Datopotamab deruxtecan Biologics License Application accepted in the US for patients with previously treated advanced nonsquamous non-small cell lung cancer

AstraZeneca and Daiichi Sankyo’s Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has been accepted in the US for the treatment of adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have received prior systemic therapy.

The Prescription Drug User Fee Act date, the Food and Drug Administration (FDA) action date for its regulatory decision, is during the fourth quarter of 2024.

The BLA is based on results from the pivotal TROPION-Lung01 Phase III trial in which datopotamab deruxtecan demonstrated a statistically significant improvement for the dual primary endpoint of progression-free survival (PFS) compared to docetaxel, the current standard of care, in patients with locally advanced or metastatic NSCLC treated with at least one prior line of therapy.

For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over docetaxel in the overall population; however, results did not reach statistical significance at the time of data cut-off.

In patients with nonsquamous NSCLC, datopotamab deruxtecan showed a clinically meaningful PFS benefit and a numerically favourable OS trend. The trial is ongoing and OS will be assessed at final analysis.

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo. If approved, AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan may be the first TROP2-directed antibody drug conjugate for patients with lung cancer

Key Highlights and Potential Implications:

• The BLA acceptance of Dato-DXd presents a direct high threat in this setting, and it remains to be seen whether other drugs could follow the same regulatory pathway or if either drug will be eventually approved
  • It was previously uncertain whether the FDA would accept the filing for Dato-DXd in 2L+ mNSCLC for two reasons:
    1. The FDA may not accept a filing with only positive PFS data. Because OS was not statistically significant in the powered ITT population (HR=0.90) at interim analysis (IA), it is unclear whether statistically significant PFS (HR=0.75) alone would lead to filing acceptance or approval. TROPION-Lung01 included both PFS and OS as dual primary endpoints, but it is widely accepted that OS would be needed for approval in 2L+ mNSCLC.
    2. The FDA may not accept a filing with only unpowered subgroup analysis. TROPION-Lung01 was not statistically significant for OS in the powered ITT population at IA, and it showed no OS benefit in the Sq sub-population (HR=1.32). However, there was a benefit seen in the Nsq (mOS HR=0.77; mPFS HR=0.63) and AGAs (mPFS HR=0.38) sub-populations
  • The FDA accepted Dato-DXd’s filing based off positive, yet unpowered Nsq results, potentially setting the precedent for the FDA to accept the EVOKE-01 filing based off positive results in an unpowered sub-population. However, because Trodelvy’s EVOKE-01 only includes OS as a primary endpoint, and showed a positive trend but was not statistically significant for OS in the ITT population, it remains to be seen whether the FDA will accept Gilead’s filing.
• Dato-DXd is currently positioned to be first-to-market TROP2 ADC approved to treat patients with Nsq NSCLC after disease progression on prior systemic therapy, and is a direct competitor in 2L+ mNSCLC
  • AZ/DS are expected to announce OS full analysis (FA) for TROPION-Lung01 in H1’24
  • The PDUFA date for Dato-DXd’s potential approval in 2L+ mNSCLC is Dec. 20, 2024, potentially signaling Standard Review. AZ also stated that additional regulatory submissions for Dato-DXd in lung and breast cancer are underway globally, including a pending FDA acceptance of their breast cancer filing
  • Although EVOKE-01 was not statistically significant for OS in the ITT population, the study demonstrated a benefit in patients non-responsive to PD-(L)1 in both Sq and NSq NSCLC patients, potentially leading up to differentiation between Trodelvy’s and Dato-DXd’s addressable populations

Additional Information

• The application is based on the ongoing P3 TROPION-Lung01 ESMO’23 results where Dato-DXd showed statistically significant but not clinically meaningful improvement in PFS compared to docetaxel (SoC) in locally advanced or metastatic NSCLC treated with at least one prior line of therapy. OS benefit did not reach statistical significance at the time of data cut-off
  • Dato-DXd only demonstrated a clear benefit in the NSq population (mPFS HR=0.63; mOS HR=0.77), and there was no benefit observed in the Sq population (mPFS HR=1.38; mOS HR=1.32) 
  • Within the NSq population, the positive results were also boosted by the benefit seen in patients with AGAs (AGAs: HR=0.38 vs No AGAs: HR=0.84)
  • TROPION-Lung01’s OS was not mature at IA (HR=0.90) and will continue to FA OS readout. However, it appears unlikely OS will be positive in the overall population
• At ESMO’23, the safety profile for Dato-DXd in TROPION-Lung01 looked generally consistent to previous data from Dato-DXd monotherapy, but it is important to note that stomatitis and ILD are still a major concern  
  • ILD/pneumonitis rates (all-grade 8%; Gr3+ 3%) were numerically lower than what was seen in early phase Dato-DXd monotherapy studies, but there were still 7 adjudicated deaths due to ILD 
  • Stomatitis rates (all-grade 54%; Gr3+ 6%) were generally consistent with previous safety data but present a concern when considering patient QoL  
  • Discontinuation rate (8%) is numerically lower than that seen in previous trials 
• Results from the P3 TROPION-Lung01 were presented at ESMO in October 2023 (Abstract # LBA12, Lisberg et al.) 
  • Study Information
    • P3 TROPION-Lung01 (NCT04656652): 2L/3L Dato-DXd (TROP2 ADC) vs docetaxel in prior CPI and chemo, adv./mNSCLC
    • N=604
    • 1EP: PFS and OS
    • 2EP: ORR, DOR, AEs
    • Efficacy (Dato-DXd vs. docetaxel)
      • mPFS (mos): 4.4 vs 3.7 mo (HR=0.75)
        • Nsq: 5.6 vs 3.7 mo (HR=0.65)
        • Sq: 2.8 vs 3.9 mo (HR=1.38)
      • mOS (mos): 12.4 vs 11.0 mo (HR=0.90; interim analysis)
        • Nsq HR=0.77
        • Sq HR=1.32
      • ORR: 26% vs 13%
        • Nsq: 31% vs 13%
        • Sq: 9% vs 13%
      • Safety (Dato-DXd vs. docetaxel)
        • GR 3+ TRAEs: 25% vs 41% 
        • TRAES associated with 
          • Dose reduction: 20% vs 29% 
          • Discontinuation: 8% vs 12% 
          • Death: 1% vs 1% 
        • AEs of special interest: 
          • ILD/pneumonitis: 8% (Gr3+ 3%, Gr5 2% [7 pt deaths]) vs. 4% (Gr3+ 1%, Gr5 0.3%[1 pt death]) 
          • Mucositis/stomatitis: 54% (Gr3+ 6%) vs. 20% (Gr3+ 1%) 
          • Anemia: 15% (Gr3+ 4%) 
          • Ocular surface toxicity: 19% (Gr3+ 2%) vs. 9% (Gr3+ 0%) 
          • IRRs: 8% (1 patient Gr3+) 

source: Press Release