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Paclitaxel, one of the most frequently used anticancer drugs, is dosed by body surface area, which leads to substantial inter-individual variability in systemic drug exposure. We evaluated clinical evidence regarding the scientific rationale and clinical benefit of individualized paclitaxel dosing based on measured systemic concentrations, known as therapeutic drug monitoring (TDM). In retrospective studies, higher systemic exposure is associated with greater toxicity and efficacy of paclitaxel treatment across several disease types and dosing regimens. In prospective trials, TDM reduces variability in systemic exposure, and has been demonstrated to reduce toxicity while retaining treatment efficacy for 3-weekly dosing in patients with advanced non-small cell lung cancer. Despite the demonstrated benefits of paclitaxel TDM, clinical adoption has been limited due to the challenges with sample collection and analysis. Based on our review, we strongly recommend TDM for patients receiving every 3-week paclitaxel in combination with a platinum agent for advanced NSCLC, due to the prospectively demonstrated clinical benefits, and find moderate evidence to recommend TDM for paclitaxel 3-hour infusions for other tumor types and preliminary evidence suggesting potential usefulness for paclitaxel administered by 1-hour infusions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hertz, none declared;. Joerger, none declared;. Bang, Consulting/Advisory Board: Astellas, Amgen, Hanmi, Daewoong, SK Biopharm;. Mathijssen, none declared;. Zhou, none declared;. Zhang, none declared;. Gandara, none declared;. Stahl, none declared;. Monk, none declared;. Jaehde, none declared;. Beumer, none declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m 2 every 2 weeks (Q2W). Here we report results for two alternative schedules., Experimental Design: Adults ages ≥18 years (range, 34-73) with locally advanced/metastatic solid tumors ( N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m 2 [loading dose (LD)], then 100 mg/m 2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m 2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W)., Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m 2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m 2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W., Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m 2 (LD) followed by 100 mg/m 2 Q2W, and 170 mg/m 2 Q3W as a fixed dose. (NCT02187848)., Significance: The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are potentially valuable in predicting the effectiveness of immune checkpoint inhibitors (ICI). However, clinical application remains challenging because of methodologic limitations and laborious process involved in spatial analysis of TIL distribution in whole-slide images (WSI)., Methods: We have developed an artificial intelligence (AI)-powered WSI analyzer of TIL in the tumor microenvironment that can define three immune phenotypes (IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated with tumor response to ICI and survival in two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC)., Results: Inflamed IP correlated with enrichment in local immune cytolytic activity, higher response rate, and prolonged progression-free survival compared with patients with immune-excluded or immune-desert phenotypes. At the WSI level, there was significant positive correlation between tumor proportion score (TPS) as determined by the AI model and control TPS analyzed by pathologists ( P < .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and 18.9% were immune-desert. Incidence of inflamed IP in patients with programmed death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%, respectively. Median progression-free survival and overall survival were, respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0 months with immune-excluded IP, and 2.4 months and 10.6 months with immune-desert IP., Conclusion: The AI-powered spatial analysis of TIL correlated with tumor response and progression-free survival of ICI in advanced NSCLC. This is potentially a supplementary biomarker to TPS as determined by a pathologist., Competing Interests: Sehhoon ParkStock and Other Ownership Interests: Lunit Chan-Young OckEmployment: LunitLeadership: LunitStock and Other Ownership Interests: Lunit, Medpacto, Y-BiologicsConsulting or Advisory Role: Medpacto, Y-Biologics, Idience Sergio PereiraEmployment: LunitStock and Other Ownership Interests: Lunit Seonwook ParkEmployment: LunitStock and Other Ownership Interests: LunitResearch Funding: Lunit Minuk MaEmployment: LunitStock and Other Ownership Interests: Lunit Seunghwan ShinEmployment: LunitStock and Other Ownership Interests: Lunit Jaehong AumEmployment: LunitStock and Other Ownership Interests: Lunit Kyunghyun PaengEmployment: LunitLeadership: LunitStock and Other Ownership Interests: Lunit Donggeun YooEmployment: LunitLeadership: LunitStock and Other Ownership Interests: LunitPatents, Royalties, Other Intellectual Property: Having several patents about medical AI developments in Lunit Inc Se Hyun KimConsulting or Advisory Role: Ono Pharmaceutical Jin Seok AhnHonoraria: Pfizer, Roche, BC World, Yuhan, Hanmi, Novartis, JW Pharmaceutical, Amgen, Boehringer IngelheimConsulting or Advisory Role: Bixink, Bayer, Yooyoung Pharmaceutical Co Ltd, Pharmbio Korea, Vifor Pharma Myung-Ju AhnHonoraria: AstraZeneca, Lilly, MSD, TakedaConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Takeda, Alpha Pharmaceutical Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Merck KGaA, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Geinus, IMBdxSpeakers' Bureau: Boehringer IngelheimResearch Funding: AstraZeneca, MSD Oncology Sang Yong SongEmployment: AstraZeneca/MedImmuneLeadership: AstraZeneca/MedImmuneStock and Other Ownership Interests: AstraZeneca/MedImmune Yung-Jue BangConsulting or Advisory Role: BeiGene, Green Cross, Merck Serono, AstraZeneca/MedImmune, Novartis, MSD Oncology, Hanmi, Genentech/Roche, Daiichi Sankyo, Astellas Pharma, Bristol Myers Squibb, Samyang, Alexo TherapeuticsResearch Funding: AstraZeneca/MedImmune (Inst), Novartis (Inst), Genentech/Roche (Inst), MSD (Inst), Merck Serono (Inst), Bayer (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), Lilly (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), BeiGene (Inst), Curis (Inst), GC Pharma (Inst), Daiichi Sankyo (Inst), Astellas Pharma (Inst), Genexine (Inst) Yoon-La ChoiResearch Funding: Bayer Tony S. MokEmployment: The Chinese University of Hong KongLeadership: Sanomics Limited, AstraZeneca, Hutchison China Meditech, Aurora Tele-Oncology Platform, LunitStock and Other Ownership Interests: Sanomics Limited, Hutchison China Meditech, Aurora Tele-Oncology PlatformHonoraria: AstraZeneca, Alpha Biopharma, ACEA Pharmaceutical Research, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, Lilly, Merck Sharp & Dohme, Novartis, Origimed, Pfizer, Prime Oncology, Roche, Sanofi Aventis GmbH, Taiho Pharmaceutical, Takeda, Lucence Health Inc, Medscape, P. Permanyer SL, PeerVoice, Physicans' Education Resource, Research to Practice, Shanghai BeBirds Translation & Consulting Co, Liangyihui Network Technology Co., LtdConsulting or Advisory Role: AbbVie, ACEA Pharmaceutical Research, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines, Bristol Myers Squibb, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo/UCB Japan, Eisai, Fishawack Facilitate, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Ignyta, Incyte, Inivata, IQvia, Lilly, Loxo, Lunit, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, Novartis, Pfizer, Puma Biotechnology, Roche, SFJ Pharmaceuticals Group, Takeda, Vertex, Yuhan, Qiming Development (HK) LtdResearch Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Novartis (Inst), SFJ Pharmaceuticals Group (Inst), Roche (Inst), Merck Sharp & Dohme (Inst), Bristol Myers Squibb (Inst), Xcovery (Inst), G1 Therapeutics (Inst), Merck Serono (Inst), Takeda (Inst) Se-Hoon LeeHonoraria: AstraZeneca/MedImmune, Roche, Bristol Myers Squibb, MerckConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, RocheResearch Funding: MerckTravel, Accommodations, Expenses: NovartisNo other potential conflicts of interest were reported.

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C ., Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1., Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma., Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC)., Patients and Methods: A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0-1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC)., Results: Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment-related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression., Conclusion: Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression., (Copyright © 2020 Eli Lilly and Company. Published by Elsevier Ltd.. All rights reserved.)

Background: In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001., Patients and Methods: ROS1 status was determined by FISH or reverse transcriptase-polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily., Results: Fifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2-45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2-39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment., Conclusions: These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup., Trial Registration Number: ClinicalTrials.gov identifier NCT00585195., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor., Objective: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455., Patients and Methods: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC). Part A: 36 patients in 11 dose cohorts ranging from 2 to 24 mg twice daily (BID). RP2D was 16 mg BID. Part B: GC cohort, 29 patients, NSCLC cohort, 27 patients, all treated at the RP2D., Results: LY2874455 was slowly absorbed and generally showed linear PK. The effective half-life was ∼12 h. PD properties of LY2874455 occurred at doses ≥10 mg by increases in serum phosphorus. Phosphate binders were administered to control serum phosphorus. LY2874455 was generally well tolerated; most toxicities were grade 1 or 2; most frequent were hyperphosphatemia, diarrhea, and stomatitis., Efficacy: part A: 24 patients evaluable: 1 patient in the 14-mg BID cohort with GC had a partial response (PR); 14 patients had stable disease (SD); part B: NSCLC cohort: 11 of 12 evaluable patients had SD; GC cohort: 15 patients evaluable: 1 patient with PR; 12 patients with SD., Conclusions: LY2874455 has an RP2D of 16 mg BID and demonstrated good tolerability and activity in solid-organ cancer patients. The role of FGFR inhibition on tumor growth in patients requires further study. (NCT01212107).

Background: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET., Methods: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays., Results: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC., Conclusions: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Introduction: We sought to evaluate the clinical and pathological characteristics of patients with non-small-cell lung cancer (NSCLC) that harbored a ROS1 rearrangement., Methods: Four hundred fifty-one Korean patients with resected NSCLC (the resected group) were examined for ROS1 rearrangements using a tissue microarray and ROS1 fluorescence in situ hybridization and analyzed for clinical and pathological features. Sixty-four patients with advanced pulmonary adenocarcinoma with no known oncogenic aberrations (the advanced group) were also screened for ROS1 rearrangements., Results: Of the 451 consecutive patients from the resected group, ROS1 rearrangements were detected in eight cases (1.8%). In the advanced group, an additional eight patients (12.5%) were identified as harboring ROS1 rearrangements. ROS1 rearrangement was detected exclusively in adenocarcinomas and occurred more frequently in women than in men. With the exception of one patient with an EGFR deletion mutation in exon 19, ROS1-positive adenocarcinomas in all patients revealed no alterations in ALK, EGFR, KRAS, or MET genes. Most ROS1-rearranged tumors showed solid and papillary patterns., Conclusions: ROS1 rearrangements were detected in 1.8% of patients with resected NSCLC and were detected exclusively in adenocarcinomas, which is similar to the frequency detected in non-Asian patients. We suggest that ROS1 screening in adenocarcinoma patients with no known oncogenic aberrations is an effective strategy to find ROS1 rearrangements in NSCLC.

DLC1 encodes a RhoA GTPase-activating protein and tumor suppressor lost in cancer by genomic deletion or epigenetic silencing and loss of DLC1 gene transcription. We unexpectedly identified non-small cell lung cancer (NSCLC) cell lines and tumor tissue that expressed DLC1 mRNA yet lacked DLC1 protein expression. We determined that DLC1 was ubiquitinated and degraded by cullin 4A-RING ubiquitin ligase (CRL4A) complex interaction with DDB1 and the FBXW5 substrate receptor. siRNA-mediated suppression of cullin 4A, DDB1, or FBXW5 expression restored DLC1 protein expression in NSCLC cell lines. FBXW5 suppression-induced DLC1 reexpression was associated with a reduction in the levels of activated RhoA-GTP and in RhoA effector signaling. Finally, FBXW5 suppression caused a DLC1-dependent decrease in NSCLC anchorage-dependent and -independent proliferation. In summary, we identify a posttranslational mechanism for loss of DLC1 and a linkage between CRL4A-FBXW5-associated oncogenesis and regulation of RhoA signaling.

Background: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study., Methods: In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195., Findings: Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1-39·6) and median duration of response was 49·1 weeks (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6)., Interpretation: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Crizotinib (Xalkori), the first inhibitor of both anaplastic lymphoma kinase (ALK) and c-Met receptor kinases, has been approved in the United States, Korea, and other countries for the treatment of ALK-positive non-small cell lung cancer (NSCLC). This approval came within just 4 years of the discovery of rearrangements in the ALK gene in a subset of patients with NSCLC. Oral crizotinib 250 mg twice daily showed excellent efficacy in patients with advanced ALK-positive NSCLC, with objective response rates of 61% and 51% in ongoing phase I and II studies, respectively. Objective response rates of current standard, single-agent, second-line therapies are less than 10%. Median progression-free survival was 10 months (95% confidence interval, 8.2-14.7) in the phase I study expanded cohort and has yet to be reached in the phase II study; progression-free survival with current therapies is less than 3 months. Crizotinib was well tolerated; grade 1/2 gastrointestinal toxicity and visual disturbances were the most common adverse events. Patients in the phase II study reported improvements in fatigue, dyspnea, and cough, based on quality of life assessments. Phase III studies investigating crizotinib for the first- and second-line treatment of advanced ALK-positive NSCLC, versus current standards of care, are ongoing. Crizotinib represents a new standard of care for patients with ALK-positive NSCLC and highlights the importance of the role of the pathologist, as molecular profiling becomes a part of initial workups for newly diagnosed patients with NSCLC. This approach will ensure effective individualized treatment for patients with NSCLC.

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer (NSCLC) are mutually exclusive. However, several exceptional cases harboring both genetic alterations have been reported. In this study, a total of 444 patients with lung adenocarcinoma were examined for their EGFR and ALK status at Seoul National University Hospital between July 2008 and September 2011. EGFR mutations and ALK translocations were detected in 228 (51.4%) and 34 (7.7%) patients, respectively. Four patients (0.9%) had both genetic alterations and three underwent curative surgery. One patient who received both EGFR tyrosine kinase and ALK inhibitors, separately showed an objective response to the ALK inhibitor alone. Considering our and previous studies, patients harboring both EGFR mutation and ALK translocation showed differential sensitivities to both targeted therapies, suggesting a variable dependence on EGFR and ALK oncogenes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The purpose of this study was to investigate the overall survival (OS) of patients with advanced ALK-positive nonsmall cell lung cancer (NSCLC) who were managed in the pre-ALK inhibitor era and to compare their survival with that of a matched case cohort of ALK wild-type (WT) patients., Methods: Data from 1166 patients who had stage IIIB/IV NSCLC with nonsquamous histology were collected from the NSCLC database of Seoul National University Hospital between 2003 and 2009. ALK fluorescence in situ hybridization (FISH) was used to analyze 262 patients who either had the WT epidermal growth factor receptor (EGFR) or were nonresponders to previous EGFR tyrosine kinase inhibitor (TKI) therapy. Overall survival (OS) was compared between 3 groups: 1) ALK-positive patients, 2) EGFR mutation-positive patients, and 3) ALK-WT/EGFR-WT patients. Progression-free survival (PFS) after first-line chemotherapy and EGFR TKIs also was analyzed., Results: Twenty-three patients were ALK-positive according to FISH analysis and did not receive ALK inhibitors during follow-up. The median OS for ALK-positive patients, EGFR mutation-positive patients, and WT/WT patients was 12.2 months, 29.6 months, and 19.3 months, respectively (vs EGFR mutation-positive patients, P = .001; vs WT/WT, P = .127). The PFS after first-line chemotherapy for the 3 groups was not different. However, the PFS for patients who received EGFR TKIs was shorter in ALK-positive patients compared with the other 2 groups (vs EGFR mutation-positive patients, P < .001; vs WT/WT, P < .021)., Conclusions: In the pre-ALK inhibitor era, ALK-positive patients experienced the shortest survival, although it did not differ statistically from that of WT/WT patients. Although their responses to platinum-based chemotherapy were not different from comparator groups, ALK-positive patients were even more resistant to EGFR TKI treatment than WT/WT patients., (Copyright © 2011 American Cancer Society.)

Background: ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period., Methods: We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients., Findings: Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244)., Interpretation: In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC., Funding: Pfizer Inc, V Foundation for Cancer Research., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: This study compared the efficacy of pemetrexed in patients with anaplastic lymphoma kinase (ALK)-positive versus ALK-negative (epidermal growth factor receptor [EGFR] mutant or wild type [WT] for both ALK and EGFR) non-small cell lung cancer (NSCLC)., Methods: Patients with advanced NSCLC who received second-line pemetrexed and beyond between March 2007 and April 2010 were screened for EGFR mutations and ALK rearrangements at Seoul National University Hospital. The clinical and in vitro efficacy of pemetrexed was evaluated for each genotypic group., Results: Ninety-five NSCLC patients were genotyped as follows: 43 (45%) EGFR mutation, 15 (16%) ALK translocation, and 37 (39%) WT. The overall response rate was superior in ALK-translocated patients compared with EGFR mutant or WT patients (46.7 versus 4.7 versus 16.2%, p = 0.001). ALK-positive patients showed longer time to progression than EGFR mutant or WT patients (9.2 versus 1.4 versus 2.9 months, p = 0.001). ALK positivity alone was a significant predictor for overall response rate (hazard ratio [HR] = 0.07, 95% confidence interval [CI]: 0.01-0.32; p = 0.001) and time to progression (HR = 0.44, 95% CI: 0.24-0.80; p = 0.007). ALK positivity remained independently significant regardless of treatment line (HR = 0.43, 95% CI: 0.24-0.77; p = 0.005). Thymidylate synthase mRNA levels in ALK-positive cells were significantly lower compared with control cells (p < 0.05)., Conclusion: Pemetrexed is an effective treatment in patients with ALK-positive NSCLC. ALK positivity was independently predictive of pemetrexed efficacy in NSCLC patients.

Crizotinib is a dual MET and ALK inhibitor. Currently, clinical development of crizotinib is focused primarily on ALK rearranged non-small cell lung cancer (NSCLC). Here we report an NSCLC patient with de novo MET amplification but no ALK rearrangement who achieved a rapid and durable response to crizotinib indicating is also a bona fide MET inhibitor.

Background: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase., Methods: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy., Results: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects., Conclusions: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Background: We sought to identify the relationship between response to previous systemic treatment and the efficacy of subsequent pemetrexed therapy in advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Two hundred and fifty clinical stage IIIB or IV NSCLC patients treated with pemetrexed as a second-line or further-line treatment between April 2007 and June 2008 were analyzed retrospectively. Prior therapies were divided into four types (gemcitabine-based [G], paclitaxel-based [P], docetaxel-based [D], and EGFR tyrosine kinase inhibitor [I]). Objective response rates (ORR) and progression-free survivals (PFS) for pemetrexed therapy were analyzed according to the response outcome with each previous treatment., Results: The ORR of pemetrexed therapy was higher for patients who had achieved partial response with previous [G] therapy than others (15.0% vs. 4.3%, p=0.02). In addition, median PFS for pemetrexed therapy was greater for responders to [G] than for nonresponders (3.0 months vs. 1.7 months, p=0.004). The longer PFS for responders to [G] was also shown in the analysis among patients with squamous cell carcinoma (3.2 months vs. 1.7 months, p=0.056). By univariate analyses, the variables of the responder to [G] therapy, female, adenocarcinoma, never smoking status, and ECOG performance status of 0-1 were good predictive factors for pemetrexed therapy in terms of PFS. Multivariate analysis revealed that only response to [G] had statistical significance (hazard ratio=0.62, p=0.006)., Conclusion: Response outcome to prior [G] therapy might predict the efficacy of subsequent pemetrexed therapy in advanced NSCLC., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: We analyzed the significance of class III beta-tubulin (TUBB3) expression in curatively resected non-small cell lung cancer as a prognostic marker along with previously reported excision repair cross complementation group 1 (ERCC1)., Methods: One hundred and thirty-six consecutive patients were included in this retrospective study. Patients who received adjuvant chemotherapy were excluded. We used immunohistochemistry to evaluate TUBB3 and ERCC1 expression on tissue microarray in duplicate. Semiquantitative H score was used for the scoring of tumor staining., Results: Sixty percent of patients had stage I disease, 17% stage II, 18% stage IIIA, and 5% stage IIIB. TUBB3 H score showed bimodal distribution with the minimum at the value of 4, which was used as a cutoff value for determination of TUBB3 positivity. TUBB3 was expressed in 60 patients (44%). Patients with a positive TUBB3 expression survived shorter than did the patients with a negative expression (5-year overall survival [OS] rate was 40% versus 61%; p = 0.005/5-year disease-free survival rate was 34% versus 55%; p = 0.024). ERCC1 expression showed tendency for prolonged OS without reaching statistical significance. A multivariate analysis that incorporated covariates including TUBB3 expression, age, stage, EGFR mutation status, histology, and ERCC1 expression showed that TUBB3 was an independent unfavorable prognostic factor for OS (hazard ratio 2.083; p = 0.008) and relapse free survival (hazard ratio 1.978; p = 0.020)., Conclusions: TUBB3 expression is an independent unfavorable prognostic marker in patients with curatively resected non-small cell lung cancer who did not receive adjuvant chemotherapy.

The purpose of this study was to demonstrate the beneficial effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of leptomeningeal metastasis (LM) for a select group of non-small cell lung cancer (NSCLC) patients who had a sensitive EGFR mutation or good predictive clinical factors for EGFR TKI treatment. Eleven patients with NSCLC and LM were treated with a standard dose of erlotinib (n=9), or higher than standard dose of gefitinib followed by erlotinib (n=2). They were treated with various therapies including whole brain radiotherapy or intrathecal chemotherapy for CNS lesion previously and concurrently with EGFR TKI. Nine of 11 patients showed overt improvement in ECOG performance status. Six patients were alive >6 months, and 2 additional patients were alive 2.5+ and 4.4+ months with clinical improvement. Two patients showed responses to higher than standard dose of gefitinib. The median overall survival was not reached. In conclusion, EGFR TKIs are effective in the treatment of LM from NSCLC when patients were selected properly.

Expression of excision repair cross-complementation group 1 (ERCC1) is important for resistance to platinum agents. Mutations of epidermal growth factor receptor (EGFR) are related to the responsiveness to tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). This study was performed to determine if ERCC1 expression and EGFR are related to the prognosis of resected NSCLC, and to determine if ERCC1 expression and EGFR mutations are related. We used immunohistochemistry (IHC) to evaluate ERCC1 expression in tumors from 130 patients with curatively resected NSCLC. The median H-score was used as a cut-off for ERCC1 IHC. EGFR mutations were analyzed in exons 18, 19 and 21. ERCC1 expression was detected in tumors from 80 patients (61.5%). ERCC1 was expressed more frequently in smokers and in squamous cell carcinomas. Patients with a positive ERCC1 expression survived longer than ERCC1-negative patients (median overall survival 7.6 years for ERCC1-positive vs. 4.0 years for ERCC1-negative, P=0.046). Subsequent multivariate analysis suggested that ERCC1 expression is an independent prognostic marker of longer survival (hazard ratio: 0.598, 95% confidence interval: 0.357-1.001). EGFR mutations were found in 25 patients (19.2%) but did not 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). In conclusion, ERCC1 expression was identified as a positive prognostic marker in resected NSCLC. In addition, EGFR mutations were more frequently found in ERCC1-negative tumors.

Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full-length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the anti-tumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-delta1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC., ((c) 2007 Wiley-Liss, Inc.)

The purpose of this study was to investigate the prognostic value of tumour-associated macrophages with a focus on micro-anatomical localisation and determine whether molecular changes of the epidermal growth factor receptor (EGFR) are related to macrophage infiltration in resected non-small cell lung cancer (NSCLC). One hundred and forty-four patients were included in this study. Immunohistochemistry was used to identify CD68+ macrophages in the tumour islet and surrounding stroma. Epidermal growth factor receptor mutations were studied by direct sequencing. The EGFR gene copy number and protein expression were analysed by fluorescence in situ hybridisation and immunohistochemistry. Patients with a high tumour islet macrophage density survived longer than did the patient with a low tumour islet macrophage density (5-year overall survival rate was 63.9 vs 38.9%, P=0.0002). A multivariate Cox proportional hazard analysis revealed that the tumour islet macrophage count was an independent prognostic factor for survival (hazard ratio 0.471, 95% confidence interval 0.300-0.740). However, EGFR mutations, gene copy number, and protein expression were not related to the macrophage infiltration. In conclusion, tumour islet macrophage infiltration was identified as a strong favourable independent prognostic marker for survival but not correlated with the molecular changes of the EGFR in patients with resected NSCLC.

Although non-small cell lung cancer (NSCLC) cells with somatic mutations in their epidermal growth factor receptors (EGFR) initially show a dramatic response to tyrosine kinase inhibitor (TKI), these cells eventually develop resistance to TKI. This resistance may be caused by a secondary T790M mutation in the EGFR tyrosine kinase, which leads to the substitution of methionine for threonine in 790. In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC.

EGF receptor (EGFR) activation has an important role in various steps of carcinogenesis and progression of non-small-cell lung cancer (NSCLC), implying that EGFR is a potential target for cancer therapy. Therefore, targeted treatments aimed at EGFR have been developed, of which tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib have shown activity in NSCLC. The unexpected findings of a lack of association between expression of EGFR, the target and efficacy of EGFR TKIs and higher response in selective subgroups of patients were puzzling. Identification of somatic activating mutations in the EGFR tyrosine kinase domain solved the mystery and provided new insight. Several lines of study provided information on various molecular targets for EGFR TKI therapy. A target-based patient-selection strategy is expected to eventually lead to tailored therapy for lung cancer.

Objective: Limited availability of tumoral tissue in non-small-cell lung cancer and presence of epidermal growth factor receptor mutation-independent responses call for investigation of other molecular predictive marker of gefitinib responsiveness. Therefore, CA repeat polymorphism in intron 1 was analyzed for its association with gefitinib responsiveness together with epidermal growth factor receptor mutation in Korean patients., Patients and Methods: For 86 advanced non-small-cell lung cancer patients treated with gefitinib, epidermal growth factor receptor mutation was analyzed by direct sequencing (exons 18-21) from tumor tissue and CA repeat polymorphism was assessed by fragment length analysis from tumor and/or normal tissue., Results: CA repeat status was identical in 33 patients with matched tumor and normal tissue. CA repeat was low (sum of both alleles < or =37) in 40 (46.5%) and high (sum > or =38) in 46 (53.5%) patients. Although epidermal growth factor receptor mutation was more frequent in high CA repeat patients [17.5% (7/40) in low vs. 28.3% (13/46) in high, P=0.18], response rate was higher in low CA repeat patients [25.0% (10/40) in low vs. 13.0% (6/46) in high, P=0.16]. In multivariate analysis, low CA repeat was associated with better objective response (odds ratio 7.1, 95% confidence interval 1.2-40.8; P=0.029) and time-to-progression (hazard ratio 0.54, 95% confidence interval 0.34-0.88; P=0.014), independent of the epidermal growth factor receptor mutational status. CA repeat status was not associated with epidermal growth factor receptor expression., Conclusion: Low number of CA repeats in intron 1 of epidermal growth factor receptor is associated with gefitinib responsiveness in non-small-cell lung cancer patients independent of epidermal growth factor receptor mutation.

Background: Clinical predictors including Asian, female, adenocarcinoma and never-smoker and epidermal growth factor mutation are associated with gefitinib responsiveness in non-small-cell lung cancer. Direct comparison between clinical predictors and EGFR mutation for their predictive power has not been reported., Patients and Methods: For 120 Korean NSCLC patients treated with gefitinib, we have analyzed EGFR mutational status in exons 18, 19 and 21. Patients were grouped according to the number of clinical predictors (female, adenocarcinoma and never-smoker). Response rate (RR), time-to-progression (TTP) and overall survival (OS) were analyzed. Multivariate analysis was performed to investigate which approach yielded better prediction., Results: RRs according to number of clinical predictors were 0: 3.4%, 1: 17.1%, 2: 29.4% and 3: 33.3% (p=0.002). Patients with gefitinib-sensitive EGFR mutation showed 61.9% RR compared with 12.1% in the remaining patients (p<0.001). RRs were higher in patients with the EGFR mutations regardless of the number of clinical predictors. In multivariate analysis, gefitinib-sensitive EGFR mutation showed higher odds ratio of response (9.6, 95% confidence interval [CI] 3.2-28.7) compared with number of clinical predictors (1.7, 95% CI 1.1-2.7). Hazard ratio (HR) of TTP was also better in gefitinib-sensitive EGFR mutation (0.24, 95% CI 0.12-0.47) than number of clinical predictors (0.83, 95% CI 0.69-0.99). Only gefitinib-sensitive EGFR mutation was associated with improved OS (HR 0.25, 95% CI 0.12-0.52)., Conclusion: EGFR mutation should be analyzed whenever possible for effective prediction of objective benefit from gefitinib in NSCLC patients with one or more clinical predictors.

Purpose: To evaluate response and survival for platinum-based combination chemotherapy in chemonaive patients with non-small cell lung cancer (NSCLC) according to pretreatment standardized uptake values (SUV) by fluorodeoxyglucose positron emission tomography., Experimental Design: Patients with advanced NSCLC who had not previously received chemotherapy were eligible. Response rates and survivals were analyzed according to maximal SUVs [low (7.5), where 7.5 was the median value] before the first cycle of chemotherapy., Results: Eighty-five consecutive patients were included in the retrospective study. Patients with high SUV tumors exhibited significantly higher response rates (34.1% for low SUVs versus 61.0% for high SUVs; P = 0.013). Other factors, including sex, age, histology, performance status, number of involved organs, regimens used, and disease stage, did not affect response. However, high SUVs were related with a shorter response duration (279 days for low SUVs versus 141 days for high SUVs; P = 0.003) and time to progression (282 days for low SUVs versus 169 days for high SUVs; P = 0.015). Overall survival was unaffected by maximal SUVs (623 days for low SUVs versus 464 days for high SUVs; P = 0.431)., Conclusions: Patients having NSCLC with high maximal SUVs showed a better response to platinum-based combination chemotherapy but had a shorter time to progression. Tumor glucose metabolism, as determined by SUVs on fluorodeoxyglucose positron emission tomography, was found to discriminate NSCLC subsets with different clinical and biological features.

Background: The association of epidermal growth factor receptor (EGFR) mutations with the response to conventional cytotoxic chemotherapeutic agents in non-small-cell lung cancer patients has not been investigated. We retrospectively analyzed the associations between response to chemotherapy and molecular markers associated with gefitinib responsiveness including EGFR mutations., Methods: EGFR (exons 18, 19 and 21) and K-ras mutations (exon 2) were studied by direct sequencing and p-Erk and p-Akt expressions were studied by immunohistochemistry in archival paraffin embedded tissues. Response rate (RR) and time-to-progression (TTP) of prior chemotherapy by platinum, paclitaxel and gemcitabine were analyzed with respect to the presence of EGFR and K-ras mutations, and p-Erk and p-Akt expressions., Results: Of 90 patients investigated, 75 received platinums and 45 received paclitaxel as first-line chemotherapy agents. The RRS and TTPS of platinum- and paclitaxel-containing regimens were not affected by EGFR or K-ras mutations, nor by p-Erk or p-Akt expression. Fifty-seven patients received gemcitabine as first- or second-line chemotherapy. RR was not affected by EGFR or K-ras mutations or by p-Akt expression. However, all responders to gemcitabine exhibited (+) p-Erk expression [RR 30.6% for p-Erk (+) versus 0% for p-Erk (-), P = 0.01]. TTP was not affected by EGFR or K-ras mutations or by p-Erk or p-Akt expression., Conclusions: EGFR mutations did not affect response to conventional chemotherapeutic agents, namely platinums, paclitaxel and gemcitabine. Our results also suggest that it may be undesirable to use gemcitabine in patients with tumors not expressing p-Erk.

Purpose: Mutations in epidermal growth factor receptor (EGFR) are strongly predictive of gefitinib efficacy in non-small-cell lung cancer. However, the presence of EGFR mutant nonresponses and nonmutant responses points out the need for more comprehensive analysis., Patients and Methods: For 69 non-small-cell lung cancer patients treated with gefitinib, we have extended our analysis to EGFR gene copy number by fluorescence in situ hybridization, mutations in K-ras, HER2, and exon 20 of EGFR by direct sequencing, and phosphatase and tensin homologue expression by immunohistochemistry, in addition to EGFR exons 18, 19, and 21, and phosphorylations of Akt and extracellular signal-regulated kinase reported previously., Results: EGFR mutation and high gene copy number were associated with better objective response in univariate analysis. However, only gefitinib-sensitive EGFR mutation was independently predictive of both response (P = 0.011) and survival (P = 0.002) in multivariate analysis. No patients with K-ras mutation, including two EGFR mutants, showed response. In EGFR nonmutants, patients with either K-ras mutation or p-Akt overexpression exhibited poor response and time-to-progression whereas patients with high gene copy number tended to have better outcomes in univariate analysis. In multivariate analysis of time-to-progression in EGFR nonmutants, K-ras mutation or p-Akt overexpression was associated with shorter time-to-progression (P = 0.017). No patient with HER2 mutation showed response to gefitinib. Reduced phosphatase and tensin homologue expression was not associated with gefitinib sensitivity., Conclusion: Gefitinib-sensitive EGFR mutation is the single most important predictor of gefitinib sensitivity. In addition to EGFR mutation, K-ras mutation and Akt phosphorylation aid in better prediction of gefitinib responsiveness in non-small-cell lung cancer.

This study was conducted to assess the efficacy of systemic chemotherapy in patients with brain metastasis from non-small cell lung cancer. Sixty-three consecutive patients who were diagnosed as having non-small cell lung cancer (NSCLC) with synchronous brain metastasis (BM) and had not been previously treated were included in this study. After cranial radiation therapy (RT), all patients in 'the chemotherapy arm' (CTX) were treated with platinum-based combination chemotherapy, and best supportive care was selected for patients in 'the no-chemotherapy arm' (no-CTX). Thirty-one of the 63 patients received systemic chemotherapy. The median age of all patients was 55 years. The performance status of all patients was ECOG grade 1-2. Twenty-two patients had a solitary brain metastasis, 37 patients had more than two masses, and 38 patients had extracranial metastatic lesions. In the CTX arm, a paclitaxel-based combination chemotherapy was administered in 38.7%, gemcitabine-based in 25.8%, and vinorelbine-based in 25.8% as the first-line chemotherapy. Seventeen patients were treated with a second-line chemotherapy, and paclitaxel plus gemcitabine was used in 8 patients. For the first-line and second-line chemotherapies, extracranial overall responses were 36 and 35%, the median response durations were 29.1 weeks (range: 9.1-58.1 weeks) and 30.4 weeks (range: 19.4-44.0 weeks), respectively. 'Progression of the extracranial lesion' (58.1%) was more frequent than an 'aggravation of neurologic status' (19.4%) for the pattern of treatment failure in the first-line chemotherapy. The causes of failure were identical in the second-line chemotherapy. The median survival of the CTX arm was longer than that of the no-CTX arm (58.1 vs. 19.0 weeks, p<0.001). Toxicity in the CTX arm was tolerable. The systemic chemotherapy showed an effectiveness to increase the survival of patients with BM from NSCLC, and extracranial progression was the main cause of chemotherapeutic failure, although consideration for non-randomized methods should be made in this study.

Purpose: This study was undertaken to investigate the effects of epidermal growth factor receptor (EGFR) mutation and its downstream signaling on response and survival in non-small-cell lung cancer (NSCLC) patients treated with gefitinib., Patients and Methods: For 90 consecutive NSCLC patients who had received gefitinib, EGFR mutation was analyzed by DNA sequencing of exons 18, 19, 21, and 23 in the EGFR tyrosine kinase domain. Expressions of phosphorylated (p) -Akt and p-Erk were determined via immunohistochemistry. Response rate, time to progression (TTP), and overall survival were compared between each group according to EGFR mutation, as well as p-Akt and p-Erk expression., Results: Seventeen patients (18.9%; 95% CI, 10.8 to 27.0) harbored EGFR mutations. These mutations include deletions in exon 19 in seven patients, L858R in six patients, G719A in three patients, and a novel A859T in one patient. Response rate in patients with EGFR mutation was 64.7% (11 of 17 patients; 95% CI, 42.0 to 87.4), in contrast to 13.7% (10 of 73 patients; 95% CI, 5.8 to 21.6) in patients without mutation (P < .001). Moreover, these 17 patients with EGFR mutation had significantly prolonged TTP (21.7 v 1.8 months; P < .001) and overall survival (30.5 v 6.6 months; P < .001) compared with the remaining 73 patients without mutation. Although no significant correlation was detected between EGFR mutation and expressions of p-Akt or p-Erk, p-Akt overexpression was associated with prolonged TTP in patients with EGFR mutation., Conclusion: Our data further support the importance of EGFR mutation with regard to gefitinib sensitivity. In addition to its predictive role, EGFR mutation confers significant survival benefits on NSCLC patients treated with gefitinib.

Gefitinib has shown meaningful antitumor activity with tolerable toxicity in chemotherapy-refractory NSCLC in previous studies. Moreover, EGFR expression failed to show a correlation with response. In an attempt to identify predictive markers of response, we have investigated the tumoral expression of key signaling molecules of EGFR (EGFR, p-EGFR, p-Akt, p-Erk, p-STAT3) by immunohistochemistry and analyzed their correlations with response. Of 65 patients who received gefitinib (250 mg/day) for chemotherapy-refractory NSCLC, there were 14 partial responses (21.5%), 21 stable diseases (32.3%) and 21 progressive diseases (32.3%). Median durations of overall survival and time to progression were 6.7 months and 2.8 months, respectively. Immunohistochemistry was performed in 34 patients with evaluable tissue specimens. EGFR was overexpressed (2+ or 3+) in 32.4% and p-EGFR was positive in 26.5%. The expressions of p-Akt, p-Erk and p-STAT3 were positive (1+ or 2+) in 50%, 38.2% and 79.4%, respectively. The EGFR expression was not correlated with p-EGFR or the downstream molecules. EGFR or p-EGFR status did not correlate with response. Positive expression of p-Erk was significantly associated with poor response (38.1% in -, 14.3% in 1+, 0% in 2+; p = 0.046). Furthermore, tumors with positive p-Akt and negative p-Erk nuclear expression exhibited the best response (60%), whereas there was no response in the opposite [p-Akt (-), p-Erk (+)] cases. Intense nuclear staining of p-Akt (2+) was associated with prolonged TTP (HR 0.25, 95% confidence interval [CI] 0.08-0.79, p = 0.018) and OS (HR 0.16, 95% CI 0.04-0.62, p = 0.008). These results support the assumption that gefitinib responsiveness might be predicted by activated EGFR downstream molecules such as p-Akt and p-Erk.

Objective: The objectives of the present study were to assess the efficacy and tolerability of perioperative paclitaxel/platinum-based chemotherapy and surgery in patients with stage IIIA clinical N2 (cN2) non-small cell lung cancer (NSCLC)., Methods: Clinical N2 was defined as either >15 mm or >10 mm and multiple nodes on computed tomography (CT) scan. Thirty-four chemotherapy-naive patients with stage IIIA cN2 received preoperative paclitaxel/cisplatin for two cycles and then underwent surgery. The treatment with paclitaxel/carboplatin was repeated for three cycles after the operation., Results: Of the 34 patients, none achieved a complete response (CR) and 22 achieved a partial response (PR), resulting in a response rate of 65%. Among 29 patients (85%) who had received thoracotomy, 25 (74%) underwent complete resection. Two pathological CRs were observed and mediastinal nodes were free of tumor in 21%. Grade 3-4 toxicity was uncommon and treatment-related mortality was not observed. The median time to progression (TTP) was 12.1 months [95% confidence interval (CI) 8.3-15.9 months] and median overall survival (OS) was 23.6 months (95% CI 17.7-30.2 months)., Conclusions: Paclitaxel/platinum-based perioperative chemotherapy and surgery for patients with stage IIIA cN2 NSCLC is effective and well tolerated.

Purpose: We conducted this study to evaluate the activity and toxicity of a combination regimen of paclitaxel plus carboplatin in patients with advanced NSCLC aged 65 years or older and/or in those with an ECOG performance status (PS) 2., Materials and Methods: Chemotherapy-naive patients with unresectable pathologically-proven NSCLC and of either age >or=65 or ECOG PS 2 were eligible. Patients received modified regimen with attenuated doses of paclitaxel (135 mg/m(2) i.v. for 3 h D1) and carboplatin (AUC=5, D1) every 3 weeks., Results: Thirty-five patients were enrolled. Nineteen patients were aged 65 or older (54%) and 26 patients (74%) were ECOG PS 2. The objective response rate was 40% with 14 partial responses. The median time to progression was 22 weeks. Grade 3 leucopenia occurred in 1 cycle and one case of neutropenic fever., Conclusions: The modified regimen with attenuated doses of paclitaxel plus carboplatin combination chemotherapy was effective and well tolerated in patients with advanced NSCLC aged 65 years or older and/or in those with ECOG PS 2.

A phase III randomized trial was conducted to investigate whether induction chemotherapy followed by radiation can influence survival as compared with radiation alone in unresectable, locally advanced non-small-cell lung cancer (LADNSCLC). A total of 101 patients with unresectable stage IIIA or IIIB NSCLC were enrolled. Patients were stratified by performance status, weight loss, histology and stage, and then randomized to receive combined chemoradiotherapy or radiotherapy alone. Radiotherapy was administered in 1.8 Gy to 2.0 Gy standard fractions daily 5 times weekly for a total dose of 60 Gy to 65 Gy. The combined group received induction of cisplatin, etoposide, and vinblastine (PEV) chemotherapy with cisplatin 20 mg/m2 on days 1 to 5, etoposide 100 mg/m2 on days 2 to 4, and vinblastine 6 mg/m2 on day 1, which wasrepeated every 3 weeks for 3 courses, after which time the patients underwent radiotherapy. Of 101 patients registered, 89 patients (43 combined, 46 radiotherapy alone) were eligible for analysis. The response rates for the combined and radiotherapy groups were 65% (28/43) and 70% (32/46), respectively. The median survival time (MST) showed a tendency to be more prolonged in the combined group than in the group receiving radiotherapy alone (13.8 vs. 8.5 months). The MST in patients with nonsquamous histology was strikingly prolonged in the combined group as compared with the radiotherapy group (14 vs. 3.6 months, p 0.027). Likewise, the MST in patients with stage IIIB was significantly prolonged in the combined group as compared with the radiotherapy group (11.1 vs. 7.2 months, p 0.045). Together, the MST of the high-risk group with nonsquamous or stage IIIB was significantly higher in the combined group than that seen in the radiotherapy group (11.6 vs. 8 months, p 0.046), whereas the MST of the low-risk group, defined as having both squamous histology and stage IIIA, was similar in the two treatment groups (18.3 vs. 20.8 months, p = 0.293). In conclusion, induction PEV chemotherapy plus radiotherapy is superior to radiotherapy alone in high-risk subsets of unresectable LAD-NSCLC and therapeutic strategy should be based on the identification of prognostic factors.

Purpose: This is the first report of a Phase I study on concomitant weekly cisplatin and docetaxel chemotherapy with thoracic radiation for Stage III non-small-cell lung cancer (NSCLC). The study objectives were to determine the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of docetaxel used in this regimen, and to evaluate the feasibility of weekly concurrent chemoradiotherapy., Methods and Materials: Patients with histologically proven and unresectable Stage III NSCLC were the subjects of this study. Cisplatin was administered at a fixed dose of 20 mg/m2, while the dose of docetaxel was increased from 0 to 30 mg/m2 in increments of 10 mg/m2. Chemotherapy was given on the first day of each week for 6 weeks. The primary tumor and regional lymph nodes were irradiated to 54 Gy, followed by an additional 9 Gy boost to the primary tumor, making the total dose 63 Gy at 1.8 Gy/fraction., Results: Sixteen men and 2 women with advanced NSCLC without prior treatment were enrolled. The median age of the group was 58 years (range 49-67). Three patients had Stage IIIa disease and 15 patients had IIIb disease. Dose-limiting Grade 3 esophagitis was encountered at a docetaxel dose level of 30 mg/m2 in 2 of 3 patients. No dose-limiting, nonhematologic toxicity occurred in the other patients and no dose-limiting hematologic toxicity occurred in any patient., Conclusion: The treatment schedule for NSCLC was feasible, with the DLT being esophagitis. We determined the recommended dose of docetaxel to be 20 mg/m2 for a Phase II study when combined with weekly cisplatin and concomitant thoracic RT.