Daiichi Sankyo and AstraZeneca have applied to the FDA for their second-generation ADC, datopotamab deruxtecan (Dato-DXd). However, the latest clinical information prevents it from achieving approval. Dato-DXd, an antibody-drug conjugate that targets TROP2, follows Enhertu and focuses on non-squamous non-small cell lung cancer (NSCLC).
The application for FDA approval was submitted in February, with decisions expected by year-end. Moreover, a clinical application for HR-positive, HER2-negative breast cancer has also been made.
The lung cancer data submission is based on the TROPION-Lung01 trial, a phase 3 study. This trial showed that the median progression-free survival (PFS) of patients who received Dato-DXd treatment was 5.6 months, compared with 3.7 months among patients who received the chemotherapy drug docetaxel. While Dato-DXd was also tested in patients with squamous NSCLC, the study did not reveal any PFS advantage in this group, allowing for a more targeted use in non-squamous cases.
Recently, the companies released overall survival (OS) data from the trial. The survival data were “numerically favorable” to Dato-DXd, but the difference was not statistically significant. However, the drugmakers pointed out that in the subset of patients with non-squamous NSCLC, a statistically significant and ‘clinically relevant’ OS benefit was achieved.
The firms claim that the trial outcomes support the ongoing registration applications with U.S. and EU agencies. In his presentation in February 2018, Dr. Ken Takeshita, M.D., the Chief of R&D at Daiichi, noted that Dato-DXd could be a major treatment for advanced non-squamous NSCLC. He mentioned the advantages of the drug, including overall survival, progression-free survival, overall response rate, and duration of response compared to docetaxel.
Susan Galbraith, Ph.D., AstraZeneca’s Executive Vice President of Oncology R&D, expressed similar sentiments. She underscored how the findings support the use of Dato-DXd in place of conventional chemotherapy in later lines and increase confidence in current trials for first-line lung cancer therapies.
Mr. David Fredrickson, the Executive Vice President of OBU, AstraZeneca, in an earlier interview also maintained a cautiously optimistic outlook toward the last OS data set from the TROPION-Lung01 trial. He explained that while the observed trend was positive, it might be necessary to consult with regulatory authorities if the results fail to meet expectations.
Following the new OS data, an AstraZeneca representative stated positively on the ongoing talks with the FDA, especially based on the statistically significant OS benefit seen in non-squamous NSCLC patients and the better tolerability profile of Dato-DXd compared to docetaxel.
During the TROPION-Lung01 trial, certain issues such as interstitial lung disease-related deaths were reported at the previous ESMO Congress. Fredrickson noted that the FDA would consider these as adverse events and expressed confidence in the measures put in place to manage ILD, citing their experience with Enhertu.
Dato-DXd, a first-generation ADC targeting TROP2, aims to obtain approval in NSCLC. Its performance, however, contrasts with that of Trodelvy, Gilead Sciences’ main competitor, which did not show a statistical OS advantage in its phase 3 trial for lung cancer.
