Daiichi Sankyo and antibody-drug conjugate (ADC) partner AstraZeneca have already filed their Enhertu follow-up Dato-DXd with the FDA, but the latest clinical readout has cast a shadow over the application.
Datopotamab deruxtecan, or Dato-DXd for short, is a TROP2-directed ADC from the same production line that delivered the blockbuster Enhertu. The FDA accepted an application for Dato-Dxd as a treatment for non-squamous non-small cell lung cancer (NSCLC) in February, with a decision not expected until the end of this year. An approval application in HR-positive, HER2-negative breast cancer has also been submitted to the FDA.
The lung cancer submission is based on data from the phase 3 TROPION-Lung01 trial, which showed that median progression-free survival (PFS)—one of the study’s primary endpoints—was 5.6 months in patients treated with Dato-DXd versus 3.7 months among those treated with the chemotherapy docetaxel.
The trial also assessed Dato-DXd in patients with squamous NSCLC, but it didn’t demonstrate a PFS benefit in this group, resulting in the more limited non-squamous application that the FDA accepted.
Now, the companies have revealed the high level overall survival (OS) results from the same trial, and it doesn’t make for happy reading. When assessed across the overall trial population, the survival results “numerically favored” Dato-DXd “but did not reach statistical significance,” they said.
While the drugmakers didn’t go into more details about the OS data, they were keen to point out that a “clinically meaningful” improvement in OS against docetaxel was seen when they drilled down into the subgroup of patients with nonsquamous NSCLC.
The trial’s results still support the ongoing approval applications with U.S. and EU regulators, both companies stressed in the May 27 release.
“The improvement in overall survival seen with datopotamab deruxtecan coupled with the previously reported clinically meaningful progression-free survival, more than doubling of overall response and prolonged duration of response compared to docetaxel suggest that this TROP2-directed antibody-drug conjugate could potentially become an important new treatment for patients with nonsquamous non-small cell lung cancer in this advanced setting,” Daiichi’s global head of R&D Ken Takeshita, M.D., said in the release.
“These data will support our ongoing discussions with regulatory authorities globally to potentially bring datopotamab deruxtecan to patients as quickly as possible and mark another step forward in creating new standards of care for patients with cancer,” Takeshita added.
“These results reinforce the potential for datopotamab deruxtecan to replace conventional chemotherapy in this late-line setting and underscore our confidence in ongoing trials evaluating this therapy in first-line lung cancer,” said Susan Galbraith, Ph.D., executive vice president of oncology R&D at AstraZeneca.
Speaking to Fierce Biotech in February, David Fredrickson, executive vice president of AstraZeneca’s oncology business unit, avoided any firm promises about the final OS data for the TROPION-Lung01 study.
“Maintaining the trend that we’ve seen so far would certainly be very positive,” Fredrickson said at the time. “If it goes the other way, then that would be a separate review discussion that we’d have with the agency, obviously.”
When reached for comment yesterday to see whether the latest OS results would impact the approval application, a spokesperson for AstraZeneca said: “We are encouraged by our discussions with the agency to date and further by these results in patients with nonsquamous NSCLC, particularly the clinically meaningful OS improvement and the consistent and favourable safety profile of datopotamab deruxtecan compared to docetaxel.”
The TROPION-Lung01 trial has already raised other issues in the past, most notably an undetermined number of deaths attributed to interstitial lung disease that AstraZeneca and Daiichi discussed at last year’s European Society for Medical Oncology (ESMO) Congress.
In his same conversation with Fierce Biotech three months ago, Fredrickson accepted that the FDA will be taking these adverse events into account as part of its decision-making process, but he sounded confident in the solution the companies set out at that conference.
“Interstitial lung disease is certainly a serious adverse event and one that needs to be well understood,” Fredrickson said at the time. “We were able to characterize and understand it in a way that we think allows for the awareness and monitoring programs that we’ve been working on for Enhertu to also be similarly applied to this program.”
The prize at stake is to become the first TROP2-targeted ADC to reach NSCLC. The other main contender was Gilead Sciences’ Trodelvy, which was also unable to demonstrate a statistically significant OS benefit in a phase 3 lung cancer trial.