Antibody-Drug Conjugates Represent Key Area of Focus in Lung Cancer Research

Karen Reckamp, MD

Investigators specializing in lung cancer are growing increasingly excited about using antibody-drug conjugates (ADCs) to treat non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), according to a presentation from the 24th Annual International Lung Cancer Congress®.¹

“This is the most exciting area, there are lots of agents, lots of new trials that are ongoing in patients,” said Karen Reckamp, MD, professor of medicine, Division Director, Medical Oncology, Cedars-Sinai, said. “We need to increase our knowledge of these ADCs to improve the delivery and reduce toxicity may improve outcomes for our patients.”

There are several factors that contribute to the efficacy and safety associated with ADCs, she said. Outside of the cytotoxic and antibody themselves, the drug-to-antibody ratio (DAR) is also of high importance. Across agents in development, the DAR ranges from 2 cytotoxic molecules per single antibody to 8. The increase of payload results in increased efficacy but also heightens the chance for premature release, which increases adverse events (AEs), Reckamp said. Other important factors are related to the expression of the target protein, and the location and mechanism of cleavage for the linker that attaches the cytotoxic to the antibody.

For the presentation, Reckamp displayed a list of 3 dozen ADCs currently in development for NSCLC. She commented that although the list had recently been developed, it was likely already out of date, given the fast pace and high interest of development in ADCs for NSCLC. “We are moving forward at fast forward with ADCs,” she said. “Although many are biomarker agnostic, we need to find a way to select patients.”

Among the list she displayed, she selected a few agents of high interest, based on their approval status or breakthrough designations received from the FDA.

Trastuzumab Deruxtecan

The first ADC highlighted was fam-trastuzumab deruxtecan-nxki (Enhertu), which gained an accelerated approval for second-line HER2-mutated NSCLC in August 2022, based on findings from the DESTINY-Lung01 study (NCT03505710). This agent consists of an IgG1 antibody with a cleavable tetrapeptide linker connecting the HER2-targeted antibody to 8 molecules of a topoisomerase I inhibitor.

Findings from the DESTINY-Lung01 study demonstrated a median progression-free survival (PFS) of 8.2 months (95% CI, 6.0-11.9) and a median overall survival (OS) of 17.8 months (95% CI, 13.8-22.1).² This study enrolled 91 patients with a mediation duration of follow-up of 13.1 months (range, 0.7-29.1). The centrally confirmed objective response rate (ORR) was 55% (95% CI, 44%-65%). The median duration of response was 9.3 months (95% CI, 5.7-14.7).

Grade 3 or higher drug-related AEs were experienced by 46% of patients treated with trastuzumab deruxtecan. The most common grade 3 or greater AE was neutropenia (19%). Drug-related interstitial lung disease (ILD), which has emerged with this agent in other trials, occurred in 26% of patients, and resulted in death for 2 patients.

Datopotamab Deruxtecan

Datopotamab deruxtecan consists of a humanized anti-TROP2 IgG1 antibody utilizing a plasma stable, tumor-selective, cleavable tetrapeptide-based linker in a 4:1 DAR. The payload for this agent is a topoisomerase I inhibitor. Findings for this ADC in NSCLC from the TROPION-Lung02 trial (NCT04526691) were recently presented at the 2023 ASCO Annual Meeting.³

In the multicenter, open-label phase 1b TROPION-Lung02 study, datopotamab deruxtecan was combined with pembrolizumab (Keytruda) with or without platinum-based chemotherapy in the first- and second-line setting. For patients who received datopotamab deruxtecan plus pembrolizumab (n = 61), the ORR was 38% (95% CI, 26%-51%) and those who received the ADC and immunotherapy plus platinum-based chemotherapy (n = 71) the ORR was 49% (95% CI, 37%-61%). Specifically in the first line, this who received the double (n = 34) had an ORR of 50% (95% CI, 32%-68%) and those who received the triplet (n = 53) has an ORR of 57% (95% CI, 42%-70%).

The median duration of response across all patients was not yet reached. The median PFS with the doublet was 8.3 months (95% CI, 6.8-11.8) and 7.8 months with the triplet (95% CI, 5.6-11.1). The most common treatment emergent AE (TEAE) was stomatitis, which officered in 56% of patients in the doublet arm and for 35% of patients in the triplet arm. These were predominately grade 1/2 in severity.

Tusamitamab Ravtansine

This agent consists of a humanized IgG1 antibody specific to CEACAM5 that has been conjugated to maytansinoid DM4, which inhibits tubular polymerization. The antibody and payload are connected with a cleavable spark plasma diffusion bonding linker, with a DAR of 3.8 to 1.

In findings presented in 2020 at the ASCO Annual Meeting,⁴ CEACAM5 expression was explored, with patients reported based on high expression (n = 64; 2+ or more ≥50% stains) or moderate expressers (n = 28; 2+ or more on 1% to 49% expression). In patients with nonsquamous pretreated NSCLC, the ORR with tusamitamab ravtansine in the high expressers was 20.3% (95% CI, 12%-32%). In those with moderate expression, the ORR was 7.1% (95% CI, 2%-23%).

The most intriguing AEs that emerged in this study were ocular events, specific to the cornea. Overall, a corneal AEs of grade 3 in severity occurred in 10.9% of patients. Grade 3 keratitis was seen in 7.6% and grade 3 keratopathy was observed in 1.1% of patients. “This is manageable but a unique toxicity,” Reckamp said.

The ongoing phase 3 CARMEN-LC03 study (NCT04144956) is currently looking at tusamitamab ravtansine compared with docetaxel for patients with nonsquamous NSCLC following chemotherapy and immunotherapy treatment in patients with CEACAM5 high expression.

Telisotuzumab Vedotin

This agent consists of a humanized recombinant IgG1κ antibody conjugated to the microtubule inhibitor and cytotoxin monomethyl auristatin E (MMAE) using a valine-citrulline cleavable linker. The DAR with this agent is 3.1 to 1.

The agent has demonstrated monotherapy activity in a MET-positive enriched population of NSCLC across 52 patients in a phase 1 study (NCT02099058).⁵ Treatment was administered once every 2 weeks and once every 3 weeks. Across both doses, there was an ORR of 23% with a median duration of response of 8.7 months. The median PFS was 5.2 months.

In a phase 2 study (NCT03539536),⁶ telisotuzumab vedotin given every 2 weeks was further analyzed in MET-positive NSCLC across biomarker subgroups, specifically looking at EGFR. In this analysis, those with nonsquamous, EGFR wild-type MET-high status (n = 13) had an ORR of 53.8%. In those with EGFR-mutated NSCLC, the ORR in the MET high group (n = 22) was 18.2%.

In the phase 2 study, 71% of patients experienced a TEAE related to telisotuzumab vedotin, according to investigator assessment. Overall, 44% of patients experienced a grade 3 or higher in severity TEAE. The most common serious TEAEs were pneumonia (5%), malignant neoplasm progression (4%), and pneumonitis (4%).

Further studies have assessed telisotuzumab vedotin in combination with erlotinib (Tarceva) for patients with MET-positive, EGFR-mutant NSCLC. In this study (NCT02099058),⁷ in EGFR-mutated MET-high tumors, the ORR was 52.6%. Median PFS was 6.8 months in those without a T790M resistance mutation. Further studies are ongoing with telisotuzumab vedotin and osimertinib (Tagrisso), Reckamp noted.

Patritumab Deruxtecan

The anti-HER3 IgG1 antibody patritumab is conjugated to a topoisomerase I inhibitor using a cleavable tetra peptide-based linker. The DAR for this ADC is 8 to 1. In general, HER3 is expressed in 83% of patients with NSCLC, Reckamp noted, and no specific selection criteria was used in studies.

In the phase 1 study (NCT03260491),⁸ treatment with an EGFR TKI with or without platinum-based chemotherapy, the confirmed ORR with patritumab deruxtecan was 39%. The median duration of response was 6.9 months. Of these patients, 44 had received osimertinib specifically. In this group of patients, the ORR with patritumab deruxtecan was also 39%, which consisted of 1 complete response and 16 partial responses.

Treatment-emergent adverse events of grade 3 or higher in severity were seen in 74% of patients at the phase 2 dose of 5.6 mg/kg (n = 57). Grade 3 or greater treatment-related TEAEs were seen in 54% of patients, including ILD in 7% of patients. Most other events were hematologic in nature, with the most common grade 3 or greater events being platelet count decrease and neutrophil count decrease. Moreover, responses to patritumab deruxtecan were observed regardless of type of TKI resistance, Reckamp noted.

ABBV-011

The ADC ABBV-011 contains an anti-SEZ6 IgG1 antibody labeled SC17 that is fused to a calicheamicin payload via a non-cleavable LD19.10 linker. The DAR for this agent is 2 to 1. SEZ6 expression on tumor cells of 1% or more has been identified in 86% of SCLC tumor samples, with 55% having expression of 25% or more, Reckamp noted in her presentation.¹

Findings from a phase 1 open-label dose escalation study of 99 patients with small cell lung cancer was presented at the 2023 ASCO Annual Meeting (NCT03639194).⁹ In this study, the confirmed ORR with ABBV-011 was 19% in 98 evaluable patients. The clinical benefit rate, with stable disease lasting longer than 12 weeks, was 36%. In the 1-mg/kg dose cohort (n = 40), which was explored in an expansion phase, the ORR was 25%. The duration of response was 4.2 months with this dose.

The most common TEAEs of grade 3 or higher were fatigue (10%) and platelet count decrease (10%). TEAEs of interest included hepatotoxicity, the most common was which was hyperbilirubinemia, which had an all-grade severity rate of 17%.

AEs With ADCs

The cause of AEs with ADCs is multifaceted, Reckamp noted. It could be related to expression of the target protein on non-cancer cells, location and mechanism of the linker, payload-specific toxicity, and the effect of the DAR. Moreover, in some cases, there could be a bystander effect wherein the linker degrades and the cytotoxic payload is released prior to entering the cell or it exits the tumor cell and enters surrounding tissue.

In a panel discussion following the talk, panelists expressed their concern around a lack of understanding behind the mechanism of the unique AEs seen with ADCs. One contributing factor, Narjust Florez, MD, from Dana-Farber Cancer Institute, noted was that the bystander effect in lung cancer might be more negative or severe than has been seen in other types of cancer, like breast cancer. “In the case of lung cancer, the surrounding tissue is different and perhaps more sensitive,” she postulated.

The current cytotoxic payloads being utilized fall roughly toward the middle of the pack, in terms of toxicity, Reckamp noted. Other studies have looked at the association of each payload and target with AEs, Reckamp noted. In some studies, the payload was not fully to blame, with the on-target effects themselves also contributing to toxicity, especially if those targets had broader roles outside of the tumor.

As familiarity grows with the ADCs, AE management must also improve, panelists agreed. With ILD specifically, algorithms have been developed, Reckamp noted. If ILD from an ADC is suspected, treatment should be discontinued. If the ILD is in fact related to the ADC, and not another cause, grade 1 and 2 ILD can be treated with oral corticosteroids. Beyond that, for grade 3 and 4, patients should be hospitalized, and IV steroids administered.¹⁰ “ADC-associated ILD management is very similar to management with other agents,” Reckamp said.

Next Frontier in ADCs

The next phase for ADCs will involve combining or improving upon already existing approaches. Four chief examples include ADCs that utilize bispecific antibodies, antibodies linked with 2 separate payloads, antibodies linked with immune-stimulating payloads, and those linked with radionuclides.

As an example of a bispecific, Reckamp discussed BL-B01D1, which has an affinity for HER3 and EGFR with a cleavable linker to the TOP1 inhibitor Ed-04. The DAR for this ADC is 8 to 1. In early findings from a phase 1 trial (NCT05194982) that was presented at the 2023 ASCO Annual Meeting,¹¹ BL-B01D1 demonstrated an ORR of 45.3% in patients treated with a median of 3 prior treatments.

In the study, BL-B01D1 was examined across several types of cancer, with the highest level of efficacy seen in EGFR mutant (n = 38) and wild-type (n = 49) NSCLC and also in nasopharyngeal carcinoma (n = 28). The ORRs with BL-B01D1 were 63.2%, 44.9%, and 53.6% in each of these groups, respectively. The agent was less effective in patients with SCLC (n = 7) and head and neck squamous cell carcinoma (n = 15). In these groups, respectively, the ORRs were 14.3% and 6.7%.

The recommended phase 2 dose was identified as 2.5 mg/kg on day 1 and 8 every 3 weeks. Higher doses were found to elicit bone marrow suppression. Across all doses and cancer types, the most common treatment-related AEs were hematologic in nature, with the highest grade 3 or greater being neutropenia (34%) and leukopenia (30%). Treatment-related AEs of interest included mouth ulceration, diarrhea, and rash, which occurred at an all-grade frequency of 17%, 17%, and 13%, respectively. There were no cases of ILD at a median follow up of 4.1 months.

Several other bispecific ADC studies continue to enroll patients for a variety of agents. The 5 agents and trials to watch, Reckamp noted, were zanidatamab zovodotin (dual HER2 targeting; NCT03821233), M1231 (EGFR and MUC1; NCT04695847), REGN5093-M114 (dual MET targeting; NCT04982224), CBP-1008 (FRα and TRPV6; NCT04740398), and AZD9592 (EGFR and MET targeted; NCT05647122).

References

1. Reckamp K. ADCs: New agents and targets in development. Presented at: 24th Annual International Lung Cancer Congress®; July 27-29, 2023; Huntington Beach, CA.
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3. Goto Y, Su WC, Levy BP, 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(suppl 16):9004. doi:10.1200/JCO.2023.41.16_suppl.9004
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8. Jänne PA, Baik C, Su W-C, 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(1):74-89. doi:10.1158/2159-8290.CD-21-0715
9. Morgensztern D, Ready NE, Johnson ML, et al. First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer. J Clin Oncol. 2023;41 (suppl 16):abstr 3002. doi:10.1200/JCO.2023.41.16_suppl.3002.
10. Tarantino P, Modi S, Tolaney SM, et al. Interstitial Lung Disease Induced by Anti-ERBB2 Antibody-Drug Conjugates: A Review. JAMA Oncol. 2021 Dec 1;7(12):1873-1881. doi:10.1001/jamaoncol.2021.3595.
11. Zhang L, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study. J Clin Oncol. 2023;41(suppl 16):3001. doi:10.1200/JCO.2023.41.16_suppl.3001.