Multidisciplinary Treatment of Stage III ALK+ NSCLC With Neoadjuvant Alectinib and Chemotherapy

A Multicenter, Phase 2 Non-Randomized Study of Unresectable Stage III ALK+ NSCLC Treated With Neoadjuvant Alectinib Plus Chemotherapy Followed by Multidisciplinary Approach for Optimal Local Treatment

This is a multicenter, phase 2 non-randomized study to investigate the clinical feasibility and therapeutic efficacy of employing a MDT-based strategy in unresectable stage III ALK positive NSCLC following neoadjuvant alectinib in combination with platinum-based chemotherapy. Participants in this study must not have received any previous systemic anticancer therapy before enrollment.

The study will consist of a 42-day screening period, a neoadjuvant treatment period, a local radical treatment period, a post-local treatment period, a safety follow-up visit occurring 28 days after the final dose of alectinib, and a survival follow-up period.

In the neoadjuvant treatment period, participants will be provided with alectinib (600mg PO BID for 3 cycles) plus platinum-based chemotherapy for a maximum of 3 cycles (each cycle is 21 days).

Following the completion of neoadjuvant therapy, all participants who are reassessed by MDT to be resectable after neoadjuvant treatment and have adequate lung functions would be provided with definite surgery. Otherwise, patients would be provided with radical radiotherapy through MDT discussion.

For the surgery cohort, participants meet both the R0 resection, the pathological assessment criteria of pCR and have two consecutive landmark ctDNA tests that are negative will receive surveillance after surgery. Participants who do not meet all the above conditions will receive alectinib after surgery, adjuvant treatment should be initiated ideally 4-12 weeks after surgery, or according to local standard of care, treatment will continue until completion of treatment period (24 months), disease recurrence, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.

For the radical radiotherapy cohort, participants will receive alectinib after radiotherapy, adjuvant treatment should be initiated ideally 4-12 weeks after surgery, or according to local standard of care, the treatment will continue until completion of treatment period (24 months), disease progression, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• Signed Informed Consent Form

• Age ≥ 18 years at time of signing Informed Consent Form

• Ability to comply with the study protocol

• Eligible to receive a platinum-based chemotherapy according to local labels or guidelines

• Cytologically and/or histologically documented locally advanced, unresectable Stage III NSCLC

  • Staging should be based on Version 8 of the American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system.
  • Participants with T4 primary NSCLC with a separate nodule in a different ipsilateral lobe are not eligible.

• Documented ALK fusion positivity by an eligible result from:

  ○ Previously obtained local test results as ordered by a healthcare provider from a high-quality and appropriately validated ALK fusion test on tumor tissue performed in a Clinical Laboratory Improvement Amendments Certified or equivalent laboratory. Acceptable local test methods include the following

  • Next-generation sequencing; immunohistochemistry; fluorescence in situ hybridization; reverse transcription-polymerase chain reaction; NanoString.
  • Only National Medical Products Administration (NMPA)-approved tests for ALK fusions are acceptable.
  • Identification of a specific gene fusion partner is required (exceptions: ALK immunohistochemistry and certain PCR tests for which the gene fusion partner is not pre-specified as part of the test design). The use of positional 5/3 imbalance probe gene expression is not acceptable.

• Eastern Cooperative Oncology Group Performance Status of 0, or 1

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study drug (i.e., Day 1 of Cycle 1):

  • ANC ≥1.5 * 109/L (≥1500/L), without granulocyte colony-stimulating factor support
  • Platelet count ≥100* 109/L ( 100,000/L), without the need for transfusion
  • Hemoglobin ≥ 90 g/L (≥9.0 g/dL)
  • Participants may be transfused or receive erythropoietic treatment as per local SOC to meet this criterion.
  • AST, ALT, and ALP ≤ 2.5 *upper limit of normal (ULN)
  • Bilirubin≤1.5*ULN with the following exception: Participants with known Gilbert disease: bilirubin level ≤ 3* ULN
  • Creatinine clearance (CrCl) ≥ 60 mL/min, calculated using the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of CrCl
  • Albumin ≥ 25 g/L (≥ 2.5 g/dL)
  • For participants not receiving therapeutic anticoagulation: INR and aPTT≤1.5 * ULN
  • For participants receiving therapeutic anticoagulation: stable anticoagulant regimen

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below:

  • Women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for at least 90 days after the final dose of alectinib. While additionally adhering to the local label for alectinib and chemotherapy. Women must refrain from donating eggs during this same period.
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis).
  • Examples of contraceptive methods with a failure rate of<1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The use of oral contraceptives should be supplemented with a barrier method (preferably a male condom).
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the cohort and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of contraception.
  • Women should seek advice on fertility preservation before treatment with pemetrexed, cisplatin and carboplatin

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below:

  • With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 90 days after the final dose of alectinib. Men must refrain from donating sperm during this same period.
  • With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 90 days after the last final dose of alectinib to avoid exposing the embryo. The reliability of sexual abstinence should be evaluated in relation to the duration of the cohort and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of preventing drug exposure.
  • Men should seek advice on fertility preservation before treatment with pemetrexed, cisplatin, and carboplatin.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Any exclusion criteria based on local labels or guidelines for chemotherapy

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 90 days after the final dose of alectinib or or according to local labels or guidelines for chemotherapy longer), whichever is longer.

  ○ Women of childbearing potential must have a negative serum pregnancy test result prior to enrollment and within 7 days prior to the first dose of alectinib.

• Any history of previous NSCLC and/or any history of prior treatment for NSCLC (participants must be newly diagnosed with unresectable Stage III disease)

• Any evidence of Stage IV disease, including, but not limited to, the following:

  • Pleural effusion
  • Pericardial effusion
  • Brain metastases
  • History of intracranial hemorrhage or spinal cord hemorrhage
  • Bone metastases
  • Distant metastases

• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (T4 disease):

  ○ When pleural fluid is visible on both the CT scan and chest X-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative.

  • Participants with exudative pleural effusions are excluded regardless of cytology.
  • Participants with effusions that are minimal (i.e., not visible on chest X-ray) that are too small to safely tap are eligible.

• NSCLC known to have one or more of the following ALK point mutations: I1171X (where X is any other amino acid), V1180L, G1202R

• NSCLC known to have a known or likely oncogenic-driver mutation in the EGFR gene

• Liver disease, characterized by any of the following:

  ○ Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices or Active viral or active autoimmune, alcoholic, or other types of acute hepatitis

• Positive hepatitis B surface antigen (HBsAg) test at screening

  ○ Participants with a previous hepatitis B virus (HBV) infection or resolved HBV infection (hepatitis B core antibody [HBcAb] positive, but negative HBsAg are eligible only if the HBV DNA test is negative.

• Participants known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with the following exception:

  ○ Participants who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible.

• HIV infection, participants are excluded if they meet any of the following:

  • CD4+ T-cell (CD4+) counts<350 cells/L
  • On established antiretroviral therapy<4 weeks
  • Have a detectable HIV viral load at screening
  • History of AIDS-defining opportunistic infections within the past 12 months.

• Known active tuberculosis

• Symptomatic bradycardia

• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

  ○ Participants with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.

• Any gastrointestinal (GI) disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest CT scan

• History of malignancy other than NSCLC within 5 years prior to enrollment, with the exception of malignancies with a negligible risk of metastasis or death , such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer

• Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer

  ○ Note: Local treatment of isolated lesions, excluding target lesions, with palliative intent is acceptable (e.g., by local surgery or radiotherapy).

• Major surgical procedure, within 4 weeks prior to initiation of study treatment

• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

• Treatment with investigational therapy within 28 days prior to initiation of study treatment

• Prior treatment with ALK inhibitors

• Known sensitivity to any component of alectinib and chemotherapy

  ○ This includes, but is not limited to, participants with galactose intolerance, a congenital lactase deficiency, or glucose-galactose malabsorption.

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study

• Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of participant safety or study results.