12 August 2022 - Project Optimus is another initiative of the FDA Oncology Center of Excellence.

On 11 August 2022, the FDA granted accelerated approval to trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo) for the treatment of adult patients with unresectable or metastatic non-small-cell lung cancer whose tumours have activating human epidermal growth factor receptor 2 HER2 (ERBB2) mutations, as detected by an FDA approved test, and who have received a prior systemic therapy.

Efficacy for the accelerated approval was based on DESTINY-Lung02, a multi-centre multi-cohort, randomised, blinded, dose-optimisation trial.

This application used advice from the FDA Oncology Center of Excellence's Project Optimus to conduct a dose randomisation trial, which led to a lower dose being approved.

Project Optimus is an initiative to reform the dose optimisation and dose selection paradigm in oncology drug development. According to the FDA "too often, the current paradigm for dose selection—based on cytotoxic chemotherapeutics—leads to doses and schedules of molecularly targeted therapies that are inadequately characterised before initiating registration trials."

That all sounds great BUT:

• Trastuzumab deruxtecan has been approved (albeit under accelerated approval) for a major new indication without any comparative evidence. The approval letter states that Daiichi Sankyo needs to "complete a clinical trial to obtain data on the clinical efficacy of famtrastuzumab deruxtecan-nxki for the treatment of patients with unresectable or metastatic non-small cell lung cancer whose tumours have an activating HER2 (ERBB2) mutation and have previously received systemic therapy, to provide a more precise estimation of the blinded independent central review-assessed overall response rate and duration of response." The letter does not name the trial but presumably it is the DESTINY-Lung02 trial. The letter also states that Daiichi Sankyo also conduct a multi-centre, randomised clinical trial of fam-trastuzumab deruxtecan-nxki in patients with treatment naïve, unresectable or metastatic non-small-cell lung cancer whose tumours have an activating HER2 (ERBB2) mutation. This trial is not named in the letter but presumably is the DESTINY-Lung04 trial.
• There appears to be no planned comparative clinical trials of trastuzumab deruxtecan in the second-line setting. The DESTINY-Lung03 trial is a non-randomised Phase 1b study and the DESTINY-Lung05 trial is a single-arm Phase 2 study.

This does not bode well for comparative benefit assessments. A suitable control group will have to be found somewhere; does one exist? To those who will need to find one, we way "good luck."

In the light of the recent brouhaha about accelerated approvals for cancer medicines and the (accelerated) approval of aducanumab for patients with Alzheimer's disease, has the FDA done the right thing here? While it might have done the right thing for some patients (and others) in the US, we think it has done a misservice (Project SubOptimus) for others in the US and many people outside the US.  Our concerns may be somewhat moot if trastuzumab deruxtecan is never registered for the second-line treatment of patients with HER2 mutation positive non-small-cell lung cancer outside the US. We will monitor this situation closely; it is very early days.

We will continue to all FDA approvals supported by advice from Project Optimus.

Read FDA News