TULIP - SYD985 vs Physician’s Choice for HER2-positive Breast Cancer
Research type
Research Study
Full title
A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the antibody-drug conjugate SYD985 to physician's choice in patients with HER2-positive unresectable locally advanced or metastatic breast cancer.
IRAS ID
230951
Contact name
Nicholas Turner
Contact email
Sponsor organisation
Synthon Biopharmaceuticals BV
Eudract number
2017-001994-18
ISRCTN Number
ISRCTN00000000
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
RPC 999 / 9000 / 37235, ARSAC Reference Number
Duration of Study in the UK
1 years, 5 months, 16 days
Research summary
Research Summary
Advanced and metastatic breast cancer accounts for an estimated 450,000 deaths globally annually, approximately 15-20% of these patients have Human Epidermal Growth Factor 2 (HER2) positive disease. Four HER2-targeting therapies have been approved so far in the EU and US, three of which are used in combination therapy regimens to treat locally advanced or metastatic breast cancer. However, disease often progresses and patients become refractory to the treatment regimen they are on. For this reason it is important that additional anti-HER2 therapies can be offered with subsequent treatments.
This study will be conducted at five hospitals in the UK, it is a multi-centre, open-label, randomised clinical trial comparing the efficacy and safety of the antibody-drug conjugate SYD985 to physician's choice in participants with HER2-positive unresectable locally advanced or metastatic breast cancer. SYD985 is an antibody specific to the HER2 protein, bound to a drug molecule with a linker molecule. The antibody recognises HER2 on the tumour cell surface and through this antibody specificity helps deliver the drug directly into the tumour cells. For this reason, only people with HER2 positive cancer will be eligible for this study.
Participants in this study, so long as they are well enough, will attend the hospital for treatments until their disease progresses or until the treatment is discontinued. They will be randomised between treatment groups 2:3 SYD985 and 1:3 Physician’s choice. Participants taking SYD958 will be treated every 3 weeks, with SYD958 administered intravenously over 60 minutes for the first infusion, and over 30 minutes for subsequent infusions. Participants in the physician's choice group will be treated with an approved therapy as per local practice and according to the needs of the participant. Subsequently participants will return to the hospital for a treatment discontinuation visit and will be followed up every 3 months thereafter.
Summary of Results
"Number of Patients: A total of 437 patients were randomized, with 291 patients randomized to the SYD985 group and 146 patients to the physician’s choice group.
Study drug: SYD985 1.2 mg/kg administered by intravenous infusion every 3 weeks (±3 days). Physician’s choice was to be administered according to local practice.
SUMMARY OF RESULTS
For all analysis described below data until the data cut-off date of 31 March 2021 for the primary PFS analysis was included, except for the overall survival analysis for which data up to 30 June 2022 was included.
Primary Efficacy Analysis
The primary efficacy endpoint was Progression Free Survival (PFS) based on central tumor evaluation. The primary PFS analysis showed that SYD985 was superior to physician’s choice combination treatment in prolonging PFS as assessed by central tumor evaluation; the median PFS was 7.0 months in the SYD985 group and 4.9 months in the physician’s choice group, which was a statistically significant difference. There was a 36% lower risk of progression with SYD985.
Secondary Efficacy Analysis
Overall response rate: In the SYD985 group 27.8% of patients were responders (best overall response of complete response or partial response) compared with 29.5% of patients in the physician’s choice group. This difference between both treatment groups was not statistically significant.
Investigator-assessed PFS: The median PFS was 6.9 months in the SYD985 group and 4.6 months in the physician’s choice group, which was a statistically significant difference. There was a 40% lower risk of progression with SYD985.
Quality of life (QoL) outcome: The variable of main interest was the global health status/QoL scale score of the EORTC QLQ-C30, which is a questionnaire developed to assess the quality of life of cancer patients. Data for QoL scores were widely spread and no noteworthy differences between both treatment groups were seen.
Overall survival (OS): At the time of the final OS analysis, 62.2% of patients died in the SYD985 group compared with 64.4% of patients in the physician’s choice group. The Median OS was 21.0 months in the SYD985 group and 19.5 months in the physician’s choice group. The difference was not statistically significant. The 1-year survival estimate was 69.8% in the SYD985 group and 68.0% in the physician’s choice group. Although these differences were not statistically significant, these results are supportive of the primary analysis of PFS.
Safety Results:
Adverse events (AEs) overall
The percentage of patients with AEs was very similar between the treatment groups (96.5% in the SYD985 group and 96.4% in the physician’s choice group). In the SYD985 group, conjunctivitis (38.2% of patients receiving SYD985), keratitis (38.2%), fatigue (33.3%), dry eye (30.2%), and nausea (25.3%) were the 5 most frequently reported AEs, compared with diarrhoea (35.8% of patients receiving physician’s choice), nausea (31.4%), fatigue (29.9%), neutropenia (24.1%), and palmar plantar erythrodysaesthesia syndrome (23.4%) in the physician’s choice group.
Treatment-related AEs
The number of patients with AEs considered related to study drug by the investigator was similar in both treatment groups (SYD985, 91.0%; physician’s choice, 89.1%). In the SYD985 group, keratitis (37.5%), conjunctivitis (35.4%), dry eye (28.5%), fatigue (28.1%), and alopecia (19.4%) were the 5 most frequently reported related treatment related AEs. The 5 most frequently reported treatment related AEs in the physician’s choice group were diarrhoea (29.9%), fatigue (25.5%), nausea (24.8%), palmar plantar erythrodysaesthesia syndrome (23.4%) and neutropenia (21.2%).
Serious AEs (SAEs)
Most AEs were non-serious in both treatment groups. The percentage of patients with serious AEs was higher in the SYD985 group (18.4%) than in the physician’s choice group (8.8%). Serious AEs that were reported for more than 2 patients in either treatment group were pneumonitis (2.4%) and pneumonia (1.0%) in the SYD985 group and pneumothorax (2.2%) in the physician’s choice group.
Treatment related SAEs
Serious TEAEs were considered related to study treatment in 8.7% of patients in the SYD985 group and 4.4% of patients in the physician’s choice group. The serious treatment related AEs that were reported for more than 1 patient were pneumonitis (2.4%), abdominal pain (0.7%), platelet count decreased (0.7%), keratitis (0.7%), and infusion related reaction (0.7%); all occurred in the SYD985 group.
Fatal TEAEs
Six patients in the SYD985 group died due to AEs during the study. Four of the 6 fatal events (2 cases of pneumonitis, 1 case of respiratory failure, and 1 case of pneumonia) were considered related to study drug. The other 2 fatal events (1 case of acute respiratory failure and 1 case of COVID 19 pneumonia) were considered unlikely related to SYD985 treatment. No patient in the physician’s choice group had a fatal AE."REC name
London - Riverside Research Ethics Committee
REC reference
17/LO/1942
Date of REC Opinion
16 Nov 2017
REC opinion
Favourable Opinion