Neoadjuvant Afatinib Combination With Chemotherapy for Stage Ⅱa-Ⅲb NSCLC With EGFR Activating Mutation
Neoadjuvant Afatinib Combination With Chemotherapy for Stage Ⅱa-Ⅲb NSCLC With EGFR Activating Mutation
The recommended adjuvant therapy for stage Ⅱa-Ⅲb Non-small cell lung cancer (NSCLC) were
 perioperative chemotherapy. The adjuvant or neoadjuvant chemotherapy for early stage lung
 cancer improved about 5% 5-year survival. As for advanced NSCLC with epidermal growth factor
 receptor (EGFR) activating mutation, epidermal growth factor receptor-tyrosine kinase
 inhibitor (EGFR-TKI) combination with chemotherapy had improved progression-free survival
 (PFS) compared with EGFR-TKI alone. We propose this trial of Neoadjuvant Afatinib Combination
 With Chemotherapy for Stage Ⅱa-Ⅲb NSCLC With EGFR Activating Mutation, which would maximize
 benefit early in a patient's treatment course. At the same time, dynamic
 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) was used to
 evaluate the standardized uptake value (SUV) and uptake rate constant (Ki) changes of lesions
 before and after treatment, so as to accurately and quantitatively monitor the tumor response
 of different therapy.
The prognosis of stage Ⅱa-Ⅲb Non-small cell lung cancer (NSCLC) was worse, with 5-year
 survival rate between 26%-60%. The recommended adjuvant therapy for stage Ⅱa-Ⅲb NSCLC were
 adjuvant or neoadjuvant chemotherapy. As for advanced NSCLC with EGFR activating mutation,
 EGFR-TKI combination with chemotherapy had improved survival compared with EGFR-TKI alone.
 The Chinese Thoracic Oncology Group-1103 (CTONG-1103) trial showed that neoadjuvant erlotinib
 has better PFS than neoadjuvant chemotherapy.

 The investigators propose that neoadjuvant EGFR-TKI combination with chemotherapy for stage
 Ⅱa-Ⅲb NSCLC with EGFR activating mutation might have better pathological response and
 disease-free survival (DFS) than chemotherapy alone, and maximize benefit early in a
 patient's treatment course. At the same time, dynamic 18F-2-fluoro-2-deoxy-D-glucose positron
 emission tomography (18F-FDG PET) was used to evaluate the standardized uptake value (SUV)
 and uptake rate constant (Ki) changes of lesions before and after treatment, so as to
 accurately and quantitatively monitor the tumor response of different therapy.
Inclusion Criteria:

 -  Histologically or cytologically confirmed NSCLC, performed on a biopsy that occurred
 within the last 60 days

 -  Computed tomography (CT) or PET-CT within the last 30 days showing radiographic stage
 Ⅱa to Ⅲb lung cancer (mediastinal staging biopsy is allowed but not required) by the
 American Joint Committee on Cancer (AJCC) 8th edition

 -  Deemed surgically resectable by a senior thoracic surgeon

 -  Age≥18 years, and ≤75 years

 -  Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as
 assessed by the investigator

 -  Adequate tissue specimens for correlative biomarker analysis. The patient should be
 willing to provide tissue from a newly obtained biopsy of a tumor lesion and surgical
 resected tumor lesion.

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical
 procedures to NCI CTCAE version (v)5.0 grade 1

 -  Be willing and able to provide written informed consent for the trial

 -  Absolute neutrophil count (ANC) >= 1500 cells/ microlitre(uL) (within 10 days prior to
 the start of trial treatment)

 -  Platelets >= 100 000 cells/uL (within 10 days prior to the start of trial treatment)

 -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (criteria must be met without erythropoietin
 dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks)
 (within 10 days prior to the start of trial treatment)

 -  Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
 clearance, glomerular filtration rate (GFR) can also be used in place of creatinine or
 creatinine clearance (CrCl) >= 30 mL/min for patients with creatinine levels > 1.5 x
 institutional ULN (within 10 days prior to the start of trial treatment)

 -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
 bilirubin levels > 1.5 x ULN (within 10 days prior to the start of trial treatment)

 -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and
 alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
 ULN (=< 5 x ULN for patients with liver metastases) (within 10 days prior to the start
 of trial treatment)

 -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
 patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
 time (PTT) is within therapeutic range of intended use of anticoagulants (within 10
 days prior to the start of trial treatment)

 -  Activated partial thromboplastin time (aPTT)/PTT =< 1.5 x ULN unless patient is
 receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is
 within therapeutic range of intended use of anticoagulants (within 10 days prior to
 the start of trial treatment)

 -  Female patients of childbearing potential must have a negative urine or serum
 pregnancy test within 72 hours prior to receiving the first dose of trial medication.
 If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
 test will be required

 -  Male and female patients of childbearing potential must be willing to use an adequate
 method of contraception as outlined, for the course of the trial through 120 days
 after the last dose of trial drug

 -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
 contraception for the patient

 Exclusion Criteria:

 -  Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
 radiotherapy, within 3 years prior to initiation of study treatment; however, the
 following are allowed:

 -  Hormone-replacement therapy or oral contraceptives

 -  Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as
 anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1)

 -  Malignancies other than the disease under study within 3 years prior to Cycle 1, Day
 1, with the exception of those with a negligible risk of metastasis or death and with
 expected curative outcome or undergoing active surveillance per standard-of-care
 management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with
 Gleason score ≤ 6, and prostate-specific antigen (PSA) ≤ 10 mg/mL, etc.)

 -  Patients who are receiving any other investigational agents concurrently.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to afatinib, cisplatin, carboplatin, pemetrexed or gemcitabine.

 -  Patients with active hepatitis B or C infections or a history of HIV infection.

 -  Patients with past or resolved hepatitis B infection, defined as having a
 negative hepatitis B surface antigen (HBsAg) test and a positive for the antibody
 test to detect antibodies to hepatitis B core antigen (anti-HBc) are eligible.

 -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
 polymerase chain reaction (PCR) is negative for HCV RNA.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection including tuberculosis (TB), symptomatic congestive heart failure, unstable
 angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
 would limit compliance with study requirements.

 -  Known clinically significant liver disease, including active viral, alcoholic, or
 other hepatitis; cirrhosis; fatty liver; and inherited liver disease

 -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may
 be eligible.

 -  Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
 hospitalization for complications of infection, bacteremia, or severe pneumonia

 -  Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 Received oral or
 IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic
 antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive
 pulmonary disease) are eligible

 -  Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
 need for a major surgical procedure during the course of the study

 -  Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
 anticipation that such a live, attenuated vaccine will be required during the study

 -  Pregnant women

 -  History of interstitial lung disease or pneumonitis of any cause

 -  Is ineligible for an operation based on medical or oncologic contraindications to
 surgery

 -  Is currently participating in or has participated in a trial of an investigational
 agent or has used an investigational device within 4 weeks prior to the first dose of
 trial treatment

 -  Note: Patients who have entered the follow-up phase of an investigational trial
 may participate as long as it has been 4 weeks after the last dose of the
 previous investigational agent