Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer

Michiels, Stefan; Pugliano, Lina; Marguet, Sophie; Grun, Daniel; Barinoff, Jana; Cameron, David; Cobleigh, Melody A.; Leo, Angelo Di; Johnston, S.; Gasparini, G; Kaufman, Bella; Marty, M; Nekljudova, Valentina; Paluch‐Shimon, Shani; Penault–Llorca, F; Slamon, Dennis J.; Vogel, Charles L.; Minckwitz, Gϋnter von; Buyse, Marc; Piccart, Martine

doi:10.1093/annonc/mdw132

Cited by 44 publications

(33 citation statements)

References 40 publications

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“…Of note, the prognostic effect of TILs seems to be stronger for overall survival than for progression-free survival, although progression-free survival has been reported to be only a modest surrogate for overall survival in HER2-positive metastatic disease. 22 This effect has been previously reported in the context of pertuzumab treatment, with similar differences in progression-free survival and overall survival effects seen in the PHEREXA study. 23 Although the reasons remain unclear, we have also noted the difference between disease-free survival and overall survival previously in the early-stage setting.…”

Section: Discussionsupporting

confidence: 80%

Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study

Luen

Salgado

Fox

et al. 2017

The Lancet Oncology

243

177

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Summary Background High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel. Methods CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer. We assessed the quantity of stromal TILs in prospectively collected tumour samples and investigated their association with progression-free survival, overall survival, clinicopathological characteristics, and pertuzumab treatment. We estimated hazard ratios (HR) and 95% CIs with multivariate Cox regression models fitting stromal TILs as a continuous variable (per 10% increment). The CLEOPATRA trial is registered with ClinicalTrials.gov, number NCT00567190. Findings Tumour samples from 678 (84%) of 808 participants were evaluable for TILs, including 519 (77%) archival samples, 155 (23%) freshly obtained samples (collected 45 days or fewer before randomisation), and four samples of unknown archival status. Median follow-up was 50 months (IQR 41–54) for progression-free survival and 51 months (IQR 46–57) for overall survival. 519 progression-free survival events occurred and 358 patients died. The median TIL value was 10% (IQR 5–30). Freshly obtained tumour samples had significantly lower TIL values than did archival samples (10·00% [95% CI 5·00–20·00] vs 15·00% [5·00–35·00]; p=0·00036). We detected no significant association between TIL values and progression-free survival (adjusted HR 0·95, 95% CI 0·90–1·00, p=0·063). However, for overall survival, each 10% increase in stromal TILs was significantly associated with longer overall survival (adjusted HR 0·89, 95% CI 0·83–0·96, p=0·0014). The treatment effect of pertuzumab did not differ significantly by stromal TIL value for either progression-free survival (pinteraction=0·23) or overall survival (pinteraction=0·21). Interpretation In patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo, higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting. Future clinical studies in this cancer subtype should consider TILs as a stratification factor and investigate whether therapies that can augment immunity could potentially further improve survival.

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Section: Discussionsupporting

confidence: 80%

Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study

Luen

Salgado

Fox

et al. 2017

The Lancet Oncology

243

177

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“…Thus, PFS may be a reasonable surrogate endpoint for OS. However, in trials of HER2-targeted agents in HER2-positive metastatic breast cancer, PFS moderately correlates with OS at the individual level, suggesting that PFS does not completely substitute for OS in this setting [25]. Kasahara et al verified that PPS has more impact on OS than PFS in recurrent small cell lung cancer patients [15].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of apatinib on overall survival is mediated by prolonged progression-free survival in advanced gastric cancer patients

et al. 2016

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Apatinib is reported to significantly improve the overall survival (OS) of patients with advanced gastric cancer who have previously failed second-line chemotherapy. However, it is not well understood whether apatinib acts by improving progression or by prolonging post-progression survival. Here, based on phase III clinical trial data, the mediating effect of apatinib on patient overall survival was systematically quantified, through progression-free survival (PFS), post-progression survival (PPS), and the disease control rate (DCR). PFS was the primary mediator of the association between apatinib treatment and OS, with an indirect-effect mean survival time ratio of 1.63 (95%CI 1.35-1.97), which mediated 93.5% of the treatment effect. The DCR was also a significant mediator among secondary efficacy endpoints, and had an indirect-effect mean survival time ratio of 1.47 (95%CI 1.20-1.79, 50.9% mediated). Both primary and other targets of the DCR had similar results. The results indicated that apatinib treatment prolongs progression-free survival rather than post-progression survival, and in turn, leads to improved overall survival. Additionally, our study highlights the value of mediation analysis in clinical trials in providing additional information to build upon traditional primary analysis.

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“…In general, PFS has not been statistically validated for surrogacy of OS yet in breast cancer studies [2,4]. Reported results regarding association between Hazard ratio of PFS and OS in the metastatic breast cancer studies are mixed: For example, Hackshaw et al [7] found a correlation of 0.87; Burzykowski et al [8] reported correlation of 0.48; Michiels et al [9] reported R 2 (i.e. proportion of the variance in the true endpoint that is explained by the surrogate endpoint) as 0.51.…”

Section: Introductionmentioning

confidence: 99%

Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies

Kundu

Acharyya

2017

Contemporary Clinical Trials

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Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer

Cited by 44 publications

References 40 publications

Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study

Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study

Therapeutic effect of apatinib on overall survival is mediated by prolonged progression-free survival in advanced gastric cancer patients

Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies

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