FDA Accepts BLA for Datopotamab Deruxtecan for Nonsquamous NSCLC

Datopotamab deruxtecan (Dato-DXd; Daiichi Sankyo and AstraZeneca) is the latest antibody drug conjugate (ADC) up for review with the FDA. The FDA accepted a biologics license application (BLA) for the TROP2-directed ADC for the treatment of adults with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) who have received prior systemic therapy.¹

If approved, Dato-DXd could be the first TROP2-directed ADC in lung cancer. The action date for an FDA decision is December 20, 2024. Currently, the standard of care in metastatic NSCLC is second-line chemotherapy; however, this provides modest benefits and significant toxicity.

ADCs are designed to deliver a potent, cancer-fighting payload into a tumor while sparing nearby tissues.²

“Datopotamab deruxtecan has the potential to offer patients with previously treated advanced nonsquamous non-small cell lung cancer an effective and tolerable alternative to conventional chemotherapy,” Susan Galbraith, PhD, executive vice president, Oncology R&D, AstraZeneca, said in a statement.¹

The application is based on the results from the pivotal TROPION-Lung01 phase 3 trial that were presented by Aaron Lisberg, MD, assistant clinical professor of medicine, University of California, Los Angeles, at the 2023 European Society for Medical Oncology (ESMO) Congress, held October 20-24, 2023.³

TROPION-Lung01 is an ongoing global, randomized, multicenter, open-label phase 3 trial comparing the safety and efficacy of Dato-DXd with docetaxel in patients with metastatic NSCLC with or without actionable genomic mutations.

According to the results presented at ESMO, there was a statistically significant improvement in progression-free survival (PFS) for patients on Dato-DXd. The median PFS was 4.4 months for Dato-DXd vs 3.7 months for docetaxel (HR, 0.75; 95% CI, 0.62-0.91). Dato-DXd also showed a superior objective response rate of 26.4% compared with 12.8% for docetaxel.

Patients on Dato-DXd also had a longer duration of response (7.1 vs 5.6 months) and stayed on treatment longer. More than half of patients on docetaxel discontinued treatment within 3 months compared with 40% on Dato-DXd.

Treatment-related adverse events of grade 3 or higher occurred in 25% of patients on Dato-DXd vs 41% on docetaxel, and only 8% of patients on Dato-DXd discontinued their treatment compared with 12% on docetaxel.

According to the subgroup analysis, patients with nonsquamous NSCLC clearly derived a benefit compared with patients with squamous cancer. The median PFS for patients on Dato-DXd was 5.6 months for nonsquamous NSCLC vs 2.8 months for squamous NSCLC.

In his ESMO presentation, Lisberg said it was clear that the PFS benefit observed in the overall trial was “primarily driven by patients with nonsquamous histology.”

At ESMO, results of TROPION-Breast01 were also presented³ that showed Dato-DXd delivered statistically significant and clinically meaningful improvements in PFS over chemotherapy in hormone receptor–positive/HER2-negative (HER2–) breast cancer. A BLA is already under review for Dato-DXd in the treatment of adults with metastatic hormone receptor–positive/HER2-negative breast cancer, according to the pharma companies.¹

Daiichi Sankyo and AstraZeneca also jointly developed trastuzumab deruxtecan (Enhertu), which received its latest approvalin August 2022⁴ to treat adults with unresectable or metastatic HER2-low breast cancer (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-). The first approval came in December 2019 for the treatment of HER2+ unresectable or metastatic breast cancer following at least 2 previous lines of anti–HER2-based regimens.⁵

Now, trastuzumab deruxtecan is being reviewed by the FDA² for the treatment of adults with HER2+ solid tumors who previously received treatment or have no other options. If granted, this would be the first tumor-agnostic approval for an ADC.

References

1. Datopotamab deruxtecan Biologics License Application accepted in the US for patients with previously treated advanced nonsquamous non-small cell lung cancer. AstraZeneca. News release. February 19, 2024. Accessed February 19, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/fda-accepts-dato-dxd-bla-for-nonsquamous-nsclc.html

2. Caffrey M. Priority review granted for trastuzumab deruxtecan; would be first tumor-agnostic ADC. The American Journal of Managed Care^®. January 30, 2024. Accessed February 19, 2024. https://www.ajmc.com/view/priority-review-granted-for-trastuzumab-deruxtecan-would-be-first-tumor-agnostic-adc

3. Joszt L. TROPION-Breast01, TROPION-Lung01 demonstrate PFS benefit of datopotamab deruxtecan in metastatic breast cancer, NSCLC. The American Journal of Managed Care. October 23, 2023. Accessed February 19, 2024. https://www.ajmc.com/view/tropion-breast01-tropion-lung01-demonstrate-pfs-benefit-datopotamab-deruxtecan-metastatic-breast-cancer-nsclc

4. Caffrey M. Trastuzumab deruxtecan wins rapid approval for HER2-low breast cancer. The American Journal of Managed Care. August 6, 2022. Accessed February 19, 2024. https://www.ajmc.com/view/trastuzumab-deruxtecan-wins-rapid-approval-for-her2-low-breast-cancer

5. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. News release. December 20, 2019. Accessed February 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer