Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): An international, multicentre, single-arm, phase 2 trial
Abstract
Background The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation.Methods BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028.Findings Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4-14·2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis.Interpretation The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations.Funding European Thoracic Oncology Platform, Roche.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the phase II BELIEF study, a substantial benefit was noted from erlotinib plus bevacizumab in the subgroup of patients with pretreatment T790M.
“In the phase II study BELIEF, a substantial benefit was noted from the combination of erlotinib plus bevacizumab in the subgroup of patients with pretreatment T790M [97].”
Cites
Rosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Garcia-Gomez, R., Pallares, C., Sanchez, J. M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70393-x · Cited by 5,489 · see citing works
Self-citationScreening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C., Majem, M., Lopez-Vivanco, G., Isla, D., Provencio, M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0904554 · Cited by 2,373 · see citing works
Self-citationDetection of Mutations in <i>EGFR</i> in Circulating Lung-Cancer Cells
Maheswaran, S., Sequist, L. V., Nagrath, S., Ulkus, L., Brannigan, B., Collura, C. V., Inserra, E., Diederichs, S., Iafrate, A. J., Bell, D. W., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0800668 · Cited by 1,617 · see citing works
Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways
Sordella, R., Bell, D. W., Haber, D. A., & Settleman, J. E. (2004) · Science · doi:10.1126/science.1101637 · Cited by 1,605 · see citing works
Barlési, F., Mazières, J., Merlio, J., Debieuvre, D., Mosser, J., Léna, H., Ouafik, L., Besse, B., Rouquette, I., Westeel, V., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00004-0 · Cited by 1,003 · see citing works
Hata, A. N., Niederst, M. J., Archibald, H. L., Gomez-Caraballo, M., Siddiqui, F. M., Mulvey, H. E., Maruvka, Y. E., Ji, F., Bhang, H.-E. C., Krishnamurthy Radhakrishna, V., et al. (2016) · Nature Medicine · doi:10.1038/nm.4040 · Cited by 985 · see citing works
Seto, T., Kato, T., Nishio, M., Goto, K., Atagi, S., Hosomi, Y., Yamamoto, N., Hida, T., Maemondo, M., Nakagawa, K., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70381-x · Cited by 750 · see citing works
Gao, S. P., Mark, K. G., Leslie, K., Pao, W., Motoi, N., Gerald, W. L., Travis, W. D., Bornmann, W., Veach, D., Clarkson, B., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31871 · Cited by 666 · see citing works
Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway
Wei, L.-H., Kuo, M.-L., Chen, C.-A., Chou, C.-H., Lai, K.-B., Lee, C.-N., & Hsieh, C.-Y. (2003) · Oncogene · doi:10.1038/sj.onc.1206226 · Cited by 536 · see citing works
Su, K.-Y., Chen, H.-Y., Li, K.-C., Kuo, M.-L., Yang, J. C.-H., Chan, W.-K., Ho, B.-C., Chang, G.-C., Shih, J.-Y., Yu, S.-L., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.38.3224 · Cited by 499 · see citing works
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Bivona, T. G., Hieronymus, H., Parker, J., Chang, K., Taron, M., Rosell, R., Moonsamy, P., Dahlman, K., Miller, V. A., Costa, C., et al. (2011) · Nature · doi:10.1038/nature09870 · Cited by 396 · see citing works
Self-citationHerbst, R. S., Ansari, R., Bustin, F., Flynn, P. J., Hart, L. L., Otterson, G. A., Vlahovic, G., Soh, C.-H., O’Connor, P. G., & Hainsworth, J. D. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60545-x · Cited by 389 · see citing works
Naumov, G. N., Nilsson, M. B., Cascone, T., Briggs, A., Straume, O., Akslen, L. A., Lifshits, E., Byers, L. A., Xu, L., Wu, H.-K., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2904 · Cited by 348 · see citing works
Rosell, R., Molina, M. A., Costa, C., Simonetti, S., Gimenez-Capitan, A., Bertran-Alamillo, J., Mayo, C., Moran, T., Mendez, P., Cardenal, F., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2158 · Cited by 304 · see citing works
Self-citationAssociation of<i>EGFR</i>L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial
Karachaliou, N., Mayo-de las Casas, C., Queralt, C., de Aguirre, I., Melloni, B., Cardenal, F., Garcia-Gomez, R., Massuti, B., Sánchez, J. M., Porta, R., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2014.257 · Cited by 239 · see citing works
Self-citationCosta, C., Molina, M. A., Drozdowskyj, A., Giménez-Capitán, A., Bertran-Alamillo, J., Karachaliou, N., Gervais, R., Massuti, B., Wei, J., Moran, T., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2233 · Cited by 229 · see citing works
Self-citationAstrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling
Lee, S.-G., Su, Z.-Z., Emdad, L., Sarkar, D., Franke, T. F., & Fisher, P. B. (2007) · Oncogene · doi:10.1038/sj.onc.1210713 · Cited by 217 · see citing works
Watanabe, M., Kawaguchi, T., Isa, S.-I., Ando, M., Tamiya, A., Kubo, A., Saka, H., Takeo, S., Adachi, H., Tagawa, T., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2151 · Cited by 216 · see citing works
Yu, H. A., Arcila, M. E., Hellmann, M. D., Kris, M. G., Ladanyi, M., & Riely, G. J. (2014) · Annals of Oncology · doi:10.1093/annonc/mdt573 · Cited by 206 · see citing works
Godin-Heymann, N., Bryant, I., Rivera, M. N., Ulkus, L., Bell, D. W., Riese, D. J., Settleman, J. E., & Haber, D. A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4625 · Cited by 154 · see citing works
Large-scale screening for somatic mutations in lung cancer
Rosell, R., & Karachaliou, N. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01125-3 · Cited by 140 · see citing works
Self-citationIchihara, E., Hotta, K., Nogami, N., Kuyama, S., Kishino, D., Fujii, M., Kozuki, T., Tabata, M., Harada, D., Chikamori, K., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000434 · Cited by 104 · see citing works
Fan, W., Tang, Z., Yin, L., Morrison, B., Hafez-Khayyata, S., Fu, P., Huang, H., Bagai, R. K., Jiang, S., Kresak, A. M., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2668 · Cited by 83 · see citing works
High T790M detection rate in TKI-naive NSCLC with EGFR sensitive mutation: truth or artifact?
Ye, X., Zhu, Z.-Z., Zhong, L., Lu, Y., Sun, Y., Yin, X., Yang, Z., Zhu, G., & Ji, Q. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e31829f691f · Cited by 79 · see citing works
Rexer, B. N., Ghosh, R., Narasanna, A., Estrada, M. V., Chakrabarty, A., Song, Y., Engelman, J. A., & Arteaga, C. L. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1038 · Cited by 73 · see citing works
Ichihara, E., Ohashi, K., Takigawa, N., Osawa, M., Ogino, A., Tanimoto, M., & Kiura, K. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4204 · Cited by 67 · see citing works
Chen, L.-Y., Molina-Vila, M. A., Ruan, S.-Y., Su, K.-Y., Liao, W.-Y., Yu, K.-L., Ho, C.-C., Shih, J.-Y., Yu, C.-J., Yang, J. C.-H., et al. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.01.019 · Cited by 67 · see citing works
Self-citationNinomiya, T., Takigawa, N., Ichihara, E., Ochi, N., Murakami, T., Honda, Y., Kubo, T., Minami, D., Kudo, K., Tanimoto, M., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0885 · Cited by 64 · see citing works
Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression
Cagnoni, G., & Tamagnone, L. (2013) · Oncogene · doi:10.1038/onc.2013.474 · Cited by 51 · see citing works
Gautschi, O. P., Mach, N., Rothschild, S. I., Li, Q., Stahel, R. A., Zippelius, A., Cathomas, R. L., Früh, M., Betticher, D. C., Peters, S., et al. (2015) · Clinical Lung Cancer · doi:10.1016/j.cllc.2015.02.007 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Russo, A., Franchina, T., Ricciardi, G., Battaglia, A., Picciotto, M., & Adamo, V. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061431 · Cited by 110 · see citing works
Girard, N. (2018) · Future Oncology · doi:10.2217/fon-2017-0636 · Cited by 103 · see citing works
Leduc, C., Merlio, J. P., Besse, B., Blons, H., Debieuvre, D., Bringuier, P. P., Monnet, I., Rouquette, I., Fraboulet-Moreau, S., Lemoine, A., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx404 · Cited by 96 · see citing works
- Authors
- Rosell, R., Dafni, U., Felip, E., Curioni-Fontecedro, A., Gautschi, O., Peters, S., Massutí, B., Palmero, R., Aix, S. P., Carcereny, E., Früh, M., Pless, M., Popat, S., Kotsakis, A., Cuffe, S., Bidoli, P., Favaretto, A., Froesch, P., Reguart, N., Puente, J., Coate, L., Barlesi, F., Rauch, D., Thomas, M., Camps, C., Gómez-Codina, J., Majem, M., Porta, R., Shah, R., Hanrahan, E., Kammler, R., Ruepp, B., Rabaglio, M., Kassapian, M., Karachaliou, N., Tam, R., Shames, D. S., Molina-Vila, M. A., & Stahel, R. A.
- Affiliations
- Institut Català d'Oncologia (ES)
- National and Kapodistrian University of Athens (GR)
- Vall d'Hebron Hospital Universitari (ES)
- Luzerner Kantonsspital (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- Hospital General Universitario de Alicante Doctor Balmis (ES)
- Hospital Universitario 12 De Octubre (ES)
- Kantonsspital St. Gallen (CH)
- Kantonsspital Winterthur (CH)
- Royal Marsden Hospital (GB)
- University Hospital of Heraklion (GR)
- Cancer Trials Ireland (IE)
- Azienda Ospedaliera San Gerardo (IT)
- Istituto Oncologico Veneto (IT)
- Swiss Group For Clinical Cancer Research (CH)
- Hospital Clínico San Carlos (ES)
- University Hospital Limerick (IE)
- University Hospital Heidelberg (DE)
- Hospital de Sant Pau (ES)
- Universitat de Girona (ES)
- Maidstone Hospital (GB)
- European Thoracic Oncology Platform (CZ)
- Frontier Science Foundation-Hellas (GR)
- Instituto Oncológico Dr. Rosell (ES)
- Genentech (US)
- University Hospital Zurich (CH)
- Corresponding author
- Stahel, Rolf A
- ORCID
- Rosell, Rafael
- Dafni, Urania
- Felip, Enriqueta
- Gautschi, Oliver
- Peters, Solange
- Massutí, Bartomeu
- Carcereny, Enric
- Früh, Martin
- Pless, Miklos
- Popat, Sanjay
- Kotsakis, Athanasios
- Favaretto, Adolfo
- Froesch, Patrizia
- Puente, Javier
- Coate, Linda
- Thomas, Michael
- Camps, Carlos
- Majem, Margarita
- Shah, Riyaz
- Kammler, Roswitha
- Ruepp, Barbara
- Rabaglio, Manuela
- Karachaliou, Niki
- Shames, David S
- Stahel, Rolf A
- Venue
- The Lancet Respiratory Medicine
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 5
- Issue
- 5
- Pages
- 435-444
- ISSN
- 2213-2600 (ISSN-L)
- OpenAlex
- W2606131767
- Cited by
- 182
- References
- 30
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 9 · 2022: 18 · 2021: 27 · 2020: 22 · 2019: 31 · 2018: 40 · 2017: 25
- FWCI
- 26.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Respiratory Medicine (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- BORIS (University Library Bern) (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Health Research Board (ICORG-2016-1)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- erlotinib, bevacizumab, non-small cell lung cancer, EGFR mutation, T790M mutation, EGFR tyrosine kinase inhibitor resistance, lung adenocarcinoma, exon 19 deletion, L858R mutation, combination therapy, progression-free survival, treatment-naive patients, biomarker stratification
- MeSH terms
- Bevacizumab, Erlotinib Hydrochloride, Proof of Concept Study, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, International Cooperation, Lung Neoplasms, Male, Middle Aged, Mutation, Disease-Free Survival, Intention to Treat Analysis, Response Evaluation Criteria in Solid Tumors, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
