Brigatinib Post Definitive Chemo-radiotherapy in Patients with ALK-fusion Non-small Cell Lung Cancer

A Multicentre, Randomised, Phase II Trial of Brigatinib Consolidation Versus Observation or Durvalumab in Patients with Unresectable Stage III NSCLC and ALK-rearrangement, After Definitive Chemo-radiotherapy

BOUNCE is an international multicentre randomised phase II trial. The trial treatment consists of brigatinib 180 mg once daily p.o., with seven day lead-in at 90 mg once daily, for 3 years or until progression of disease. The primary objective of this trial is to evaluate the efficacy in terms of progression-free survival (PFS) for brigatinib consolidation, compared to observation/durvalumab, in patients with unresectable stage III NSCLC and ALK-rearrangement who completed definitive chemo-radiotherapy without disease progression.

Inclusion Criteria:

Inclusion criteria for enrolment

• Pathologically documented, treatment naïve unresectable stage III NSCLC
• Documented ALK-fusion, tested locally on tumour tissue by a validated method (DNA NGS, RNA NGS, FISH, IHC, or ctDNA)
• ECOG Performance Status 0-1
• Age ≥18 years
• Patient is a candidate to receive chemo-radiotherapy, as per investigator's assessment (including adequate haematological, renal and liver function as per local guidelines).
• Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test within 5 weeks before enrolment.
• Ability to comply with the trial protocol, in the investigator's judgment.
• Written IC for trial participation must be signed and dated by the patient and the investigator prior to any trial-related intervention, including the submission of mandatory biomaterial.

Eligibility criteria for randomisation Randomisation of eligible patients must occur within 8 weeks after the last radiotherapy fraction.

• Completion of thoracic radiotherapy
• Non-PD at restaging
• Adequate haematological function
• Adequate renal function
• Adequate liver and pancreatic function
• Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test before randomisation and should be repeated within 3 days before the first dose of brigatinib.
• No radiation-pneumonitis of grade ≥2
• All other AEs from previous chemo-radiotherapy resolved to grade <2 (except for alopecia)
• ECOG 0-2
• No major surgery as defined by the investigator within 4 weeks of the the first planned dose of brigatinib.

Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.

• No systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong cyp3a inducers, or moderate cyp3a inducers within 14 days before randomisation.

Exclusion Criteria:

• Diagnosis of another primary malignancy other than NSCLC. With the exception of adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years since the diagnosis of the other primary malignancy.
• Prior treatment for NSCLC
• Any evidence of stage IV NSCLC
• Significant, uncontrolled, or active cardiovascular disease
• Uncontrolled hypertension Patients with hypertension should be under treatment on study entry to control blood pressure.
• History or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis.
• Ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics.
• Malabsorption syndrome or other GI illness that could affect oral absorption of brigatinib.
• Known or suspected hypersensitivity to brigatinib or its excipients.
• Any concurrent medical condition which, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of brigatinib.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Women who are pregnant or in the period of lactation.
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial until at least 4 months after the last dose of protocol treatment.