Treatment with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) did not meet the prespecified efficacy criterion of cohort 2 of the phase 2 MYTHOS trial (jRCT2011210017) in patients with HER2-low recurrent/metastatic salivary gland carcinoma, according to data presented at the 2026 ASCO Annual Meeting.¹
Among the first 33 patients enrolled in cohort 2, 12 confirmed objective responses were observed by independent central review (ICR), short of the 14 responses required to meet the efficacy criterion. The confirmed objective response rate (cORR) in this set was 36.4%, comprising 1 complete response (CR; 3%) and 11 partial responses (PRs; 33.3%); 19 patients (57.6%) had stable disease, 1 patient (3%) had progressive disease, and 1 patient (3%) was not evaluable.
In the full analysis set of 36 patients, a descriptive analysis showed a confirmed ORR of 38.9% (95% CI, 23.1%-56.5%) and a disease control rate (DCR) of 94.4% (95% CI, 81.3%-99.3%) by ICR. Among 14 responders, the median duration of response was 12.5 months (95% CI, 4.9-not evaluable [NE]), and the median duration of treatment was 8.5 months (range, 0.7-35.2).
How was the MYTHOS trial evaluating T-DXd in HER2-low salivary gland carcinoma designed?
MYTHOS is an open-label, multicenter, investigator-initiated phase 2 study evaluating T-DXd at 5.4 mg/kg every 3 weeks in patients with recurrent/metastatic salivary gland carcinoma, conducted as a substudy of the MASTER KEY Project. HER2 status was determined by central assessment of archival or biopsy samples using the VENTANA ultraView PATHWAY HER2 (4B5) assay and the PathVysion HER-2 DNA Probe Kit, applying ASCO/CAP 2018 breast cancer criteria. Patients were assigned to cohort 1 (HER2-overexpressing; IHC 3+ or IHC 2+/ISH-positive) or cohort 2 (HER2-low; IHC 2+/ISH-negative or IHC 1+).
T-DXd Activity in HER2-Low Salivary Gland Carcinoma
• The prespecified Simon 2-stage efficacy criterion of cohort 2 of the MYTHOS study was not met: 12 confirmed responses were observed among the first 33 patients vs the 14 required.
• In the descriptive full analysis set, the confirmed ORR was 38.9% (95% CI, 23.1%-56.5%), and the DCR was 94.4% (95% CI, 81.3%-99.3%) by ICR, with a median PFS of 8.7 months (95% CI, 6.5-13.3) and a median OS of 24.8 months (95% CI, 18.7-NE).
• ILD/pneumonitis occurred in 25.0% of patients, including 1 grade 5 event.
The primary end point was cORR by ICR. Secondary end points included progression-free survival (PFS), overall survival (OS), investigator-assessed ORR, DCR, and safety. The Simon 2-stage minimax design was applied to the first 33 patients in cohort 2, using a threshold ORR of 25% and an expected ORR of 50%, with 83% power and a 2-sided alpha of .05; at least 14 confirmed objective responses were required to meet the efficacy criterion. After those 33 patients were enrolled, 3 additional patients who had already provided informed consent were enrolled, bringing the full analysis set to 36 patients. Enrollment ran from January 2022 to April 2024, and the data cutoff was April 30, 2025.
What were the baseline characteristics of patients enrolled in MYTHOS?
Patients in the full analysis set of cohort 1 had a median age of 62.4 years (range, 28-80), and 91.7% of these patients were male. Salivary duct carcinoma accounted for 83.3% of cases, with the remaining 16.7% comprising non– salivary duct carcinoma histologies. HER2 status was IHC 1+ in 52.8% of patients and IHC 2+/ISH-negative in 47.2% of patients. Prior systemic therapy had been administered to 72.2% of patients.
What data from MYTHOS have been previously reported?
Data from MYTHOS cohort 1, which were shared at the 2024 ESMO Congress, showed a cORR by ICR of 68.4% (95% CI, 43.4%-87.4%) among 19 patients with HER2-overexpressing salivary gland carcinoma.² Additionally, the DCR was 100% (95% CI, 82.4%-100%) in this population.
What additional efficacy data from MYTHOS cohort 2 are important to note?
At a median follow-up of 28.0 months (95% CI, 13.8-NE), the median PFS by ICR was 8.7 months (95% CI, 6.5-13.3) in the full analysis set of cohort 1.1 The median OS was 24.8 months (95% CI, 18.7-NE) at a median follow-up of 25.4 months (95% CI, 15.4-32.6).
In the prespecified subgroup analysis, responses were confined to patients with salivary ductal carcinoma. Among the 30 patients with salivary ductal carcinoma, 14 achieved a CR or PR, translating to an ORR of 46.7% (95% CI, 28.3%-65.7%); none of the 6 patients with non– salivary ductal carcinoma histologies responded (ORR, 0.0%; 95% CI, 0.0%-45.9%). By HER2 status, the ORR was 47.1% (95% CI, 23.0%-72.2%) in patients with IHC 2+/ISH-negative disease (n = 17) and 31.6% (95% CI, 12.6%-56.6%) in those with IHC 1+ disease (n = 19). The investigators noted that interpretation of the subgroup findings is limited by the small size of the non– salivary ductal carcinoma subgroup.
An exploratory analysis by histology showed a median PFS of 9.0 months (95% CI, 7.0-13.8) in the salivary ductal carcinoma subgroup vs 4.3 months (95% CI, 1.6-NE) in the non– salivary ductal carcinoma subgroup (nominal log-rank P = .017).
What was the safety profile of T-DXd in HER2-low recurrent/metastatic salivary gland carcinoma?
All 36 patients experienced at least 1 treatment-emergent adverse effect (TEAE), and grade 3 or higher TEAEs occurred in 55.6% of patients. Serious TEAEs were reported in 22.2% of patients. TEAEs led to dose reduction in 36.1% of patients, dose delay in 58.3% of patients, and discontinuation of T-DXd in 19.4% of patients.
Any-grade interstitial lung disease (ILD)/pneumonitis, as assessed by investigators, occurred in 25.0% of patients, comprising grade 1/2 AEs in 19.4% of patients, a grade 3 event in 1 patient, and a grade 5 event in 1 patient. ILD/pneumonitis was the leading cause of treatment discontinuation (16.7%) and accounted for the single treatment-emergent death seen in the trial. No decreases in left ventricular ejection fraction were reported.
The most common TEAEs of any grade were nausea (69.4%), decreased neutrophil count (61.1%), decreased white blood cell count (58.3%), increased aspartate aminotransferase level (50.0%), decreased appetite (47.2%), and constipation (47.2%). The most frequent higher-grade TEAEs included decreased neutrophil count (grade 3, 30.6%; grade 4, 5.6%) and decreased lymphocyte count (16.7%; 2.8%).
The investigators concluded that the safety findings were generally consistent with the known profile of T-DXd in Japanese patients, and that ILD/pneumonitis remains an important risk requiring careful monitoring and prompt management.
References
- Kinoshita I, Kano S, Honma Y, et al. Trastuzumab deruxtecan in patients with HER2-low recurrent/metastatic salivary gland carcinoma: results from the phase II MYTHOS trial. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 6011.
- Kinoshita I, Kano S, Honma Y, et al. Phase II study of trastuzumab deruxtecan in patients with HER2-positive recurrent/metastatic salivary gland cancer: Results from the MYTHOS trial. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract 849O.
