Study of Efficacy and Safety of Nivolumab in Combination With EGF816 and of Nivolumab in Combination With INC280 in Patients With Previously Treated Non-small Cell Lung Cancer

A Phase II, Multicenter, Open-label Study of EGF816 in Combination With Nivolumab in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer and of INC280 in Combination With Nivolumab in Adult Patients With cMet Positive Non-small Cell Lung Cancer

To determine the efficacy and safety of nivolumab in combination with EGF816 and of nivolumab in combination with INC280 in previously treated NSCLC patients

This was a phase II, multi-center, open-label study in patients with advanced non-small cell lung cancer (NSCLC). Patients were allocated based on their epidermal growth factor receptor (EGFR) status to one of the 2 groups: Group 1 - EGFR T790M NSCLC treated with EGF816 150 mg once daily (QD) + nivolumab 3 mg/kg every 2 weeks (Q2W), and Group 2 - EGFR wild type (wt) NSCLC treated with INC280 400 mg twice daily (BID) + nivolumab 3 mg/kg Q2W. Patients in Group 2 were subdivided into 2 subgroups based on c-Mesenchymal-epithelial transition (cMet) status: Subgroup A - high cMet (referred to as Group 2A) and Subgroup B- low cMet (referred to as Group 2B).

Patients could continue study treatment until patients experienced unacceptable toxicity that precluded any further treatment, disease progression and/or treatment was discontinued at the discretion of the investigator or withdrawal of consent, or the patient was transferred to a Novartis roll-over study or an alternative treatment option that could continue to provide study treatments. Following the approval of a protocol amendment, the maximum treatment duration for nivolumab could not exceed 2 years and patients who had received nivolumab beyond 2 years were discontinued from nivolumab treatment and continued on EGF816 or INC280 alone.

The primary objective of the trial was to estimate the clinical activity of nivolumab in combination with EGF816 or INC280.

Inclusion Criteria:

• Written informed consent must be obtained prior to any screening procedures
• Presence of at least one measurable lesion according to RECIST v.1.1
• ECOG performance status ≤ 2
• Patients with histologically documented locally advanced, recurrent and/or metastatic NSCLC
• Tumor tissue for determination and/or confirmation of genetic pre-requisites (i.e. EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis

Group 1 patients:

• Patients with EGFR T790M NSCLC (adenocarcinoma)
• Documented progression of disease according to RECIST v1.1 following primary standard of care (e.g. erlotinib, gefitinib)

Group 2 patients:

• Patients with EGFR wild-type NSCLC
• Documented progression of disease according to RECIST v1.1 following standard of care (e.g. platinum doublet).

Exclusion Criteria:

• Patients who have received more than one prior line of EGFR TKI therapy1 (applies only to Group 1)

• Previous treatment with a c-MET inhibitor or HGF-targeting therapy (applies only to Group 2)

• Patients with brain metastases. However, if radiation therapy and/or surgery has been completed and serial evaluation by CT (with contrast enhancement) or MRI over a minimum of one month demonstrates the disease to be stable and if the patient remains asymptomatic without the need for treatment with steroids

• Patients who require emergent use of systemic steroids, chronic use of prednisone (greater than 10mg or an equivalent steroid dose daily) or emergent surgery and/or radiotherapy.

• History of allergy or hypersensitivity to nivolumab components

• Patients with any known or suspected, current or past history of, autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll

• Patients with a condition requiring chronic systemic treatment with either corticosteroids(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment start. Inhaled or topical steroids, and adrenal replacement steroid doses> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease

• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection

• Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity

• Patients who have been treated with prior PD-1 and PD-L1 agents

• Patients who previously received agents targeting c-MET and/or EGFR T790M Note: Previous treatment with afatinib may be allowable after discussions between Novartis and Investigator.

• Patients with the following laboratory abnormalities:

  • Absolute Neutrophil Count (ANC) <1.5 x 109/L
  • Hemoglobin (Hgb) <9 g/dL
  • Platelets <100 x 109/L
  • Total bilirubin >1.5 x upper limit of normal (ULN). For patients with Gilbert's syndrome total bilirubin >2.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN
  • Serum creatinine >1.5 x ULN and/or measured or calculated creatinine clearance <75% LLN
  • For patients being screened for Group 2, asymptomatic serum amylase > CTCAE Grade 2 (1.5-2.0 x ULN). Patients with Grade 1 or Grade 2 serum amylase at the beginning of the study must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
  • For patients being screened for Group 2: Serum lipase > ULN

• Female patients who are either pregnant or nursing.

• Women of child bearing potential who refuse or are not able to use a highly effective method of contraception as defined in the study protocol.

• Sexually active males unless they use a condom during intercourse while taking drug and for 31 weeks after the last dose of study treatment.