FDA grants accelerated approval to Enhertu (trastuzumab deruxtecan) for unresectable or metastatic HER2-positive solid tumors. First HER2-directed therapy and antibody drug conjugate with a tumour-agnostic indication.

On April 5, 2024, the Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

Full prescribing information for Enhertu are posted here.

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of:

- adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:

o in the metastatic setting, or

o in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy.

- adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

- adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.*

- adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. (1.4) - adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.*

* These indications are approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 

Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status >1. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.

The major efficacy outcome measure in all three trials was confirmed objective response rate (ORR), and an additional efficacy outcome was duration of response (DOR). All outcomes were assessed by independent central review (ICR) based on RECIST v1.1. In DESTINY-PanTumor02, ORR was 51.4% (95% CI: 41.7, 61.0) and median DOR was 19.4 months (range 1.3, 27.9+). In DESTINY-Lung01, ORR was 52.9% (95% CI: 27.8, 77.0) and median DOR was 6.9 months (range 4.0, 11.7+). In DESTINY-CRC02, ORR was 46.9% (95% CI: 34.3, 59.8), and DOR was 5.5 months (range 1.3+, 9.7+).

The most common adverse reactions (≥20%), including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea,  decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. The prescribing information includes a Boxed Warning advising health professionals of the risk of interstitial lung disease and embryo-fetal toxicity.

The recommended fam-trastuzumab deruxtecan-nxki dosage for this indication is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

This tumor agnostic indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, where FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and Singapore’s Health Sciences Authority (HSA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application almost 2 months ahead of the FDA goal date. This application was granted Priority Review and Breakthrough Therapy Designation. 

Key Highlights:

• US accelerated approval was based on ORR and DOR results from the P2 DESTINY-PanTumor02 trial where Enhertu monotherapy showed benefit across multiple HER2-expressing, previously treated solid tumors including mUC and GYN tumors (endometrial, cervical, ovarian)
  • Path for confirmatory approvals remains unclear, with no commentary on postmarket requirements
• mUC: Enhertu could compete with Trodelvy in the 2L+ setting but restriction to an IHC 3+ population (est. up to ~15% mUC) and other key limitations may temper competitive impact
  • With results from a P3 mUC-specific trial, Trodelvy will have an advantage over Enhertu’s much smaller dataset
    • Enhertu’s label only includes N=27 mUC patients and cORR in the label is lower (37%) than shared in prior data presentations (56%), lessening the degree of Enhertu’s potential differentiation in bladder
  • HER2 expression is not well defined in mUC and HER2 testing is not standard practice, which could impact Enhertu uptake near-term. Testing delaying treatment start has also been raised as a concern by some KOLs
    • AstraZeneca & Daiichi can leverage previous experience in defining HER2 expression across tumor types and supporting HER2 testing uptake
  • While Enhertu may be positioned as a 2L treatment option to 1L EV+P in HER2+ patients based on indication language, there is currently no data showing Enhertu’s efficacy and safety following EV+P; note that RWE/HEOR data will be collected for Trodelvy post-EV+P
• NSCLC: This new approval appears to slightly increase the potential patient pool eligible for Enhertu in the 2L+ setting, though the reported rates of HER2-overexpression (IHC 3+) is found in only 2-6% in NSCLC
  • Enhertu’s previous NSCLC label was only for 2L+ patients with HER2 mutations, which comprises ~2-4% of the population
  • Like that of mUC, testing for HER2 overexpression is not routine in NSCLC, and it remains to be seen how testing uptake will progress
  • Enhertu remains a minor threat to Trodelvy in NSCLC, and any current threat would be contingent on Trodelvy gaining a label in 2L+ mNSCLC.
  • Enhertu is currently enrolling DESTINY-Lung04 in 1L HER2m mNSCLC, and Trodelvy will compete only in the broader 1L PD-L1>50% setting if approved.
• Endometrial: Enhertu is a competitor to Trodelvy in mEC (planned P3 trial) and potentially in other GYN tumors should internal development expand
  • Ahead of this approval, particularly promising data in GYN led to NCCN guideline updates for endometrial, cervical, and ovarian cancer to include Enhertu for both IHC 3+ and 2+ populations
  • Similar to bladder, the cORR data for both endometrial and cervical is lower in the USPI than previously presented, though still strong
    • Endometrial and cervical reported as 56% and 70% (vs 85% and 75% in prior presentations) while ovarian has marginally increased to 67% (vs 64%)
  • HER2 expression in mEC is not defined but insights suggest IHC 2+/3+ could represent ~30% of the market, although AZ has previously provided a more aggressive estimate ranging from 30-56%
  • Importantly, AZ/Daiichi may be pursuing a tumor-agnostic HER2-low label for GYN tumors, which could increase addressable market and thus threat
    • New cohorts were added to P2 DP-02 is February enrolling HER2-low pts in EC, CC, and OC