Nivolumab plus Platinum-Based Doublet Chemotherapy or Erlotinib in Patients with Advanced Lung Cancer
Despite major treatment advances made in advanced non–small-cell lung cancer (NSCLC), the prognosis remains poor. The 1-year overall survival rate with standard first-line therapy of platinum-based doublet chemotherapy (PT-DC) is approximately 30% to 40% for patients with advanced NSCLC, with response rates of 20% to 30%. Although higher response rates and improvement in progression-free survival (PFS) may be achieved with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy compared with PT-DC, acquired resistance to these therapies inevitably occurs. Nivolumab is a fully human immune checkpoint inhibitor antibody directed toward the programmed death-1 (PD-1) receptor, which is implicated in immune escape mediated by the constitutive activation of EGFR signaling. At ESMO 2014, Gettinger and colleagues reported interim data from a phase 1 study evaluating the safety and antitumor activity of nivolumab in combination with 3 standard PT-DC regimens or erlotinib in patients with advanced chemotherapy-naïve NSCLC (Gettinger et al. ESMO 2014; Abstract 1054PD).
Based on NSCLC histology, 56 eligible patients were assigned to receive intravenous (IV) nivolumab 10 mg/kg every 3 weeks concurrently with 3 different standard PT-DC regimens: cisplatin 75 mg/m2 + IV gemcitabine 1250 mg/m2 (squamous) or pemetrexed 500 mg/m2 (nonsquamous), or nivolumab 5 or 10 mg/kg IV every 3 weeks + IV paclitaxel 200 mg/m2 + carboplatin AUC6 (any histology), or nivolumab 3 mg/kg IV every 2 weeks + erlotinib 150 mg PO daily (EGFR mutation–positive).
At the time of analysis, 66% and 57% of patients in the nivolumab plus PT-DC and nivolumab plus erlotinib arms had discontinued treatment because of disease progression. In the nivolumab plus PT-DC subgroup (n = 56) at a median follow-up of 75 weeks, grade 3 or 4 treatment-related adverse events occurred in 45% of patients, with nivolumab plus paclitaxel/carboplatin showing the highest frequency (73%), but many of which were laboratory abnormalities. Treatment discontinuations because of adverse events were reported in 11 patients (20%) across the arms. Four patients had grade 3/4 pneumonitis, with any grade pneumonitis occurring in 7% of patients. In terms of antitumor activity, patients achieved an overall response rate (ORR) ranging from 33% to 47%, a PFS rate at week 24 ranging from 38% to 71%, and a 1-year overall survival (OS) rate ranging from 50% to 87%.
In the nivolumab plus erlotinib subgroup (n = 21) at a median follow-up of 72 weeks, grade 3–related adverse events were reported in 24% of patients; no pneumonitis occurred in this cohort. Treatment discontinuation due to treatment-related adverse events were reported in 4 patients because of grade 3 elevations in AST, grade 3 diarrhea, grade 2 nephritis, and grade 2 flushing. In the efficacy cohort (n = 20), ORR was 15%, with an additional 9 patients achieving disease stabilization as best response.
The estimated median duration of response was not reached (range, 60.1 at ?70 weeks), 24-week PFS rate was 51% (median PFS, 29.4 months), and 1-year OS was 73% (median OS, not reported).
Gettinger and colleagues concluded that concurrent use of nivolumab and platinum-based chemotherapy demonstrated promising antitumor activity in chemotherapy-naïve patients with advanced NSCLC, which was associated with some additive effects of each agent or regimen on toxicity. Nivolumab plus erlotinib showed durable clinical benefit and an acceptable safety profile in EGFR mutation–positive patients with advanced NSCLC. These data support further evaluation of nivolumab-combination regimens in patients with advanced NSCLC.