Back Back
TROP2 ADCs for NSCLC 2023
Progress in the Development of Antibody–Drug Conjugates Targeting TROP-2 for Advanced NSCLC

Released: July 19, 2023

Yasushi Goto
Yasushi Goto, MD, PhD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • The TROP-2–targeting ADCs datopotamab deruxtecan and sacituzumab govitecan are under active development for the management of advanced NSCLC, with overall response rates in the range of 15% to 30% in the setting of heavily pretreated disease.
  • Differences in notable adverse events have been observed in patients receiving datopotamab deruxtecan and sacituzumab govitecan.
  • Updated preliminary data from the phase Ib TROPION-Lung02 trial showed that combination therapy with datopotamab deruxtecan and pembrolizumab was safe and yielded encouraging efficacy in the first-line setting.
  • Ongoing trials of datopotamab deruxtecan and sacituzumab govitecan, including randomized phase III trials, aim to further evaluate the efficacy and safety of these TROP-2 ADCs across the spectrum of NSCLC.

Antibody–drug conjugates (ADCs) targeting the transmembrane protein TROP-2, including datopotamab deruxtecan and sacituzumab govitecan, have emerged as a potential treatment option for patients with advanced non-small-cell lung cancer (NSCLC), with overall response rates (ORRs) in the range of 15% to 30% in the setting of heavily pretreated disease. In this commentary, Yasushi Goto, MD, PhD, discusses progress in the development of these agents for NSCLC, including differences in key toxicities between these TROP-2 ADCs, promising early results for datopotamab deruxtecan in the frontline setting, and directions for future research.

Comparing Toxicities Between Datopotamab Deruxtecan and Sacituzumab Govitecan

Key differences in notable toxicities between datopotamab deruxtecan and sacituzumab govitecan have emerged, likely attributable to their different chemotherapy payloads. Stomatitis, dry eye, and interstitial lung disease are among the most common notable adverse events (AEs) associated with datopotamab deruxtecan, whereas diarrhea and neutropenia are associated with sacituzumab govitecan. AEs common with chemotherapy that are observed with both of the TROP-2 ADCs include fatigue, alopecia, and nausea.

ASCO 2023 Update of Phase Ib TROPION-Lung02 Trial: Datopotamab Deruxtecan + Pembrolizumab ± Platinum-Based Chemotherapy for Advanced NSCLC

Early-phase studies of datopotamab deruxtecan have shown promising results in patients with heavily pretreated advanced NSCLC. When used as monotherapy, datopotamab deruxtecan achieved an ORR of 28% at a dose of 6 mg/kg and a median duration of response of 10.5 months. These results led to trials of datopotamab deruxtecan in combination treatment, including the phase Ib TROPION-Lung02 study evaluating the combination of datopotamab deruxtecan plus the PD-1 inhibitor pembrolizumab with or without platinum-based chemotherapy in patients with previously untreated or treated advanced/metastatic NSCLC.

Preliminary data from TROPION-Lung02 showed ORRs in the overall patient population of 37% (median follow-up: 6.5 months) with the doublet combination of datopotamab deruxtecan plus pembrolizumab and 41% (median follow-up: 4.4 months) with the triplet combination of datopotamab deruxtecan, pembrolizumab, and platinum-based chemotherapy. For patients who had not been previously treated, ORRs of 62% and 50% were observed with doublet and triplet therapy, respectively.

Updated data from this study were presented at ASCO 2023. With a data cutoff of April 7, 2023, the study duration for doublet therapy with datopotamab deruxtecan plus pembrolizumab was 14.8 months (range: 1.0-30.2), and it was 12.9 months (range: 2.6-23.4) for triplet therapy with datopotamab deruxtecan, pembrolizumab, and platinum-based chemotherapy. In the overall patient population, ORRs of 38% and 49% were achieved with doublet and triplet therapy, respectively. In the first-line setting, an ORR of 50% was demonstrated among 34 patients who received doublet therapy, and an ORR of 57% was demonstrated among 53 patients who received triplet therapy. Median duration of response has not been reached for any group in the study.

Treatment-emergent AEs led to discontinuation of datopotamab deruxtecan in 23% and 28% of patients receiving doublet and triplet therapy, respectively. The most common AE of special interest was stomatitis, with an incidence of 58% with doublet therapy and 43% with triplet therapy. Interstitial lung disease occurred in 17% and 22% of patients, respectively, and was generally grade 1 or 2, with no attributable deaths. Ocular toxicities, mostly cases of dry eye, were seen in 16% and 24% of patients, respectively.

Ongoing Trials Evaluating TROP-2 ADCs for NSCLC

Based on the promising results seen so far, ongoing trials of datopotamab deruxtecan (Table 1) and sacituzumab govitecan (Table 2), including randomized phase III trials, aim to further evaluate the efficacy and safety of these TROP-2 ADCs across the spectrum of NSCLC in the hope of bringing much-needed new treatment options to the clinic for our patients.

 

Your Thoughts?

Which study evaluating datopotamab deruxtecan and sacituzumab govitecan in NSCLC are you most excited about? Please answer the polling question and join the conversation by posting a comment.

Continue

Poll

1.

In your practice, how often do you discuss clinical trials investigating ADCs with your patients with advanced NSCLC?

Submit