Tucatinib plus trastuzumab for HER3-mutant, HER2-not amplified metastatic breast cancer

Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer: a Proof of Concept Study (H3RAKLES)

This trial will test whether combining tucatinib and trastuzumab helps people with metastatic or unresectable breast cancer whose tumors are HER2-negative but carry activating ERBB3 (HER3) mutations.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Institut Curie (Academic / other)
• Drugs / interventions: trastuzumab, tucatinib, chemotherapy, radiation, lapatinib
• Locations: 9 sites (Bordeaux and 8 other locations)
• Trial ID: NCT07193394 on ClinicalTrials.gov

What this trial studies

H3RAKLES is a single-arm, phase II trial using a Bayesian design to give all enrolled patients the combination of tucatinib (a HER2 tyrosine kinase inhibitor) and trastuzumab (a HER2-directed antibody). Eligible participants are adults with HER2-not amplified metastatic or unresectable breast cancer harboring class IV/V somatic ERBB3 mutations who have received at least two prior lines of chemotherapy. Treatment is administered in three-week cycles and continued until disease progression or unacceptable toxicity, with tumor response monitored by RECIST v1.1. The trial builds on preclinical data and small clinical series suggesting HER2-targeted agents can be active in ERBB3-mutant tumors despite lack of HER2 amplification.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18) with unresectable or metastatic HER2-negative breast cancer, documented class IV/V somatic ERBB3 mutation, ECOG ≤2, adequate organ function and LVEF ≥50%, and at least two prior chemotherapy lines for advanced disease.

Not a fit: Patients whose tumors lack activating ERBB3 mutations, who have HER2-amplified disease, or who have poor cardiac or organ function that prevents HER2-directed therapy are unlikely to benefit from this trial.

Why it matters

Potential benefit: If effective, this combination could offer an additional treatment option that induces tumor responses and extends disease control for heavily pretreated patients with ERBB3-mutant, HER2-negative metastatic breast cancer.

How similar studies have performed: There is limited but encouraging evidence from preclinical studies and small patient series that combining a HER2-directed antibody with a HER2 TKI can produce responses in ERBB3-mutant, HER2-non-amplified cancers, though larger confirmatory trials are lacking.

Eligibility criteria

Inclusion Criteria:

* Age ≥ 18 years
* Metastatic or unresectable breast cancer
* HER2-negative (defined as having an IHC 0+, IHC 1+, or IHC 2+ and ISH non-amplified, per ASCO/CAP guidelines) on last assessable tumor sample
* Having received ≥ 2 previous chemotherapy lines for advanced breast cancer: including at least one line of conjugated antibody, at the investigator's discretion or if a germinal BRCA mutation is present, a PARP inhibitor.
* Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step
* ECOG performance status ≤ 2 (Appendix A)
* Evaluable disease, per RECIST v1.1 inclusion criteria
* Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment
* Adequate organ function:

  1. Creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines
  2. Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with known Gilbert's disease, who may enroll if the conjugated bilirubin is ≤1.5 X ULN.
  3. Transaminases (aspartate aminotransferase and alanine aminotransferase) ≤ 2.5 X ULN (≤ 5 X ULN if the patient has liver metastases)
* Women of childbearing potential (WCBP) must have a negative serum pregnancy test \< 7 days prior to first dose of treatment. A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as the absence of menses for 12 months without an alternative cause.
* WCBP (as defined above) and men with partners of childbearing potential must agree to use a highly effective birth control method during the study and for 3 months after completion of investigational treatment.
* Patients should be eligible for the treatment step according to the investigator's opinion.
* Patients must be covered by a health insurance plan.
* Patients able to provide signed informed consent.

Exclusion Criteria:

* Having received any prior treatment targeting HER2. Prior treatment with trastuzumab deruxtecan is allowed, per label, in patients with HER2-low metastatic breast cancer (IHC 1+ or 2+, ISH non-amplified)
* History of allergic reactions to trastuzumab or tucatinib or chemically similar drugs
* Patients who are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug
* Inability to swallow pills or having a significant gastro-intestinal disease or a history of surgery which would preclude the adequate oral absorption of medications
* Having used a strong CYP2C8 inhibitor within a duration of 5 half-lives prior to the first dose of study treatment, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment (see Appendix B and Appendix C)
* Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-central nervous system (CNS) radiation, or experimental agent ≤ 3 weeks prior to the first dose of study treatment, except gonadotropin releasing hormone (GnRH) agonists
* Participation in another interventional clinical trial.
* Symptomatic and untreated brain metastases or brain metastases requiring urgent treatment, or brain metastases requiring a dose \> 2 mg of dexamethasone (or equivalent)
* Whole brain radiotherapy \< 21 days prior to first dose of treatment, stereotactic radiotherapy \< 7 days prior to first dose of treatment
* Leptomeningeal metastases
* Major surgery (including surgery of brain metastases) \< 21 days prior to first dose of treatment
* Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
* Have known myocardial infarction or unstable angina within 24 weeks prior to first dose of study treatment
* Have clinically significant cardiopulmonary disease such as:

  * Ventricular arrhythmia requiring therapy,
  * Uncontrolled hypertension (defined as persistent systolic blood pressure \>150 mmHg and/or diastolic blood pressure \> 100 mm Hg on antihypertensive medications)
  * Any history of symptomatic congestive heart failure
  * Severe dyspnea at rest (CTCAE v5.0 Grade 3 or above) due to complications of advanced malignancy
  * Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea
  * Presence of ≥ Grade 2 QTc prolongation on screening ECG
* Conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes:

  * Congenital or acquired long QT syndrome
  * Family history of sudden death
  * History of previous drug-induced QT prolongation
  * Current use of medications with known and accepted associated risk of QT prolongation (see row "Accepted Association" in Appendix D)
* Are known carriers of active Hepatitis B or Hepatitis C or have other known chronic liver disease
* Are known to be positive for human immunodeficiency virus (HIV)
* Altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
* Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons
* Person deprived of liberty or under guardianship

Where this trial is running

Bordeaux and 8 other locations

• Polyclinique Bordeaux Nord Aquitaine — Bordeaux, France (Not_yet_recruiting)
• Chu Dupuytren- Limoges — Limoges, France (Not_yet_recruiting)
• Institut Paoli-Calmettes — Marseille, France (Not_yet_recruiting)
• Centre Antoine Lacassagne — Nice, France (Not_yet_recruiting)
• CHU de Nîmes — Nîmes, France (Not_yet_recruiting)
• Centre Eugène Marquis — Rennes, France (Not_yet_recruiting)
• Institut Curie_ Site Saint-Cloud — Saint-Cloud, France (Recruiting)
• Institut Universitaire du Cancer de Toulouse (IUCT) - Oncopole Claudius Regaud — Toulouse, France (Not_yet_recruiting)
• Institut de Cancérologie de Lorraine — Vandœuvre-lès-Nancy, France (Not_yet_recruiting)

Study contacts

• Principal investigator: François-Clément Bidard, Prof. — Institut Curie
• Study coordinator: Sandra Clinical Project Manager

Conditions Metastatic Breast Cancer; Unresectable Breast Cancer; Breast; Cancer; HER2; tucatinib; trastuzumab; HER3