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e21135 Background: There is an unmet need for reliable biomarkers predictive of treatment outcome with immunotherapy in patients with non-small cell lung cancer (NSCLC). The aim of our study is to examine, in front-line patients, the potential utility of a proteomic signature, PIR (primary immune response), developed and validated in 2nd line patients (M. Muller Clin Cancer Res. 2020 Oct 1;26(19):5188-5197. doi: 10.1158/1078-0432.CCR-20-0538. Epub 2020 Jul 6) as a predictive biomarker of response to treatment with pembrolizumab in a first-line setting. Methods: Pretreatment serum samples were collected from stage IV NSCLC patients treated with a pembrolizumab-containing regimen in first-line at the Netherlands Cancer Institute and Erasmus Medical Center between 2016 and 2020. Data on demographics, ECOG performance status (PS), PD-L1 expression, treatment, progression free survival (PFS) and overall survival (OS) were collected. The PIR test was performed and classified in two groups: resistant vs. intermediate/sensitive (not-resistant). Results: Serum samples of 119 patients were available for analysis. Median age was 65 (36-82) years; 49% female; PS 0-1 80%. 45 samples failed QC and were excluded allowing for the analysis of 74 patients: 24 receiving pembrolizumab monotherapy, and 50 receiving a combination of chemotherapy and pembrolizumab. Overall, median PFS was 5.3 months in the resistant group vs. 9.0 months in the not-resistant group (HR 0.60 (95%CI 0.33-1.08; p = 0.09). In patients receiving pembrolizumab monotherapy, the resistant group had a trend toward shorter PFS (median PFS 3.4 months vs. 10.3 months) then the non-resistant group, (HR 0.42 (95% CI 0.15-1.21; p = 0.11))). No difference was observed in patients treated with a combination of chemotherapy and pembrolizumab (median PFS 5.8 months vs. 9.0 months, respectively; HR = 0.65 (95% CI 0.31-1.36; p = 0.25). Median OS was not reached vs 17.0 months, respectively (HR 0.90 (95% CI 0.34-2.36; p = 0.83)). We did not observe any significant association between performance score and PD-L1 expression, and the PIR test. Conclusions: These data encourage further study of PIR as a predictive biomarker for first-line treatment with pembrolizumab in NSCLC patients.

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.

Objectives Both bone and brain are frequent sites of metastasis in non-small cell lung cancer (NSCLC). Conflicting data exist whether EGFR mutant (+) patients are more prone to develop brain metastases or have a better outcome with brain metastases compared to EGFR/KRAS wildtype (WT) or KRAS+ patients. For bone metastases this has not been studied. Methods In this retrospective case-control study all EGFR+ (exons 19 and 21) patients diagnosed at two pathology departments were selected (2004/2008 to 2012). For every EGFR+ patient a consecutive KRAS+ and WT patient with metastatic NSCLC (mNSCLC) was identified. Patients with another malignancy within 2 years of mNSCLC diagnosis were excluded. Data regarding age, gender, performance score, histology, treatment, bone/brain metastases diagnosis, skeletal related events (SRE) and subsequent survival were collected. Results 189 patients were included: 62 EGFR+, 65 KRAS+, 62 WT. 32%, 35% and 40%, respectively, had brain metastases (p = 0.645). Mean time to brain metastases was 20.8 [±12.0], 10.8 [±9.8], 16.4 [±10.2] months (EGFR+–KRAS+, p = 0.020, EGFR+–WT, p = 0.321). Median post brain metastases survival was 12.1 [5.0–19.1], 7.6 [1.2–14.0], 10.7 [1.5–19.8] months (p = 0.674). 60%, 52% and 50% had metastatic bone disease (p = 0.528). Mean time to development of metastatic bone disease was 13.4 [±10.6], 23.3 [±19.4], 16.4 [±9.6] months (p = 0.201). Median post metastatic bone disease survival was 15.0 [10.6–20.3], 9.0 [5.2–12.9], 3.2 [0.0–6.9] months (p = 0.010). Time to 1st SRE was not significantly different. Conclusions Incidence of brain and bone metastases was not different between EGFR+, KRAS+ and WT patients. Post brain metastases survival, time from mNSCLC diagnosis to metastatic bone disease and 1st SRE did not differ either. Post metastatic bone disease survival was significantly longer in EGFR+ patients. Although prevention of SRE's is important for all patients, the latter finding calls for a separate study for SRE preventing agents in EGFR+ patients.

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.

To the Editor: With interest we read the article by Nadal et al. entitled “KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma”. The authors retrospectively studied a group of 179 patients with surgically resected adenocarcinoma of the lung with known KRAS mutational status. The aim of this study was to investigate the effects, if any, of KRAS mutant subtypes on survival probabilities. Here, patients with any KRAS mutation had significant poorer survival compared with patients with KRAS wild type. In particular, patients with a G12C mutation had worse outcome compared with other types of mutation. We would like to comment on this article. First, the authors report that patients with a G12C KRAS mutation have a poorer prognosis compared with other types of KRAS mutations, which is illustrated in Figure 1. The authors also refer to a univariate analysis presented in Table 3 (p.1518). However, the univariate analysis provides a comparison between G12C KRAS mutation and wild type, but not G12C and non-G12C KRAS mutations. A difference in prognosis between types of KRAS mutation could possibly point toward differences in tumor biology. This is relevant data and we would like to invite the author to present the data of a multivariate analysis comparing G12C and other types of KRAS mutations. Furthermore, it is interesting to know how many patients had an EGFR mutation among the patients with KRAS wild type. This group of patient is known to a have favorable prognosis and can provide a relevant bias. We agree that the prognostic value of KRAS mutation is a controversial topic. As discussed in the article, two large studies on KRAS mutational status in resected non–small-cell lung carcinoma did not found a prognostic value for KRAS mutation or types of mutation. Over the past decade, almost a dozen studies investigated the same question in non–smallcell lung carcinoma with conflicting results. The study by Nadal et al. should therefore be interpreted carefully, despite methodological differences. Nonetheless, the data on KRAS addiction is interesting and we hope that future studies will point out the clinical relevance.

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.

Introduction: K-Ras mutation is thought to be related with poor outcome of NSCLC patients with an advanced stage of disease. The role of K-Ras mutation as a predictor of response for these patients treated only with chemotherapy is poorly understood. Patients and methods: From a retrospective database from 2 university hospitals all patients with advanced stage, nonsquamous, NSCLC treated with palliative platinum containing chemotherapy were selected. Patients were included when archive tumour tissue was available for DNA extraction. High resolution melting followed by PCR sequencing was performed for KRAS exon1 and 2. Response to treatment was assessed by RECIST. The databases were matched by treatment. Results: A total of 179 patients were included in this study. All patients were treated with chemotherapy and were no candidate for treatment with curative intent. There were 59 patients with a K-Ras mutation (32.9%). There was no significant difference in basic characteristics between the group with a K-Ras mutation and the group with K-Ras wild-type. Mean age 59 years (range 32–83 years), 108 males and 71 females. ECOG performance score 0/1/2/3 73/77/13/2. Thirty patients with stage IIIb disease, 149 patients with stage IV disease. Progression as best response to treatment was reported in 21/59 patients with a K-ras mutation (35.6%) and 34/120 patients (28.3%) with a K-Ras wild type, this was not significant (p=0.611). The median progression free survival (PFS) in the group with a K-Ras mutation was 4.1 months (95% CI 3.12–5.0 months) compared to 5.4 months (95% CI 4.4–6.4 months) in patients with K-Ras wild type (p=0.202). The overall survival (OS) in the group with a K-Ras mutation, was 8.3 months (95% CI 5.2–11.4 months) compared to 12.5 months (95% CI 10.2–14–7 months) in patients with K-Ras wild type (p=0.037). Conclusion: In our series K-Ras mutation was not predictive for response to platinum containing chemotherapy in patients with advanced NSCLC. K-Ras mutational status was prognostic for overall survival.