A Phase II Study of Combination Immunotherapy With Ipilimumab and Nivolumab in Patients With Advanced Non-small Cell Lung Cancer Resistant to Anti-PD-1-axis Therapy

Brief Summary

Detailed Description

Approximately 20 percent of unselected patients with advanced non-small cell lung cancer (NSCLC) and progression during or after standard first line chemotherapy will experience tumor response to nivolumab. Treatment options for patients who are not responsive to programmed death 1 (PD-1) axis inhibitor therapy are limited, and the mechanisms of primary resistance are poorly understood. The combination of nivolumab and ipilimumab is currently FDA approved for the treatment of advanced melanoma based on superiority to either agent alone5. The results of a phase I study evaluating combination therapy with nivolumab and ipilimumab in patients with advanced NSCLC (NCT01454102) were presented at the annual American Society of Clinical Oncology (ASCO) meeting in 20166. Dosing of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks yielded an objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of 39%, with one-year survival rate of 69% and grade 3-4 treatment-related adverse event rate of 33%. These results prompted an ongoing phase III study comparing this regimen to standard first line chemotherapy, nivolumab monotherapy or combination therapy with chemotherapy and nivolumab for patients with advanced NSCLC (NCT02477826). The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary resistance to anti-PD-1 axis therapy can lead to objective radiographic tumor regression. It is hypothesized that ipilimumab will enable more effective immune priming in some patients, resulting in the trafficking of tumor-specific cytotoxic T cells to the tumor, as well as depletion of tumor-permissive T regulatory cells. With concurrent nivolumab, PD-1 inhibition in the tumor will enable effective anti-tumor attack by tumor-specific T cells. Serial tumor biopsies and blood collections will allow interrogation of changes in the tumor microenvironment (and periphery) that support this hypothesis. The investigators will primarily enroll patients who have experienced progression of NSCLC after anti-PD-1- axis therapy without initial response to such therapy ('primary resistance'). A smaller cohort of patients with acquired resistance to anti-PD-1 axis therapy (i.e. progression after initial response) will additionally be accrued. The study record was updated to add individual arms for those with primary resistance and acquired resistance. The intent of the study is not to compare these treatment arms.

Primary Outcomes

Secondary Outcomes

• Objective Response Rate in in Advanced Non-small Cell Lung Cancer (NSCLC) With ACQUIRED Resistance to Anti-programmed Death (PD)-1 Axis Therapy as Their Last Line of Systemic Therapy.(Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.)
• Progression-free Survival With Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre- Treated Advanced NSCLC Who Have Experienced Primary Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy(Until disease progression, unacceptable toxicity, or study termination, up to four years.)
• Progression Free Survival by RECIST v1.1 With Nivolumab and Ipilimumab in Patients With Pre-treated Advanced NSCLC Who Have Experienced Acquired Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy.(Until disease progression, unacceptable toxicity, or study termination, up to four years from enrollment.)
• Overall Survival (OS) With Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre- Treated Advanced NSCLC Who Have Experienced PRIMARY Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy.(Until death or day of last follow-up, up to four years from enrollment.)
• Overall Survival With Nivolumab and Ipilimumab in Patients With Pre-treated Advanced NSCLC Who Have Experienced ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy.(Until death or day of last follow-up (up to four years from study enrollment).)
• Objective Response Rate Using irRC to Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Last Line of Systemic Therapy.(Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.)
• Safety of Nivolumab and Ipilimumab When Administered in Combination in Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy.(Up to 4 years)
• Feasibility of Sequential Biopsies in Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy.(Tumor biopsies performed at 9 to 10 weeks after receiving first dose of trial therapy.)