bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of continuous daily sunitinib dosing in previously treated advanced non-small cell lung cancer (NSCLC): Results from a phase II study
Authors: Brahmer J. R. , Govindan R. , Novello S. , Rosell R. , Belani C. P. , Atkins J. N. , Gillenwater H. H. , Tye L. , Chao R. , Socinski M. A.
Published: March 2020

7542

Background: Sunitinib malate (SU), an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, has demonstrated activity in recurrent advanced NSCLC on the 4/2 schedule (4 weeks [wks] on treatment followed by 2 wks off), with a partial response (PR) rate of 11% (Socinski, ESMO 2006). A continuous dosing (CD) schedule of SU was additionally evaluated for safety and efficacy in this multicenter phase II study. Methods: Eligible patients (pts) had stage IIIB/IV NSCLC previously treated with 1–2 chemotherapy regimens, ECOG PS =1, and adequate organ function. Pts with brain metastases or recent gross hemoptysis were excluded. Pts received oral SU 37.5 mg/day continuously in 4-wk cycles. The primary endpoint was objective response rate per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results: Forty-seven pts were treated on the CD schedule: median age 60 yrs (range 37–81); male 57%; ECOG PS 0/1/2 49%/49%/2%; adenocarcinoma 53%, squamous cell carcinoma 15%, other 32%; median number of SU cycles initiated: 3 (range 1–10). One pt (2%) had a confirmed PR and 8 pts (17%) had stable disease >3 months. Median PFS was 12.1 wks (95% CI: 8.6–13.7). SU was generally well tolerated; most adverse events (AEs) were grade 1/2 and included fatigue/asthenia, pain/myalgia, nausea/vomiting, diarrhea, dyspnea, and stomatitis/mucosal inflammation. Grade =3 AEs included fatigue/asthenia (15%), hypertension (6%), hypoxia (6%), dyspnea (4%), and hemoptysis (2%). Treatment-related serious AEs included congestive heart failure (CHF; 1 pt), gastrointestinal bleeding (1 pt), hypomagnesemia (1 pt), and hypoxic respiratory failure (1 pt). One pt died due to possible treatment-related CHF. Conclusions: SU on a CD schedule is associated with an acceptable safety profile when administered to previously treated NSCLC pts, and there is documented preliminary evidence of activity, with 1 PR and a median PFS of 12.1 wks. These data support further study of continuous dosing of SU in combination with other treatments for NSCLC.

No significant financial relationships to disclose.
A phase II study of enzastaurin as second- or third-line treatment of non-small cell lung cancer (NSCLC)
Authors: Bepler G. , Oh Y. , Burris H. , Cleverly A. , Lahn M. , Herbst R. S.
Published: March 2020

7543

Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKC and the PI3K/AKT pathway, induces tumor cell apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Over-expression and activity of PKC and PI3K/AKT are associated with poor prognosis and treatment resistance in NSCLC. This multicenter phase II trial of enzastaurin as second- and third-line treatment of NSCLC determined the rate of progression-free survival (PFS) at 6 months (mos). Secondary objectives included safety and the rate of overall survival (OS) at 12 mos. Methods: Eligibility included metastatic (stage IV and wet IIIB) NSCLC and prior platinum-based chemotherapy. Patients (pts) received 500 mg of oral enzastaurin, once daily, until disease progression or unacceptable toxicity occurred. All pts were eligible for 2nd or 3rd line treatment. Results: In the 54 pts enrolled [54% M, 46% F; median age: 63 (range: 43–82); 22.2% stage III, 77.8% stage IV, ECOG PS=2], adenocarcinoma was the most frequent diagnosis (67%). Prior therapies included radiotherapy (74%) and EGFR inhibitors (28%). At the final analysis, the median PFS was 1.9 mos (95% CI: 1.7–1.9), and the PFS rate at 6 mos was 14% (95% CI: 4.4%–23.6%). The median OS was 9.9 mos (95% CI: 6.5–14.6). The OS rate at 12 mos was 46.3% (95% CI: 32.1%–60.5%). Nineteen pts (35%) had stable disease (SD); none had a complete or partial response. Ten (19%) pts were on-study for =6 cycles, 3 of whom continued for >10 months. The most common toxicity, fatigue (grade =2, n=15), occurred within 1 week of enrollment and was not reported in pts with SD. Grade =3 toxicities observed were ataxia (n=1), fatigue (n=2), thrombo-embolism (n=1), and anemia (n=1). Two pts discontinued due to fatigue and dizziness. Five pts died on-study and 4 within 30 days of discontinuation due to PD. Post-study chemotherapy (n=28) included bevacizumab, erlotinib, pemetrexed, gemcitabine, cisplatinum and paclitaxel. Conclusion: Although no objective tumor responses occurred, 14% of the pts were progression-free at 6 months. Based on encouraging survival and tolerability data, further evaluation of enzastaurin as a single agent or in combination, is warranted in NSCLC.

No significant financial relationships to disclose.
Proposed staging system modifications for advanced bronchioloalveolar carcinoma supported with a population-based validation study
Authors: Zell J. A. , Ou S. , Ziogas A. , Anton-Culver H.
Published: March 2020

7559

Background: Concordant with surgical series, our prior analysis of US SEER data demonstrates improved survival for BAC patients with stage IIIB disease due to multiple lesions in the same lobe compared to other stage IIIB patients, and also for patients with ipsilateral multicentric BAC compared to those with distant metastasis. In order for the BAC staging system to accurately reflect survival for these distinct patient subsets, we propose a revised staging system for advanced BAC and validate this system using California Cancer Registry (CCR) data. Methods: A case-only analysis of incident BAC cases in CCR during 1999–2003 was conducted. Based on modeling from our prior SEER analysis, the T4 descriptor for multiple tumors in the same lobe was downstaged to T3, and the M1 descriptor for ipsilateral multicentric BAC was downstaged to T4. The primary outcome measured was overall survival (OS). OS univariate analyses were conducted using the Kaplan-Meier method; multivariate survival analyses were performed using Cox proportional hazards ratios. Results: 1909 incident cases of histologically-confirmed BAC were analyzed. Using the proposed criteria, 162 (25%) of the 654 advanced BAC cases were reclassified: 73 cases with multiple lesions in the same lobe as T3 (stage II T3N0M0 [n=53] or T3NXM0 [n=1], stage IIIA T3N1–2M0 [n=18], stage IIIB T3N3M0 [n=1]); 89 cases with ipsilateral intrapulmonary metastasis were reclassified as T4 (stage IIIB, T4N1- 3M0). Univariate OS analysis of this validation set reveals an improved fit for the proposed staging system compared to the existing staging system ( Table 1 ). Analysis by stage reveals improvement in this proposed prognostic model over the existing staging system on multivariate survival analysis after adjustment for relevant clinicopathologic variables ( Table ). Conclusions: Our proposed BAC staging system modifications more accurately reflect survival characteristics for this unique type of non-small-cell lung cancer.

[Table: see text]
Updated molecular analyses of exons 19 and 21 of the epidermal growth factor receptor (EGFR) gene and codons 12 and 13 of the KRAS gene in non-small cell lung cancer (NSCLC) patients treated with erlotinib in National Cancer Institute of Cancer
Authors: Shepherd F. A. , Ding K. , Sakurada A. , Da Cunha Santos G. , Zhu C. , Seymour L. , Whitehead M. , Kamel-Reid S. , Squire J. , Tsao M. S.
Published: March 2020

7571

Background: BR.21 demonstrated significant survival benefit from erlotinib for NSCLC patients (Shepherd, NEJM 2005). EGFR gene point mutations in exon 21 and deletions in exon 19 predict response to EGFR TKIs, but the predictive value of EGFR mutations (Mut) or high copy number (Amp) on survival remains unclear. Methods: The sensitivity of PCR-sequencing to detect EGFR mutations may be suboptimal. Thus, we re-analyzed all BR.21 samples with available material using a fluourescent-based PCR technique (Pan, JMD 2005;7:396) and ScorpionIM kits (DxS, Manchester, UK) as they may detect mutations in samples with only 5–10% tumor DNA. 204 samples were analyzed successfully for EGFR Mut, 206 for KRAS Mut and 159 by FISH for EGFR Amp. Results: Exon 19 deletion and/or exon 21 L858R Mut were identified in 34 patients (overall Mut rate 17%). EGFR high polysomy or true amplification was present in 61 patients (38%), and 30 patients (15%) had KRAS Mut. Overall response rates were EGFR wildtype (WT)/Mut: 7%/27%, p=0.03; KRAS WT/Mut: 10%/5%, p=0.69; No Amp/Amp: 5%/21%, p=0.02. Hazard ratios for survival benefit were EGFR WT: 0.74 (0.52–1.05, p=0.09), Mut: 0.55 (0.25–1.19, p=0.12); KRAS WT: 0.69 (0.9–0.97, p=0.03), Mut: 1.67 (0.62–4.50, p=0.31); no Amp: 0.80 (0.49–1.29, p=0.35), Amp: 0.43 0.23–0.78, p=0.004). The test for interaction was borderline for KRAS Mut (0.09) but was not significant for EGFR Mut (p=0.47) or EGFR Amp (0.12). It was significant only for non-smokers with EGFR Amp (p=0.04). In the multiple Cox regression model, including all markers, EGFR Amp was both prognostic for poorer survival (p=0.005) and predictive of a differential survival benefit from erlotinib (p=0.009). EGFR and KRAS Mut were not significant prognostic or predictive markers. Conclusion: EGFR genotype and copy number are predictive of objective response to erlotinib. In BR.21, EGFR gene copy number is the strongest molecular prognostic marker and the only significant molecular predictor of a differential survival benefit from treatment.

[Table: see text]
Combined inhibition of mTOR and EGFR with everolimus (RAD001) and gefitinib in patients with non-small cell lung cancer who have smoked cigarettes: A phase II trial
Authors: Kris M. G. , Riely G. J. , Azzoli C. G. , Heelan R. T. , Krug L. M. , Pao W. , Milton D. T. , Moore E. , Rizvi N. A. , Miller V. A.
Published: March 2020

7575

Background: Most non-small cell lung cancers (NSCLC) are primarily resistant to the EGFR tyrosine kinase inhibitor gefitinib. One strategy to overcome resistance is to block parallel or downstream effectors that maintain tumor growth and proliferation. Preclinical data supports this hypothesis as inhibition of the PIK3CA/Akt/mTOR pathway restores gefitinib sensitivity in resistant cells. In a phase I study, gefitinib (250 mg) and the mTOR inhibitor everolimus (5 mg) were safely administered orally once-a-day (Milton Proc ASCO 2005). This combination induced regressions in patients with NSCLC. To assess the efficacy of this regimen, we designed this phase II trial. Methods: Two cohorts of patients with measurable stage IIIB/IV NSCLC were entered: (1) untreated with chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel. A Simon two-stage design proposed to enroll up to 31 patients in each cohort. Response was assessed after 1 month then every 2 months. Pretreatment tumor specimens were collected on all patients. Results: To date, 25 patients have entered, 11 untreated and 14 previously treated. The median age was 66 years and KPS 80%. 52% were women, 68% had adenocarcinoma, and all were current (n=1) or former smokers. Partial responses (RECIST) have been observed in 4 of 23 evaluable patients (17%, 95% CI 5 to 39%) One of these 4 tumors harbored a KRAS mutation and one an EGFR exon 19 deletion. Responses lasted 3, 4, 9+, and 16+ months. Responses were observed in 2 of 13 untreated and 2 of 10 previously treated individuals. Toxicities: Grade 2/3 diarrhea in 13%, Grade 2 pustular rash in 25%, and Grade 2 mucosal ulcerations in 38%. 8% had dose reductions. There were no Grade 4 toxicities or treatment-related deaths. Conclusions: The combination of everolimus and gefitinib produced a 17% partial response rate in smokers with NSCLC, a group less likely to benefit from gefitinib. Enough responses have been seen in both untreated and previously treated cohorts to complete enrollment according to the two stage design of this trial. We plan to correlate outcomes with the molecular profile of tumors. Supported by Novartis, USA

No significant financial relationships to disclose.
Increased incidence of brain metastases in ERCC1-negative NSCLC patients treated with adjuvant cisplatin-based chemotherapy
Authors: Besse B. , Massard C. , Haddad V. , André F. , Dunant A. , Pirker R. , Olaussen K. A. , Brambilla E. , Fouret P. , Soria J.
Published: March 2020

7581

Background: We have recently demonstrated that ERCC1 is a predictor of the benefit of cisplatin-based adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Non-squamous carcinomas have an increased risk of brain metastases (BM). Since brain is considered as a sanctuary site for chemotherapy, we hypothesised that there was an increased incidence of BM in ERCC1- negative non-squamous NSCLC patients treated with adjuvant cisplatin-based chemotherapy. Methods: Incidence of BM and histo- clinical parameters were analyzed in a population of 783 patients enrolled in the IALT trial. A subgroup analysis was performed in ERCC1 negative non-squamous NSCLC patients. Results: One hundred and one patients out of 783 (13%) developed BM alone or in association with other metastatic sites. In multivariate analysis, the clinical parameters associated with the occurrence of BM were nodal status (p=0.02), histological type (p=0.001) and pleural invasion (p=0.02). There is no effect of chemotherapy on BM (HR 1.38 [0.91–2.07], p=0.13). In patients with non-squamous histology (n=335) adjuvant chemotherapy was associated with an increased risk of BM (HR=2.10, [1.01–4.32], p=0.04) for ERCC1-negative tumours whereas there was no evidence of an effect on brain metastasis for ERCC1-positive tumours (HR=1.07 [0.38–2.99] p=0.90). These 2 effects are nevertheless not different (p for interaction=0.30) possibly by lack of power in this subsample. Conclusions: This study would suggest that cisplatin-based adjuvant chemotherapy is associated with an increased risk of BM in resected NSCLC patients with chemosensitive tumors. This data, if confirmed, could provide a rationale to evaluate prophylactic strategies in this subset of patients.

No significant financial relationships to disclose.
Clinical and molecular characteristics of advanced non-small cell lung cancer (NSCLC) patients (pts) with rapid progressive disease (RPD) on gefitinib therapy (G)
Authors: Fidler M. J. , Buckingham L. , Gale M. , Coon J. , Mauer A. , Villaflor V. , Kaiser K. A. , McCormack S. , Morrison L. , Bonomi P.
Published: March 2020

7592

Background: Prognostic factors associated with better outcomes (EGFR mutations (mut), high EGFR gene copy number, never smoking) can be used to select pts for EGFR tyrosine kinase inhibitor (TKI) combination trials, but would exclude the majority of NSCLC pts. Excluding pts with the worst likely outcomes is another strategy that may result in more pts who could benefit from the combination of a TKI with other agents. Our objective was to identify clinical and molecular characteristics associated with RPD (=70 days) and shorter progression-free survival (PFS) in previously treated NSCLC pts receiving G. Methods: Consecutive Expanded Access Trial pts with >1 week G were included for analysis. Tissue from 87 pts was evaluated for EGFR, pAKT and PTEN protein expression by immunohistochemistry; 58 tumors were analyzed for mut and sum of CA dinucliotide repeats (ΣCA rpts) by SSCP, PCR and sequencing. Results: There were 150 pts; 77 female, median (md) age 67. Md follow-up was 5.8 months (mo). Objective response was 8% (2CR, 10PR, 56 SD, 82 RPD). Md Kaplan-Meier PFS and survival were 2.0 and 5.8 mo, respectively. See table for univariate results. Smoking, Mut-PTEN-, EGFR-PTEN- and EGFR-pAKT- tumors were associated with shorter PFS. Separate clinical and molecular multivariate models were developed. In logistic regressions, non-adenocarcinoma histology (N- A), p=0.004, =12 mo from diagnosis to G (dx-G =12 mo), p=0.0009, lack of mut (p=0.0298) and ΣCA rpts <34 (p=0.0622) were associated with RPD. In Cox regressions, N-A (p=0.0256), dx-G =12 mo (p=0.0166) and lack of mut (p=0.0298) were associated with shorter PFS. Conclusions: N-A, dx-G =12 mo and lack of mut were associated with RPD and shorter PFS in univariate and multivariate analyses. ΣCA rpts <34 and double-negative molecular combinations were also related to worse outcome. These clinical and molecular characteristics may warrant further study as exclusion criteria for TKI combination clinical trials.

[Table: see text] [Table: see text]
The quantification of epidermal growth factor receptor (EGFR) in plasma is a prognostic factor in advanced non-small cell lung cancer (NSCLC) patients
Authors: Camps C. , Sirera R. , Muñoz-Navarro M. , Lopez-Vivanco G. , Alonso G. , Provencio M. , Gonzalez-Larriba J. , de las Peñas R. , Taron M. , Rosell R.
Published: March 2020

7597

Background: EGFR has an extracellular ligand-binding domain that can be proteolitically cleaved from the cell surface and can be accurately quantified in blood by ELISA. We have investigated the usefulness of plasma EGFR measurements as prognostic marker in advanced NSCLC. Methods: The cohort consisted in 329 patients (p) with advanced NSCLC that received first-line therapy with cisplatin and docetaxel. The concentration levels of the EGFR extracellular binding domain were determined by a sandwich quantitative ELISA in the baseline, before therapy. Results: Median age was 61, range [39–80], 84% males, 100% caucasian, 68% stage IIIB and 32% IV and 99% PS 0–1. The histological subtypes were: 31% squamous cell carcinoma, 49% adenocarcinoma, 15% large cell, and 5% undifferentiated. 181 p achieved complete response (CR), partial response (PR) or stable disease (SD) and 109 p progressive disease (PD). Median patient's plasma levels of EGFR were 32.4 ng/ml. There were not differences in p according to histology, site of metastasis and ECOG. There were differences in response to therapy; CR+PR+SD p presented median EGFR of 31.97 ng/ml [13.2–48.6] vs 30 ng/ml [16.9–46.8] in the PD group (p=0.024). Dividing the cohort in two sets according to EGFR median we found two significantly different groups in terms of Overall Survival (OS) and Time To Progression (TTP). Patients with EGFR<32.4 ng/ml had a median TTP of 3.9 months (m) [3.3–4.6] while for EGFR>32.4 ng/ml was 4.7 m [4.0–5.4], (p=0.024). OS when EGFR<32.4 ng/ml was 6.9 m [5.9–7.8] and for EGFR>32.4 ng/ml was 9.1 m [8.2–10.1], (p=0.038). Conclusions: Patients with PD presented significantly lower levels of serum EGFR than those patients with CR+PR+SD. There is a relationship among lower EGFR concentration in serum with a worst prognosis in advanced NSCLC p in terms of TTP and OS.

No significant financial relationships to disclose.
Excision repair cross complementing 6 (ERCC6) single nucleotide polymorphism (SNP) and outcome to gemcitabine (gem)/cisplatin (cis) or docetaxel (doc)/cis in stage IV non-small cell lung cancer (NSCLC) patients (pts)
Authors: Etxaniz O. , Provencio M. , Terrasa J. , Carrato A. , Lianes P. , Bover I. , Perez-Cano M. , Sanchez J. , Taron M. , Rosell R.
Published: March 2020

7605

Background: ERCC6 (alternate name CSB) is involved in both transcription coupled and base excision DNA repair, and the ERCC6 C-6530>G SNP is involved in gene regulation. Different levels of ERCC6 mRNA expression have been observed in cells according to ERCC6–6530 genotype. Methods: We investigated the ERCC6 C-6530>G SNP in 309 stage IV NSCLC pts treated with doc/cis (196 pts) and gem/cis (113 pts). DNA was extracted from peripheral lymphocytes and Taqman assay was used for SNP typing. Results: Distribution of ERCC6 genotypes was: CC 113 pts (36.6%); CG 157 pts (50.8%); GG 39 pts (12.6%). No differences in genotype were observed according to age, gender, performance status (PS), histology, chemotherapy regimen or second-line treatment. Overall time to progression (TTP) was 5.4 months (m) and median survival (MS) 9.9 m. No differences in TTP or MS were observed according to ERCC6 SNP types. However, when pts were broken down by chemotherapy regimen, TTP was 7 m for 31 CC pts treated with gem/cis and 5.4 m for 71 CC pts treated with doc/cis (P=0.04) ( Table ). MS was longer for CC pts treated with gem/cis (11 m) than for CC pts treated with doc/cis (8.9 m) (P=0.46). Differences were also observed in pts with PS 0 and in younger pts. Conclusions: ERCC6 C-6530>G SNP may confer differential sensitivity to gem or doc in combination with cis. We hypothesize that ERCC6 6350 CC is a surrogate of ERCC6 transcript, where lower ERCC6 expression levels may increase the activity of gem/cis in comparison to doc/cis.

No significant financial relationships to disclose.

[Table: see text]
A phase II multicenter trial comparing two schedules of lapatinib (LAP) as first or second line monotherapy in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) with either bronchioloalveolar carcinoma (BAC) or no smoking history
Authors: Smylie M. , Blumenschein G. R. , Dowlati A. , Garst J. , Shepherd F. A. , Rigas J. R. , Hassani H. , Berger M. S. , Zaks T. , Ross H. J.
Published: March 2020

7611

Background: LAP (GW572016) is an oral reversible, dual tyrosine kinase inhibitor of EGFR (ERBB1) and HER2/neu (ERBB2). This study was designed to test the activity of 2 dose schedules of LAP in chemotherapy naïve pts with NSCLC; it was amended to target patients with either BAC or no smoking history in the first or second line and to evaluate the relationship of mutations in target genes to responses. Methods: LAP was given orally 1,500 mg once (QD) or 500 mg twice daily (BID) until progression or intolerance. Safety and efficacy (RECIST) were assessed every 4 & 8 weeks. The primary endpoint was response. The target (BAC/no smoking) and non- target populations were assessed for efficacy, and tumor tissue was analyzed for ERBB1 and ERBB2 mutations and/or amplifications. Results: The study was stopped for futility after 131 pts were randomized (65 QD, 66 BID). Median age 66 (range 32–86); female 56%; BAC 20%, No BAC 71%; previously untreated 98.5%; current/former smokers 70%, never smoker 30%. There were no complete responses. Of 56 pts in the target population, 1 (2%) achieved partial response (PR), 11 (20%) had stable disease (SD) of ≥24 wks; in the non-target population, 1 pt had a PR (1.3%) and 12 (16%) had SD of ≥24 wks. 3 pts had ERBB1 mutations (G719S, S768I, KRAS G12S; L858R and T790M; L858R) but none of them responded. There were no ERBB2 mutations. Three of 77 pts evaluated had ERBB1 gene copy increase (none of whom responded) and 2 had ERBB2 gene copy increase (one had a 51% decrease in tumor size). The most common adverse events were grade 1/2 diarrhea, nausea, rash, vomiting and fatigue, and were similar in both groups. Conclusions: LAP was well-tolerated, with no notable difference in toxicity between the QD and BID groups. Very few responses were seen, stable disease was sometimes prolonged. The prevalence of mutations was low even in the target population. Given the preclinical synergy between LAP and other agents, further studies will be necessary to determine whether LAP is active in combination with other agents for the treatment of NSCLC.

[Table: see text]
Expression profile of 29 genes by real-time quantitative PCR (RT-QPCR) in early-stage (I-IIIA) squamous cell carcinoma of the lung (SCCL)
Authors: Skrzypski M. , Jassem E. , Mendez P. , Chaib I. , Szymanowska A. , Rzyman W. , Gulida G. , Jassem J. , Taron M. , Rosell R.
Published: March 2020

7612

Background: 5-year survival for surgically resected SCCL patients (p) is still limited. cDNA microarray studies have identified gene expression patterns that correlate with survival. We have examined the expression pattern of 29 genes selected by these studies to test their clinical prognostic value in early-stage SCCL. Methods: From 2000 to 2004, freshly frozen primary tumor specimens were obtained at the time of surgery from 66 Polish SCCL p. Sections were taken from blocks of tumor tissue for RNA extraction, and gene expression of the 29 genes was assessed by RT-QPCR (AB7900HT) using low density arrays (LDAs, Applied Biosystems). Expression values were dichotomized using the median value as the cut-off. Results: The univariate analysis showed 10 genes with prognostic value: PH4 (P=0.01); macrophage- colony stimulating factor (CSF1) (P=0.002); EGFR (P=0.05); KIAA0974 (P=0.02); ANLN (P=0.02); carbonic anhydrase IX (CA IX) (P=0.007); VEGFC (P=0.03); neurotrophic tyrosine receptor kinase 1 (P=0.04); fibronectin (P=0.002); insulin receptor (P=0.03). In the multivariate analysis of survival, CSF1, EGFR, CA IX and tumor size emerged as significant variables ( Table ). Conclusions: Tumor cells secrete CSF1, which attracts macrophages and induce them to express EGF, which in turn binds to EGFR in tumor cells. CA IX is regulated by hypoxia and plays a role in chemoresistance. Our findings highlight the relevance of tumor size and these markers in selecting p to receive adjuvant chemo- and targeted therapy.

No significant financial relationships to disclose.

[Table: see text]
Extent of nodal dissection and patient age impact recurrence-free survival (RFS) after surgery for non-small cell lung cancer (NSCLC)
Authors: Dy G. K. , Dy P. K. , Chua P. C. , Nelson G. D. , Foster N. R. , Mandrekar S. , Jett J. R. , Yang P. , Deschamps C.
Published: March 2020

7613

Background: Factors influencing the pattern of disease relapse after curative surgical resection in early stage NSCLC is unknown. We sought to evaluate the effect of tumor- and patient-related characteristics on the pattern of disease recurrence (local relapse and/or metastatic disease) and survival in relation to surgical resection for NSCLC. Methods: A consecutive retrospective series of 488 patients seen at Mayo Clinic Rochester who had complete resection of NSCLC between 1997 and 1998 was utilized. Cox proportional hazards model was used to evaluate the effect of age, gender, smoking status, TNM stage, number of lymph node (LN) involved, number of LN resected, and histopathologic diagnosis on RFS. Logistic regression was used to evaluate the effect on recurrence or death within the first 2 years after surgical resection. Results: Data on 342 patients with a median follow-up of 85 months (range: 0.1 to 162) are reported. 60% were male, and 81% had N0 stage at diagnosis. There were 26 (7.6%) never smokers. Median number of LN resected was 20 (interquartile range [IQR]: 14–29). Median age at surgery was 71 years (IQR: 64 to 76). A bi-modal pattern of local recurrence (N=62) after surgery for early stage NSCLC was observed, with 57% of patients having a local recurrence within 2 years and 21% of patients having a local recurrence from 5–7 years post-surgery. The median duration from surgery to first documented recurrence was 16 months (IQR: 8 to 39). While age, N stage, number of LN involved, and T stage were significant predictors of RFS univariately, only lesser LN resected (p=0.008), older age (p<0.0001) and higher T-stage (p=0.003) were significant adverse predictors of RFS in the multivariate analysis when adjusted for all factors. Higher T-Stage was associated with a significantly increased risk of recurrence or death within the first 2 years after surgical resection (p =0.004). Updated results using data from all 488 patients will be presented in the meeting. Conclusions: A trend towards a bimodal distribution of local recurrences after surgical resection of early stage NSCLC was observed. Increased number of LN resected, younger age and lower T stage were associated with better RFS.

No significant financial relationships to disclose.
Phase II randomized study of dose-dense docetaxel (Doc) and cisplatin (Cis) every two weeks with pegfilgrastim (Pfil) and darbepoetin alfa (Darb) with and without the chemoprotector BNP7787 in patients with advanced non-small cell lung cancer (NSCLC): CAL
Authors: Green M. R. , Miller A. A. , Wang X. F. , Gu L. , Vokes E. E.
Published: March 2020

7617

Background: We sought to explore the toxicity, feasibility, and response rate of dose-dense Doc and Cis with growth factor support without [A] and with [B] a novel chemoprotector in patients with NSCLC. Methods: Patients with measurable disease, stage IIIB (effusion) or IV, performance status (PS) 0–1, no prior chemotherapy, and adequate organ function were eligible. Treatment with Doc 75 mg/m2 ? Cis 75 mg/m2 both IV over 1 hr day 1 with Darb 200 mcg SC day 1 and Pfil 6 mg SC day 2 randomized to without/with BNP before Cis was repeated every other week (1 cycle = 2 weeks) for up to 6 cycles. Response was determined after 3 and 6 cycles. Because of anticipated neurotoxicity (NT), the primary statistical endpoint was to differentiate between grade =2 NT rates of 30% in [A] and 10% in [B]: 90% power, two-tailed p<0.10, 76 patients per arm. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and =1 treatment delay per cycles 1–3 and 4–6 in <20% of patients. Objective response rates of >35% were required to merit further investigation. Results: Between 8/04 and 3/06, 160 patients were enrolled but 5 never started therapy and 4 were ineligible: male/female, 99/52; white/black/other, 126/23/2; median age 62 (range, 30–88); PS 0/1, 69/82; stage IIIB/IV 14/137; [A]/[B], 76/75 well balanced. Sensory/motor/either NT grade =2 occurred in 28/14/32% on [A] and 19/19/29% on [B]. The incidence of febrile neutropenia was 1%. Treatment was delayed in cycles 1–3/cycles 4–6 in 3/3 patients in [A] and 1/5 patients in [B]. Completion rates for 3/6 cycles were 87/51% in [A] and 84/52% in [B]. By intent to treat, complete/partial response rates were 4/46% in [A] and 3/47% in [B]. Median estimated overall/progression-free survival times are10/6 months in [A] and 11/6 months in [B]. Overall, grade 3+4 neutropenia and thrombocytopenia occurred in =10% and anemia in 12% of patients. Non-hematologic toxicity was mild. Six deaths were thought to be treatment related. Conclusions: This dose-dense treatment regimen is feasible, tolerable, and worthy of further investigation in NSCLC. BNP did not result in significant protection from NT.

No significant financial relationships to disclose.
Pharmacodynamic separation of erlotinib and docetaxel (DOC) in advanced non-small cell lung cancer (NSCLC): Overcoming hypothesized antagonism
Authors: Davies A. M. , Hesketh P. J. , Beckett L. , Lau D. , Mack P. C. , Lara P. N. , Jernigan J. , LaPointe J. , Gandara D. R.
Published: March 2020

7618

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) given concurrently with chemotherapy do not improve patient (pt) outcomes compared with chemotherapy alone in advanced NSCLC. Based on our preclinical data, we hypothesized that G1 cell cycle arrest from EGFR-TKI antagonizes the cytotoxicity of concurrent chemotherapy, and that pharmacodynamic separation (PDS) by intermittent delivery of EGFR-TKIs with chemotherapy would increase efficacy (Gumerlock, ASCO 2003, Davies, ASCO 2005). To test this concept, we conducted a phase I-II study of intermittent erlotinib combined with DOC. Methods: 37 previously treated IIIB (pleural effusion) or IV NSCLC pts received DOC 70–75 mg/m2 IV on day 1 every 21 days and erlotinib orally days 2–16 (150–200 mg). Patients without progression after 6 cycles continued erlotinib alone. Primary endpoint was response rate. Results: Pt characteristics: Age: median/range 57/35–80; Sex: 14 M; KPS ≥90=13; smoker/non-smoker/unknown 20/13/4, Median cycles: 5. Adenoca: 18. Prior chemotherapy regimens: 1 - 26; >1 - 11. In 34 evaluable pts: 1 CR, 11 PR (35% response rate), 16 stable disease. Median time to progression (TTP) was 5.6 months (95% CI: 3.7 - 7.9). MST: not reached. Treatment was generally well tolerated. Most common grade (Gr) 3/4 toxicities included: neutropenia (60%), diarrhea (16%), infection (11%), febrile neutropenia (8%). Gr 1/2 acneform rash: 88%. PK analysis showed that PDS was achieved in nadir levels of erlotinib in 4 pts tested. Correlative studies examining biomarkers for response with EGFR TKIs are ongoing. Conclusions: 1) DOC every 3 weeks plus intermittent dosing of erlotinib (2 weeks on, 1 week off) achieved PDS in limited PK sampling. 2) This combination resulted in a favorable response rate and TTP in previously treated NSCLC, with MST not yet reached. 3) Febrile neutropenia necessitated the prophylactic use of G-CSF. 4). Further clinical study of this concept is warranted, and trials are currently ongoing.

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A randomized phase II trial of early change of a chemotherapeutic doublet compared to four cycles of chemotherapy in advanced non-small cell lung cancer (NSCLC): The 03–01 Groupe Francais de Pneumo-Cancerologie (GFPC) study
Authors: Vergnenegre A. , Corre R. , Barlési F. , Bérard H. , Vernejoux J. , Le Caer H. , Fournel P. , Delhoume J. , Arpin D. , Thomas P. , Tillon J.
Published: March 2020

7631

Background: The optimal strategy in advanced NSCLC with stable disease is not well known. There is no published study assessing an early change of chemotherapeutic drugs in these patients. This study was designed to evaluate the efficacy and safety of early modification of chemotherapy doublets in patients with advanced non small cell lung cancer with stable disease (SD). Methods: Patients with stage IV NSCLC and measurable disease were included in a randomized phase II trial comparing for patients with stable disease after 2 cycles of a platin (P)-gemcitabine doublet (P d1: 75 mg/m2, gemcitabine 1 250 mg/m2 d1, d8 every three weeks) two subsequent cycles of this doublet (arm A) to a switch to another doublet (arm B): paclitaxel 100 mg/m2 d1, d8, d15, gemcitabine 1 250 mg/m2 d1, d8, every four weeks. Results: Between October 2003 and august 2006, 228 patients (pts) were enrolled (187 males, 41 females), median age 57 y (30–70). Evaluation (EVA) 1 showed 11.8% not assessable patients (NA), 19.3% with objective responses (OR), 25.9% with progressive diseases. 98 patients (43%) had stable diseases. 87 patients were randomized in the study. 48.3% with PS0, 51.7% with PS1 and a majority of adenocarcinoma (62.1%). 41.4% had only one metastatic site. There were no differences between the two groups. Efficacy at eva 2 is depicted above. Overall survival (OS) was similar between the two arms: 9.8 months (m) [7.0 - 14.2] for arm A, 9.2 m [7.4 - 10.5] for arm B. TTP was 5.4 m in arm A and 5.7 in arm B. There were 1 grade III/IV haematological toxicities in arm A (1.2%) and 2 in arm B (2.4%). There were 4 grade III/IV non haematological toxicities in arm A (4.8%) and 6 in arm B (7.3%). Conclusions: The switch between the two regimen is feasible without any major toxicities. Despite higher response rate in favour of the switch strategy, OS and TTP are similar between the two arms.

No significant financial relationships to disclose.

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MDM2 309 and TP53 Arg72Pro single nucleotide polymorphisms (SNPs) and clinical outcome in advanced lung cancer patients
Authors: Novello S. , Mandrile G. , Giachino D. F. , Ghio P. , Selvaggi G. , Gregori D. , De Marchi M. , Scagliotti G. V.
Published: March 2020

7636

Background: The TP53 Arg72Pro (rs1042522:C>G) and MDM2 SNP309 (rs2279744:T>G) SNPs of the DNA damage response pathway have been shown to affect lung cancer risk. We aimed to investigate their relationship with the clinical outcome of chemotherapy (CT). Methods: We prospectively recruited 426 consecutive patients with advanced disease (352 NSCLC and 74 SCLC, 57% metastatic) referred for chemotherapy at our institution from July 2002 to January 2006: 82% male, median age at diagnosis 63 years, 56% current and 11% never smokers, 81% receiving combined platinum CT. Median follow up time was 10.5 months. Controls were 254 medical students. We designed specific TP53 and MDM2 primers for typing both SNPs using the Pyrosequencing assay. Results: Patients genotype frequencies were: TP53 Arg/Arg 51%, Arg/Pro 40%, Pro/Pro 8%, (61%, 35%, 4% among controls, p=0.02), MDM2 T/T 37%, T/G 46%, G/G 17%, (31%, 55%, 14% among controls, p=0.07). Both groups were in Hardy-Weinberg equilibrium. At multivariable analysis adjusted for gender, smoking status, type of chemotherapy, disease stage, and side effects, survival was significantly associated with performance status (PS) [HR 1.54 (1.2–2.0)], histology [SCLC vs. NSCLC - HR 1.51(1.1–2.1)] and objective response [yes vs. no HR 0.56 (0.4–0.7)] but with neither SNP; in contrast, grade 3–4 toxicity and objective response were concomitantly associated with the SNPs of TP53 [Pro carriers vs. Arg/Arg HR 1.40 (1.1–1.8) and 1.44 (1.0–2.0)] and MDM2 [GG vs. TT 0.57 (0.4–0.9) and 0.61 (0.4–0.97)]. These findings are in agreement with the notion that MDM2 GG homozygous cells express higher levels of mdm2, thus attenuating the p53 pathway, but don’t easily fit with the alleged greater apoptotic potential of p53 Arg72. We also observed significant associations of toxicity with platinum therapy, of objective response with histology and of both outcomes with PS (not shown). Conclusion: The study provides preliminary evidence that germ-line TP53 and MDM2 SNPs affect toxicity and objective response to CT in lung cancer patients, probably depending on a variable DNA damage response but not survival time that may mainly result from the tumor aggressiveness and somatic mutational status.

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Promising preliminary results of erlotinib in previously chemotherapy treated Taiwanese NSCLC patients in a large expanded access program study
Authors: Perng R.
Published: March 2020

7641

Background: Erlotinib is the first EGFR tyrosine kinase inhibitor which demonstrated the survival benefit to NSCLC patients in randomized trial. An expanded access program (EAP) was conducted to evaluate the efficacy and safety profiles of erlotinib in Taiwanese patients with NSCLC. Methods: Patients with proven stage IIIB/IV NSCLC and received at least first line standard chemotherapy or radiation therapy were enrolled in this study. No more than 2 prior chemotherapy regimens are permitted. All patients were given oral erlotinib, 150 mg/day till disease progression. Patients were monitored monthly and tumor assessments were evaluated every 2 months according to RECIST criteria. Results: From Apr. 2005 to Mar. 2006, 300 patients were entered from 15 medical centers in Taiwan. This interim study evaluated the first 297 patients (data cut-off date of November 8, 2006). Of them, 53% pts were male, 80% pts were with ECOG PS 0 or 1, 68% pts had adenocarcinoma, 62% pts receiving erlotinib as 2nd-line treatment, and 55% patients were non- smoker. The best response rate was 27.8% PR and 47.1% SD in 263 evaluable patients according to RECIST (disease control rate= 74.9%). Non-smoker (p=0.048 and 0.002), adenocarcinoma (p=0.001 and <0.001), female (p=0.0005 and <0.0001), and skin rash (Gr 3–4, p=0.0095 and 0.0019) were significantly correlate with best response and disease control to the treatment. Skin rash was a common adverse event (any grade: 83%, Gr 3–4: 15%). Erlotinib-related SAEs were seen in 4% patients and 3% patients discontinued treatment due to treatment-related SAEs. 24% of patients needed dose reductions, mainly due to skin rash. The median time to progression and median overall survival will be matured at the time of ASCO annual meeting. Conclusions: This is the largest multicenter prospective clinical study of NSCLC in Taiwan. This interim results demonstrating the superb response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese or Chinese in previous chemotherapy or radiotherapy treated NSCLC patients.

No significant financial relationships to disclose.
ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer
Authors: Lee K. , Han S. , Min H. , Oh D. , Lee S. , Kim D. , Kim Y. , Kim T. , Heo D. , Bang Y.
Published: March 2020

7646

Background: To investigate whether excision repair cross-complementation group 1 (ERCC1) expression, as determined immunohistochemically, and mutations of epidermal growth factor receptor (EGFR) are related to the prognosis of curatively resected non-small cell lung cancer (NSCLC), and whether these two markers are related. Methods: One-hundred and thirty-three consecutive patients with NSCLC who did not receive adjuvant chemotherapy after curative surgery were included in this study. Representative areas from formalin-fixed paraffin-embedded tumor samples were chosen for tissue microarray analysis. Immunohistochemistry was performed for ERCC1 and the median semiquantitative H-score was used as a cut-off. EGFR mutations (exons 18, 19, and 21) were analyzed by the direct sequencing of tumor samples. Results: ERCC1 expression was evaluable in 130 patients and ERCC1 was found to be positive in 80 patients (61.5%). Moreover, ERCC1 was expressed more frequently in smokers and in squamous cell carcinomas. Patients with positive ERCC1 expression survived longer (median overall survival 2,742 days for ERCC1-positive vs. 1,423 days for ERCC1-negative, P=.0463). EGFR mutations were found in 27 patients (20.3%) but they were not found to affect overall survival. Interestingly, EGFR mutations were more frequent in ERCC1-negative tumors (12.5% in ERCC1-positive vs. 30% in ERCC1-negative tumors, P=0.014). Conclusions: ERCC1 expression was identified as a prognostic marker of longer survival in resected NSCLCs. In addition, EGFR mutations were more frequently found in ERCC1-negative tumors, but were not found to affect survival in our patient group.

No significant financial relationships to disclose.
Correlation of tumor response and survival in advanced NSCLC patients treated with paclitaxel plus carboplatin (PC) versus paclitaxel plus carboplatin plus gemcitabine (PCG)
Authors: Paccagnella A. , Oniga F. , Bearz A. , Favaretto A. , Barbieri F. , Chella A. , Ceresoli G. , Biason R. , D'Amanzo P. , Ghi M. G.
Published: March 2020

7650

Background: We showed that PCG significantly increases both response rate (RR) (43.6% vs 20%) and median survival (10.8 mo vs 8.3 mo) over PC and that at Cox analysis, the only independent prognostic factors were PS and treatment (Paccagnella et al, J Clin Oncol 2006;24: 681–687). According to the Prentice criteria (Stat Med 1989;8: 431–440), to directly relate response and survival it is necessarily that responding patients (and non responding) of both arms have a similar survival and that the survival difference between the two arms disappear when the response factor is included in the multivariate analysis. Methods: Out of 324 pts included in the original analysis, 26 pts were not evaluable for response (early death, toxicity, refusal) before the planned response evaluation at two months and were excluded (15 pts from PC arm and 11 pts from PCG arm). The analysis however was also performed considering the non evaluable patients as non responders. Results: Overall, Responder patients had a median Survival that nearly doubled that of no responders: 14.73 mo vs 7.67 mo (HR: 0.49; CI: 0.31–0.54; P=0.000). No responder pts from PC and PCG arms had a similar survival (median 7.53 mo and 8.07 mo respectively; P= 0.96) as well as responder (CR + PR) patients (median 14.13 mo and 15.40 mo respectively; P=0.38). The principal difference between the two arms was that more than the double of patients in PCG arm responded (43.6% vs 20%) and consequently had a survival advantage of clinical relevance in comparison to patients in PC arm. When tumor response was introduced in the Cox model (as a four level variable), the difference in Overall Survival between PCG and PC changed from a significant level (HR=1.28; CI 1.00–1.63; P=0.049) to a not significant level (HR=0.99; CI: 0.76 - 1.28; P=0.97). Conclusions: To our knowledge this is the first report showing a significant direct correlation between response and survival in advanced NSCLC according to Prentice criteria.

No significant financial relationships to disclose.
Association between different potential predictive markers from TRUST, a trial of erlotinib in non-small cell lung cancer (NSCLC)
Authors: Laack E. , Schneider C. , Gutjahr T. , Heinmöller E. , Lutz V. , Moecks J. , Rohr K. , Schmidtgen C. , Spleiss O. , Reck M.
Published: March 2020

7651

Background: Recent studies have examined potential predictive markers in NSCLC patients (pts) treated with EGFR tyrosine kinase inhibitors. However, few data are available on inter-relationships between different markers. Clinical and molecular markers were analyzed for patients from TRUST, an open label, non-randomized trial initiated to provide erlotinib access to pts with advanced NSCLC. Methods: 393 German pts (99% Caucasian) with stage IIIb/IV NSCLC were included. Markers/characteristics assessed were: EGFR (282 pts) and phosphorylated MAPK (pMAPK; 109 pts) using immunohistochemistry (IHC; positive status was defined as: ≥10% of tumor cells with any membrane staining for EGFR; and H-score ≥200 for pMAPK), EGFR gene copy number (135 pts) using fluorescence in-situ hybridization (FISH), EGFR mutations (86 pts), KRAS mutations (108 pts), tumor type (281 pts), smoking status (392 pts) and gender (393 pts). Results: EGFR FISH+ pts were likely to also be EGFR IHC+: 92.9% (26/28) of EGFR FISH+ pts were EGFR IHC+, and 92.6% of EGFR IHC- pts were also EGFR FISH- (p<0.1). pMAPK expression status was not related to other markers. 15.7% (17/108) pts had KRAS and 7.0% (6/86) had EGFR mutations; no pts had mutations in both genes, indicating that these mutations might be mutually exclusive. Both KRAS mutations and histology were associated with smoking status. 94.1% (16/17) pts with KRAS mutations and 91.6% (87/95) pts with squamous-cell carcinoma were smokers. In female pts, the occurrence of adenocarcinoma was significantly higher (73.6% vs 55.4% in males; p<0.001), possibly influenced by a lower incidence of smokers in this group (51.3% vs 92.2% in males; p<0.001). Conclusions: The availability of a large number of tumor samples from the TRUST study, and assessment of a broad range of markers allows investigation of relationships between various tumor/patient characteristics. Understanding these complex inter-relationships may shed light on the role of each marker. Specific combinations of markers may prove useful in predicting clinical benefit from erlotinib. As the study is ongoing, additional data will be available and presented.

No significant financial relationships to disclose.