction	Paz-Ares et al. [50]
PhIII (EVOKE-01)	299/603	44.1% ≥ 2 prior lines	41/299 (13.7)	202/299 (67.6)	4.1 (3-4.4)	11.1 (9.4-12.3)		Neutropenia (24.7%), fatigue (12.5%), diarrhea (10.5%)	9.8% Discontinuation	Paz-Ares et al. [50]
Sacituzumab tirumotecan
Ph II (OptiTROP-Lung01)	63/103^c)	1st line	45/58 (77.6)	58/58 (100)	NR (8.4-NR)	-	Anemia, neutropenia, alopecia	54%	31.7% Dose reduction	Fang et al. [51]
Ph II (OptiTROP-Lung01)	63/103^c)	1st line	45/58 (77.6)	58/58 (100)	NR (8.4-NR)	-	Anemia, neutropenia, alopecia	No ILD	3.2% Discontinuation	Fang et al. [51]

Agent/Study	Sample size (n)	Population	Safety and treatment modification						Reference
Agent/Study	Sample size (n)	Population	ORR n (%)	Median PFS (95% CI, mo)	Median OS (95% CI, mo)	All grade Aes	Grade 3-5	Dose reduction/Discontinuation	Reference
HER3 Patritumab deruxtecan
PhI dose-expansion (NCT03260491)	57/81^a)	Median prior lines 4 (1-9)	22/57 (39)	8.2 (4.4-8.3)	NR (9.4-NR)	Fatigue (64%), nausea (60%)	Thrombocytopenia (26%), neutropenia (15%), fatigue (10%)	Dose reduction 22%	Janne et al. [57]
PhI dose-expansion (NCT03260491)	57/81^a)	Median prior lines 4 (1-9)	22/57 (39)	8.2 (4.4-8.3)	NR (9.4-NR)	ILD 5%	ILD 1.2%	Discontinuation 9%	Janne et al. [57]
PhIII (HERTHENA-Lung01)	225	Median prior (1-11)	66/225 (29.8)	5.5 (5.1-5.9)	11.9 (11.2-13.1)	Nausea (66%), thrombocytopenia (44%), anorexia (42%), neutropenia 36%), constipation (34%), anemia (33%), fatigue (31%)	Thrombocytopenia (20.9%), neutropenia (19.1%)	Dose reduction 21.3%	Yu et al. [59]
PhIII (HERTHENA-Lung01)	225	Median prior (1-11)	66/225 (29.8)	5.5 (5.1-5.9)	11.9 (11.2-13.1)	ILD 5.3%	ILD 1.3%	Discontinuation 7.1%	Yu et al. [59]
MET Telisio-V
Ph I/II dose-escalation/expansion (NCT02099058)	16	-	18.8	5.7 (1.2-15.4)	-	Fatigue (42%), nausea (27%), constipation (27%), anorexia (23%), dyspnea (21%), diarrhea (19%), edema (19%), neuropathy (17%)	Fatigue (4%), anemia (4%), neutropenia (4%), hypoalbuminemia (4%)	-	Strickler et al. [67]
PhII Single arm (LUMINOSITY)	161^b)	≤ 2 prior lines (≤ 1 line of ChT)	34.6 vs. 22.9%	5.7 (4.6-69)	14.5 (9.9-16.6)	Neuropathy (40%), nausea (22.1%), hypo-albuminemia (20.6%), corneal epitheliopathy (18.6%)	Neuropathy (9.3%)	-	Camidge et al. [69,70]
PhII Single arm (LUMINOSITY)	161^b)	≤ 2 prior lines (≤ 1 line of ChT)	34.6 vs. 22.9%	5.7 (4.6-69)	14.5 (9.9-16.6)		ILD 5.2%	-	Camidge et al. [69,70]
CEACAM-5 Tusamitamab ravtansine
PhI dose-expansion (NCT02187848)	92^c)	Median prior lines 3 (1-10)	20.3 vs. 7.1%	-	-	Asthenia (38%), keratopathy (38%), neuropathy (26.1%), dyspnea (23.9%), diarrhea (22.8%)	Neutropenia (42.4%), febrile neutropenia (5.3%)	-	Gazzah et al. [82]
INTEGRIN β-6 Sigvotatug vedotin
PhI dose-escalation/expansion (NCT04389632)	117^d)	Median prior lines 3 (1-10)	31%	6.4 (4.5-10.5)	16.3 (11.5-NR)	Fatigue (51.6%), neuropathy (48.4%), anorexia (35.5%), diarrhea (32.3%), dyspnea (32.3%), nausea (29%), alopecia (29%)	Fatigue (6.5%), neutropenia (6.5%), pneumonia (6.5%)	-	Peters et al. [87]

Agent	Anti-HER2		Anti-TROP2			Others
Agent	Trastuzumab emtansine (T-DM1)	Trastuzumab deruxtecan (T-DXd)	Datopotamab deruxtecan (Dato-DXd)	Sacituzumab govitecan (SG)	Sacituzumab tirumotecan (Sac-TMT)	Patritumab deruxtecan (HER3-DXd)	Telisotuzumab vedotin (Teliso-V)	Sigvotatug vedotin (SV)
Linker	Non-cleavable	Cleavable	Cleavable	Cleavable	Cleavable	Cleavable	Cleavable	Cleavable
Payload	Microtubule inhibitor (emtansine)	Topoisomerase I inhibitor (MAAA-1181)	Topoisomerase I inhibitor (deruxtecan derivative)	Topoisomerase I inhibitor (SN-38)	Topoisomerase I inhibitor (belotecan derivative)	Topoisomerase I inhibitor	Microtubule inhibitor (MMAE)	Microtubule inhibitor (MMAE)
DAR	3.5	7.7	4	7.6	7.4	8	3.1	-
Dose/Schema	3.6 mg/kg Q3W	6.4 mg/kg Q3W	6 mg/kg Q3W	10 mg/kg d1, d8 Q3W	5 mg/kg Q2W	5.6 mg/kg Q3W	1.9 mg/kg Q2W	1.8 mg/kg Q2W