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

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.


Eligibility Criteria:
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.