Antibody-drug conjugates (ADCs) represent a promising new class of targeted cancer therapies. By combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs, ADCs work like smart missiles, homing in on cancer cells and delivering a toxic payload. This unique design has made ADCs a highly anticipated development in the field of oncology.

While ADC technology has advanced rapidly, the U.S. Food and Drug Administration (FDA) did not approve any new ADCs in 2023 or 2024. However, with ongoing advancements in technology and clinical research, multiple ADC drugs are anticipated to gain approval in 2025, offering new hope to cancer patients, offering new hope to cancer patients.

ADC Drugs Expected to Receive FDA Approval

Datopotamab Deruxtecan (Dato-DXd, DS-1062)

Datopotamab deruxtecan (Dato-DXd), jointly developed by AstraZeneca and Daiichi Sankyo, is an ADC consisting of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a topoisomerase I inhibitor payload via via a  tetrapeptide-based cleavable linker. Datopotamab deruxtecan possesses a strong ability to penetrate cell membranes, enabling it internalizing into TROP2-expressing cells leads to death of target tumor cells and bystander killing of neighboring cells in the tumor microenvironment.

AstraZeneca and Daiichi Sankyo have submitted a new Biologics License Application (BLA) to the FDA, seeking accelerated approval for datopotamab deruxtecan as a treatment for adults with metastatic or locally advanced non–small cell lung cancer (NSCLC) previously treated and harboring EGFR mutations.[1]

The FDA previously accepted a BLA for datopotamab deruxtecan in advanced nonsquamous NSCLC in February 2024, supported by findings from the phase 3 TROPION-Lung01 trial (NCT04656652). However, the developers have voluntarily withdrawn this BLA and submitted a new one focused on the EGFR-mutated NSCLC population, based on feedback from the regulatory agency.

The updated BLA is supported by data from the phase 2 TROPION-Lung05 study (NCT04484142), along with findings from the TROPION-Lung01 and phase 3 TROPION-PanTumor01 (NCT03401385) trials. Results from a pooled analysis of patients with previously treated EGFRm NSCLC in these studies were presented this month at the European Society of Medical Oncology (ESMO) Asia 2024 Congress. [2]

Datopotamab deruxtecan demonstrated a confirmed objective response rate (ORR) of 42.7% in a pooled analysis of 117 patients with EGFR-mutated NSCLC from the TROPION-Lung05 (n=78) and TROPION-Lung01 (n=39) trials, as assessed by blinded independent central review (BICR). The median duration of response (DOR) was 7.0 months (95% CI: 4.2-9.8) and the disease control rate (DCR) was 86.3%. Median progression-free survival (PFS) was 5.8 months  and median overall survival (OS) was 15.6 months. Results in patients previously treated with osimertinib were similar to the overall pooled population. In 96 patients previously treated with osimertinib, a confirmed ORR of 44.8%, as assessed by BICR was seen. The median DOR was 6.9 months and the DCR was 85.4%. Median PFS was 5.7 months  and median OS was 14.7 months. [2]

Figure 1. TROPION-Lung05 and TROPION-Lung01 efficacy [2]

Telisotuzumab vedotin (Teliso-V, ABBV-399)

Telisotuzumab vedotin (Teliso-V) is a c-Met-targeting ADC developed primarily for the treatment of NSCLC, consisting of an anti-c-Met humanized monoclonal antibody (ABT-700) conjugated via a valine-citrulline linker (ABT-700–vcMMAE) to the cytotoxic agent monomethyl auristatin E (MMAE). It is designed to specifically bind with high affinity to tumor cells that overexpress c-Met and deliver MMAE directly to the tumor cells.

On September 27, 2024, AbbVie announced that it had submitted a BLA to the FDA for telisotuzumab vedotin for the treatment of adult patients with previously treated, c-Met protein-overexpressing, epidermal growth factor receptor (EGFR) wild-type, advanced/metastatic nonsquamous NSCLC. This marks the first ADC targeting c-Met to submit for regulatory approval and is also AbbVie’s first in-house ADC to reach the BLA stage. [3]

The BLA submission is primarily supported by positive results from the single-arm phase II LUMINOSITY trial. The trial demonstrated the following results assessed by independent central review (ICR): [4]

• Overall population: ORR of 28.6%, median DOR of 8.3 months, median OS of 14.5 months, and median PFS of 5.7 months.

• c-Met high: ORR of 34.6%, median DOR of 9.0 months, median OS of 14.6 months, and median PFS of 5.5 months.

• c-Met intermediate: ORR of 22.9%, median DOR of 7.2 months, median OS of 14.2 months, and median PFS of 6.0 months.

Figure 2. Efficacy of phase II LUMINOSITY trial [4]

These promising results highlight telisotuzumab vedotin’s potential as a new treatment option for patients with advanced/metastatic NSCLC.

FDA Rejections of ADCs in 2023 and 2024

Trastuzumab duocarmazine (SYD985)

Trastuzumab duocarmazine (SYD985) is an innovative HER2-targeting ADC composed of trastuzumab, a cleavable linker, and a cytotoxic payload (duocarmycin). It exerts potent anti-tumor effects through its unique mechanism of action.

On July 12, 2022, the BLA for SYD985 was accepted by the FDA for the treatment of HER2-positive, unresectable locally advanced or metastatic breast cancer (la/mBC). However, on May 15, 2023, Byondis announced that it had received a Complete Response Letter (CRL) from the FDA. The CRL indicated that the FDA had suspended its decision on SYD985's approval and requested additional information. [5]

Currently, ClinicalTrials.gov shows that all six clinical trials initiated for SYD985 are either completed or have been withdrawn.

Patritumab Deruxtecan (HER3-DXd) 

Patritumab deruxtecan (HER3-DXd), co-developed by Daiichi Sankyo and Merck, is a potential first-in-class HER3-targeting ADC designed using Daiichi Sankyo's proprietary technology.

In December 2023, Merck and Daiichi Sankyo submitted a BLA for patritumab deruxtecan to the FDA, supported by data from the single-arm, registrational phase II HERTHENA-Lung01 trial, which reported an ORR of 29.8%. The application, granted priority review, seeks approval for treating EGFR-mutated locally advanced or metastatic NSCLC in patients who have received at least two prior systemic therapies. Patritumab deruxtecan is the first HER3-targeting ADC to be submitted for regulatory approval globally.

On June 26, 2024, the FDA issued a Complete Response Letter (CRL) regarding the accelerated approval BLA. The CRL pointed to issues found during inspections of a third-party manufacturing facility but did not identify any concerns with the efficacy or safety data included in the application. [6]

Huateng Pharma is dedicated to being your most reliable partner to provide chemical synthesis and high-quality PEG linkers for ADC drugs. We are committed to promoting the progress of your ADC discovery and development projects.

References:
[1] https://daiichisankyo.us/press-releases/-/article/datopotamab-deruxtecan-new-bla-submitted-for-accelerated-approval-in-the-u-s-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell
[2] https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241206_E.pdf Datopotamab Deruxtecan Demonstrated Meaningful Clinical Activity in Patients with Previously Treated Advanced EGFRMutated Non-Small Cell Lung Cancer in TROPION-Lung05 and TROPION-Lung01 Pooled Analysis
[3] https://news.abbvie.com/2024-09-27-AbbVie-Submits-Biologics-License-Application-to-the-FDA-for-Telisotuzumab-Vedotin-Teliso-V-in-Previously-Treated-Non-Small-Cell-Lung-Cancer
[4] https://ascopubs.org/doi/10.1200/JCO.24.00720 Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein–Overexpressing Advanced Nonsquamous EGFR-Wildtype Non–Small Cell Lung Cancer in the Phase II LUMINOSITY Trial
[5] https://www.cancernetwork.com/view/fda-issues-crl-for-trastuzumab-duocarmazine-in-advanced-her2-breast-cancer
[6] https://www.merck.com/news/patritumab-deruxtecan-bla-submission-receives-complete-response-letter-from-fda-due-to-inspection-findings-at-third-party-manufacturer/