Avvio in EMA dell'iter registrativo per datopotamab deruxtecan nel cancro del polmone non squamoso localmente avanzato o metastatico e nel cancro al seno HR positivo/HER2 negativo

On March 4^th, 2024, AstraZeneca and Daiichi Sankyo announced that the European Medicines Agency (EMA) validated two marketing authorization applications (MAAs) for datopotamab deruxtecan (Dato-DXd; TROP2 ADC) in two types of cancer, including locally advanced or metastatic non-squamous (Nsq) NSCLC in pre-treated patients and HR Positive, HER2 Negative breast cancer patients who have progressed on and are not suitable for endocrine therapy and received at least one additional systemic therapy.

The submission of two MAAs instead of packaging both indications into one MAA likely allows AZ the flexibility for the MAAs to proceed on two different timelines (e.g., while waiting for OS to mature) or pull one of the filings if needed (e.g., if OS is negative and it appears that an application will not be approved).

EMA approval currently projected for both indications in Q1’25.

Implications for Breast Cancer

• With this submission, Dato-DXd is now positioned to be the second TROP2 ADC to market in the EU in HR+/HER2- BC behind Trodelvy 
  • Dato-DXd has the ability to enter the HR+/HER2- mBC setting in an earlier LoT compared to Trodelvy’s current label; however, Trodelvy potentially has a current advantage with statistically significant OS, and may also move up to the chemo-naïve setting in the future with the ongoing P3 ASCENT-07 study
  • While TROPION-Breast01 demonstrated higher mPFS compared to Trodelvy in TROPiCS-02 (mPFS: 6.9 mo vs 5.5 mo), this is likely due to the study population being less heavily pre-treated given the HR did not significantly favor Dato-DXd (HR: 0.63 vs 0.66)
• The submission was based on data from the Phase 3 TROPION-Breast01 trial presented at ESMO 2023 which was positive for PFS while OS remained immature; the companies made no mention of additional mature OS data
• In the press release, the companies reiterated that regulatory submission in the US (still awaiting FDA acceptance) and other global geographies for Dato-DXd in HR+/HER2- mBC are currently underway

Implications for NSCLC

• The MAA acceptance of Dato-DXd presents a direct high threat in this setting, and it remains to be seen whether Trodelvy could follow the same regulatory pathway or if either drug will be eventually approved
  • It was previously uncertain whether the EMA would accept the filing for Dato-DXd in 2L+ Nsq mNSCLC for several reasons:
    1. The EMA 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 EMA 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 EMA accepted Dato-DXd’s filing based off positive, yet unpowered Nsq results, potentially suggesting that the EMA could 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 EMA will accept Gilead’s filing.
• Even if approved, it remains uncertain whether individual EU member states will reimburse Dato-DXd in 2L+ Nsq mNSCLC given lack of clinically meaningful benefit and the high cost in comparison to docetaxel
• The MAA for NSCLC is based on the ongoing P3 TROPION-Lung01 trial 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 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 to Trodelvy in 2L+ mNSCLC
  • AZ and Daiichi have stated that OS full analysis for TROPION-Lung01 is expected to read out H1’24
  • AstraZeneca and Daiichi previously announced that the FDA accepted the BLA for Dato-DXd in 2L+ Nsq mNSCLC and has set a PDUFA date of 20^th December, 2024
  • 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