Lung cancer is the leading cause of both cancer and cancer-related mortality in the United States. Targeting different receptor tyrosine kinase pathways has proven to be a potent therapeutic strategy for such cancers.

Background

Non-small cell lung cancer (NSCLC) is uncommonly diagnosed in patients younger than 50 years of age. We analyzed the California Cancer Registry (CCR) to describe epidemiologic characteristics and outcomes in this patient subset and to identify factors prognostic for cause-specific survival (CSS).

Methods

Patients diagnosed with NSCLC between 1/1/98 through 12/31/09 and reported to the (CCR) as of October 2011 were included. The primary outcome measure was CSS. Cox regression models were used to evaluate predictors of CSS in young patients with NSCLC, adjusted for potential confounders. Interaction analysis was performed between age groups (<50 vs. ≥50) and specific demographic and tumor covariates.

Results

We identified 132,671 lung cancer cases, of which 114,451 (86.3%) had NSCLC. Of these, 6389 (5.6%) were<50 years of age (median, 46 years). The most common histology was adenocarcinoma (3697, 57.9%). Most patients had stage III (1522, 23.8%) or IV (3655, 57.2%) disease. Fewer young patients were diagnosed in recent years (n, % of total NSCLC population of that era): 1998-2001 (2355, 6.0), 2002-2005 (2182, 5.7), and 2006-2009 (1852, 5.0), P<0.001. Multivariate analysis showed that age <50 years was an independent predictor of improved CSS (HR 0.827, P<0.001). Significant predictors of better CSS in patients <50 years included female sex, Asian or Hispanic ethnicity, lower stage, later year of diagnosis, and higher socioeconomic status, among others. Adenocarcinoma histology was not associated with improved CSS in this patient subset (HR 0.987, P=0.78). Interaction analysis revealed that Hispanic race and bronchioloalveolar histology had differential CSS outcomes dependent on age group.

Conclusions

This large registry study found that age <50 years is an independent predictor of improved CSS. Variables prognostic for CSS differed somewhat from those in older patients.

Background

Although the epidermal growth factor receptor (EGFR) inhibitor erlotinib is initially effective in non-small-cell lung cancer (NSCLC) patients with tumors harboring activating mutations of EGFR, most subsequently develop acquired resistance. One recognized resistance mechanism occurs through activation of bypass signaling via the hepatocyte growth factor (HGF)-MET pathway. INC-280 is a small molecule kinase inhibitor of MET. We sought to demonstrate the activity of INC-280 on select NSCLC cell lines both as a single agent and in combination with erlotinib using exogenous HGF to simulate MET up-regulation.

Methods

Four NSCLC cell lines (HCC827, PC9, H1666, and H358) were treated with either single-agent INC-280 or in combination with erlotinib with or without HGF. The activity of the drug treatments was measured by cell viability assays. Immunoblotting was used to monitor expression of EGFR/pEGFR, MET/pMET, GAB1/pGAB1, AKT/pAKT, and ERK/pERK as well as markers of apoptosis (PARP and capase-3 cleavage) in H1666, HCC827, and PC9.

Results

As a single agent, INC-280 showed minimal cytotoxicity despite potent inhibition of MET kinase activity at concentrations as low as 10 nM. Addition of HGF prevented erlotinib-induced cell death. The addition of INC280 to HGF-mediated erlotinib-resistant models restored erlotinib sensitivity for all cell lines tested, associated with cleavage of both PARP and caspase-3. In these models, INC-280 treatment was sufficient to restore erlotinib-induced inhibition of MET, GAB1, AKT, and ERK in the presence of HGF.

Conclusion

Although the MET inhibitor INC-280 alone had no discernible effect on cell growth, it was able to restore sensitivity to erlotinib and promote apoptosis in NSCLC models rendered erlotinib resistant by HGF. These data provide a preclinical rationale for an ongoing phase 1 clinical trial of erlotinib plus INC-280 in EGFR-mutated NSCLC.

Introduction

In patients with NSCLC harboring oncogenic ALK or ROS1 rearrangements, tyrosine kinase inhibitors have yielded high response rates and improvements in progression-free survival compared with cytotoxic chemotherapy; however, acquired resistance eventually develops. In preclinical models, ALK and MEK coinhibition was able to overcome ALK inhibitor resistance.

Methods

A phase 1 study of the ALK/ROS1 inhibitor ceritinib and the MEK inhibitor trametinib in patients with refractory NSCLC harboring ALK or ROS1 fusions was initiated. A three plus three dose-escalation scheme was used. Two dose levels were investigated. The primary end point was to determine the safety and tolerability of the combination.

Results

Nine patients (n = 8 ALK+, n = 1 ROS1+) were enrolled in the study and completed at least one cycle of therapy. The most common adverse events (all grades) were diarrhea (n = 9; 100%), rash (n = 8; 89%), abdominal pain (n = 5; 56%), and elevated aspartate transaminase/alanine transaminase level (n = 4; 44%). The overall response rate was 22%, whereas disease control rate was 56%. Median duration of response was 7.85 months. The median progression-free survival was 3.0 months (95% confidence interval: 1.5-7.0 mo). The median overall survival was 8.9 months (95% confidence interval: 2.0-not reached).

Conclusions

Data from this trial indicate that the combination of ceritinib and trametinib had no unexpected toxicities and that a tolerable dose could be identified. A subset of patients seemed to obtain clinical benefit from this treatment after progression on prior ALK/ROS1 inhibitor treatment.ClinicalTrials.gov Identifier: NCT03087448.