【medical-news】Lancet Oncol：无进展生存期能评价转移性黑色素瘤患者的临床获益
发布于 2014-02-12 · 浏览 1030 · IP 上海上海
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Surrogate endpoints for overall survival inmetastatic melanoma: a meta-analysis of randomised controlled trials
KeithT Flaherty, Michael Hennig, Sandra J Lee, Paolo A Ascierto, Reinhard Dummer,Alexander M M Eggermont, Axel Hauschild, Richard Keff ord, John M Kirkwood,Georgina V Long, Paul Lorigan, Andreas Mackensen, Grant McArthur, Steven O’Day, Poulam M Patel, Caroline Robert,Dirk Schadendorf
Summary
Background Recent phase 3 trials have shown an overall survivalbenefit in metastatic melanoma. We aimed to assess whether progression-freesurvival (PFS) could be regarded as a reliable surrogate for overall survivalthrough a meta-analysis of randomised trials.
Methods We systematically reviewed randomised trialscomparing treatment regimens in metastatic melanoma that included dacarbazineas the control arm, and which reported both PFS and overall survival with astandard hazard ratio (HR). We correlated HRs for overall survival and PFS,weighted by sample size or by precision of the HR estimate, assuming fixed andrandom effects. We did sensitivity analyses according to presence of crossover,trial size, and dacarbazine dose.
Findings After screening 1649 reports and meeting abstractspublished before Sept 8, 2013, we identified 12 eligible randomised trials thatenrolled 4416 patients with metastatic melanoma. Irrespective of weightingstrategy, we noted a strong correlation between the treatment effects for PFSand overall survival, which seemed independent of treatment type. Pearsoncorrelation coefficients were 0·71 (95% CI 0·29–0·90) with arandom-effects assumption, 0·85 (0·59–0·95) with a fixed-effectsassumption, and 0·89 (0·68–0·97) with sample-size weighting. For ninetrials without crossover, the correlation coefficient was 0·96 (0·81–0·99), which decreased to 0·93 (0·74–0·98) when two additionaltrials with less than 50% crossover were included. Inclusion of maturefollow-up data after at least 50%
crossover (in vemurafenib and dabrafenib phase 3trials) weakened the PFS to overall survival correlation (0·55, 0·03–0·84). Inclusion of trials with no or littlecrossover with the random-eff ects assumption yielded a conservative statementof the PFS to overall survival correlation of 0·85 (0·51–0·96).
Interpretation PFS can be regarded as a robust surrogate foroverall survival in dacarbazine-controlled randomized trials of metastaticmelanoma; we postulate that this association will hold as treatment standardsevolve and are adopted as the control arm in future trials.
Introduction
Substantialadvances have been made in the treatment of metastatic melanoma on the basis ofinsights gained into the unique molecular biology of this disease and the mechanismsby which immune effector cells are silenced. The identification of activating BRAF mutations in about 50% of advanced melanomas in 2002 was a watershed eventthat pointed the specialty toward a molecularly targeted treatment approach.1In addition, identification of CTLA4 and PD1 as negative regulators of effectorT-cell function that could be countered with monoclonal antibodies has made theprospect of reversal of immune tolerance a tractable therapeutic approach.
Two BRAFinhibitors, vemurafenib and dabrafenib, and a MEK inhibitor, trametinib, haveall proven superior to dacarbazine—the only cytotoxic chemotherapy approved
by the USFood and Drug Administration for melanoma—in randomised phase 3 trials.4–6 Ipilimumabwas superior to an investigational vaccine in patients refractory to chemotherapyand to dacarbazine alone when combined with dacarbazine in the first-linemetastatic setting,2,7 and nab-paclitaxelimproved progression-free survival (PFS) compared with dacarbazine.8 Numerous randomizedtrials that have compared investigational therapies with dacarbazine in recentyears have failed to show a signifi cant improvement in overall survival.
As melanomaresearchers continue to develop new treatment approaches to extend the effectsof molecularly targeted treatments and immunotherapies, the next generation ofinvestigational melanoma therapies will undergo definitive, randomised trialsin an environment in which patients will have access to therapies with known effectson overall survival. Furthermore, targeted therapy or immunotherapy controlarms are increasingly incorporated into such trials. Provided that patientsremain on protocol-assigned therapy until disease progression, PFS is notconfounded by post-protocol therapy in the same way that overall survival canbe. If a strong correlation between treatment eff ects for PFS and overallsurvival can be established from analysis of previous randomised trials inmetastatic melanoma, a significant improvement in progression-free survivalnoted in a future trial could be regarded as defi nitive evidence of clinicalbenefit. Establishment of such surrogacy would permit the next generation ofexperimental therapies in melanoma to be judged on their individual merits anddiminish the risk that a potentially effective therapy is deemed ineffective becauseoverall survival endpoints are affected by postprotocol therapy with other effective drugs. Similar analyses have been done for metastatic breast cancer and colorectalcancer. In both cases, the observed correlations between PFS and overallsurvival were regarded as sufficiently robust to support PFS as a surrogateendpoint in definitive phase 3 trials.
Whether improved PFScan be regarded as a predictor of improved overall survival in metastaticmelanoma needs to be understood. In several cancer types, including melanoma,PFS has been adopted as the primary endpoint in definitive phase 3 trialswithout supporting evidence in those cancers that an effect on PFS is areliable predictor of overall survival. Therefore, we aimed to assesscorrelation between PFS and overall survival in randomised, dacarbazine-controlledtrials of treatments for metastatic melanoma.
KeithT Flaherty, Michael Hennig, Sandra J Lee, Paolo A Ascierto, Reinhard Dummer,Alexander M M Eggermont, Axel Hauschild, Richard Keff ord, John M Kirkwood,Georgina V Long, Paul Lorigan, Andreas Mackensen, Grant McArthur, Steven O’Day, Poulam M Patel, Caroline Robert,Dirk Schadendorf
Summary
Background Recent phase 3 trials have shown an overall survivalbenefit in metastatic melanoma. We aimed to assess whether progression-freesurvival (PFS) could be regarded as a reliable surrogate for overall survivalthrough a meta-analysis of randomised trials.
Methods We systematically reviewed randomised trialscomparing treatment regimens in metastatic melanoma that included dacarbazineas the control arm, and which reported both PFS and overall survival with astandard hazard ratio (HR). We correlated HRs for overall survival and PFS,weighted by sample size or by precision of the HR estimate, assuming fixed andrandom effects. We did sensitivity analyses according to presence of crossover,trial size, and dacarbazine dose.
Findings After screening 1649 reports and meeting abstractspublished before Sept 8, 2013, we identified 12 eligible randomised trials thatenrolled 4416 patients with metastatic melanoma. Irrespective of weightingstrategy, we noted a strong correlation between the treatment effects for PFSand overall survival, which seemed independent of treatment type. Pearsoncorrelation coefficients were 0·71 (95% CI 0·29–0·90) with arandom-effects assumption, 0·85 (0·59–0·95) with a fixed-effectsassumption, and 0·89 (0·68–0·97) with sample-size weighting. For ninetrials without crossover, the correlation coefficient was 0·96 (0·81–0·99), which decreased to 0·93 (0·74–0·98) when two additionaltrials with less than 50% crossover were included. Inclusion of maturefollow-up data after at least 50%
crossover (in vemurafenib and dabrafenib phase 3trials) weakened the PFS to overall survival correlation (0·55, 0·03–0·84). Inclusion of trials with no or littlecrossover with the random-eff ects assumption yielded a conservative statementof the PFS to overall survival correlation of 0·85 (0·51–0·96).
Interpretation PFS can be regarded as a robust surrogate foroverall survival in dacarbazine-controlled randomized trials of metastaticmelanoma; we postulate that this association will hold as treatment standardsevolve and are adopted as the control arm in future trials.
Introduction
Substantialadvances have been made in the treatment of metastatic melanoma on the basis ofinsights gained into the unique molecular biology of this disease and the mechanismsby which immune effector cells are silenced. The identification of activating BRAF mutations in about 50% of advanced melanomas in 2002 was a watershed eventthat pointed the specialty toward a molecularly targeted treatment approach.1In addition, identification of CTLA4 and PD1 as negative regulators of effectorT-cell function that could be countered with monoclonal antibodies has made theprospect of reversal of immune tolerance a tractable therapeutic approach.
Two BRAFinhibitors, vemurafenib and dabrafenib, and a MEK inhibitor, trametinib, haveall proven superior to dacarbazine—the only cytotoxic chemotherapy approved
by the USFood and Drug Administration for melanoma—in randomised phase 3 trials.4–6 Ipilimumabwas superior to an investigational vaccine in patients refractory to chemotherapyand to dacarbazine alone when combined with dacarbazine in the first-linemetastatic setting,2,7 and nab-paclitaxelimproved progression-free survival (PFS) compared with dacarbazine.8 Numerous randomizedtrials that have compared investigational therapies with dacarbazine in recentyears have failed to show a signifi cant improvement in overall survival.
As melanomaresearchers continue to develop new treatment approaches to extend the effectsof molecularly targeted treatments and immunotherapies, the next generation ofinvestigational melanoma therapies will undergo definitive, randomised trialsin an environment in which patients will have access to therapies with known effectson overall survival. Furthermore, targeted therapy or immunotherapy controlarms are increasingly incorporated into such trials. Provided that patientsremain on protocol-assigned therapy until disease progression, PFS is notconfounded by post-protocol therapy in the same way that overall survival canbe. If a strong correlation between treatment eff ects for PFS and overallsurvival can be established from analysis of previous randomised trials inmetastatic melanoma, a significant improvement in progression-free survivalnoted in a future trial could be regarded as defi nitive evidence of clinicalbenefit. Establishment of such surrogacy would permit the next generation ofexperimental therapies in melanoma to be judged on their individual merits anddiminish the risk that a potentially effective therapy is deemed ineffective becauseoverall survival endpoints are affected by postprotocol therapy with other effective drugs. Similar analyses have been done for metastatic breast cancer and colorectalcancer. In both cases, the observed correlations between PFS and overallsurvival were regarded as sufficiently robust to support PFS as a surrogateendpoint in definitive phase 3 trials.
Whether improved PFScan be regarded as a predictor of improved overall survival in metastaticmelanoma needs to be understood. In several cancer types, including melanoma,PFS has been adopted as the primary endpoint in definitive phase 3 trialswithout supporting evidence in those cancers that an effect on PFS is areliable predictor of overall survival. Therefore, we aimed to assesscorrelation between PFS and overall survival in randomised, dacarbazine-controlledtrials of treatments for metastatic melanoma.
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