Enhertu successor advances toward US approval in non-squamous lung cancer
19 Feb 2024
Clinical ResultPhase 3ADCPhase 2Priority Review
AstraZeneca is looking to make up some ground after a rather shaky start to 2024, announcing a flurry of positive lung cancer news on Monday, including that the FDA has agreed to review datopotamab deruxtecan (dato-DXd) for second-line, locally advanced or metastatic non-squamous lung cancer patients.
While the focus on the non-squamous population is not a major surprise given results from the supporting Phase III trial, the FDA's decision to go ahead and accept the application without overall survival (OS) data in hand might come as a bit of welcome news for investors. Susan Galbraith, who heads oncology R&D at AstraZeneca, said the TROP2-directed antibody-drug conjugate (ADC) could offer patients "an effective and tolerable alternative to conventional chemotherapy."
Recall that AstraZeneca and its partner Daiichi Sankyo reported results from the TROPION-Lung01 study showing a modest progression-free survival (PFS) benefit of less than one month and no OS benefit with dato-DXd in the overall population, compared to docetaxel. However, certain groups in the trial performed better; non-squamous patients who make up about 75% of NSCLC patients had a PFS extension of 1.9 months, or a 37% reduction in the risk of disease progression or death, while those with some actionable genomic alterations, particularly EGFR, saw a benefit of 4.2 months.
Non-squamous patients on dato-DXd also showed a "numerically favourable OS trend," the companies said. By contrast, there was no PFS benefit with dato-DXd among patients with squamous NSCLC, who also appeared to fare worse than the docetaxel arm. TROPION-Lung01 is ongoing and OS will be assessed at final analysis. In a recent note, Macquarie analysts said they "continue to believe the TROPION-Lung01 overall survival data will be positive."
There were also several cases of interstitial lung disease (ILD) deaths in the trial, including four among non-squamous patients.
PDUFA data in Q4
AstraZeneca and Daiichi Sankyo anticipate a decision in the fourth quarter, and if approved, dato-DXd could become the first TROP2-directed ADC used in lung cancer treatment. When the TROPION-Lung01 data were detailed late last year, BMO Capital markets analysts highlighted one key opinion leader (KOL) as saying that an approval in patients with non-squamous histology would be sufficient for using dato-DXd over chemotherapy if the PFS benefit seen in TROPION-Lung01 remains consistent.
The drug is a follow up to the companies' ADC Enhertu (fam-trastuzumab deruxtecan-nxki), which is approved for several caner types including HER2-mutant metastatic non-small-cell lung cancer (NSCLC) in 2022. Galbraith noted that regulatory discussions are ongoing around the world, while a parallel submission for dato-DXd is underway in the US in breast cancer based on the Phase III TROPION-Breast01 trial.
AstraZeneca and Daiichi Sankyo are looking to expand Enhertu's label for use as a pan-tumour ADC. The FDA recently granted a priority review for that filing based on data from the ongoing Phase II DESTINY-PanTumor02 study.
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