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Antibody-Drug Conjugate Makes Progress as Second-Line Therapy for Advanced NSCLC


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Datopotamab deruxtecan (Dato-DXd), a TROP-2–directed antibody-drug conjugate, improved progression-free survival by 25% on blinded independent committee review in previously treated patients with advanced or metastatic non–small cell lung cancer (NSCLC), and it was reported to be less toxic than standard docetaxel chemotherapy. These results of the TROPION-Lung01 trial were presented at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2023.1

In patients with nonsquamous NSCLC, Dato-DXd reduced the risk of disease progression or death by 37% compared with docetaxel as assessed by blinded independent committee review. Median progression-free survival was 5.6 months with Dato-DXd vs 3.7 months with docetaxel, a modest but clinically meaningful improvement.

“This is a positive trial. Dato-DXd is the first antibody-drug conjugate to demonstrate significantly improved progression-free survival in patients with previously treated locally advanced or metastatic NSCLC. The progression-free survival benefit was primarily driven by nonsquamous histology with or without genomic alterations. There were fewer grade 3 or higher adverse events with Dato-DXd than with docetaxel despite a longer median duration of therapy for Dato-DXd-treated patients. That said, grade 3 or higher interstitial lung disease did occur on trial and warrants monitoring and adherence to guidelines,” stated lead author Aaron Lisberg, MD, a thoracic medical oncologist at the University of California, Los Angeles (UCLA).

Aaron Lisberg, MD

Aaron Lisberg, MD

The current standard of care, second-line chemotherapy docetaxel, has limited benefit along with substantial toxicity. “The improvement in progression-free survival, especially for patients with nonsquamous tumors, and the improved tolerability of this antibody-drug conjugate compared with docetaxel represent a meaningful advance for patients with nonsquamous NSCLC,” Dr. Lisberg added.

Study Details

The study randomly assigned 587 previously treated patients, of whom 57% had one prior line of therapy, 35% had received two lines, and 88% had previously received an immune checkpoint inhibitor. Patients were enrolled regardless of histology or genomic alterations. At baseline, treatment arms were well balanced. About 25% had squamous histology, and 17% had genomic alterations, primarily EGFR alterations.

“At this point, the number of patients on treatment at the time of data cutoff is three times higher with Dato-DXd (18%) than with docetaxel (6%),” Dr. Lisberg said.

Key Results

At a median follow-up of 13 months, median progression-free survival in the overall trial population was longer with Dato-DXd than with docetaxel: 4.4 months vs 3.7 months, respectively (P = .004). At 6 months, in the intention-to-treat population, the rate of progression-free survival was 40.8% with the antibody-drug conjugate vs 28.2% with docetaxel. At 9 months, the corresponding rates were 30.1% and 17.8%, respectively.

All subgroups for age, sex, race, smoking status, and presence of baseline brain metastases had a progression-free survival benefit with Dato-DXd vs docetaxel, with one exception. No benefit in progression-free survival was observed for patients whose tumors had squamous histology over that of docetaxel, whereas those with nonsquamous histology with and without genomic alterations had a progression-free survival benefit with Dato-DXd vs docetaxel.

Progression-free survival was improved with Dato-DXd by 37% in the nonsquamous group: a median of 5.6 months vs 3.9 months, respectively. In those with squamous histology, median progression-free survival was 2.8 months vs 3.9 months, respectively.

The second dual primary endpoint was overall survival, and Dr. Lisberg presented an interim overall survival analysis. Median overall survival was 12.4 months for Dato-DXd vs 11 months with docetaxel. However, patients whose tumors were nonsquamous derived the greatest survival benefit, with a 23% improvement in survival.

Objective response rate in the intent-to-treat population was 26.4% with Dato-DXd vs 12.8% with docetaxel. Median duration of response was 7.1 months vs 5.6 months, respectively. Objective response rate in the nonsquamous population was 31.2% with Dato-DXd vs 12.8% with docetaxel. In those with squamous histology, objective response rates were 9.2% and 12.7%, respectively.

Adverse Events

The most common treatment-related adverse events seen with Dato-DXd were stomatitis (47%, mostly grade 1 or 2) and nausea (34%). Of note, fewer grade ≥ 3 treatment-related adverse events leading to dose reduction or discontinuation were seen with Dato-DXd than docetaxel. “Hematologic toxicity was more frequent with docetaxel, including neutropenia and febrile neutropenia,” Dr. Lisberg added.

The incidence of interstitial lung disease, a concern in NSCLC, was slightly higher with Dato-DXd: all grades, 8% vs 4% with docetaxel. Grade 3 or higher interstitial lung disease was reported in 3% vs 4%, respectively. The rate of infusion-related reactions was 8% in each arm.

Ongoing trials of Dato-DXd in advanced/metastatic NSCLC will be evaluating combinations of the agent with immune checkpoint inhibitors with or without chemotherapy, as potential first-line treatment options. 

DISCLOSURE: The study was sponsored by Daiichi Sankyo and AstraZeneca. Dr. Lisberg has a family member employed by Boston Scientific; owns stock in Boston Scientific; has received research grants from AstraZeneca, Calithera Biosciences, Daiichi Sankyo, Dracen Pharmaceuticals, Duality Biologics, eFFECTOR Therapeutics, and WindMIL; served as consultant or advisor for Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli-Lilly, G1 Therapeutics, IQVIA, Janssen, Jazz Pharmaceuticals, Leica Biosystems, Molecular Axiom, MorphoSys, Novartis, Novocure, Oncocyte, Pfizer, Regeneron, and Sanofi.

REFERENCE

1. Ahn M, et al: ESMO Congress 2023. Abstract LBA12. Presented October 23, 2023.


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