Antibody–drug conjugates (ADCs) in lung cancer treatment

The treatment landscape in lung cancer has changed dramatically over the past few years and now incorporates targeted therapy, immunotherapy, and systemic chemotherapy. Novel antibody–drug conjugates (ADCs) join the list as potential options for lung cancer patients and signify a fundamental shift in the treatment paradigm, with Fam-trastuzumabderuxtecan (T-DXd) already approved and several anticipated approvals on the horizon. ADCs merge the cytotoxic effect of conjugated payload and monoclonal antibody targeted on a specific cancer cell membrane antigen—preferably not expressed on normal tissue, thus with the possibility for more precise treatment and to broaden the therapeutic index of the attached payload—compounds that would otherwise be too toxic for use. Comprising of three key components, ADCs include (a) a monoclonal antibody that binds selectively to an antigen on the tumor cell surface, (b) a cytotoxic drug payload, and (c) a cleavable or noncleavable linker [1].

Components vary between different ADCs, but the mode of action stays the same: the monoclonal antibody binds to its target on the tumor cell, the substance is then internalized by tumor cells, fuses with lysosomes, which leads to the release of the payload. To avoid delivering the cytotoxic payload to nontumor cells, the antibody should preferably recognize targets that are overexpressed on tumor cells. Linkers connecting the antibody to the payload can either be cleavable or noncleavable and, thus, are important for the ADC stability [2, 3].

In the setting of non-small cell lung cancer (NSCLC), there are multiple agents with different targets under development. This review article will summarize the most important findings from recent clinical trials examining ADCs in NSCLC, which demonstrated encouraging antitumor activity and manageable safety profiles. These new drugs provide a panel of opportunities, especially in the second-line setting, where the efficacy of chemotherapy, mainly docetaxel, is limited and toxic side effects are frequent. Improving the outcomes of patients is important to move forward in treating lung cancer; thus, continued research is necessary to improve understanding of the clinical activity, safety, and optimal treatment sequence of ADCs in lung cancer treatment.

ADCs in lung cancer treatment can be categorized into oncogene-directed or biomarker related. Hence, some of these ADCs may be efficacious for patients expressing driver alterations, such as epidermal growth factor receptor (EGFR)- or human epidermal growth factor receptor 2 (HER2)-mutations, hepatocyte growth factor receptor (MET) or carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) overexpression. Other ADCs do not require biomarker selection such as trophoblast cell surface antigen 2 (TROP-2) or human epidermal growth factor receptor 3 (HER3) directed agents.

HER2 is a transmembrane protein encoded by the erb-b2 receptor tyrosine kinase 2 (ERBB2) gene, which belongs to the ErbB or EGFR family. In NSCLC, HER2 alterations include HER2 gene amplification, HER2 mutations, and HER2 protein overexpression. The frequency of HER2 protein overexpression varies considerably in the literature, although it has been observed in up to 20% of patients with NSCLC and correlates with inferior survival outcomes. Targetable HER2 mutations are rare and occur in approximately 2% of advanced NSCLC cases [4, 5].

Fam-trastuzumab deruxtecan (T-DXd) is an ADC that contains the humanized anti-HER2 monoclonal antibody trastuzumab connected to the topoisomerase inhibitor deruxtecan (DXd) using a protease-cleavable peptide linker [6].

It is currently the only ADC approved in Europe for the treatment in second line of adult patients with unresectable or metastatic NSCLC harboring activating HER2 mutations. Results from the multicenter randomized phase 2 DESTINY-Lung02 trial, which evaluated the safety and efficacy of T‑DXd in patients with metastatic NSCLC harboring an activating HER2 mutation and who had previously received at least one line of platinum-based chemotherapy, supported the approval. Two different doses (5.4 mg/kg every 3 weeks or 6.4 mg/kg) were evaluated.

Regarding baseline characteristics, most patients in the 5.4 mg/kg arm and the 6.4 mg/kg arm had HER2 mutations predominantly in the kinase. Slightly more than half of patients in both arms were never smokers. At baseline, 34.3% and 44.0% of patients had stable central nervous system (CNS) metastases. The median number of prior regimens received for both arms was 2, with a range of 1 to 12. All patients enrolled in the trial had prior exposure to platinum-based chemotherapy and the majority (73.5% and 78.0%) previously had received immunotherapy [7].

If given at a dose of 5.4 mg/kg every 3 weeks (n = 102), it elicited a confirmed objective response rate (ORR) of 49.0% (95% confidence interval [CI] 39.0–59.1%) by blinded independent central review (BICR) in this population. Complete response (CR) was seen in 1% of patients, 48% had a partial response (PR), and 44.1% had stable disease (SD), whereas 3.9% experienced disease progression (PD) and 2.9% were not evaluable for response. The disease control rate (DCR) was 93.1% (95% CI 86.4–97.2%). The median duration of response (DOR) was 16.8 months (95% CI 6.4–not evaluable) and the median time to initial response (TTIR) was 1.8 months (range 1.2–7.0) [7].

Responses with the ADC were reported in both treatment arms, and irrespective of number or type of prior systemic treatment and baseline CNS metastases. Moreover, patients in both arms experienced tumor reduction from baseline, which was sustained over time.

The toxicity profile of T‑DXd at both doses was in line with previously reported adverse events with this ADC, including nausea, decreased red and white blood cell count and interstitial lung disease (ILD). Treatment-emergent adverse effects of grade 3 or higher occurred in 38.6% of those who received the ADC at 5.4 mg/kg, and the most common included neutropenia (18.8%) and anemia (10.9%). Moreover, 12.9% of patients in this group were diagnosed with ILD or pneumonitis determined to be related to treatment, the majority grade 1 or 2 (10.9%), with one grade 3 and one grade 5 event [7].

In summary, T‑DXd demonstrated deep and durable responses at both treatment doses. The safety profile was acceptable and generally manageable at both doses and favored the 5.4 mg/kg dose. Lower incidence of drug-related treatment-emergent adverse events (TEAEs), drug discontinuations, dose reductions, and drug interruptions as well as lower rates of drug-related ILD were observed with the 5.4 mg/kg dose. These results are very exciting, as this is the first targeted drug to effectively treat patients with this alteration and introduces ADCs as a novel class of drugs into the field of lung cancer treatment.

Patients with EGFR-mutated NSCLC treated with a tyrosine kinase inhibitor (TKI) often experience recurrence due to resistance mechanisms. In this setting few effective treatment options remain. The HER3-directed ADC patritumab deruxtecan (HER3-DXd) demonstrated encouraging results for patients with locally advanced or metastatic, EGFR-mutated NSCLC who previously received at least two systemic therapies according to findings from the multicenter, open-label phase 2 HERTHENA-Lung01 trial. Patients were initially randomly assigned to receive intravenous patritumab deruxtecan every 3 weeks at a fixed dose of 5.6 mg/kg (n = 225) or via an uptitration dosing schedule (n = 50). Patients enrolled in the study were heavily pretreated with a median of three prior lines of therapy (range 1–11)—the majority had received a third-generation EGFR TKI (93%) and 40% immunotherapy. At baseline, most patients were female (58.7%), never smokers (64.0%), younger than 65 years of age (53.8%), had EGFR exon 19 deletions (63.1%), a history of CNS metastasis (51%), and had an ECOG performance status (PS) of 1 (66.2%) [8].

Data were presented during the IASLC 2023 World Conference on Lung Cancer and demonstrated an ORR of 29.8% (95% CI 23.9–36.2%) among patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression after an EGFR-directed TKI and platinum-based chemotherapy (n = 225). In addition, the disease control rate (DCR) was 73.8% (95% CI 67.5–79.4%), the median duration of response (DOR) was 6.4 months (95% CI 4.9–7.8), and the median progression-free survival (PFS) was 5.5 months (95% CI 5.1–5.9). The confirmed intracranial ORR in patients with brain metastasis at baseline who did not undergo prior radiotherapy (n = 30) was 33.3% (95% CI 17.3–52.8%). Clinically meaningful responses were observed among various mechanisms of EGFR TKI resistance including EGFR-dependent (ORR 32.4%) and EGFR-independent pathways (ORR 27.2%) as well as those without any identified resistance mechanism (ORR 27.3%) [8]. At a median follow-up of 18.9 months, the median OS was 11.9 months (95% CI 11.2–13.19).

Patritumab deruxtecan displayed a manageable and tolerable toxicity profile. However, most patients experienced at least one any-grade TEAE (99.6%). TEAEs were associated with treatment discontinuation (7.1%), dose reduction (21.3%), and dose interruption (40.4%). Grade 3 or higher TEAEs occurred at a rate of 64.9%. Treatment-related TEAEs occurred in most patients (95.6%), events of grade 3 or higher severity (45.3%), and serious TEAEs (15.1%).

Interstitial lung disease occurred sparingly (5.3%) and was reported at grade 1 (0.4%), grade 2 (3.6%), grade 3 (0.9%), and grade 5 (0.4%) severity. Other common grade 1 or 2 TEAEs included nausea (63%), thrombocytopenia (44%), decreased appetite (39%), and constipation (34%). Grade 3 or higher TEAEs included thrombocytopenia (21%), neutropenia (19%), anemia (14%), and leukopenia (10%) [8].

These data are very encouraging in heavily pretreated patients with advanced EGFRm NSCLC as efficacy was observed across a broad range of HER3 expression and various mechanisms of EGFR TKI resistance. Furthermore, antitumor activity was seen in patients with brain metastases, which underlines the importance of patritumab deruxtecan as a treatment option for patients with EGFRm NSCLC after TKI failure.

Ongoing trials with patritumab deruxtecan include a phase 3 trial vs platinum-based chemotherapy in patients with EGFR-mutated NSCLC after progression on third-generation EGFR TKI therapy (HERTHENA-Lung02) and a phase 1 trial in combination with osimertinib in patients with EGFRm NSCLC after progression on first-line osimertinib or in previously untreated patients.

The tyrosine kinase receptor c‑Met is commonly overexpressed in many different solid tumor types and is present in approximately one quarter of patients with NSCLC. Patients with c‑Met overexpression have poor prognosis and opposed to patients with MET exon 14 mutations currently no approved targeted treatment options are available [9‐11]. Telisotuzumab vedotin (Teliso-V) is a first-in-class, c‑Met protein directed ADC, composed of anti-c-Met humanized mAb ABT-700 attached to monomethyl auristatin E (MMAE) via a valine-citrulline linker. It was investigated for patients with MET overexpression, but also in the resistant setting for patients with EGFR mutant NSCLC who had received a prior TKI [12, 13].

According to findings from an interim analysis of the single-arm, phase 2 LUMIOSITY/M14-239 trial, Teliso‑V produced meaningful response rates in patients with c‑Met protein overexpressed, EGFR wild-type, advanced or metastatic nonsquamous NSCLC. Patients whose disease has progressed on, or after, platinum-based chemotherapy received 1.9 mg/kg of intravenous Teliso‑V every 2 weeks as second- or third-line therapy.

In the nonsquamous population c‑Met overexpression was defined as intermediate (IHC 3+, ≥ 25 to < 50%) or high (IHC 3+, ≥ 50%); 75% or greater expression (IHC 1+) was required in the squamous population.

The ORR was 35% in patients with c‑Met high expression and 23% in patients with intermediate expression. With a median duration of response (DOR) of 9 months and 7.2 months in the c‑Met high and intermediate populations, respectively, Teliso‑V seems to be a promising agent for this patient cohort. The median overall survival (OS) was similar in both groups at 14.6 and 14.2 months. Treatment-related adverse effects were manageable and tolerable, with no new safety signals and a consistent toxicity profile as reported previously. The most common any-grade AEs were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs potentially related to Teliso‑V occurred in 2 patients with squamous disease from sudden death and pneumonitis [14].

TROP2 is a transmembrane glycoprotein calcium signal transducer that mediates cell migration and anchorage-independent growth, and is expressed across many epithelial tumors [15]. It has been associated with poor OS and disease-free survival (DFS) in several types of solid tumors [16]. In lung cancer, Trop2 overexpression was observed in up to 64% of adenocarcinoma and up to 75% of squamous cell carcinoma NSCLC and is associated with reduced survival [17].

Two TROP-2-directed ADCs are currently under development: sacituzumab govitecan and datopotamab deruxtecan (Dato-DXd).

Sacituzumab govitecan is a first-in-class anti-Trop2 ADC, which consists of humanized anti-Trop2 monoclonal antibody sacituzumab linked to the topoisomerase I inhibitor SN-38 by a hydrolysable cleavable linker. Dato-DXd is a TROP2-directed ADC consisting of a humanized anti-TROP2 IgG 1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker [18]. Both ADCs have demonstrated efficacy in the second-line setting and in highly pretreated patients [19].

At the 2023 ESMO Congress, data from the phase 3 TROPION-LUNG01 study, investigating Dato-DXd versus docetaxel in the second-line setting, were presented. Patients treated with Dato-DXd (n = 299) experienced an increased PFS of 4.4 months (95% CI 4.2–5.6) vs 3.7 months as compared to docetaxel. The PFS advantage was driven by patients with nonsquamous histology with an PFS of 5.6 months (95% CI 4.4–7.0) in the Dato-DXd arm (n = 229) vs 3.7 months (95% CI 2.9–4.2) in the docetaxel arm (n = 232; HR 0.63; 95% CI 0.51–0.78) [20]. The interim OS findings also favor Dato-DXd, and the trial is continuing to the final analysis.

In the phase 1 TROPION-PanTumor01 study, Dato-DXd showed promising efficacy in patients with actionable genomic alterations [21]. TROPION-Lung05, a phase 2, single-arm study is currently evaluating Dato-DXd in patients with advanced or metastatic NSCLC with actionable genomic alterations that progressed on or after targeted therapy and platinum-based chemotherapy. In this heavily pretreated group of patients, Dato-DXd achieved a median ORR of 43.6% (95% CI 32.4–55.3%) for those with EGFR mutations (n = 78) and 23.5% (95% CI 10.7–41.2%) for those with ALK rearrangements (n = 34), with a median DOR of 7 months. The median PFS was 5.8 months (95% CI 5.4–8.3) and 4.3 months (95% CI 2.6–6.9), respectively [22]. Specific toxicities of grade 3 or higher found with Dato-DXd include stomatitis (11%), ocular toxicities (2%) and ILD (1%).

Data from the phase 3 EVOKE-01 trial of sacituzumab govitecan versus docetaxel are awaited in order to be able to better compare the two agents [23]. From smaller datasets in the first-line setting in combination with immunotherapy, similar efficacy data have been demonstrated for the two substances.

Initial results from the ongoing phase 2 EVOKE-2 trial demonstrated that the addition of sacituzumab govitecan to pembrolizumab produced high response rates in the frontline setting for patients with advanced NSCLC. Across all patients, the ORR with the combination regimen was 56%, with a DCR of 82% and responses were durable [24, 25].

Toxicity profiles of the two TROP‑2 directed ADCs differ—sacituzumab govitecan resulted in more cytopenias but less mucositis. Hence, proactive, specific management of the specific side effects will likely become highly important.

ADCs open up an entirely new treatment strategy for patients with advanced lung cancer and currently very limited treatment options. The armamentarium will be expanded to include this new class of drugs, as individual treatment substances or in combination with immunotherapy and/or chemotherapy. Currently, additional novel targets under further investigations in advanced NSCLC include CEACAM5, NECTIN4, tissue factor, mesothelin, and LIV1. Due to their comparably larger size, blood–brain barrier penetration and, thus, intracranial efficacy might be of concern. It is assumed that large molecules such as monoclonal antibodies and ADCs do not cross the blood–brain barrier, so that combination strategies with smaller molecules and radiation might be necessary. However, analyses from the DESTINY-Lung 01 and DESTINY-Lung02 study demonstrated that T‑DXd achieved intracranial response rates between 30 and 50% with a reduction in brain lesion size from baseline of approximately 80%, indeed suggesting a considerable and rather unexpected cerebral efficacy of these ADCs.

Currently, ADCs are investigated in advanced NSCLC and preferably later therapy lines only. Until today, there are no registered trials of ADCs in early stage NSCLC, although the previous evolution of immunotherapy and targeted therapies suggest that this may change rapidly in the next few years.

New challenges will occur with these new promising types of therapies and physicians and patients will have to face them; furthermore, different therapy-associated side effects may require different therapeutic strategies than under currently used anticancer drugs.

The optimal position in the therapy sequence still needs to be established.

The optimal strategy for patient selection for these treatments is not yet known. Hence, ongoing research in biomarkers to better predict treatment responses is urgently needed.