Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. Methods The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. Discussion Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. Trial registration This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn, ChiCTR-IIR-17013471.

Background Dysregulation of the HGF/Met pathway has been associated with tumorigenesis in many malignancies, including the basal sub-type of triple-negative breast cancer. MetMAb (RG3638) is a recombinant, humanized, monovalent monoclonal antibody directed against Met. By binding to the extracellular domain of Met, MetMAb selectively blocks ligand binding and subsequent activation by HGF. Pre-clinical data support the efficacy of combining MetMAb with numerous chemotherapy agents and with targeted agents including bevacizumab and erlotinib. In clinic, MetMAb has been generally well tolerated as a single agent (Phase I), in combination with bevacizumab (Phase Ib) and with bevacizumab in a dose escalation/expansion study (Phase Ib)1 as well as in combination with erlotinib in patients with previously treated NSCLC2. The combination of MetMAb + erlotinib in NSCLC demonstrated significant benefit in both PFS and OS in patients with Met diagnostic positive tumors whereas those patients with Met diagnostic negative tumors demonstrated a detrimental effect in both PFS and OS. The most commonly reported adverse events associated with MetMAb are peripheral edema and fatigue. Methods: This clinical trial is a randomized three-arm Phase II study in patients with triple-negative metastatic breast cancer, which makes up the majority of basal sub-type breast cancer. Patients will be randomized (1:1:1) to either paclitaxel + bevacizumab + placebo; paclitaxel + placebo + MetMAb; or paclitaxel + bevacizumab + MetMAb. The primary endpoint of this study is PFS in all patients and by Met diagnostic status. Secondary endpoints include an evaluation of OS, ORR, safety, and pharmacokinetics. To date, 11 patients have been enrolled, and 10 patients have been treated. Primary and secondary analyses will include all randomized patients, with patients analyzed according to the treatment arm to which they were assigned. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm. An estimate of the HR with 95% CI will be determined using a Cox regression model with an indicator variable for the MetMAb-containing arm. Safety will be assessed through summaries of adverse events and will include all patients who receive any amount of study treatment. This study remains open for accrual; further details on the trial can be found on the ClinicalTrials.gov website under NCT01186991. 1. Moss et al, In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2–6; Orlando, FL; AACR 2011 (abstr 4717). 2. Spigel et al, J Clin Oncol 29:2011 (suppl; abstr 7505). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-11.

Gefitinib has shown good efficacy in patients with EGFR mutation-positive non-small-cell lung cancer, but acquired resistance is inevitable. Here we report a patient with an advanced lung adenocarcinoma with the EGFR mutation who achieved surgical opportunity and long-term survival following treatment with chemotherapy and bevacizumab, followed by sequential gefitinib combined with allogeneic haploidentical CD8+ CD56+ natural killer T cells. Our case provides a potential effective strategy for delaying acquired gefitinib resistance and extending progression-free survival among patients with non-small-cell lung cancer who harbor common EGFR mutations.