Article

Treating Lung Cancer with Antibody-Drug Conjugates: Advancing Clinical Trials

Key Takeaways

  • Lung cancer is the leading cause of cancer-related death in the U.S.
  • The 5-year relative survival rate of patients diagnosed with metastatic lung cancer is 6%
  • ADCs targeting oncogenic sites have extended the progression-free survival of patients in clinical trials

 

Non-Small Cell Lung Cancer

According to the National Cancer Institute (NCI), lung cancer is the leading cause of cancer-related mortality in the United States1, and Non-Small Cell Lung Cancer (NSCLC) accounts for 81% of cases2. The NCI defines NSCLC as any type of epithelial lung cancer other than Small Cell Lung Cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked.3

Most patients are diagnosed with advanced lung cancer, and the 5-year relative survival rate of patients diagnosed with metastatic lung cancer is 6%. Traditional chemotherapy and surgery offer limited efficacy in these patients.4 Clearly, new treatments are required for this large unmet medical need.

 

What Are Targeted Treatments in Non-Small Cell Lung Cancer?

An important area of research and drug development for NSCLC, as with many other cancers, is targeted therapies. Targeted therapies are a type of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spread. With the arrival of targeted therapies, the prognosis of patients with NSCLC has improved. Several clinical trials have shown that the Progression-Free Survival (PFS) of patients who have treatments that target oncogenic sites has been extended compared with that associated with chemotherapy drugs.5 The NCI website lists over 30 targeted therapies approved for lung cancer.6

 

Antibody-Drug Conjugates in Non-Small Cell Lung Cancer

The Antibody-Drug Conjugate (ADC) drug class has perhaps the largest number of targeted therapies under development. While not all ADCs being developed for NSCLC are used for a genomically defined subset of lung cancer, they can still be considered targeted agents in the sense that they act against a specific target.7

ADCs are made up of three components: a monoclonal antibody that binds selectively to an antigen on the tumor cell surface, a cytotoxic drug payload, and a cleavable or non-cleavable linker. They offer the one-of-a-kind potential of delivering highly effective cytotoxic agents to cancer cells that express a pre-defined cell surface target, thereby exploiting the capabilities of both cytotoxic chemotherapy and targeted therapy.8

 

Reflections from ASCO 2023

ASCO 2023 featured thousands of abstracts, and fifty or more provided information on ADCs. One abstract of particular interest was “SKB264 (TROP2-ADC) for the treatment of patients with advanced NSCLC: Efficacy and safety data from a phase 2 study.”9 SKB264 is a new anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor. SKB264 showed promising anti-tumor activity and a manageable safety profile in patients with relapsed or refractory metastatic NSCLC. Treatment-related adverse events were mainly hematologic.

The following table provides an overview of additional ADC treatment abstracts for NSCLC presented at ASCO 2023.

ABSTRACT TITLENCT NUMBERPOPULATION
TROPION-Lung04: Phase 1b, multicenter study of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy ± carboplatin in advanced/metastatic non-small cell lung cancer (mNSCLC).NCT04612751NSCLC
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.NCT03639194SCLC
TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC).NCT04526691NSCLC
Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated MET-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC).NCT05513703NSCLC

 

Recent Clinical Trials for Antibody-Drug Conjugates in Non-Small Cell Lung Cancer

The following are early phase trials. Late preclinical and Phase 1 studies with preliminary images collected would benefit from safe and quality-controlled curation of those images, thus avoiding unnecessary confusion and potential mishandling of crucial data that supports future research and funding efforts.

Traztuzumab deruxtecan (T-DXd) was the first ADC to receive FDA approval for patients with HER-2+ NSCLC in August 2022, based on results from the DESTINY-Lung01 and DESTINY-Lung02 trials. Since then, ADCs aimed at additional targets are being developed. The following is a sampling of Phase 1 and 2 clinical trials of ADCs in NSCLC that are currently recruiting or not yet recruiting that were first listed on ClinicalTrials.gov in 2022 or 2023.

 

Patritumab Deruxtecan (HER3-DXd), a HER3 Targeting ADC

A Phase 2 clinical trial that was just posted to ClinicalTrials.gov in May 2023 is studying patritumab deruxtecan (HER3-DXd), a HER3 directed ADC being developed by Daiichi Sankyo. HER3-DXd is a potential first-in-class HER3 directed ADC. It was granted FDA breakthrough therapy designation in 2021 in patients with metastatic EGFR-mutated NSCLC.10

This Phase 2 clinical trial (NCT05865990), sponsored by MedSIR in collaboration with Daiichi Sankyo, will enroll patients with metastatic breast cancer, advanced NSCLC with active brain metastases, or active solid tumor Leptomeningeal Carcinomatosis/Disease (LMD).

 

MYTX-011, a cMET-Targeting ADC

Mythic Therapeutics developed MYTX-011, an ADC incorporating the clinically validated vcMMAE linker-payload conjugated to a novel, pH-dependent anti-cMET antibody. An AACR 2023 abstract reported encouraging preclinical findings on the hypothesis that engineering the antibody to rapidly lose affinity at acidic endosomal pH would boost ADC uptake and efficacy in cMET+ tumor cells for a broader range of patients, including more of those with moderate cMET levels.11

A Phase I open-label multi-center study to evaluate the safety, tolerability, pharmacokinetics, and preliminary effectiveness of MYTX-011 in patients with locally advanced, recurrent, or metastatic NSCLC was posted to ClinicalTrials.gov in December of 2022 (NCT05652868). The study will be conducted in 2 parts. Part 1 will assess the safety and tolerability of MYTX-011 and identify the dose to be studied in Part 2. Part 2 will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations. These are populations with currently unmet medical needs.

 

Farletuzumab ecteribulin (MORAb-202), a FRα-targeting ADC

Eisai and Bristol Myers Squibb co-developed farletuzumab ecteribulin (formerly known as MORAb-202) . MORAb-202 is a novel antibody–drug conjugate that comprises farletuzumab (anti-folate receptor α [FRα] antibody) linked to eribulin (microtubule inhibitor) as a payload. Results of a first-in-human Phase 1 study published in Clinical Cancer Research demonstrated promising anti-tumor activity in FRα-positive solid tumors.12

A Phase 2, open-label, randomized Study of MORAb-202 in participants with metastatic NSCLC adenocarcinoma (AC) who experienced progression on prior therapies was posted to ClinicalTrials.gov (NCT05577715) in October of 2022. The aim of this study is to characterize the safety and tolerability of MORAb-202, and to assess the objective response rate in participants with previously treated, metastatic NSCLC AC.

 

PRO1184, a FRα-targeting ADC

Another FRα-targeting ADC, PRO1184, is under development by ProfoundBio. PRO1184 consists of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. PRO1184 was shown to exert potent antitumor activity in preclinical models.13

A Phase 1/2 clinical trial was posted to ClinicalTrials.gov in October 2022 (NCT05579366). This study will assess the safety, including side effects, and determine the characteristics of PRO1184 in participants with solid tumors, including metastatic NSCLC. The study will consist of two parts: dose escalation and dose expansion. ADC Review reported in January 2023 that first patient dosed had occurred in the study.14

 

Summary

Given that the relative survival rate of patients diagnosed with metastatic lung cancer is low, and that traditional chemotherapy and surgery are of limited efficacy, ADCs represent a potentially important treatment option. While trastuzumab deruxtecan [Enhertu] remains the only FDA-approved ADC for NSCLC, there are numerous new treatments being studied in clinical trials.

 

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References

1https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq

2American Cancer Society. Cancer Facts & Figures 2023. Atlanta: American Cancer Society; 2023.

3https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq

4Xiao Y, Liu P, Wei J, Zhang X, Guo J and Lin Y (2023), Recent progress in targeted therapy for non-small cell lung cancer. Front. Pharmacol. 14:1125547. doi: 10.3389/fphar.2023.1125547

5Ibid.

6https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/approved-drug-list#targeted-therapy-approved-for-lung-cancer

7Liu SV. Novel targets in advanced non-small cell lung cancer. Clin Adv Hematol Oncol. 2022 Jul;20(7):426-429. PMID: 35802873.

8Coleman N, Yap TA, Heymach JV, Meric-Bernstam F, Le X. Antibody-drug conjugates in lung cancer: dawn of a new era? NPJ Precis Oncol. 2023 Jan 11;7(1):5. doi: 10.1038/s41698-022-00338-9. PMID: 36631624; PMCID: PMC9834242.

9https://meetings.asco.org/abstracts-presentations/218898

10https://www.daiichisankyo.com/files/news/pressrelease/pdf/202112/20211223_E1.pdf

11Nimish Gera, Kyle Fitzgerald, Vijay Ramesh, Purvi Patel, Lena Kien, Deepak Kanojia, Simon Aoyama, Federico Colombo, Amit Deshpande, William Comb, Thomas Chittenden, Brian Fiske. MYTX-011: A novel cMET-targeting antibody drug conjugate (ADC) engineered to increase on-target uptake in and efficacy against cMET expressing tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5000.

12Shimizu T, Fujiwara Y, Yonemori K, Koyama T, Sato J, Tamura K, Shimomura A, Ikezawa H, Nomoto M, Furuuchi K, Nakajima R, Miura T, Yamamoto N. First-in-Human Phase 1 Study of MORAb-202, an Antibody-Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-Positive Advanced Solid Tumors. Clin Cancer Res. 2021 Jul 15;27(14):3905-3915. doi: 10.1158/1078-0432.CCR-20-4740. Epub 2021 Apr 29. PMID: 33926914.

13DOI: 10.1200/JCO.2023.41.16_suppl.TPS3157 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) TPS3157-TPS3157.

14https://www.adcreview.com/news/first-patient-dosed-with-pro1184-and-pro1160-cleared-for-study-initiation-in-the-us/