Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up.

BACKGROUND: The natural histories of, and treatment options for, epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancers (NSCLCs) are distinctly different from those of lung cancer that lacks actionable mutations. Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor that has been approved in other malignancies. OBJECTIVE: A phase I trial of ipilimumab plus targeted therapy with either erlotinib or crizotinib was performed to assess the safety of the combination in patients with EGFR-mutated or ALK-rearranged advanced NSCLC. METHODS: Patients with EGFR-mutated or ALK-rearranged NSCLC on a stable dose of erlotinib or crizotinib for > 28 days were eligible for the study. Patients were treated with ipilimumab 3 mg/kg for four cycles plus erlotinib or crizotinib. RESULTS: Treatment of the EGFR cohort resulted in dose-limiting toxicity in three of eight patients, with grade 3 diarrhea. The protocol was amended to reduce the ipilimumab dose to 1 mg/kg. Excessive toxicity resulted in the study being closed after 14 patients. Four of 11 EGFR-mutated patients ultimately developed grade 3 colitis. Of three ALK-rearranged patients, one developed hypophysitis and another grade 2 pneumonitis. For 11 EGFR-mutated patients, progression-free survival (PFS) from the start of ipilimumab was 17.9 months. Erlotinib treatment began a median 7.7 months before ipilimumab; therefore, erlotinib PFS was 27.8 months. Median overall survival (OS) has not been reached but will be > 42.3 months from erlotinib initiation. For three ALK-rearranged patients, ipilimumab PFS was 24.1 months. Median OS has not been reached but will be at least 47.2 months from the initiation of crizotinib. CONCLUSION: Erlotinib plus ipilimumab caused excessive short-term gastrointestinal toxicity leading to early study closure. However, PFS and OS were notable; therefore, targeted therapies with immunotherapy in NSCLC merit further study. Clinicaltrials.gov registration number: NCT01998126.