Abstract
Activation of cell survival pathways such as autophagy represents a potential resistance mechanism to chemotherapy in NSCLC. Preclinical studies report that autophagy inhibition suppresses lung tumor development and progression. We report the safety and efficacy for adding autophagy inhibitor, hydroxychloroquine, to chemotherapy in a phase Ib/II single-arm study in patients with metastatic NSCLC.
We treated patients with untreated metastatic NSCLC with carboplatin, paclitaxel (and bevacizumab if criteria met) and hydroxychloroquine 200 mg BID. Patients continued on hydroxychloroquine (+/- bevacizumab) maintenance after 4-6 cycles of therapy.
We enrolled 40 patients, 8 on phase Ib and 32 on phase II. Forty-three percent were female; 50% with squamous histology. Median age was 62 years (range, 43-73). Thirteen patients developed ≥grade 3 treatment-related adverse event. Common adverse events (all grades) were neutropenia (35%), neuropathy (32.5%), and anemia (32.5%). The objective response rate (ORR) was 33% in the 30 patients (phase II) evaluable for response. Additionally, 20% of the patients demonstrated stable disease (clinical benefit rate of 53%). The median PFS was 3.3 months (95% CI 2.1-6.8 months). In 9 patients with KRAS positive tumors, ORR was 44% and median PFS was higher than expected at 6.4 months (95% CI 1.8-15.6).
Addition of hydroxychloroquine is safe and tolerable with a modest improvement in clinical responses compared to prior studies. Autophagy inhibition may overcome chemotherapy resistance in advanced NSCLC and further study in a more molecularly selected population such as KRAS-positive tumors is warranted.