FDA approves datopotamab deruxtecan for unresectable or metastatic, HR-positive, HER2-negative breast cancer
On January 17, 2025, the Food and Drug Administration approved datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo, Inc.), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for for the treatment of adult patients with unresectable or metastatic HR+/HER2- (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease (see product label).
Efficacy was evaluated in TROPION-Breast01 (NCT05104866), a multicenter, open-label, randomized trial. Patients must have experienced disease progression, been deemed unsuitable for further endocrine therapy, and have received one or two lines of prior chemotherapy for unresectable or metastatic disease. Patients were excluded for a history of ILD/pneumonitis requiring steroids, ongoing ILD/pneumonitis, clinically active brain metastases, or clinically significant corneal disease. Patients also were excluded for ECOG performance status >1.
The major efficacy outcome measures were progression-free survival (PFS), assessed by blinded independent central review (BICR), based on RECIST v1.1 and overall survival (OS). Additional efficacy outcomes included confirmed objective response rate (ORR) and duration of response (DOR) by BICR. Median PFS was 6.9 months (95% CI: 5.7, 7.4) in the datopotamab deruxtecan-dlnk arm and 4.9 months (95% CI: 4.2, 5.5) in the chemotherapy arm (Hazard ratio 0.63 [95% CI: 0.52, 0.76] two-sided p-value <0.0001). Median OS was 18.6 months (95% CI: 17.3, 20.1) in the datopotamab deruxtecan-dlnk arm and 18.3 months (95% CI: 17.3, 20.5) in the chemotherapy arm (Hazard ratio 1.01 [95% CI: 0.83, 1.22]; two-sided p-value was not statistically significant). Confirmed ORR was 36% (95% CI: 31, 42) and 23% (95% CI: 19, 28) and median DOR was 6.7 months (95% CI: 5.6, 9.8) and 5.7 months (95% CI: 4.9, 6.8) in the datopotamab deruxtecan-dlnk and chemotherapy arms, respectively.
The most common adverse reactions (≥20%), including laboratory abnormalities, were stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased ALT, keratitis, increased AST, and increased alkaline phosphatase.
The recommended datopotamab deruxtecan-dlnk dose is 6 mg/kg (maximum of 540 mg for patients ≥90 kg), administered as an intravenous infusion, once every 3 weeks (21-day cycle), until disease progression or unacceptable toxicity.
This review used the Assessment AidExternal Link Disclaimer, a voluntary submission from the applicant to facilitate the FDA’s assessment.
Implications:
- Dato-DXd’s first US approval came slightly ahead of the Jan 29th PDUFA date and is based on data from the Phase 3 TROPION-Breast01 trial, where Dato-DXd demonstrated a statistically significant improvement in PFS vs. investigator’s choice chemo (6.9 mo vs 4.9mo HR: 0.63)
- The FDA label also includes first time OS data from TROPION-Breast01 showing numerically similar OS between Dato-DXd and chemotherapy (18.6mo vs 18.3mo; HR: 1.01)
- Similar to the recent Japanese approval in Dec 2024, TROPION-Breast01’s lack of significant OS data does not appear to have had a negative impact on Dato-DXd’s regulatory pathway in the US; However, ex-US reimbursement may be challenging without any OS benefit
- Regulatory submissions based on TROPION-Breast01 are noted to be under review in other regions, including the EU and China
- In Mar 2024, the MAA based on TROPION-Breast01 was validated by the EMA; AZ/DS has not communicated any guidance regarding the timing for potential EU approval
- Overall, Dato-DXd’s US label is mostly in line with expectations and positions the TROP2 ADC slightly ahead of Trodelvy in HR+/HER2- mBC, as the TROPICS-02 label stipulates HR+/HER2- mBC patients “ at least two additional systemic therapies in the metastatic setting” post ET
- Interestingly and unlike Enhertu, Dato-DXd was not given a black box warning for ILD, likely due to the relatively low rates of ILD (4.3% all grades vs. the ~10+% seen in Enhertu BC trials)
- Additional safety recommendations for Dato-DXd include:
- Ophthalmic assessment prior to initiation, annually during treatment, and at end of treatment as well as usage of prophylactic lubricating eye drops due to the risk of ocular toxicities (51% all grades)
- Prophylactic steroid mouthwash due to the risk of stomatitis, including mouth ulcers and oral mucositis (59% all grades)
- DS also shared the list price for Dato-DXd in the US will be $4,891.07 per 100 mg vial, resulting in approximately a monthly list price of $28,259.52 at the recommended dose of 6mg/kg Q3W
- Dato-DXd is the second-to-market TROP2-ADC in the US and poses a high competitive threat given its approval in an earlier LoT in HR+/HER2- mBC
- AZ/DS will also likely emphasize safety and convenience as a key differentiator of Dato-DXd given its lack of black box warnings and Q3W dosing schedule
- However, this threat is somewhat mitigated by the fairly unimpressive OS data;
- This approval will continue to build on AZ’s portfolio within the breast cancer space which now includes two ADCs with differing targets
- At present, AZ’s BC portfolio includes Dato-DXd, T-DXd (Enhertu), capivasertib (Truqap; AKTi), olaparib (Lynparza, PARP inhibitor), and fulvestrant (Faslodex, SERD) with on-going pivotal trials to bring camizestrant (oral SERD) and saruparib (PARP inhibitor) into the market
- Given their broad offerings across BC, AZ will likely leverage their internal portfolio synergies as well as their existing relationships with HCPs, Payers, and patients to support Datroway’s first US launch