Publications by authors named "Barbara Klughammer"

19 Publications

  • Page 1 of 1

The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria.

Blood 2020 03;135(12):912-920

Université de Paris, Centre de Référence Aplasie Médullaire-HPN, Service d'Hématologie-Greffe, Centre d'Investigation Clinique, Hôpital Saint-Louis, Paris, France; and.

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).
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http://dx.doi.org/10.1182/blood.2019003399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082616PMC
March 2020

ReadMax-a novel reading and scoring approach for EGFR gene copy number to predict therapeutic benefit of erlotinib treatment in EGFR wild-type non-small-cell lung cancer.

J Pathol Clin Res 2015 Jul 2;1(3):134-43. Epub 2015 Apr 2.

F. Hoffmann-La Roche Ltd Basel Switzerland.

EGFR mutation testing is now well established as a means of selecting the optimal first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). However, deciding on the correct treatment for EGFR wild-type NSCLC remains a challenge. EGFR fluorescence in-situ hybridization (FISH) testing of gene copy number has been a promising marker, but has provided mixed results despite attempts to standardize the reading and scoring process. The novel ReadMax reading and scoring system focuses on the most aberrant cells, to identify oncogene addiction, rather than taking a representative reading as in the Colorado method. The methodology was developed using historical samples from the TRUST and MERIT studies, followed by re-reading of the samples from the SATURN trial. Analysis of samples using the ReadMax methodology revealed that progression-free survival (PFS) and overall survival (OS) were improved in patients with ReadMax FISH-positive (RM FISH+) tumours, compared with those whose tumours were not RM FISH+: PFS hazard ratios (HRs) were 0.52 for RM FISH+ versus 0.93 for not RM FISH+; OS HRs were 0.69 and 0.92, respectively. For PFS, HR for RM FISH+ versus not RM FISH+ in the SATURN erlotinib group was 0.53 (p = 0.003). The PFS and OS results were also similar in the EGFR wild-type population (PFS HRs were 0.63 and 0.96; OS HRs were 0.61 and 0.84, respectively), although amplification of the EGFR gene in patients with EGFR wild-type disease was not found to be predictive of treatment outcomes, which was unexpected but not unprecedented. KRAS status was not found to affect outcomes. Further experience is required to refine the ReadMax methodology and fully establish its validity and robustness. In conclusion, the ReadMax scoring system to identify patients with EGFR FISH-positive NSCLC is a promising technique, which could improve treatment options and outcomes for patients with advanced NSCLC, in particular for EGFR wild-type tumours.
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http://dx.doi.org/10.1002/cjp2.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939878PMC
July 2015

Tumor marker analyses from the phase III, placebo-controlled, FASTACT-2 study of intercalated erlotinib with gemcitabine/platinum in the first-line treatment of advanced non-small-cell lung cancer.

Lung Cancer 2016 08 3;98:1-8. Epub 2016 May 3.

Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address:

Objectives: The FASTACT-2 study of intercalated erlotinib with chemotherapy in Asian patients found that EGFR mutations were the main driver behind the significant progression-free survival (PFS) benefit noted in the overall population. Further exploratory biomarker analyses were conducted to provide additional insight.

Materials And Methods: This multicenter, randomized, placebo-controlled, double-blind, phase III study investigated intercalated first-line erlotinib or placebo with gemcitabine/platinum, followed by maintenance erlotinib or placebo, for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Provision of samples for biomarker analysis was encouraged but not mandatory. The following biomarkers were analyzed (in order of priority): EGFR mutation by cobas(®) test, KRAS mutation by cobas(®)KRAS test, HER2 by immunohistochemistry (IHC), HER3 by IHC, ERCC1 by IHC, EGFR gene copy number by fluorescence in-situ hybridization (FISH) and EGFR by IHC. All subgroups were assessed for PFS (primary endpoint), overall survival (OS), non-progression rate and objective response rate.

Results: Overall, 256 patients provided samples for analysis. Considerable overlap was noted among biomarkers, except for EGFR and KRAS mutations, which are mutually exclusive. Other than EGFR mutations (p<0.0001), no other biomarkers were significantly predictive of outcomes in a treatment-by-biomarker interaction test, although ERCC1 IHC-positive status was predictive of improved OS for the erlotinib arm versus placebo in EGFR wild-type patients (median 18.4 vs 9.5 months; hazard ratio [HR] HR=0.32, 95% confidence intervals [CI]: 0.14-0.69, p=0.0024).

Conclusion: Activating EGFR mutations were predictive for improved treatment outcomes with a first-line intercalated regimen of chemotherapy and erlotinib in NSCLC. ERCC1 status may have some predictive value in EGFR wild-type disease, but requires further investigation.
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http://dx.doi.org/10.1016/j.lungcan.2016.04.023DOI Listing
August 2016

Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer Whose Tumors Harbor Uncommon EGFR Mutations.

J Thorac Oncol 2016 Apr 8;11(4):545-55. Epub 2016 Jan 8.

Oncology Biomarker Development, Genentech Inc., San Francisco, California.

Introduction: Exon 19 deletions and the exon 21 L858R mutation of the epidermal growth factor receptor gene (EGFR) predict activity of EGFR tyrosine kinase inhibitors, including erlotinib; however, the ability of less common EGFR mutations to predict efficacy of erlotinib is unclear.

Methods: The efficacy of erlotinib in individual patients with rare EGFR mutations from the MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 trials was analyzed and compared with data from the literature.

Results: In the patients tested for biomarkers, the frequency of rare mutations identified here ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS. Some rare mutations were associated with greater clinical benefit from EGFR tyrosine kinase inhibitor therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis. In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome. Owing to the small number of patients with each mutation, however, it is difficult to confirm whether these rare mutations do indeed confer sensitivity or resistance to erlotinib.

Conclusions: Erlotinib can have different efficacy depending on the specific EGFR mutation. More research is needed to create a central database such as the My Cancer Genome database of rare mutations to definitively confirm whether these mutations are activating, resistant, or neutral.
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http://dx.doi.org/10.1016/j.jtho.2015.12.107DOI Listing
April 2016

Erlotinib therapy after initial platinum doublet therapy in patients with EGFR wild type non-small cell lung cancer: results of a combined patient-level analysis of the NCIC CTG BR.21 and SATURN trials.

Transl Lung Cancer Res 2015 Aug;4(4):465-74

1 Multidisciplinary Thoracic Oncology Program, Baptist Cancer Center, Memphis, TN, USA ; 2 Department of Oncology, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy ; 3 Institute of Oncology Ion Chiricuta, Cluj-Napoca, Romania ; 4 Genentech Inc., South San Francisco, CA, USA ; 5 F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Background: The clinical benefit of erlotinib in treating epidermal growth factor receptor (EGFR) wildtype non-small cell lung cancer (NSCLC) has been questioned. We examined the impact of erlotinib in confirmed EGFR wildtype patients in two placebo-controlled phase III trials: the National Cancer Institute of Canada Clinical Trials Group BR.21 (BR.21) and Sequential Tarceva in Unresectable Non-Small Cell Lung Cancer (SATURN) trials.

Methods: Combined re-analysis of progression-free survival (PFS) and overall survival (OS) in patients with known wildtype EGFR, estimated by Kaplan-Meier curves and compared by two-sided log-rank test. Cox proportional hazards model was used to estimate hazard ratios (HR) adjusted for potential confounders. Additional analyses assessed comparability of patients with known and unknown EGFR mutation status to determine generalizability of the two study populations.

Results: Mutation status was known in 25% (n=184 of 731) of the BR.21, and 49% (n=437 of 889) of the SATURN populations, of which 82% (n=150) and 89% (n=388) respectively had wildtype EGFR. HR for PFS was 0.71 (95% CI, 0.59-0.85; P<0.01) and for OS was 0.72 (95% CI, 0.59-0.88; P<0.01). Baseline characteristics and outcome (PFS and OS) distributions were similar for patients with known and unknown EGFR status, suggesting generalizability of the EGFR wildtype data. Erlotinib benefit was sustained in all clinical subsets.

Conclusions: Erlotinib provided a consistent and significant improvement in survival for patients with EGFR wildtype NSCLC in both studies, individually and in combination. The benefit of erlotinib does not appear to be limited to patients with activating mutations of EGFR.
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http://dx.doi.org/10.3978/j.issn.2218-6751.2015.07.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549481PMC
August 2015

PTPRF Expression as a Potential Prognostic/Predictive Marker for Treatment with Erlotinib in Non-Small-Cell Lung Cancer.

J Thorac Oncol 2015 Sep;10(9):1364-1369

Department of Oncology Biomarkers, Genentech Inc., SanFrancisco, California. Electronic address:

Introduction: EGFR mutations and anaplastic lymphoma kinase rearrangements are, to date, the only approved biomarkers to select treatment for non-small-cell lung cancer (NSCLC). However, there is considerable interest in identifying other predictive markers. The PTPRF gene has been suggested as a marker of interest in NSCLC and other tumor types.

Methods: This hypothesis-generating retrospective analysis examined data from two studies of erlotinib in NSCLC, Marker Identification Trial (MERIT; n = 102) and Sequential Tarceva in Unresectable NSCLC (SATURN; n = 262), to determine whether PTPRF expression was prognostic and/or predictive of patient outcomes. Exploratory analyses were conducted using quantitative reverse transcription polymerase chain reaction on existing formalin-fixed paraffin-embedded samples, to assess gene expression levels, including PTPRF. High versus low levels of expression were dichotomized using the median with B2M as a control comparator. Progression-free survival and overall survival were then compared for patients with high versus low levels of PTPRF in the two studies.

Results: PTPRF expression was found to be prognostic for shorter overall survival but was also significantly predictive of improved survival with erlotinib versus placebo in SATURN (hazard ratio, 0.45 [95% confidence interval, CI, 0.30-0.69] in PTPRF high versus 0.96 [95% CI, 0.62-1.48] in PTPRF low; interaction p = 0.02), even in the EGFR wild-type subpopulation (adjusted hazard ratio, 0.44 [95% CI, 0.29-0.68] versus 0.96 [95% CI, 0.62-1.48]; interaction p = 0.01).

Conclusions: PTPRF may have value as a predictive marker to identify which patients can obtain the greatest benefit from erlotinib in the post-first-line setting. Further research is warranted to determine the potential value of this marker in clinical decision-making.
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http://dx.doi.org/10.1097/JTO.0000000000000624DOI Listing
September 2015

Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy.

Clin Cancer Res 2015 Jul 31;21(14):3196-203. Epub 2015 Mar 31.

Roche Molecular Systems, Inc., Pleasanton, California.

Purpose: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study.

Experimental Design: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS).

Results: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut(+) cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14-0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut(-) cfDNA subgroup (HR, 0.83; 95% CI, 0.65-1.04, P = 0.1076). For patients with EGFR mut(+) cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut(+) cfDNA versus cycle 3 EGFR mut(-) patients, respectively (HR, 0.32; 95% CI, 0.21-0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31-0.84, P = 0.0066).

Conclusions: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2594DOI Listing
July 2015

Biomarker analyses from a randomized, placebo-controlled, phase IIIb trial comparing bevacizumab with or without erlotinib as maintenance therapy for the treatment of advanced non-small-cell lung cancer (ATLAS).

J Thorac Oncol 2014 Sep;9(9):1411-7

*University of California Los Angeles, Los Angeles, CA; †Kaiser Permanente Northern CA, Antioch, CA; ‡Sarah Cannon Research Institute, Nashville, TN; §Northwest Medical Specialties, Tacoma, WA; ‖Sibley Memorial Hospital, Washington, DC; ¶Integrated Community Oncology Network, Jacksonville, FL; #The Mark H. Zangmeister Center, Columbus, OH; **Florida Cancer Specialists, Bonita Springs, FL; ††Arch Medical Services Inc., The Center for Cancer Care and Research, Saint Louis, MO; ‡‡National Taiwan University, Taipei, Taiwan; §§F. Hoffmann-La Roche Ltd., Basel, Switzerland; ‖‖Genentech Inc., South San Francisco, CA; ¶¶Weill Cornell Medical College and Thoracic Oncology Service, New York, NY; and ##Dana-Farber Cancer Institute, Boston, MA.

Introduction: ATLAS compared bevacizumab plus erlotinib (B+E) with bevacizumab plus placebo (B+P) as maintenance therapy after first-line bevacizumab plus chemotherapy (B+C) for advanced non-small-cell lung cancer (NSCLC). Prespecified biomarkers were prospectively evaluated.

Methods: Tumor samples were analyzed for: epidermal growth factor receptor (EGFR) expression (immunohistochemistry [IHC]); EGFR gene copy number (fluorescence in-situ hybridization [FISH]); EGFR mutations (exon 19 deletions/L858R mutations); and KRAS mutations (exons 2/3). Progression-free survival (PFS) and overall survival (OS) were estimated.

Results: Of 743 patients randomized to receive maintenance treatment (after four cycles of B+C without progression), 190 (B+E) and 177 (B+P) were evaluable for biomarker status. Median PFS (from randomization) was 4.4 months (B+E) versus 3.7 months (B+P; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57-0.99), which was numerically similar to the intent-to-treat PFS. PFS benefit of B+E was observed across most biomarker subgroups. EGFR IHC, EGFR FISH, and EGFR/KRAS mutation status were not predictive of outcome. B+E-treated patients with EGFR mutation-positive NSCLC had longer PFS compared with B+P-treated patients (HR, 0.44; 95% CI, 0.22-0.86; p = 0.0139). Patients with KRAS wild-type disease had significant PFS improvements with B+E, compared with B+P (HR, 0.66; 95% CI, 0.485-0.914; p = 0.0105). No OS benefit of B+E was observed.

Conclusions: Patients with KRAS wild-type or EGFR mutation-positive NSCLC derived PFS benefits from B+E. However, EGFR IHC, EGFR FISH, and EGFR or KRAS mutation status were not strongly predictive of survival. A larger sample size would be needed to confirm the initial trends observed in this study.
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http://dx.doi.org/10.1097/JTO.0000000000000274DOI Listing
September 2014

Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC.

J Cell Mol Med 2014 Aug 6;18(8):1519-39. Epub 2014 Aug 6.

Department of Medical Oncology, Instituto de Biomedicina de Sevilla (HUVR, US and CSIC) and Hospital Universitario Virgen del Rocio, Seville, Spain.

Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6-13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0-9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3-6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy.
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http://dx.doi.org/10.1111/jcmm.12278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190899PMC
August 2014

Clinical validation of a PCR assay for the detection of EGFR mutations in non-small-cell lung cancer: retrospective testing of specimens from the EURTAC trial.

PLoS One 2014 25;9(2):e89518. Epub 2014 Feb 25.

Pangaea Biotech SL, Barcelona, Spain ; Medical Oncology Service-ICO, Hospital Germans Trias i Pujol, Badalona, Spain.

The EURTAC trial demonstrated that the tyrosine kinase inhibitor (TKI) erlotinib was superior to chemotherapy as first-line therapy for advanced non-small cell lung cancers (NSCLC) that harbor EGFR activating mutations in a predominantly Caucasian population. Based on EURTAC and several Asian trials, anti-EGFR TKIs are standard of care for EGFR mutation-positive NSCLC. We sought to validate a rapid multiplex EGFR mutation assay as a companion diagnostic assay to select patients for this therapy. Samples from the EURTAC trial were prospectively screened for EGFR mutations using a combination of laboratory-developed tests (LDTs), and tested retrospectively with the cobas EGFR mutation test (EGFR PCR test). The EGFR PCR test results were compared to the original LDT results and to Sanger sequencing, using a subset of specimens from patients screened for the trial. Residual tissue was available from 487 (47%) of the 1044 patients screened for the trial. The EGFR PCR test showed high concordance with LDT results with a 96.3% overall agreement. The clinical outcome of patients who were EGFR-mutation detected by the EGFR PCR test was very similar to the entire EURTAC cohort. The concordance between the EGFR PCR test and Sanger sequencing was 90.6%. In 78.9% of the discordant samples, the EGFR PCR test result was confirmed by a sensitive deep sequencing assay. This retrospective study demonstrates the clinical utility of the EGFR PCR test in the accurate selection of patients for anti-EGFR TKI therapy. The EGFR PCR test demonstrated improved performance relative to Sanger sequencing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089518PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934888PMC
December 2014

Evaluation of EGFR protein expression by immunohistochemistry using H-score and the magnification rule: re-analysis of the SATURN study.

Lung Cancer 2013 Nov 7;82(2):231-7. Epub 2013 Aug 7.

Service de Pneumologie, Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse III (Paul Sabatier), Toulouse 31059, France. Electronic address:

Introduction: The phase III SATURN study demonstrated that first-line maintenance erlotinib extended progression-free survival (PFS) and overall survival (OS) versus placebo in patients with advanced non-small cell lung cancer (NSCLC). Analysis of epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) found no significant interaction between EGFR IHC status and PFS (p = 0.63) or OS (p = 0.52). The FLEX study of first-line cetuximab plus chemotherapy demonstrated that EGFR IHC expression was predictive of improved OS with cetuximab when assessed by H-score with a magnification rule. This novel method was used to reassess samples from SATURN.

Methods: The H-score method assigned a score of 0-300 to each patient, based on the percentage of cells stained at different intensities viewed at various magnifications. The discriminatory threshold was set at 200, per the FLEX study, and existing samples were re-read and classed as low (H-score < 200) or high (≥200) EGFR expression. PFS and OS were re-analyzed based on these new classifications.

Results: In the overall and EGFR wild-type populations, erlotinib provided a consistent survival benefit versus placebo. Hazard ratios (HRs) in the overall population were similar between EGFR IHC-positive and -negative patients for median PFS (HR 0.68 [95% confidence interval (CI) 0.53-0.86] and 0.76 [95% CI 0.62-0.93], respectively) and OS (HR 0.80 [95% CI 0.62-1.05] and 0.80 [95% CI 0.64-1.01] for IHC-positive and IHC-negative, respectively). In the EGFR wild-type population, HRs were again similar between EGFR IHC-positive and -negative subpopulations for PFS (HR 0.69 [95% CI 0.51-0.95] and 0.84 [95% CI 0.63-1.12], respectively) and OS (HR 0.78 [95% CI 0.55-1.10] and 0.76 [95% CI 0.55-1.05], respectively).

Conclusions: These data suggest that EGFR IHC does not have value as a marker to predict erlotinib benefit in the first-line maintenance setting for advanced NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2013.07.016DOI Listing
November 2013

Quantitative chemical proteomics profiling differentiates erlotinib from gefitinib in EGFR wild-type non-small cell lung carcinoma cell lines.

Mol Cancer Ther 2013 Apr 31;12(4):520-9. Epub 2013 Jan 31.

Translational Research Sciences, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.

Although both erlotinib and gefitinib target the EGF receptor (EGFR), erlotinib is effective in patients with EGFR wild-type or mutated tumors, whereas gefitinib is only beneficial for patients with activating mutations. To determine whether these differences in clinical outcomes can be attributed to their respective protein interaction profiles, a label-free, quantitative chemical proteomics study was conducted. Using this method, 24 proteins were highlighted in the binding profiles of erlotinib and gefitinib. Unlike gefinitib, erlotinib displaced the ternary complex formed by integrin-linked kinase (ILK), α-parvin, and PINCH (IPP). The docking of erlotinib in the three-dimensional structure of ILK showed that erlotinib has the ability to bind to the ATP-binding site, whereas gefitinib is unlikely to bind with high affinity. As the IPP complex has been shown to be involved in epithelial-to-mesenchymal transition (EMT) and erlotinib sensitivity has been correlated with EMT status, we used a cellular model of inducible transition and observed that erlotinib prevented EMT in a more efficient way than gefitinib by acting on E-cadherin expression as well as on IPP levels. A retrospective analysis of the MERIT trial indicated that, besides a high level of E-cadherin, a low level of ILK could be linked to clinical benefit with erlotinib. In conclusion, we propose that, in an EGFR wild-type context, erlotinib may have a complementary mode of action by inhibiting IPP complex activities, resulting in the slowing down of the metastatic process of epithelial tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-0880DOI Listing
April 2013

Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.

Lancet Oncol 2012 Mar 24;13(3):300-8. Epub 2012 Jan 24.

Institute of Oncology Ion Chiricuta, Cluj-Napoca, Romania.

Background: Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC.

Methods: TITAN was an international, randomised multicentre, open-label, phase 3 study that was done at 77 sites in 24 countries. Chemotherapy-naive patients with locally advanced, recurrent, or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy, after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN. Enrolled patients were randomly assigned (1:1) by a minimisation method to ensure balanced stratification, to receive erlotinib 150 mg/day or chemotherapy (standard docetaxel or pemetrexed regimens, at the treating investigators' discretion), until unacceptable toxicity, disease progression, or death. Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, smoking history, and region of residence. The primary endpoint was overall survival in the intention-to-treat population. TITAN was halted prematurely because of slow recruitment. This study is registered with ClinicalTrials.gov, number NCT00556322.

Findings: Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27·9 months (IQR 11·0-36·0) in the erlotinib group and 24·8 months (12·1-41·6) in the chemotherapy group. Median overall survival was 5·3 months (95% CI 4·0-6·0) with erlotinib and 5·5 months (4·4-7·1) with chemotherapy (hazard ratio [HR] 0·96, 95% CI 0·78-1·19; log-rank p=0·73). The adverse-event profile of each group was in line with previous studies. Rash (98/196 [50%] in the erlotinib group vs 10/213 [5%] in the chemotherapy group for all grades; nine [5%] vs none for grade 3 or 4) and diarrhoea (36 [18%] vs four [2%] for all grades; five [3%] vs none for grade 3 or 4) were the most common treatment-related adverse events with erlotinib, whereas alopecia (none vs 23 [11%] for all grades; none vs one [<1%] for grade 3/4) was the most common treatment-related adverse event with chemotherapy.

Interpretation: No significant differences in efficacy were noted between patients treated with erlotinib and those treated with docetaxel or pemetrexed. Since the toxicity profiles of erlotinib and chemotherapy differ, second-line treatment decisions should take into account patient preference and specific toxicity risk profiles.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(11)70385-0DOI Listing
March 2012

Tissue sampling in lung cancer: a review in light of the MERIT experience.

Lung Cancer 2011 Oct 11;74(1):1-6. Epub 2011 Jun 11.

Grosshansdorf Hospital, Grosshansdorf, Wöhrendamm 80, 22927 Grosshansdorf, Germany.

Lung cancer continues to present an enormous global burden of morbidity and mortality, despite an increasing therapeutic armamentarium of chemotherapy and targeted agents. Recent research efforts have been directed towards identifying predictors of response to treatment, in order to facilitate the selection of patients likely to obtain the greatest benefit from specific therapeutic interventions, with the ultimate goal of providing customized therapy. A strong scientific basis exists for the use of markers to identify patients who are most likely to respond to biological and targeted therapies, based on characteristics such as tumour genotype and histology. Biomarkers have the potential to aid in patient stratification (risk assessment), treatment-response identification (surrogate markers), or differential diagnosis (identifying individuals who are likely to respond well to specific therapies). Numerous trials have demonstrated correlations between molecular biomarkers and the outcome of treatment with targeted therapies such as epidermal growth factor inhibitor tyrosine-kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). The recently completed MarkER Identification Trial (MERIT) found some evidence of a link between the molecular profile of a tumour and the clinical response to erlotinib in patients with relapsed NSCLC. However, MERIT also highlighted the difficulties in obtaining adequate samples for the various procedures involved in genetic analyses in clinical trials. Routine clinical practice brings its own challenges relating to biopsy techniques and tissue availability and this has implications for the application of molecular analyses in treatment decision-making. Applying the lessons learned from tissue sampling and molecular testing in MERIT and other major NSCLC trials will be essential in paving the way for the routine use of biomarker analyses in clinical practice.
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http://dx.doi.org/10.1016/j.lungcan.2011.05.002DOI Listing
October 2011

Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.

Lancet Oncol 2010 Jun 20;11(6):521-9. Epub 2010 May 20.

Department of Medical Oncology, Ospedale Civile di Livorno, Livorno, Italy.

Background: First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy.

Methods: Between December, 2005, and May, 2008, 1949 patients were included in the run-in phase (four cycles of platinum-based chemotherapy). At the end of the run-in phase, 889 patients who did not have progressive disease were entered into the main study, and were randomly allocated using a 1:1 adaptive randomisation method through a third-party interactive voice response system to receive erlotinib (150 mg/day; n=438) or placebo (n=451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analysable patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein overexpression, as determined by immunohistochemistry. This study is registered with www.ClinicalTrials.gov, number NCT00556712.

Findings: 884 patients were analysable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11.4 months for the erlotinib group and 11.5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR 0.71, 95% CI 0.62-0.82; p<0.0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12.3 weeks in the erlotinib group vs 11.1 weeks in the placebo group; HR 0.69, 0.58-0.82; p<0.0001). The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs none of 445 in the placebo group) and diarrhoea (seven [2%] of 443 patients vs none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [<1%] with placebo).

Interpretation: Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo. First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy.

Funding: F Hoffmann-La Roche Ltd.
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http://dx.doi.org/10.1016/S1470-2045(10)70112-1DOI Listing
June 2010

Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis.

J Cell Mol Med 2010 Jan 8;14(1-2):51-69. Epub 2009 Dec 8.

Hospital Universitario Virgen del Rocío, Seville, Spain.

Non-small-cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) is a distinct subgroup of NSCLCs that is particularly responsive to EGFR tyrosine-kinase inhibitors (TKIs). A weighted pooled analysis of available studies was performed to evaluate clinical outcome in patients with EGFR-mutated NSCLC who were treated with chemotherapy or EGFR TKIs. Median progression-free survival (PFS) times were pooled from prospective or retrospective studies that evaluated chemotherapy or single-agent EGFR TKIs (erlotinib or gefitinib) in patients with NSCLC and EGFR mutations. Among the studies identified for inclusion in the analysis, 12 evaluated erlotinib (365 patients), 39 evaluated gefitinib (1069 patients) and 9 evaluated chemotherapy (375 patients). Across all studies, the most common EGFR mutations were deletions in exon 19 and the L858R substitution in exon 21. In the weighted pooled analysis, the overall median PFS was 13.2 months with erlotinib, 9.8 months with gefitinib and 5.9 months with chemotherapy. Using a two-sided permutation, erlotinib and gefitinib produced a longer median PFS versus chemotherapy, both individually (P= 0.000 and P= 0.002, respectively) and as a combined group (EGFR TKI versus chemotherapy, P= 0.000). EGFR TKIs appear to be the most effective treatment for patients with advanced EGFR-mutant NSCLC. Ongoing prospective trials comparing the efficacy of first-line chemotherapy and EGFR TKIs in EGFR-mutant disease should provide further insight into the most appropriate way to treat this specific group of patients.
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http://dx.doi.org/10.1111/j.1582-4934.2009.00991.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837609PMC
January 2010

Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034.

J Clin Oncol 2009 Mar 9;27(8):1268-74. Epub 2009 Feb 9.

Neuro-Oncology Unit, Daniel den Hoed Cancer Center, PO Box 5201, 3008AE Rotterdam, the Netherlands.

Purpose: Approximately 50% of glioblastomas (GBMs) are characterized by overexpression of the epidermal growth factor receptor (EGFR) and EGFR gene amplification. In approximately 25% of instances, constitutively activated EGFR mutants are present. These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM.

Patients And Methods: In a randomized, controlled, phase II trial, 110 patients with progressive GBM after prior radiotherapy were randomly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine (BCNU). The primary end point was 6-month progression-free survival (PFS). Tumor specimens obtained at first surgery were investigated for EGFR expression; EGFRvIII mutants; EGFR amplification; EGFR mutations in exons 18, 19, and 21; and pAkt. These results were correlated with outcome. Pharmacokinetic analysis was part of the study. RESULTS; Treatment was well tolerated in general; skin toxicity was the most frequent adverse effect of erlotinib. The 6-month PFS rate in the erlotinib arm was 11.4% (95% CI, 4.6% to 21.5%), and it was 24% in the control arm. Of all explored biomarkers, only low pAkt expression appeared to be of borderline significance to an improved outcome. None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS. The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance, but pharmacokinetic findings were not related to outcome.

Conclusion: Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified.
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http://dx.doi.org/10.1200/JCO.2008.17.5984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667826PMC
March 2009

A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy.

Clin Cancer Res 2008 Jun;14(12):3867-74

Medical Oncology Service and Pathology Service, Vall d'Hebron University Hospital, Barcelona, Spain.

Purpose: To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non-small cell lung cancer patients refractory to platinum-based chemotherapy.

Experimental Design: Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks' treatment.

Results: Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease >/=12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR (P = 0.002), p-MAPK (P = 0.001), and Ki-67 (P = 0.025) levels were significantly reduced after 6 weeks' treatment. Apoptosis was significantly increased in patients with clinical benefit (P = 0.029), and may be a marker of clinical benefit.

Conclusion: In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-5186DOI Listing
June 2008