Abstract: Over the past decade, the lung cancer landscape has been dominated by targeted and immunotherapeutic approaches that have drastically shifted treatment paradigms for patients with advanced non–small cell lung cancer (NSCLC). Despite these scientific and clinical advances, there are still many unmet needs underscoring the importance of novel strategies. Antibody-drug conjugates (ADCs) represent one such strategy that is beginning to alter the therapeutic strategies for patients with advanced NSCLC. The rationale of ADCs is simple: selectively deliver cytotoxic payloads through an antibody-mediated process to target antigens expressed by cancer cells, sparing normal tissue and inflicting damage to tumors. Although this concept has been the leading view, preclinical and clinical observations are demonstrating that only a nascent mechanistic understanding of these agents exists. In this review, we discuss the underlying biology of ADCs and their structure and potential mechanisms of action, examine approved and promising ADC targets in lung cancer, and review emerging ADC targets and combinatorial strategies. Importantly, we address the unanswered questions surrounding ADCs in lung cancer, including biomarker selection, treatment sequencing, and mechanisms of resistance, as well as management of unique ADC-associated toxicities.
Introduction
Over the past decade, the lung cancer treatment landscape has been dominated by targeted and immunotherapeutic approaches that have drastically shifted treatment paradigms for patients with advanced non–small cell lung cancer (NSCLC). These advances have been predicated on a firmer understanding of the tumor microenvironment and deep sequencing efforts that have unearthed targetable genomic alterations. Despite these scientific and clinical advances, there are still many unmet needs, underscoring the importance of novel strategies. Antibody-drug conjugates (ADCs) represent one such strategy that is beginning to alter the therapeutic strategies for patients with advanced NSCLC.
The historical roots of ADCs trace back to the early 20th century when scientist Dr Paul Ehrlich, a founder of chemotherapy, conceived of a more targeted delivery of anticancer therapy, termed “the magic bullet.”1 Although early ADCs were limited by pharmacokinetic and pharmacodynamic properties such as poor tumor penetration2 and insufficient potency of the cytotoxic component,3 advancements in synthetic biochemistry have culminated in contemporary ADCs that deliver a more selective cytotoxic payload to the tumor. The rationale of ADCs is simple: selectively deliver cytotoxic payloads through an antibody-mediated process to target antigens expressed by cancer cells, sparing normal tissue and inflicting damage to tumors. Although this proposed concept has been the leading view, preclinical and clinical observations are demonstrating that we have only a nascent understanding of the mechanistic actions of these agents. In this review, we discuss the underlying biology of ADCs. We review their structure and potential mechanisms of action, examine approved and promising ADC targets in lung cancer, and review emerging ADC targets and combinatorial strategies. Importantly, we attempt to address the unanswered questions surrounding ADCs in lung cancer, including biomarker selection, treatment sequencing and mechanisms of resistance, and the management of unique ADC-associated toxicities.
Basic Structure and Mechanism of Action
Antibody
An ideal ADC antibody must exhibit a strong binding affinity for its target while maintaining conformational and colloidal stability in circulation, with low cross-reactivity and immunogenicity. The antibody is made up of 2 key components: (1) the antigen-binding fragment, which recognizes and binds the target antigen; and (2) the constant fragment (Fc), which engages immune effector cells and influences serum half-life. The main class of antibody that optimizes these attributes is the humanized immunoglobulin G (IgG) class, of which the IgG1 subtype is the most commonly deployed.4-6
There are many candidate antigens for ADC engagement. Ideally, the antigen should be selectively overexpressed on tumors but not normal tissue to limit on- and off-target toxicity. Additionally, the antigen should be consistently accessible to circulating antibodies, reinforcing the importance of high antigen density on the cell surface. Finally, the antigen must exhibit high internalization capacity to facilitate transmembrane trafficking of the ADC construct, enhancing intracellular cytotoxicity.
Linker
The linker is the biochemical compound that connects the antibody to the cytotoxic payload and serves 2 vital roles: (1) maintaining ADC stability in circulation and intact delivery to target tissues; and (2) ensuring appropriate payload uncoupling upon tumor uptake.
Linkers can be divided into 2 categories: noncleavable and cleavable. Noncleavable linkers form nonreducible bonds between amino acid residues with the antibody and payload, which leads to enhanced stability in the bloodstream and limited potential for off-target toxicity.7 However, ADCs that incorporate noncleavable linkers require trafficking to mature lysosomes for payload uncoupling,8 resulting in enhanced cellular payload retention, poor payload diffusion across cell membranes, and limiting potential cytotoxic effects on neighboring cells lacking target expression.9,10
Conversely, cleavable linkers rely on various components of cell physiology, including pH and the presence of glutathione and proteases, to promote payload uncoupling.6 Because of this, ADCs with cleavable linkers are generally not reliant on trafficking to mature lysosomes. In addition, payload permeability across cell membranes is typically greater with ADCs that contain cleavable linkers.11 This results in a greater “bystander effect,” which can be particularly important in tumors with heterogeneous target expression and in dense tumors that require significant drug diffusion.
Payload and Drug-to-Antibody Ratio
The payload or “warhead” is the cytotoxic effector of an ADC. A prototypical payload is a cytotoxic compound with effective toxicity at sub-nanomolar and picomolar concentrations. An ideal payload is stable in circulation and does not interfere with ADC target binding and internalization. Modern payloads typically consist of DNA damaging agents, tubulin polymerization inhibitors, or topoisomerase inhibitors. Beyond their direct antitumor effects, the unique physiochemical properties of a specific payload likely affect bystander properties via effects on drug distribution, diffusion, and tumor efflux.12
A related attribute of the payload is the number of payload moieties attached to a given antibody, a term referred to as the drug-to-antibody ratio (DAR). The majority of US Food and Drug Administration (FDA)-approved and emerging ADCs in lung cancer have DARs ranging from 2 to 8.13 Site-specific conjugation techniques have led to improved DAR consistency for modern ADCs. Interestingly, although in vitro data suggest that higher DAR should equate to greater potency, preclinical studies indicate that increased payload loading may result in more rapid hepatic clearance, exacerbating toxicity and narrowing the therapeutic index.14
Mechanism of Action
Although the cytotoxic effect of the payload is believed to be the primary mediator of tumor killing, an effective ADC must engage its target antigen through proper antibody-antigen binding, resulting in prompt internalization, linker degradation, and payload release. Beyond ADC internalization, properties of the payload and linker are important in mediating cytotoxic effects on neighboring cells (ie, the bystander effect). The permeability of a given payload and linker cleavability play critical roles in this process. Finally, although direct cytotoxicity is believed to be the primary mechanism of action for ADCs, antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis, and complement-mediated cytotoxicity likely play roles as well.6 For example, the human epidermal growth factor receptor 2 (HER2)-targeting ADC trastuzumab deruxtecan, also known as T-DXd (Enhertu, Daiichi-Sankyo/AstraZeneca), has been shown to induce antibody-dependent cellular cytotoxicity in preclinical models through engagement of the Fc region of trastuzumab with immune effector cells.15
Emerging ADC Targets and Therapeutics in Lung Cancer
HER2
Gene mutations in the erb-b2 (ERBB2) receptor tyrosine kinase (RTK) gene, typically occurring as in-frame insertions in exon 20, may be present in 1% to 4% of patients with NSCLC.16 Additionally, HER2 gene amplification and protein overexpression have been described in approximately 5% and 10% to 30% of NSCLC cases, respectively,17-19 although the therapeutic implications of these alterations remain unclear.20
Trastuzumab Emtansine. Trastuzumab emtansine, also known as T-DM1 (Kadcyla, Genentech), was the first ADC targeting the HER2 receptor. It incorporates the HER2-directed antibody trastuzumab and the microtubule-disrupting agent DM-1 via a noncleavable linker. The average DAR is 3.5.21 Li and colleagues first presented results from a basket trial of 18 patients with HER2-mutated NSCLC treated with T-DM1, reporting an overall response rate (ORR) of 44%, with a median progression-free survival (PFS) of 5 months.22 A more recent phase 2 trial enrolled 22 patients with pretreated NSCLC harboring HER2 exon 20 insertion mutations and reported an ORR of 38.1%. The median duration of response (DOR), PFS, and overall survival (OS) were 3.5, 2.8, and 8.1 months, respectively.23 T-DM1 was well-tolerated overall, with the most frequent grade 3/4 adverse events (AEs) being thrombocytopenia (18.2%), appetite loss (4.5%), cardiac dysfunction (4.5%), anemia (4.5%), and hypertension (4.5%).
Trastuzumab Deruxtecan. T-DXd is a novel ADC that utilizes the anti-HER2 monoclonal antibody trastuzumab and a cytotoxic payload of the topoisomerase inhibitor deruxtecan (DXd), conjugated via a tetrapeptide-based cleavable linker.15 T-DXd has a DAR of 8, with engineered properties to improve stability within the systemic circulation and exert increased bystander effect via a membrane-permeable payload, resulting in enhanced cytotoxic effect in preclinical studies compared with T-DM1.24,25
An initial first-in-human, dose-expansion study explored the safety and efficacy of T-DXd in HER2-overexpressing or HER2-mutated non-breast, non-gastric solid malignancies. Encouraging efficacy signals were noted, with an ORR of 55.6%, median PFS of 11.3 months, and median DOR of 10.7 months.26 Despite overall tolerability at the 6.4 mg/kg dose, there were notably 2 treatment-related fatalities secondary to respiratory failure.
The subsequent global phase 2 DESTINY-Lung01 trial evaluated the efficacy of T-DXd at 6.4 mg/kg every 3 weeks in 2 distinct cohorts: HER2-overexpressing (defined by immunohistochemistry [IHC] of 2+ or 3+, cohort 1) and HER2-mutated tumors (cohort 2). Updated efficacy analysis from 91 patients treated in cohort 2, published by Li and colleagues, noted an ORR of 55%, disease control rate (DCR) of 92%, median PFS of 8.2 months, and OS of 17.8 months. The safety profile was consistent with prior studies of T-DXd, with a grade 3 or higher treatment-related adverse event (TRAE) rate of 46%. The authors did report a 26% incidence of drug-related interstitial lung disease (ILD), including fatal events in 2 patients.27
Following these findings, the phase 2 randomized DESTINY-Lung02 trial was designed to assess the benefit-risk profile of T-DXd at doses of 5.4 or 6.4 mg/kg. Patients with previously-treated HER2-mutated NSCLC were randomized in a 2:1 ratio to T-DXd at 5.4 mg/kg or 6.4 mg/kg every 3 weeks. Primary results from this trial, which enrolled a total of 152 patients, noted comparable ORRs of 49% and 56%, respectively. Responses were observed regardless of HER2 mutation type, amplification status, and the presence of intracranial disease. With a median duration of follow-up of 11.5 months, the median PFS was 9.9 months in the 5.4-mg/kg group and 15.4 months in the 6.4-mg/kg group, numerically favoring the higher dosing at this early efficacy analysis. Safety trends seemed to favor the 5.4 mg/kg dosing schedule, with a lower incidence of grade 3 or higher TEAEs (38.6% vs 58%) compared with the 6.4-mg/kg dose. This included lower rates of adjudicated drug-related ILD (12.9% vs 28%), with the majority being grade 1 to 2. The most common grade 3 or higher TEAEs included cytopenias, fatigue, and nausea.28 Safety results were consistent with an earlier interim analysis, which ultimately led to the FDA-accelerated approval of T-DXd at 5.4 mg/kg every 3 weeks. Importantly, T-DXd also appears to have encouraging central nervous system efficacy. Among 14 patients with measurable brain metastases treated with T-DXd at 5.4 mg/kg in the DESTINY-Lung02 trial, an intracranial ORR of 50% was seen, with intracranial DOR of 9.5 months. A similar benefit was also observed among patients treated at 6.4 mg/kg.29 Ongoing studies are now exploring the efficacy of T-DXd in the frontline setting for patients with HER2-mutated disease (Table).30,31
HER3
HER3, encoded by the ERBB3 gene, is another member of the HER/ErbB RTK family. HER3 is a partner in HER2/HER3 heterodimerization, leading to downstream intracellular activation of PI3K/AKT signaling pathways.32 HER3 overexpression and activation have been implicated in mediating resistance to endothelial growth factor receptor (EGFR)-targeted therapies.33
Patritumab Deruxtecan. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted ADC consisting of patritumab, a fully humanized anti-HER3 monoclonal antibody, conjugated to the cytotoxic payload DXd via a tetrapeptide-based cleavable linker. The DAR of HER3-DXd is 8.34 An initial phase 1 trial tested the safety and efficacy of HER3-DXd in patients with EGFR-mutated NSCLC that had progressed on an EGFR-directed tyrosine kinase inhibitor (TKI). Results from the 57-patient EGFR-mutated cohort revealed HER3-DXd to be well-tolerated, with a recommended phase 2 dose of 5.6 mg/kg every 3 weeks. Most common TRAEs included hematologic toxicities such as thrombocytopenia, neutropenia, and anemia (grade ≥3 rates of 30%, 19%, and 9%, respectively). Four patients (5%) developed ILD on therapy. In terms of efficacy, the ORR was 39%, with a median PFS of 8.2 months. Importantly, responses were observed across a broad spectrum of EGFR/TKI resistance mechanisms.35
A separate phase 1 study investigated HER3-DXd at the recommended phase 2 dose in patients without EGFR-sensitizing mutations, including those with (n=17) and without (n=26) identifiable oncogene drivers. ORRs in the 2 cohorts were 35% and 23%, respectively. Again, hematologic toxicities were the most commonly reported grade 3 and higher AEs. The investigators also noted drug-related ILD events in 4 patients, but all were low-grade (grade 1 or 2).36
The larger phase 2 HERTHENA-Lung01 trial assessed the efficacy of HER3-DXd in patients with advanced EGFR-mutated NSCLC whose disease had progressed on prior EGFR TKI and platinum-based chemotherapy. A total of 225 patients received HER3-DXd at 5.6 mg/kg every 3 weeks, with most patients having received at least 3 lines of prior therapy. After a median study duration of 18.9 months, efficacy results included a confirmed ORR of 29.8%, median DOR of 6.4 months, median PFS of 5.5 months, and median OS of 11.9 months. Early biomarker data from available patients noted responses across a broad range of pretreatment HER3 expression levels and various EGFR/TKI-associated resistance mechanisms. Subgroup analysis from 30 patients with baseline brain metastases noted encouraging intracranial activity, with an intracranial ORR of 33.3%. This included 9 patients (30%) with a complete response and a median DOR of 8.4 months.37,38 Safety signals were similar to prior phase 1 data. The incidence of adjudicated drug-related ILD was 5.3% (75% grade 1-2), including 1 death.38
TROP2
Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein calcium signal transducer encoded by the Tacstd2 gene,39,40 with expression present in multiple epithelial cancers, including NSCLC.41,42 Preclinical studies suggest TROP2 is involved in several cell signaling processes, including proliferation, invasion, and cell migration, with clinical data suggesting that overexpression may confer a poor prognosis in NSCLC.42
Sacituzumab Govitecan. Sacituzumab govitecan (SG; Trodelvy, Gilead) is a TROP2-directed ADC comprised of the anti-TROP2 antibody sacituzumab conjugated via a hydrolysable cleavable linker to the topoisomerase inhibitor SN-38. The DAR is 7.6.43 A phase 1/2 basket trial, IMMU-132-01, evaluated the safety of SG in treatment-refractory epithelial malignancies. The study enrolled 495 patients with SG dosing ranging from 8 to 18 mg/kg, given on days 1 and 8 of a 21-day cycle. Notable TRAEs included diarrhea, neutropenia, anemia, and nausea, with grade 3 or higher AEs reported in 59.6% of patients and 32% of patients requiring dose reductions.44 A dose of 10 mg/kg was selected for the expansion cohorts. One expansion cohort enrolled 54 patients with previously-treated NSCLC and noted an ORR of 17% and median PFS of 5.2 months.45 A separate cohort of 62 patients with pretreated SCLC showed an ORR of 17.7%, median PFS of 3.7 months, and median OS of 7.1 months.44
Datopotamab Deruxtecan. Datopotamab deruxtecan (Dato-DXd) is an investigational ADC comprised of a recombinant humanized anti-TROP2 IgG1 monoclonal antibody conjugated to the topoisomerase I inhibitor deruxtecan via a tetrapeptide-based cleavable linker. This optimized DAR is 4.46 Dato-DXd was first evaluated in the phase 1 TROPION-PanTumor01 trial, which included a dose-expansion cohort of 180 previously-treated patients with NSCLC who received doses ranging from 4 to 8 mg/kg every 3 weeks. Patients were selected regardless of TROP2 expression. Although the maximum tolerated dose was 8 mg/kg, the recommended dose for further development was 6 mg/kg based on the safety profile. Despite relatively equivalent efficacy between the 6-mg/kg and 8-mg/kg cohorts (ORR, 26% and 23.8%, respectively), drug-related TEAEs were lower in patients treated with 6 mg/kg, with grade 3 and higher events occurring in 26% and 36.3% of patients, respectively. The most frequent TEAEs throughout all dosing cohorts were nausea, stomatitis, and alopecia, the majority being low-grade. Drug-related ILD events were observed in all 3 dosing cohorts (4, 6, and 8 mg/kg), with adjudicated grade 3 and higher cases in 2%, 2% and 5%, respectively. Three of the deaths that were attributed to drug-related ILD were observed in the 8 mg/kg group. Responses to Dato-DXd were durable, with median DORs of 12.7, 10.5, and 9.6 months across the 4, 6, and 8 mg/kg cohorts, respectively. For patients receiving 6 mg/kg, the median PFS was 6.9 months and the median OS was 11.4 months. TROP2 expression was detected in nearly all cases, with high expression (H-score >100) observed in 73.6% of patients, but there was no discernible relationship between TROP2 expression and efficacy.47
The phase 3 TROPION-Lung01 trial enrolled 604 patients with advanced NSCLC with progression on no more than 2 prior lines of therapy. Patients were randomly assigned in a 1:1 ratio to Dato-DXd at 6 mg/kg every 3 weeks or docetaxel 70 mg/m2 every 3 weeks. At a median follow-up of 13 months, median PFS with Dato-DXd was 4.4 months compared with 3.7 months with docetaxel (hazard ratio [HR], 0.75). The PFS benefit appeared to be more pronounced in nonsquamous (HR, 0.63) compared with squamous (HR, 1.38) histology. The toxicity was consistent with previously reported data. Adjudicated drug-related ILD was observed in 8% of patients treated with Dato-DXd, with 3% experiencing grade 3 or higher ILD and 2% experiencing death secondary to ILD (grade 5).48
Updated results from the phase 1b TROPION-Lung02 trial were presented by Goto and colleagues.49 The trial included several dose-expansion cohorts evaluating the safety and efficacy of Dato-DXd as frontline therapy in either a doublet combination with pembrolizumab or a triplet regimen with platinum chemotherapy. A total of 64 patients were treated with the doublet combination and 72 patients were treated with the triplet regimen; of these, 58% and 75%, respectively, were treated in the frontline setting. Looking at all treated patients, both doublet and triplet combinations showed an encouraging ORR (38% and 49%, respectively) and DCR (84% and 87%, respectively). The median PFS for all patients was 8.3 months in the doublet arm and 7.8 months in the triplet arm. The ORRs were higher for treatment-naive patients, at 50% in the doublet arm and 57% in the triplet arm. Grade 3 and higher drug-related TEAEs occurred in 31% and 58% of the doublet and triplet cohorts, respectively. Common any-grade TEAEs included stomatitis, nausea, anemia, and fatigue. Hematologic TEAEs, particularly high grade (≥3), were more frequently observed with the triplet therapy (anemia 13%, thrombocytopenia 7%, neutropenia 13%) vs the doublet therapy (anemia 2%, thrombocytopenia 0%, neutropenia 0%). Other AEs of special interest for both the doublet and triplet therapies included adjudicated drug-related ILD (all grade: 17% and 22%) and ocular surface toxicities (all grade: 16% and 24%, respectively), with rates of grade 3 and higher ILD being 3% for both treatment groups, and rates of grade and higher 3 ocular toxicity being 2% and 3% for the doublet and triplet arms, respectively.
Dato-DXd has also shown promise in NSCLC with actionable genomic alterations. TROPION-Lung05 is a single-arm phase 2 trial evaluating Dato-DXd as subsequent-line therapy in NSCLC with actionable genomic alterations. Among 137 enrolled patients, ORR was promising at 36%, with a median PFS of 5.4 months, and a median DOR of 7.0 months. Among 78 patients with EGFR-mutated NSCLC, an ORR of 44% was observed, with a median PFS of 5.8 months, and a median DOR of 7.0 months.50
Other Prominent Therapeutics
Several other ADCs are on the precipice of changing practice in advanced NSCLC. Both tusamitamab ravtansine (Tusa) and telisotuzumab vedotin (Teliso-V) utilize a biomarker-selective approach to guide therapy, and early data suggest that efficacy is related to biomarker expression levels.51,52 Tusa is composed of an antibody targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5, tusamitamab) conjugated to a DM4 payload with DAR of 3.9.53 Early studies in subsequent-line setting have shown an ORR of 20% in patients with high (IHC ≥2+ in ≥50% of cells) CEACAM5 expression.51 Teliso-V incorporates the MET-targeted antibody telisotuzumab conjugated to a vedotin payload with a DAR of 3.1. It has shown particular promise in patients with EGFR wild-type NSCLC with high c-MET expression (IHC 3+ in ≥50% cells), with an ORR exceeding 50% in early studies.52,54 Teliso-V is also showing promise in patients with EGFR-mutated disease that has high c-MET expression following progression on osimertinib.55 Another promising ADC is the B7 homolog 3 protein (B7-H3)-targeted ADC ifinatamab deruxtecan (I-DXd). I-DXd has shown early efficacy in small cell lung cancer, where subgroup data suggest an ORR of greater than 50%, with an encouraging median duration of response of 5.9 months.56 For additional detail on these and other ADCs, refer to the online supplement at www.hematologyandoncology.net.
New and Emerging ADC Constructs
ADCs as a therapeutic class have evolved considerably. Although many current-generation ADCs are approved or on the verge of approval in lung cancer, the next generation of ADCs looks to build on this success through both novel targeting techniques and payloads.
BL-B01D1 is a first-in-class EGFR/HER3 bispecific ADC attached to a novel topoisomerase payload via a cleavable linker.57 Early data for this compound suggest promising efficacy, with an ORR of 62% in 34 patients with EGFR-mutated NSCLC and 41% among 42 patients with EGFR wild-type NSCLC.
Other novel targeting techniques include the utilization of short protein peptides in place of antibodies to preferentially target tumor tissue. One intriguing class of peptide-toxin conjugates (PTCs) utilizes a 9-20 amino acid peptide structure called a “bicycle peptide,” which appears to have slower renal clearance and deeper penetration than other PTCs.58 BT1718 is an example of a novel first-in-class bicycle-toxin conjugate that selectively binds the surface metalloproteinase MT1-MMP linked to a DM1 payload by a cleavable disulfide linker.59 This compound is currently being tested in dose escalation as part of a phase 1/2 study in advanced solid tumors (NCT03486730).
Another intriguing class of PTCs are C’Dot-drug conjugates, which utilize ultra-small (<10 nm) nanoparticles. These compounds are expected to have improved therapeutic efficacy owing to a shorter half-life and improved tumor penetration. In addition, their structure enables the conjugation of a high concentration of payload. ELU001 is a novel C’Dot-drug conjugate that targets folate receptor-α and is currently being tested in dose escalation. It consists of 12 folic acid-targeting moieties and 22 exatecan topoisomerase-1 inhibitor payloads.60
Conjugates with alternative payloads are also actively under development. A class of compounds called immune-stimulating ADCs uses immunostimulatory molecules such as toll-like receptor (TLR) agonists or stimulator of interferon genes agonists rather than cytotoxic moieties as payloads. Trastuzumab imbotolimod (BDC-1001) consists of a novel TLR 7/8 agonist conjugated to the anti-HER2 antibody trastuzumab via a noncleavable linker. BDC-1001 is being investigated in an ongoing phase 1/2 trial as monotherapy and in combination with nivolumab (Opdivo, Bristol Myers Squibb) in patients with advanced HER2-expressing solid tumors.61
Another exciting class of molecules with novel payloads is radioimmunoconjugates, which combine a radionuclide payload with an antibody target. This class of agents is currently approved in solid tumors, including lutetium (177Lu) oxodotreotide (Lutathera, Advanced Accelerator Applications) for neuroendocrine tumors62 and lutetium (177Lu) vipivotide tetraxetan (Pluvicto, Novartis) for metastatic castration-resistant prostate cancer.63
Outstanding Issues
With multiple agents on the precipice of approval in advanced NSCLC, several unanswered questions are needed to further optimize treatment strategies, including biomarker selection, toxicity management, therapeutic sequencing, and mechanisms of resistance.
Biomarkers
Which approach will prevail: biomarker-directed or biomarker-agnostic?
Given that ADCs target a unique tumor-associated antigen, it is logical to assume that the expression of this antigen may predict efficacy. However, this has not borne out in all studies. Teliso-V and Tusa appear to have enhanced efficacy in patients with high-level protein expression.51,52 However, for TROP2-targeted Dato-DXd64 and HER3-targeted HER3-DXd,35,38 target protein expression does not appear to influence treatment response. In the absence of clear efficacy differences, an agnostic approach has clear advantages, as patients could begin treatment without the need for additional biomarker testing and/or repeat biopsies. However, if a biomarker can enrich for patients more likely to experience a robust and durable response, this may outweigh the potential delays associated with biomarker testing. That said, biomarker-directed strategies raise additional questions: What is the ideal cut-off for a positive result? How quickly can novel IHC stains be validated and incorporated into clinical practice? Do prior treatments influence the expression of these biomarkers? Are surface protein markers detected by IHC staining the most appropriate biomarker for efficacy, or will other biomarkers (eg, gene amplifications, gene mutations) be more informative?
Toxicity Management
What is the mechanism for the unique toxicities associated with ADCs, and how do providers manage these toxicities?
Many of the AEs associated with ADCs (eg, nausea, vomiting, diarrhea, cytopenias, neuropathy) are commonly encountered with chemotherapeutic agents and are related to the cytotoxic payload used in the ADC. However, the frequency and intensity of AEs are likely dependent on many factors that warrant further investigation, including ADC biochemical properties.
Patient-specific factors likely also influence the AE profile of ADCs. In patients with triple-negative breast cancer receiving SG, the rate of severe neutropenia was doubled in those who were homozygous for the UGT1A1*28 allele.65 Body weight and its relation to ADC dosing may also play a role. Among patients with breast cancer receiving T-DM1, obesity (body mass index ≥30) was associated with higher rates of all-grade AEs, including cytopenias, hyperbilirubinemia, and peripheral neuropathy.66 These data suggest further optimization of the therapeutic index may be possible by accounting for both the unique construct of the ADC and patient characteristics.
Although many AEs are common across ADCs and classical chemotherapeutics, several unique ADC-related AEs have emerged, chief among them being drug-related ILD. Drug-related ILD has been most clearly associated with T-DXd. A pooled analysis of 9 phase 1/2 T-DXd monotherapy studies including 1150 patients across solid tumors identified an overall incidence of drug-related ILD of 15.4%, with a median onset of 5.4 months.67 Drug-related ILD has also been reported with HER3-DXd and Dato-DXd,35,38,68 suggesting that this may be a payload-specific toxicity. Drug exposure and dosing likely play a role as well, as the rate of drug-related ILD in the DESTINY-Lung02 trial was 5.9% at the 5.4-mg/kg dose of T-DXd compared with 28.0% at the 6.4-mg/kg dose of T-DXd.69 Critically, early identification and management appear to be key to preventing significant morbidity. In the aforementioned pooled analysis, the majority of adjudicated ILD events occurred before the implementation of updated management guidelines. Although a detailed discussion of ILD management is beyond the scope of this review, key components of a work-up when ILD is suspected include high-resolution chest computed tomography, a pulmonary consultation with pulmonary function tests, and ruling out alternative causes (eg, infection, malignancy). If no plausible alternative cause is found, prompt initiation of systemic corticosteroids is indicated.67,70
Importantly, the mechanism of T-DXd–related ILD remains largely unknown. Several theories have been postulated, including target-dependent uptake (on-target toxicity), target-independent uptake (off-target toxicity), and injury induced by circulating payload.70 Interestingly, in a preclinical study in which T-DXd or free DXd was injected into monkeys, ILD occurred only in monkeys that received T-DXd, despite the systemic exposure to the DXd payload being higher in those who received free drug.71 Upon autopsy, T-DXd localization occurred predominantly in alveolar macrophages, although HER2 expression is confined mainly to the bronchial tree in monkeys. Together, this indicates that target-independent ADC uptake may be central to T-DXd–induced lung injury, though additional investigation is warranted.
Treatment Resistance and Sequencing
How do we overcome treatment resistance and properly sequence ADCs?
Given that the use of ADCs for the treatment of lung cancer is still in its infancy, mechanisms of resistance to this therapeutic class are largely unknown and are based primarily on preclinical studies of T-DM1. Various steps in the mechanism of action of ADCs (eg, antibody-target binding, internalization, payload-linker uncoupling, payload retention) have been implicated in mediating drug resistance. These pathways will require further study to identify optimal sequencing strategies.
Conclusion
Technical advancements have led to a renaissance of ADCs as an effective therapeutic class in solid tumors. In lung cancer, we have seen the early success of modern ADCs translate to the first FDA approval in NSCLC, with many additional compounds pending approval. As we enter the clinical era of ADCs in lung cancer, many important unanswered questions remain, including the utility of biomarkers, treatment sequencing, toxicity management, and identification of resistance mechanisms. Addressing these gaps will be critical to providing optimal patient management, and developing novel approaches that maximize survival for our patients.
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