Two critical FDA approvals in 2024 included the tumor-agnostic ones of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and repotrectinib (Augtyro), the first of which changed the field for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who received prior systemic treatment and have no satisfactory alternative treatment options.1,2 The latter targeted therapy provided another option for those with an NTRK gene fusion who have experienced disease progression following treatment or have no satisfactory standard therapy and who have metastatic disease or disease where surgical resection is likely to result in severe morbidity.2-4

We compiled "cheat sheets" for each approval, rounding up everything you need to know about the agents and their safety/efficacy in the many solid tumors they were examined in. Keep reading and see below for a PDF version of the sheet!

T-DXd

FDA approval—April 5, 2024

The FDA granted accelerated approval to T-DXd for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.1 This accelerated approval is based on the agent’s objective response rate and duration of response.

Mechanism of action

T-DXd is a HER2-directed antibody-drug conjugate; the antibody is a humanized anti-HER2 IgG1, and the small molecule DXd is a topoisomerase I inhibitor attached to the antibody via a cleavable linker.5

Recommended dosing for this indication

5.4 mg/kg given as an intravenous infusion once every 3 weeks in a 21-day cycle until disease progression or unacceptable toxicity1

Pivotal clinical trials

DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) were phase 2 trials conducted examining T-DXd in adults with previously treated unresectable or metastatic HER2-positive solid tumors.1

• Patients were excluded from the trials if they had:
  • A history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease
  • Active brain metastases
  • An ECOG performance status of greater than 1

Boxed Warning

• T-DXd has boxed warnings for ILD and pneumonitis, as well as embryo-fetal toxicity.5

Repotrectinib

FDA approval—June 13, 2024

The FDA granted accelerated approval to repotrectinib for the treatment of patients 12 years or older with locally advanced or metastatic solid tumors harboring an NTRK gene fusion or where surgical resection is likely to result in severe morbidity and who have progressed after treatment or have no satisfactory alternative therapy.2

Mechanism of action

Repotrectinib is a ROS1 inhibitor.6

Recommended dosing for this indication

160 mg given orally once daily for 14 days, then increased to twice daily until disease progression or unacceptable toxicity2

Pivotal clinical trial

TRIDENT-1 (NCT03093116) was a multicenter, single-arm, open-label, phase 1/2 trial conducted in adults with locally advanced or metastatic NTRK gene fusion–positive solid tumors examining repotrectinib.2

Download the cheat sheets as a PDF below!

References

1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed January 13, 2025. bit.ly/3UYSKqk
2. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed January 13, 2025. bit.ly/4eGQtr4
3. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed January 10, 2025. bit.ly/4gNsvMp
4. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Updated August 16, 2019. Accessed January 10, 2025. bit.ly/3DPv1U1
5. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2024. Accessed January 13, 2025. bit.ly/42e1m12
6. Augtyro. Prescribing information. Bristol Myers Squibb; 2024. Accessed January 13, 2025. bit.ly/4aebIjo