Alectinib in Neo-adjuvant Treatment of Stage III NSCLC

Inclusion Criteria:

• Age ≥ 18 years.

• Histologically or cytologically confirmed adenocarcinoma of the lung. Patients withmixed histology are eligible if adenocarcinoma is the predominant histology.

• Documented ALK-positive disease according to an FDA-approved and CE-marked test.

• Locally advanced NSCLC in stage III according to the 8th American Joint Committee onCancer TNM edition, defined potentially resectable (any T with N2, T4N0-1).

• Documentation that the patient is a candidate for surgical resection of their lungcancer after multidisciplinary discussion.

• Patients must be treatment-naive for NSCLC and eligible to receive treatment withAlectinib.

• Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with CT scan.

• Brain magnetic resonance imaging (MRI) or CT scan showing no evidence of metastaticdisease.

• Positron emission tomography (PET)-computed tomography (CT) showing radiographicstage III lung cancer (mediastinal staging biopsy is allowed but not required).

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1.

• Ability to swallow oral medications.

• Adequate haematological function defined by white blood cell (WBC) count ≥ 2.500/mm3with absolute neutrophil count (ANC) ≥ 1.500/mm3, platelet count ≥ 100.000/mm3 andhaemoglobin ≥ 9 g/dL.

• Adequate hepatic function defined by a total bilirubin ≤ 1.5 x the upper limit ofnormal (ULN) range (except subjects with Gilbert Syndrome, who can have totalbilirubin < 3.0 mg/dL), serum alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤ 2.5 x ULN (≤ 5 if liver function test elevations are due toliver metastases).

• Adequate renal function defined by a serum creatinine ≤ 1.5 x ULN or an estimatedcreatinine clearance of ≥ 30 mL/minute for patients with creatinine levels aboveinstitutional limits (if using the Cockcroft-Gault formula).

• Stable medical condition, including the absence of acute exacerbations of chronicillnesses, serious infections, or major surgery within 4 weeks before trialinclusion date, and otherwise noted in other inclusion/exclusion criteria.

• Female patients with childbearing potential should be using adequate contraceptivemeasures and should not be breastfeeding during the study and for 90 days followingthe last dose of Alectinib. They and must have a negative serum pregnancy testwithin 7 days prior to the first dose of study drug.

• Female patients must have evidence of non-child-bearing potential by fulfilling oneof the following criteria at screening:

• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments;

• Women under 50 years old would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatment with LH and FSH levels in the post-menopausal range for theinstitution;

• Documentation of irreversible surgical sterilization by hysterectomy, bilateraloophorectomy or bilateral salpingectomy but not tubal ligation.

• Men with a female partner of childbearing potential must have either had a priorvasectomy or agree to use effective contraception for at least 14 days prior toadministration of the first dose of study treatment, during the study, and for 90days following the last dose of Alectinib.

• Ability to comply with protocol requirements.

• Ability to provide written informed consent. Voluntary written consent must be givenbefore performance of any study-related procedure not part of standard medical care,with the understanding that the patient may withdraw consent at any time withoutprejudice to future medical care.

Exclusion Criteria:

• Prior treatment with any systemic anti-cancer therapy for locally advanced NSCLCincluding chemotherapy, biologic therapy, including ALK-TKI, immunotherapy or anyinvestigational drug.

• Non-resectable stage III and stage IV disease with distant metastases (includingmalignant pleural effusion) identified on PET-CT scan or biopsy.

• Any concurrent and/or active malignancy that has required treatment within 2 yearsof the first dose of study drug.

• Any evidence of severe or uncontrolled systemic diseases, including uncontrolledhypertension and active bleeding diatheses, which in the investigator's opinionmakes it undesirable for the patient to participate in the trial or which wouldjeopardize compliance with the protocol; or known active infection includinghepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV);screening for chronic conditions is not required; patients with HBV with negativeHBV viral load on appropriate antiviral therapy will be permitted, if able tocontinue appropriate antiviral therapy throughout treatment period.

• Any severe infection, including COVID-19, within 4 weeks prior to initiation ofstudy treatment, including, but not limited to, hospitalization for complications ofinfections.

• History of organ transplant.

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated product or previous significant bowel resection that wouldpreclude adequate absorption of Alectinib.

• Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc)>470 msec, obtained from 3electrocardiograms (ECGs)

• Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG e.g., complete left bundle branch block, third-degree heart block,second-degree heart block, PR interval >250msec, symptomatic bradycardia <45beats/minute.

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, familyhistory of long QT syndrome or unexplained sudden death under 40 years of agein first-degree relatives or any concomitant medication known to prolong the QTinterval.

• Males and females of reproductive potential who are not using an effective method ofbirth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry.

• History of hypersensitivity to active or inactive excipients of Alectinib or drugswith a similar chemical structure or class to Alectinib. This includes, but is notlimited to, patients with galactose intolerance, a congenital lactase deficiency orglucose-galactose malabsorption.

• Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducerswithin 14 days prior to the first dose of study treatment and while on treatmentwith Alectinib except for oral corticosteroids up to 20 mg of prednisoloneequivalent per day.

• Involvement in the planning and/or conduct of the study (applies to bothinvestigator staff and/or staff at the study site).

• Judgment by the investigator that the subject should not participate in the study ifthe subject is unlikely to comply with study procedures, restrictions andrequirements.