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Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation is thought to be related with dismal outcome for non–small-cell lung cancer (NSCLC) patients. The role of KRAS mutation as a predictor of response to chemotherapy for patients with metastatic NSCLC is poorly understood. Methods: From a retrospective database of two university hospitals, all patients with advanced, nonsquamous NSCLC treated with first-line platinum-containing chemotherapy were selected. Mutation analysis for KRAS was performed and the relation with response to chemotherapy was assessed. Secondary endpoints were its relation with response to progression-free survival (PFS) and overall survival (OS). Results: A total of 161 patients, 94 men and 67 women, were included in this study. Median age was 60 years. The majority of patients (79%) had stage IV disease, of which 60 patients (37%) had a KRAS mutation. Patients with a KRAS mutation had a similar response to treatment as patients with KRAS wild-type (wt) ( p = 0.77). Median PFS in KRAS -mutated patients was 4.0 months versus 4.5 months in KRAS wt patients (hazard ratio=1.3; [95% confidence interval, 0.9–1.8]; p = 0.16). Median OS in patients with KRAS mutation was 7.0 months versus 9.3 months in patients with KRAS wt (hazard ratio=1.2; [95% confidence interval, 0.9–1.7]; p = 0.25). Type of KRAS mutation had no influence on response or outcome. Conclusion: On the basis of our multicenter data presented here, we conclude that KRAS mutation is not predictive for worse response to chemotherapy, PFS, and OS in advanced NSCLC patients treated with platinum-based chemotherapy in first-line setting.

The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin. Consistent with this, sorafenib and metformin act synergistically in inhibiting cellular proliferation in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen on phosphorylation of the AMPKα activation site. Our results provide a rationale for the synergistic antiproliferative effects, given that AMPK inhibits downstream mTOR signaling. These data suggest that the combination of sorafenib with AMPK activators could have beneficial effects on tumor regression by AMPK pathway activation. The combination of metformin or other AMPK activators and sorafenib could be tested in prospective clinical trials.

Objectives: As suggested by in-vitro data, we hypothesize that subtypes of ICRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens.Methods: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinumbased chemotherapy, were retrieved from hospital databases. Primary objective: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation.Results: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of ICRAS mutation were G12C (46%), G12V (20%) and G1 2D (10%). Platinum was combined with pemetrexed (n =334), taxanes (n = 68) or gemcitabine (n = 62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p Conclusion: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR Response to chemotherapy regimens was different in types of ICRAS mutation. Especially patients with G12V had better response to taxane treatment. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Thromboembolic events (TE) are common in patients with cancer and are potentially life-threatening. In lung cancer, little is known about thrombosis during chemotherapy treatment. The aim of this study was to describe the incidence of TE in patients with non-small cell lung cancer (NSCLC), occurring during treatment with platinum-based chemotherapy.We retrospectively selected patients with NSCLC treated with platinum-based chemotherapy at the VU University Medical Center Amsterdam between 2000 and 2012. Patients who underwent recent surgery were excluded. All TE were included that occurred from start of chemotherapy treatment until 30 days after last administration.Among 784 included patients, 63 (8.0%) patients had 69 TE during treatment. Forty-five venous TE (VTE) and 24 arterial TE (ATE). Six patients had multiple events within treatment period, 3 of which had simultaneous ATE and VTE. In total, 613 patients were treated with cisplatin, 119 patients received carboplatin and 52 patients received both in first- or second-line treatment. In 8% (55/665) of the patients exposed to cisplatin a TE had occurred vs. 5% (8/171) in patients exposed to carboplatin (p=0.42). The majority of TE occurred in the first 2 cycles (70%). History of TE was related to occurrence of TE during chemotherapy (p0.01). Median PFS was similar in patients with and without TE (6.2 vs. 7.2 months, respectively; p=0.10). Median OS was significantly shorter in patients with TE (9.5 vs. 12.9 months, respectively; p=0.03).In our series, both ATE and VTE were a common finding during chemotherapy. TE was a poor prognostic factor. No difference in TE incidence was found between patients treated with cisplatin or carboplatin.

Purpose: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non–small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. Experimental Design: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Results: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0–1.9] but not OS (HR, 1.3; 95% CI, 0.9–1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Conclusion: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy. Clin Cancer Res; 19(3); 743–51. ©2012 AACR.

e19015 Background: At present, no targeted treatment is available for KRAS-mutated non-small cell lung cancer (NSCLC). In vitro, we found support for synergistic effects of sorafenib and metformin ...

8061 Background: Improving clinical outcome of pts with advanced NSCLC with a KRAS mut is challenging. Previous research indicated that different types of KRAS mut respond differently to chemotherapy regimens. This may impact treatment strategy in this group of pts. Methods: Consecutive pts with advanced NSCLC and known KRAS mut status, treated with first-line PC were retrieved from different hospital databases. Primary objective: Differences in overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of PC per type of KRAS mut. Χ2-test and log rank test were used and pts were stratified by KRAS amino acid substitution (sub). Results: 305 pts (92% stage IV) from 10 hospitals, treated between 2008 and 2013, were included. Most common mut were G12C (47%), G12V (20%) and G12D (10%); 90% of pts had a codon 12 mut. Pts were treated with cisplatin (n=155) or carboplatin (n=150), combined with pemetrexed (PEM; n=194), gemcitabine (GEM; n=50), taxanes (TAX; n=...

Rationale. In observational and preclinical studies, metformin is found to have anticancer properties and to prolong survival in various cancer types. It is unknown whether metformin use confers a survival benefit in Small Call Lung Cancer (SCLC) patients. We studied the influence of metformin usage on the overall survival (OS) in SCLC patients. Methods. SCLC patients in the period 1998 to 2009 were selected from the population-based Eindhoven Cancer Registry. Those included were linked to the PHARMO Record Linkage System. The following data were recorded: date of diagnosis, age, gender, stage of disease, comorbidity (Charlson comorbidity index), drug usage, administration of chemotherapy and date of death. Kaplan Meier curves were used to estimate OS. Cox regression analyses were used to estimate the hazard ratio (HR), this was corrected for age, gender and stage of disease in multivariate analyses. Due to the small group of patients using metformin, a multivariate analysis to correct the HR estimation was not performed. Results. In this study, a total of 1,136 SCLC patients were included. Median age was 67 years (range 37-95), 63%/37% male/female, 63%/37% extended/limited disease. Patients were treated with chemotherapy (75%), radiotherapy (28%) or surgery (2%). A total of 256 patients (23%) did not receive active anticancer treatment. Most common comorbidities were cardiovascular diseases (35%), COPD (24%), and hypertension (19%). A total of 151 patients (12%) were diagnosed with diabetes mellitus (DM), of which 92 (68%) received antidiabetics at time of diagnosis of SCLC. Fifty patients received metformin. DM was not significantly associated with a worse prognosis, with a median OS of 6.0 vs. 7.5 months in patients without DM (HR= 1.2 (95% CI 0.9-1.5)). Patients receiving metformin had no survival benefit comparing to all other SCLC patients, with a median OS of 8.4 and 7.0, respectively (HR= 0.9 (95% CI. 0.7-1.2)). Compared to patients receiving insulin monotherapy or sulfanylureas (n= 42), outcome was non-significantly improved in patients receiving metformin monotherapy (n= 20): median OS 11.0 vs. 7.0 months (HR= 0.9 (95% CI. 0.5-1.6)). Conclusions. In our series, having diabetes was not associated with worse prognosis in SCLC patients. However, within the SCLC patients with diabetes, those receiving metformin had a clinically relevant survival benefit compared to those receiving other antidiabetics. Due to a relative small cohort we could not demonstrate significance. Larger (retro- and) prospective studies and preclinical research must be performed to elucidate the role of metformin, if any, in the clinical management of SCLC. Citation Format: Wouter W. Mellema, Mieke J. Aarts, Myrthe P.P. Van Herk-Sukel, Egbert F. Smit. A retrospective evaluation of metformin usage in patients with small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3635. doi:10.1158/1538-7445.AM2013-3635

Non-small lung cancer (NSCLC) patients with metastatic disease have a poor prognosis and platinum-based chemotherapy is the only treatment option in the majority of these patients. There is a great need for new targeted therapies in this complex and heterogeneous disease. Sorafenib is a multi-target tyrosine kinase inhibitor (TKI), which inhibits proteins involved in proliferation and angiogenesis and could be an attractive agent for patients with NSCLC. Sorafenib is studied in first- and second-line treatment as mono and combination therapy. In phase III trials, sorafenib failed to show improvement in survival as first-line treatment in addition to chemotherapy and as monotherapy in third or fourth line. Even detrimental effects were observed in patients with squamous histology. Still, a subgroup of patients derive long-term benefit from treatment with sorafenib. To identify these patients, biomarker studies have been conducted, but no predictive biomarker has yet been found. Combination therapy of sorafenib with other targeted agents is currently being studied.

Background: Sorafenib (Nexavar) is a small molecule multitargeted kinase inhibitor targeting several tyrosine protein kinases (e.g. VEGFR, PDGFR) and Raf kinases. The drug is FDA-approved for the treatment of advanced hepatocellular carcinoma and advanced clear cell renal cell carcinoma. Sorafenib is currently tested in multiple phase I-III studies for a broad range of solid tumors, including Non-Small Cell Lung Cancer (NSCLC). In a phase II clinical trial in KRASmt advanced NSCLC with single agent sorafenib overall survival was different in 5/57 patients using the oral antidiabetic drug metformin (medians 9.0 vs 4.8 months, p = 0.13). Furthermore, it was observed that the two patients with the longest progression free survival were patients using metformin. Metformin has been described as 5′ AMP-activated protein kinase (AMPK)-activator. Results: In NSCLC cell lines, sorafenib in combination with metformin was found to act synergistically in inhibiting cellular proliferation. The synergistic effect closely paralleled AMPKalpha phosphorylation on the activation site threonine-172, that can be performed by the tumor suppressor LKB1 and the Ca-activated protein kinase CaMKKII. Consistent with our findings, the drug combination of sorafenib with the synthetic allosteric AMPK activator A-769662 led to an identical synergistic growth inhibition of NSCLC cells. AMPK acts as a cellular energy sensor regulating several intracellular metabolic systems and activation leads to suppression of mTOR signalling. The combination treatment showed a synergistic effect on inhibiting the phosphorylation of the downstream mTOR targets 4E-BP1 and the ribosomal protein S6. Conclusion: Our results suggest that the combination of sorafenib with metformin could have beneficial effects on tumor regression by synergistically activating AMPK. We are currently testing this concept in a NSCLC-xenograft study of sorafenib in combination with metformin.

Background: In a pilot study (1) we found sorafenib to display clinical activity against patients with K-Ras positive NSCLC, sufficient for formal phase II testing. Methods: Patients with K-Ras mutated NSCLC that progressed after at least 1 platinum containing regimen with adequate organ reserve, ECOG 0–2, who provided written informed consent according to local IRB regulations were eligible. A tumor biopsy confirming the presence of a K-Ras mutation was mandatory. Treatment consisted of sorafenib 400 mg BID until disease progression or unacceptable toxicity. Dose reductions and delays were specified per protocol in the face of CTC toxicities grade 3 and 4. Primary endpoint: Rate of No Progression (NPR) at 6 weeks. Secondary endpoints: duration of response, progression free survival (PFS), overall survival and treatment related toxicities. A 2-stage design was implemented (Simon's optimal design; p0=40%, p1=60%, alpha=0.05, beta=0.20) for a total number of 48 pts. Results: 59 patients were entered between May 1st 2010 and February 18 2011. Median age was 58 (range 46–79) years, 17 Male/42 Female, ECOG PS 0/1/2 23/32/4. 57 patients started treatment. At 6 weeks 5 PR, 25 SD, 27 PD were observed; NPR 52.6%. Fifteen patients stopped treatment before 6 weeks, of which 10 patients stopped due to (clinical) progression. Median duration of treatment was 9 (range 0–62) weeks, 2 patients are still on treatment. Median duration of response was 32 (range 5–58) weeks. Median PFS was 2.3 months, median OS was 4.9 months, 14 patients still alive. Dose modifications were realized in 21 patients, of whom 4 discontinued treatment. Most reported adverse events were fatigue (6.4%), hand-foot reaction (5.7%), dyspnea (5.6%), anorexia (3.7%) diarrhea (3.6%) and cough (3.6%). Sorafenib related grade 3-4 toxicity was reported in 10 patients. Five patients with grade 3 skin toxicity, 4 patients with grade 3 gastrointestinal toxicity and 1 patient with both grade 3 metabolic abnormalities and a grade 3 pneumonitis. Conclusion: Treatment with sorafenib has relevant clinical activity in patients with K-Ras mutational status. Further randomized study with this agent is warranted. This abstract is also presented as Poster B18.