Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review.
<h4>Background</h4>In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatme...
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| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0121211&type=printable |
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| author | Katsuyuki Hotta Yuka Kato Natasha Leighl Nagio Takigawa Rabab Mohamed Gaafar Hiroe Kayatani Taizo Hirata Kadoaki Ohashi Toshio Kubo Masahiro Tabata Mitsune Tanimoto Katsuyuki Kiura |
| author_facet | Katsuyuki Hotta Yuka Kato Natasha Leighl Nagio Takigawa Rabab Mohamed Gaafar Hiroe Kayatani Taizo Hirata Kadoaki Ohashi Toshio Kubo Masahiro Tabata Mitsune Tanimoto Katsuyuki Kiura |
| author_sort | Katsuyuki Hotta |
| collection | DOAJ |
| description | <h4>Background</h4>In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed.<h4>Methods and findings</h4>We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%.<h4>Conclusion</h4>The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial. |
| format | Article |
| id | doaj-art-284a0d7b79d247f297344308e9ec838e |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-284a0d7b79d247f297344308e9ec838e2025-08-20T03:17:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e012121110.1371/journal.pone.0121211Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review.Katsuyuki HottaYuka KatoNatasha LeighlNagio TakigawaRabab Mohamed GaafarHiroe KayataniTaizo HirataKadoaki OhashiToshio KuboMasahiro TabataMitsune TanimotoKatsuyuki Kiura<h4>Background</h4>In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed.<h4>Methods and findings</h4>We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%.<h4>Conclusion</h4>The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0121211&type=printable |
| spellingShingle | Katsuyuki Hotta Yuka Kato Natasha Leighl Nagio Takigawa Rabab Mohamed Gaafar Hiroe Kayatani Taizo Hirata Kadoaki Ohashi Toshio Kubo Masahiro Tabata Mitsune Tanimoto Katsuyuki Kiura Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. PLoS ONE |
| title | Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. |
| title_full | Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. |
| title_fullStr | Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. |
| title_full_unstemmed | Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. |
| title_short | Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. |
| title_sort | magnitude of the benefit of progression free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non small cell lung cancer systematic review |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0121211&type=printable |
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