AstraZeneca and Daiichi Sankyo have shared the data they believe can secure approval for datopotamab deruxtecan (Dato-DXd) at the second attempt. The partners showed off subgroup overall survival data that exceeded the result seen in the broader population, providing evidence to support the pivot.
Originally, the partners applied for FDA approval of the antibody-drug conjugate (ADC) in patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). Last month, AstraZeneca and Daiichi withdrew that filing and resubmitted for approval in a subset of patients with EGFR-mutated NSCLC. The companies used the ESMO Asia Congress 2024 in Singapore to showcase the data behind the change of plan.
The analysis pooled EGFR-mutated patients from two trials of the TROP2-directed ADC Dato-DXd. Across the two studies, median overall survival (OS) in patients with EGFR-mutated NSCLC was 15.6 months.
AstraZeneca and Daiichi included 117 patients in the analysis: 78 from a phase 2 study in patients with actionable genomic alterations and 39 from a broader phase 3 trial. Median OS in the overall population of the phase 3 trial was 12.9 months, a result that was statistically no better than the 11.8 months seen in the control arm.
Median progression-free survival (PFS) was numerically higher in the pooled analysis, 5.8 months, than the phase 3 trial, 4.4 months. And a bump in the response rate, from 26.4% to 42.7%, wrapped up a set of data that suggests Dato-DXd is more effective as a later-line treatment in people with EGFR-mutated NSCLC than in the wider patient population.
The results were similar in the 96 patients who had previously received AstraZeneca’s Tagrisso, a first-line treatment for EGFR-mutated NSCLC. The response rate, PFS and OS in those patients came in at 44.8%, 5.7 months and 14.7 months, respectively.
Patients who progress on Tagrisso have a range of resistance mechanisms, and there remains a need for better treatments. Johnson & Johnson is among the companies targeting the opportunity. At the second interim analysis of a phase 3 trial, median OS was 17.7 months in people who received J&J’s Rybrevant and chemotherapy, compared to 15.3 months in the chemo control group.
AstraZeneca and Daiichi achieved their OS result without the use of chemotherapy. The safety profile in the pooled analysis was consistent with the broader trials, with 23% of patients having grade 3 or higher treatment-related adverse events. No grade 4 or 5 events of special interest—stomatitis, ocular surface events or adjudicated drug-related interstitial lung disease—occurred.
Susan Galbraith, Ph.D., executive vice president of oncology R&D at AstraZeneca, discussed what the FDA made of the data on an earnings call after disclosing the withdrawal and resubmission last month. The FDA has “noted the favorable benefit risk profile in EGFR-mutated lung cancer,” Galbraith said, and “is interested in the particular subgroups where the greatest benefit is seen.” That interest led the FDA to EGFR.
“There's, not just within the [phase 3] TLO1 study, but, obviously, within the single-arm [phase 2] TLO5 study, really very robust activity that we've seen within the patients with actionable genomic alterations and, in particular, those with EGFR mutations,” Galbraith said. “I think what you're seeing is a reflection of trying to focus initially on the subgroup where ... the greatest benefit is.”
That focus has deprived AstraZeneca and Daiichi of a shot at the broader population for now. But the partners have evidence of efficacy in the subgroup and are running trials that could expand use of the ADC.