Summary Background mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 ...study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. Methods In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov , number NCT00876395. Findings Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4–46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55–17·91) with everolimus versus 14·49 months (12·29–17·08) with placebo (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95–24·08) versus 13·08 months (10·05–16·56) with placebo (hazard ratio 0·66, 95% CI 0·48–0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 67% of 472 patients in the everolimus group vs 77 32% of 238 patients in the placebo group), diarrhoea (267 57% vs 111 47% patients), and alopecia (221 47% vs 125 53%). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 25% vs 35 15%), stomatitis (59 13% vs three 1%), anaemia (46 10% vs six 3%) and diarrhoea (43 9% vs 10 4%) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. Interpretation Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial. Funding Novartis Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Early tumor shrinkage (ETS) is associated with long-term outcome in patients with chemorefractory metastatic colorectal cancer (mCRC) receiving cetuximab. This association was investigated in the ...first-line setting in the randomized CRYSTAL and OPUS mCRC trials, after controlling for KRAS tumor mutation status.
Radiologic assessments at week 8 were used to calculate the relative change in the sum of the longest diameters of the target lesions. Time-dependent receiver operating characteristics provided Cτ-indices (time-dependent c-index). Cox regression models and subpopulation treatment effect pattern plot analysis investigated associations between ETS (radiologic tumor size decrease at week 8) and survival and progression-free survival (PFS).
In both trials, in patients with KRAS wild-type mCRC, Cτ values for PFS and survival were higher (P < .001) in those receiving chemotherapy plus cetuximab versus chemotherapy alone, indicating a stronger predictive value of ETS for long-term outcome in these patients. In the CRYSTAL and OPUS trials, respectively, the cutoff value of ETS ≥ 20% (v < 20%) identified patients with KRAS wild-type mCRC receiving chemotherapy plus cetuximab with longer PFS (medians 14.1 v 7.3 months, hazard ratio HR = 0.32; P < .001, and medians 11.9 v 5.7 months, HR = 0.22; P < .001) and survival (medians 30.0 v 18.6 months, HR = 0.53; P < .001 and medians 26.0 v 15.7 months, HR = 0.43; P = .006).
ETS was significantly associated with long-term outcome in patients with KRAS wild-type mCRC treated first-line with chemotherapy plus cetuximab. Validation in prospective trials is required to assess the value of this on-treatment marker in the clinical decision-making process.
Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome ...measure.
Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.
A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.
A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.
Purpose: Recently, several prognostic gene expression signatures have been identified; however, their performance has never been evaluated
according to the previously described molecular subtypes ...based on the estrogen receptor (ER) and human epidermal growth factor
receptor 2 (HER2), and their biological meaning has remained unclear. Here we aimed to perform a comprehensive meta-analysis
integrating both clinicopathologic and gene expression data, focusing on the main molecular subtypes.
Experimental Design: We developed gene expression modules related to key biological processes in breast cancer such as tumor invasion, immune
response, angiogenesis, apoptosis, proliferation, and ER and HER2 signaling, and then analyzed these modules together with
clinical variables and several prognostic signatures on publicly available microarray studies (>2,100 patients).
Results: Multivariate analysis showed that in the ER+/HER2− subgroup, only the proliferation module and the histologic grade were
significantly associated with clinical outcome. In the ER−/HER2− subgroup, only the immune response module was associated
with prognosis, whereas in the HER2+ tumors, the tumor invasion and immune response modules displayed significant association
with survival. Proliferation was identified as the most important component of several prognostic signatures, and their performance
was limited to the ER+/HER2− subgroup.
Conclusions: Although proliferation is the strongest parameter predicting clinical outcome in the ER+/HER2− subtype and the common denominator
of most prognostic gene signatures, immune response and tumor invasion seem to be the main molecular processes associated
with prognosis in the ER−/HER2− and HER2+ subgroups, respectively. These findings may help to define new clinicogenomic models
and to identify new therapeutic strategies in the specific molecular subgroups.
Since May 2013, researchers have been able to request access to deidentified patient-level data from GlaxoSmithKline–sponsored clinical trials, subject to oversight by an independent review panel. ...The initiative has been a productive first step in transparency.
There has been considerable interest of late in increasing the transparency of clinical trials, including increasing access to the raw data from trials sponsored by the pharmaceutical industry.
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Since May 2013, investigators have been able to request access to deidentified patient-level data from clinical trials sponsored by GlaxoSmithKline,
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subject to review and oversight by an independent review panel (https://clinicalstudydatarequest.com/Default.aspx). As the members of this panel, we now have more than 12 months of experience with this initiative — and can report that it has been a productive and successful first step.
The system was launched on May 7, 2013, and . . .
Biomarkers and surrogate end points have great potential for use in clinical oncology, but their statistical validation presents major challenges, and few biomarkers have been robustly confirmed. ...Provisional supportive data for prognostic biomarkers, which predict the likely outcome independently of treatment, is possible through small retrospective studies, but it has proved more difficult to achieve robust multi-site validation. Predictive biomarkers, which predict the likely response of patients to specific treatments, require more extensive data for validation, specifically large randomized clinical trials and meta-analysis. Surrogate end points are even more challenging to validate, and require data demonstrating both that the surrogate is prognostic for the true end point independently of treatment, and that the effect of treatment on the surrogate reliably predicts its effect on the true end point. In this Review, we discuss the nature of prognostic and predictive biomarkers and surrogate end points, and examine the statistical techniques and designs required for their validation. In cases where the statistical requirements for validation cannot be rigorously achieved, the biological plausibility of an end point or surrogate might support its adoption. No consensus yet exists on processes or standards for pragmatic evaluation and adoption of biomarkers and surrogate end points in the absence of robust statistical validation.
Making clinical trial data widely available is ethically imperative and scientifically justified, but the experience with clinicalstudydatarequest.com suggests that we need to find ways to improve ...the use and output of data-sharing projects before broadening the effort.
The past few years have seen considerable interest in the sharing of patient-level data from clinical trials. There is a clear and logical “ethical and scientific imperative”
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for doing so, to permit activities ranging from verification of the original analysis to testing of new hypotheses. This interest has resulted in many publications and meetings, attention from the Institute of Medicine,
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proposed changes in journals’ policies,
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and enormous effort from pharmaceutical sponsors and other groups to provide access to patient-level data.
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It is critical that we learn from these early experiences as we move forward.
Beginning in May 2013, GlaxoSmithKline made . . .
Time-to-event end points are the most frequent primary end points in phase III oncology trials, both in the adjuvant and advanced settings. The evaluation of these end points is important to inform ...clinical practice. However, although different measures can be used to describe the effect of treatment on these end points, we believe that any treatment benefit in a given trial is best reported using various absolute and relative measures. Our goal is to help clinicians understand the strengths and limitations of the traditional and novel measures used to denote the effect of treatment in randomized trials. Although none of these measures can reliably predict the outcome of individual patients, some measures could be added to the commonly used hazard ratio to provide a more patient-oriented assessment of treatment benefit. In particular, the difference of mean survival times quantifies the average survival benefit for a patient receiving a new treatment compared with a patient treated with standard of care, whereas the net benefit quantifies the probability of a patient receiving the new treatment to live longer by at least m months (for any number of months m of interest) than a patient receiving the standard treatment. We encourage statisticians and clinical scientists to include various measures of treatment benefit in the reports of phase III trials, acknowledging that different clinical situations may call for different measures of treatment effect. By using the various available measures, we may better inform ourselves and communicate results to our patients.
With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor-based assessments as the primary ...efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise. We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials. The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy. The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines. A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point. PPS represents nearly two thirds of patient survival after on-trial disease progression.
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