Patient case: 45-year-old female with colon cancer; genetic feature: ERBB2 amplification

Clinical trial: Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Non-small Cell Lung Cancer Patients With EGFR Mutation.

Summary: The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.


Eligibility: Inclusion criteria:
  -  Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC
  -  Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I)
  -  Presence of at least one measurable lesion according to RECIST v.1.1
  -  ECOG performance status ≤1
  -  Patients must be screened for HBV. Patients who are either HBsAg positive or HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last dose of EGF816.
  -  Patients must be screened for HCV. Patients must have negative hepatitis C antibody (HCV Ab) or are HCV Ab positive but with an undetectable level of HCV-RNA. Note: patients with detectable HCV-RNA are not eligible for the study.
  -  Phase Ib only: documented progression of disease according to RECIST v1.1 while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
  -  Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v1.1.
  -  Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation .
  -  Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting.
  -  Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting
  Exclusion Criteria:
  -  Phase Ib:
  -  More than one previous treatment line with erlotinib, gefitinib or afatinib
  -  Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
  -  Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
  -  Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant):
  -  More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
  -  More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
  -  Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
  -  Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
  -  Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve):
  -  More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting
  -  Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g.erlotinib, gefitinib, afatinib, AZD9291, CO-1686, ASP8273, EGF816) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.
  -  Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):
  -  De novo EGFR T790M mutation identified by central assessment
  -  Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. Patients who received only one cycle of antineoplastic therapy in the advanced setting are allowed).
  -  Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):
  -  More than 2 prior lines of systemic antineoplastic therapies in the advanced setting
  -  Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
  -  Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
  -  Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
  -  Patients with symptomatic brain metastases.
  -  Presence or History of another malignancy. Exception: Patients who have been disease-free for 3 years, or patients with a history of adequately treated in-situ carcinoma of the uterine cervix, completely resected basal or squamous cell carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that has been cured, are eligible.
  -  Undergone a bone marrow or solid organ transplant.
  -  Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
  -  Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry except for control of brain metastases, topical applications, inhaled sprays, eye drops or local injections
  -  Patients with clinically significant, uncontrolled cardiovascular disease
  -  Presence or history of interstitial lung disease or interstitial pneumonitis
  -  Patients have not recovered from all toxicities related to prior anticancer therapies to grade ≤1 (CTCAE v 4.03)
  -  Patients have out of range laboratory values defined as
  1. Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5x103/µL)
  2. Hemoglobin (Hb) <9 g/dL (90g/L)
  3. Platelets (PLT) <75 x 109/L (75x103/µL)
  4. Total bilirubin >1.5 x upper limit of normal (ULN).
  5. AST and/or ALT >3 x ULN
  6. Patients with liver metastasis may not be included if AST and/or ALT >5 xULN
  7. Alkaline phosphatase (ALP) >5 xULN
  8. Calculated creatinine clearance < 45mL/min (0.75 mL/sec)using Cockroft-Gault formula
  9. Asymptomatic serum amylase or lipase > Grade 2
  10. Serum amylase or serum lipase CTCAE grade ≥ 1 with signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, abnormal imaging findings of pancreas, etc)
  -  Patients have the following laboratory values outside of the laboratory normal limits or cannot be corrected to within normal limits with supplements during screening: Potassium, Magnesium, Phosphorus, Total calcium (corrected for serum albumin)
  Other protocol-defined inclusion/exclusion criteria may apply.

Relevance to patient case: not relevant