Comment
4 5
6
Hill SJ, Clark AP, Silver DP, et al. BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 2014; 34: 3828–42. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015; 33: 13–21. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014; 15: 747–56.
7
8
Tutt A, Ellis P, Kilburn L, et al. The TNT trial: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRACA 1/2 breast cancer (CRUK/07/012). San Antonio Breast Cancer Symposium, San Antonio, TX USA, Dec 9–14, 2014; abstr S3-01. Seidman AD, Berry D, Cirrincione C, et al. Randomised phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642–29.
Although the worldwide incidence of mesothelioma is increasing because of asbestos exposure,1 there are few treatment options in development for this lethal disease. Surgery is no longer regarded as a standard treatment because the disease is already systemic at onset, the role of radiotherapy is at best controversial, and systemic treatment plateaued in 2002 with the approval of pemetrexed.2 The negative results of the VANTAGE-014 study by Lee Krug and colleagues3—a phase 3 trial comparing vorinostat, a histonedeacetylase inhibitor, with placebo, with median overall survival as the primary objective—adds to this dreary scenario. The authors should be commended for the effort of launching a large trial in patients with this rare disease and the courage of attempting to fill a clearly unmet medical need with a new therapeutic strategy targeting the epigenome. At the time VANTAGE-014 was conceived, research on histone deacetylase inhibitors was very topical.4 The trial rationale was based on in-vitro data that showed: increased apoptosis in mesothelioma cell lines after treatment with histone deacetylase inhibitors (including vorinostat), either alone or in combination with chemotherapy; growth inhibition in a mouse xenograft model of a human epithelioid mesothelioma line after a combination of valproic acid and chemotherapy, but not either treatment alone; and in a phase 1 trial, four (30%) of 13 patients with mesothelioma that received vorinostat had a stabilisation of their disease lasting more than 4 months, including two unconfirmed partial responses.5 Was this evidence enough to jump-start a phase 3 trial? With the wisdom of hindsight, probably not; however, VANTAGE-014 raises awareness about the relevance and predictivity of preclinical outcomes, which is seldom addressed. www.thelancet.com/oncology Vol 16 April 2015
Although the association between surrogate and survival endpoints is under continuous scrutiny in the clinical setting, the preclinical process draws conclusions from experimental readouts, which might be difficult to translate into clinically relevant outcomes in patient trials, such as an increase in apoptosis or growth inhibition.6 The VANTAGE-014 trial epitomises the well known, but often forgotten, fact that many promising translational findings turn out to be false positives in the clinic.7 VANTAGE-014 is a pharmaceutically sponsored trial. In the past decade, accelerated clinical development was not an uncommon practice for research and development groups across the industry. The outcome has been a rise in attrition, halving the already slim 10% chance of successfully bringing a new drug to market, with the weakest link in the development chain in phase 2, in which around 50% of failures are due to lack of efficacy.8 The VANTAGE-014 study was well designed, and included three planned interim analysis for futility: why then did it take so long to realise that vorinostat was inactive in mesothelioma? Probable causes include a combination of poor accrual and incorrect clinical assumptions. The study took more than twice the planned time to accrue 661 patients from 90 centres, demonstrating the difficulties of recruiting patients with rare diseases, especially when the comparator is a placebo randomly assigned in a 1:1 ratio in a disease in which second-line chemotherapy is widely used (albeit, admittedly, without evidence-based benefit).9 The first futility boundary, which would have stopped the trial at 50 patients, had a 90% power to rule out at least 10% of patients achieving a response, or if at least 50% of patients had not progressed by 18 weeks. There was no difference in median overall survival for vorinostat (30·7 weeks [95% CI 26·7–36·1])
Centre Jean Perrin/ISM/Science Photo Library
A lesson from vorinostat in pleural mesothelioma
Published Online March 20, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70084-7 See Articles page 447
359
Comment
versus placebo (27·1 weeks [23·1–31·9]; hazard ratio 0·98 [95% CI 0·83–1·17]; p=0·86). Progression-free survival was significantly longer in the vorinostat group than in the placebo group (HR 0·75, 95% CI 0·63–0·88; p
4 5
6
Hill SJ, Clark AP, Silver DP, et al. BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 2014; 34: 3828–42. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015; 33: 13–21. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014; 15: 747–56.
7
8
Tutt A, Ellis P, Kilburn L, et al. The TNT trial: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRACA 1/2 breast cancer (CRUK/07/012). San Antonio Breast Cancer Symposium, San Antonio, TX USA, Dec 9–14, 2014; abstr S3-01. Seidman AD, Berry D, Cirrincione C, et al. Randomised phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642–29.
Although the worldwide incidence of mesothelioma is increasing because of asbestos exposure,1 there are few treatment options in development for this lethal disease. Surgery is no longer regarded as a standard treatment because the disease is already systemic at onset, the role of radiotherapy is at best controversial, and systemic treatment plateaued in 2002 with the approval of pemetrexed.2 The negative results of the VANTAGE-014 study by Lee Krug and colleagues3—a phase 3 trial comparing vorinostat, a histonedeacetylase inhibitor, with placebo, with median overall survival as the primary objective—adds to this dreary scenario. The authors should be commended for the effort of launching a large trial in patients with this rare disease and the courage of attempting to fill a clearly unmet medical need with a new therapeutic strategy targeting the epigenome. At the time VANTAGE-014 was conceived, research on histone deacetylase inhibitors was very topical.4 The trial rationale was based on in-vitro data that showed: increased apoptosis in mesothelioma cell lines after treatment with histone deacetylase inhibitors (including vorinostat), either alone or in combination with chemotherapy; growth inhibition in a mouse xenograft model of a human epithelioid mesothelioma line after a combination of valproic acid and chemotherapy, but not either treatment alone; and in a phase 1 trial, four (30%) of 13 patients with mesothelioma that received vorinostat had a stabilisation of their disease lasting more than 4 months, including two unconfirmed partial responses.5 Was this evidence enough to jump-start a phase 3 trial? With the wisdom of hindsight, probably not; however, VANTAGE-014 raises awareness about the relevance and predictivity of preclinical outcomes, which is seldom addressed. www.thelancet.com/oncology Vol 16 April 2015
Although the association between surrogate and survival endpoints is under continuous scrutiny in the clinical setting, the preclinical process draws conclusions from experimental readouts, which might be difficult to translate into clinically relevant outcomes in patient trials, such as an increase in apoptosis or growth inhibition.6 The VANTAGE-014 trial epitomises the well known, but often forgotten, fact that many promising translational findings turn out to be false positives in the clinic.7 VANTAGE-014 is a pharmaceutically sponsored trial. In the past decade, accelerated clinical development was not an uncommon practice for research and development groups across the industry. The outcome has been a rise in attrition, halving the already slim 10% chance of successfully bringing a new drug to market, with the weakest link in the development chain in phase 2, in which around 50% of failures are due to lack of efficacy.8 The VANTAGE-014 study was well designed, and included three planned interim analysis for futility: why then did it take so long to realise that vorinostat was inactive in mesothelioma? Probable causes include a combination of poor accrual and incorrect clinical assumptions. The study took more than twice the planned time to accrue 661 patients from 90 centres, demonstrating the difficulties of recruiting patients with rare diseases, especially when the comparator is a placebo randomly assigned in a 1:1 ratio in a disease in which second-line chemotherapy is widely used (albeit, admittedly, without evidence-based benefit).9 The first futility boundary, which would have stopped the trial at 50 patients, had a 90% power to rule out at least 10% of patients achieving a response, or if at least 50% of patients had not progressed by 18 weeks. There was no difference in median overall survival for vorinostat (30·7 weeks [95% CI 26·7–36·1])
Centre Jean Perrin/ISM/Science Photo Library
A lesson from vorinostat in pleural mesothelioma
Published Online March 20, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70084-7 See Articles page 447
359
Comment
versus placebo (27·1 weeks [23·1–31·9]; hazard ratio 0·98 [95% CI 0·83–1·17]; p=0·86). Progression-free survival was significantly longer in the vorinostat group than in the placebo group (HR 0·75, 95% CI 0·63–0·88; p
