Trastuzumab Duocarmazine in Pretreated Her2-Positive Breast Cancer: Has the “TULIP” Bloomed a Bit Too Late?

We read the TULIP trial by Turner et al[1] that tested the role of trastuzumab duocarmazine (T-Duo) in recurrent HER2+ metastatic breast cancer. T-Duo (SYD 985) is a novel next-generation HER2-targeted antibody-drug conjugate (ADC) with a cleavable payload (vc-seco-DUBA) conjugated with trastuzumab. In this phase 3 open-label, randomized controlled trial, patients aged ≥ 18 years were randomized (in 2:1 ratio) to receive T-Duo or physician's choice (PC) therapy (lapatinib–capecitabine, capecitabine–trastuzumab, trastuzumab–vinorelbine, or trastuzumab–eribulin). Patients received a median of three prior lines of anti-HER2 therapies; of which 60.8 and 57.5% patients received pertuzumab and 2.1 and 1.4% patients received trastuzumab deruxtecan (T-DXd) in the experimental and control arms, respectively. The study met its primary endpoint of progression-free survival (PFS) prolongation in the T-Duo arm with a median PFS of 7 months (95% confidence interval [CI], 5.4–7.2) versus 4.9 months (95% CI, 4.0N5.5) for PC therapy. The overall response rate by central imaging review was 27.8% in the T-Duo arm versus 29.5% in the PC arm. The median duration of response was 15.1 months (95% CI, 5.7–15.1) for T-Duo versus 4.6 months (95% CI, 2.8–7.1) for PC. Overall survival results are currently immature. Ocular adverse events were notable with T-Duo (78.1% any grade, 21.2% grade 3). The incidence of interstitial lung disease and pneumonitis were similar to that seen with other anti-HER 2 ADCs like ado-trastuzumab emtansine (TDM1) and T-DXd.

It is imperative that we understand that by the time this trial accrued, tremendous progress was already made in HER2-positive metastatic breast cancer space. Initially tested in third line and beyond in the DESTINY 02 trial[2] with impressive results, T-DXd went on to trump TDM1 in the subsequent DESTINY 03 study[3] and is currently the favored drug in the second-line therapy. Impressive central nervous system (CNS) response rates of 73.3 and 46.2% were received from the TUXEDO-1[4] and DEBBRAH[5] trials, respectively. Therefore, the activity of T-DXd supersedes any other anti-HER2 therapy. Hardly 2% of patients in TULIP received T-DXd and responses post-T-DXd with T-Duo are not known.

The brain is a notable sanctuary site for recurrent HER2+ disease and up to 50% of patients develop brain metastases.[6] TULIP does not give us any idea regarding the intracranial efficacy of T-Duo. The hazard ratio for patients with brain metastases is not impressive, albeit this could be explained by the small patient population. Every patient with advanced cancer needs to live longer and live better. With 78% of ocular adverse events (20% grade 3 or more), T-Duo unfortunately cuts a sorry figure and hampers the coveted parameter of “quality of life.” Despite the use of prophylactic eye drops and regular ophthalmological examinations (slit lamp exam, corneal sensitivity testing, fluorescence tear film break-up time, and pachymetry), these adverse events could not be prevented. Also, they persisted for months and were slow to recover, unlike the case with some ADCs like tisotumab vedotin, where strict prophylaxis and timely dose modifications helped.[7]

Duocarmazine payloads have an inherent risk of cardiotoxicity. In the dose-expansion study of T-Duo, reversible left ventricular dysfunction was reported in 11 patients (7% grade 1–2, 1% grade 3).[8] Readers are deprived of the same data in TULIP.

The performance of an ADC depends upon four factors, namely, the stability of the linker molecule in plasma, activity and toxicity profile of the cytotoxic moiety, drug-to-antibody ratio (DAR), and membrane permeability. For T-Duo, the poor DAR (2.8:1) is compensated by the presence of a cleavable linker and a bystander effect, unlike TDM1. Nevertheless, all is not gloomy for this late entrant. The median PFS of 7 months in TULIP augurs well with the TH3RESA[9] and HER2CLIMB[10] data with TDM1 and tucatinib, respectively. Tucatinib scores above these two drugs in its ability to elicit good CNS control. T-DXd is almost being front-lined into the management of HER2-positive metastatic breast cancer and the DESTINY BREAST 09 results will be released soon. Hence, there is a huge scope of potential for new drugs as second and subsequent options in the therapeutic armamentarium of HER2-positive breast cancer. The low incidence of myelosuppression and nausea/vomiting with T-Duo makes it an ideal option to combine with other drugs. TDM1 is already being revived in this manner through the HER2CLIMB02[11] and CompassHER2RD trials, where it is combined with tucatinib in the metastatic and post-neoadjuvant-residual disease settings, respectively.

ADC resistance may arise from defective internalization and trafficking pathways. Small molecules like tucatinib and neratinib are known to stabilize HER2 on the cell membrane facilitating the action of ADCs. Also, studies are underway combining T-Duo with poly(ADP-ribose) polymerase (PARP) inhibitors in locally advanced or metastatic solid tumors expressing HER2.[12] The rationale behind this strategy is the synthetic lethality offered by the alkylator payload and PARP inhibitors. Another possible avenue is the combination of immune checkpoint inhibitors with ADCs. ADCs are known to enhance antigen presentation through antibody-dependent cellular toxicity and increase the CD8+ flux into the tumor microenvironment. This was evident from the arm 6 of the BEGONIA trial where durvalumab + T-DXd elicited an overall response rate of 66.7%.[13] Lastly, an area where T-Duo can work wonders like T-DXd is the HER2-low subset of breast cancer. In the phase 1 study, 9/32 (28%) patients with HER2-low/HR+ and 6/15 (40%) patients with HER2-low/HR− patients had confirmed RECIST (Response Evaluation Criteria in Solid Tumors) responses.[6] T-Duo is also being tested in other HER2-positive metastatic solid tumors. Response rates as high as 25 and 39% were seen in urothelial and endometrial cancer, respectively.[8] Before writing off this drug, taking time to understand its mechanism of action and unique toxicity profile can help us better fit T-Duo into the ever-expanding therapeutic realm of targeted agents in HER2-positive breast cancer. With the arrival of T-DXd in the Indian markets and the latest cut in import taxes for novel life-saving anticancer drugs, it will be very difficult for T-Duo to find its place as a later line option in the management of HER2-positive metastatic breast cancer.

Conflict of Interest

None declared.

Patient's Consent

Patient consent is not required.

• References

• 1 Turner N, Saura C, Aftimos P. et al. Trastuzumab duocarmazine in pretreated human epidermal growth factor receptor 2–positive advanced or metastatic breast cancer: an open-label, randomized, phase III trial (TULIP). J Clin Oncol 2025; 43 (05) 513-523
• 2 André F, Hee Park Y, Kim SB. et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023; 401 (10390): 1773-1785
• 3 Hamilton EP, Hurvitz SA, Im SA. et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): updated survival results of DESTINY-Breast03. J Clin Oncol 2024; 42: 1025
• 4 Bartsch R, Berghoff AS, Furtner J. et al. Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases. Neuro-oncol 2024; 26 (12) 2305-2315
• 5 Pérez-García JM, Vaz Batista M, Cortez P. et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: the DEBBRAH trial. Neuro-oncol 2023; 25 (01) 157-166
• 6 Garcia-Alvarez A, Papakonstantinou A, Oliveira M. Brain metastases in HER2-positive breast cancer: current and novel treatment strategies. Cancers (Basel) 2021; 13 (12) 2927
• 7 Lent-Schochet D, Tauber S, Seagrave Z, Paley GL, Farooq AV. Ocular surface disease related to tisotumab vedotin-tftv. Gynecol Oncol Rep 2025; 57: 101676
• 8 Banerji U, van Herpen CML, Saura C. et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 2019; 20 (08) 1124-1135
• 9 Krop IE, Kim SB, Martin AG. et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 2017; 18 (06) 743-754
• 10 Curigliano G, Mueller V, Borges V. et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol 2022; 33 (03) 321-329
• 11 Hurvitz S, Loi S, O'Shaughnessy J. et al. Abstract GS01–10: HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Cancer Res 2024; 84: GS01-GS10
• 12 Colas E, Moiola CP, Gil CL. et al. 195P Preclinical efficacy of the trastuzumab duocarmazine SYD985 as monotherapy or in combination with the PARP inhibitor niraparib in HER2-expressing endometrial cancer. Ann Oncol 2024; 35: S293
• 13 Schmid P, Im SA, Armstrong A. et al. BEGONIA: phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd). J Clin Oncol 2021; 39: 1023

Publication History

Article published online:
30 April 2025