early-phase data to ensure target inhibition to clinical effect, selection of appropriate endpoints for randomised phase 2 and phase 3 studies, and identification of rigorous stopping rules that would protect patients from undue exposure to toxicity and ineffective treatments. However, the true lesson to learn from this study is that biomedical research cannot ignore the best interests of the patients, nor should the developmental pathways for drugs be rushed inappropriately.
Francesco Boccardo
Department of Medicine, University of Genoa Medical School and Academic Unit of Medical Oncology, IRCCS AOU San Martino- National Cancer Research Institute, Genoa 16132, Italy fboccardo@unige.it
I declare no competing interests.
1 Petrylak DP, Vogelzang NJ, Budnik N, et al. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (MAINSAIL): a randomised, double- blind, placebo-controlled phase 3 trial. Lancet Oncol 2015; published online Feb 17. http://dx.doi.org/10.1016/S1470-2045(15)70025-2.
2 Antonarakis ES, Eisenberger MA. Phase III trials with docetaxel-based combinations for metastatic castration-resistant prostate cancer: time to learn from past experiences. J Clin Oncol 2013; 31: 1709-12.
3 Aragon-Ching JB, Madan RA, Dahut WL. Angiogenesis inhibition in prostate cancer: current uses and future promises. J Oncol 2010; 2010: 361836.
4 Henry JY, Lu L, Adams M, et al. Lenalidomide enhances the anti-prostate cancer activity of docetaxel in vitro and in vivo. Prostate 2012; 72: 856-67.
5 Nabhan C, Patel A, Villines D, et al. Lenalidomide monotherapy in chemotherapy-naive, castration-resistant prostate cancer patients: final results of a phase II study. Clin Genitourin Cancer 2014; 12: 27-32.
6 Petrylak DP, Resto-Garces K, Tibyan M, et al. A phase I open-label study using lenalidomide and docetaxel in castration-resistant prostate cancer. Proc Am Soc Clin Oncol 2009; 27: abstr 5156.
7 Sanborn SL, Gibbons J, Krishnamurthi S, et al. Phase I trial of docetaxel given every 3 weeks and daily lenalidomide in patients with advanced solid tumors. Invest New Drugs 2009; 27: 453-60.
8 Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-12.
Inhibition of IGF-1R in adrenocortical carcinoma
Ism/Michel Brauner/Science Photo Library
Published Online March 18, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70130-0
See Articles page 426
Adrenocortical carcinoma is a rare tumour, with an incidence around one per million.1 With the widespread availability of CT scanning, more tumours are being detected at earlier stages in their course; however, even in the current environment the median size of an adrenocortical carcinoma is still longer than 10 cm, and more than two-thirds of patients present with locally advanced or metastatic disease. The prognosis for patients with unresectable disease remains very poor, with the best available cytotoxic chemotherapy only leading to a quarter of patients achieving a response and median overall survival of less than 15 months.2 In the present molecular and post-genomic era, extensive efforts have been made to identify driver mutations and altered signalling pathways that contribute to the development and progression of cancer. These efforts, coupled with advances in pharmacological design and testing, have enabled the development of so-called targeted or precision strategies for cancer, aimed to treat the underlying dysregulated signalling pathways in the tumour.3
Since the mid-1990s, high level overexpression of IGF-2,4 which signals predominantly through the IGF-1R, has been documented in adrenocortical carcinoma cells. Several confirmations of this finding have made the IGF-2-IGF-1R pathway an obvious target for therapy.5 In the past few years, small molecule tyrosine-kinase
inhibitors and monoclonal antibodies have been developed that target the IGF-1R tyrosine kinase, and pilot preclinical and phase 1 studies have suggested that IGF-1R inhibition might be effective for adrenocortical carcinoma.6-8
Of these drugs, linisitinib (OSI-906) is the first tyrosine-kinase inhibitor to reach phase 3 clinical studies, reported by Martin Fassnacht and colleagues9 in The Lancet Oncology. In this trial, 139 patients with advanced adrenocortical carcinoma were randomly assigned (2:1) to receive linsitinib (n=90) or placebo (n=49); overall survival was the primary endpoint. Despite a careful study design and close clinical evaluation, the study is striking for the absence of efficacy of the drug, with no difference in overall survival between the drug and placebo groups (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0.94 [95% CI 0.61-1-44]; p=0-77). Analysis of the major secondary endpoint (progression- free survival) similarly showed no effect. Other secondary endpoints, including the proportion of patients achieving disease control and duration of disease control were not statistically assessed after no change was noted in overall survival and progression-free survival. Thus, despite the hope from the adrenocortical carcinoma community that this drug would succeed, the objective evidence does not support its use at this point. As has been shown in other
cancers, the reasons why an individual patient might respond to a given tyrosine-kinase inhibitor could be pharmacogenetic.1º If it is possible to identify a (likely rare) patient subgroup that might respond to linsitinib, the use of this drug could be reassessed; however, calling linsitinib anything other than ineffective for adrenocortical carcinoma at this point seems inappropriate.
Why did the drug fail? As the authors point out, there are many possible explanations. First, the IGF-1R might not be a major driver of adrenocortical carcinoma. Overexpression of IGF-2 could represent a bystander effect caused by dysregulation of another gene at 11p15, including, p57kip2 or other transcripts at the loci.4 Second, adrenocortical carcinoma could be driven by multiple signalling abnormalities, and so inhibition of multiple pathways would be required to make treatment progress. Candidates include the Wnt-B-catenin and FGFR pathways, and combination therapy targeting these-and potentially other-pathways might be required to cause tumour regression.5 Third, the dosing strategy for linsitinib might not be the most effective; possibly higher intensity therapy during shorter time periods might be better.6
Nonetheless, despite the negative results of this trial, it is heartening to see that the infrastructure of national centres in Europe and international collaborations established for the FIRM-ACT trial2 was sufficiently intact to enable the present trial to recruit more than 130 international patients over a modest timeframe. This observation demonstrates the feasibility of further trials in adrenocortical carcinoma, and potentially in other rare cancers. Moreover, despite poor efficacy, the drug has a favourable toxicity profile, so it might still have a role in combination therapy. Finally, the present
effort was a carefully designed and well done study. Although results were negative, the information gained from these patients can hopefully be used to understand why linsitinib failed. If so, these data can then be used to develop new therapies for the next trial in adrenocortical carcinoma.
Lawrence S Kirschner Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA Lawrence.Kirschner@osumc.edu
LSK’s work is supported in part by a National Institutes of Health grant P30 CA016058 to the Ohio State University Comprehensive Cancer Center. I declare no other competing interests.
1 Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev 2014; 35: 282-326.
2 Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012; 366: 2189-97.
3 Druker BJ. Imatinib as a paradigm of targeted therapies. Adv Cancer Res 2004; 91: 1-30.
4 Gicquel C, Raffin-Sanson ML, Gaston V, et al. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 1997; 82: 2559-65.
5 Kirschner LS. The next generation of therapies for adrenocortical cancers. Trends Endocrinol Metab 2012; 23: 343-50.
6 Jones RL, Kim ES, Nava-Parada P, et al. Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 693-700.
7 Haluska P, Worden F, Olmos D, et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 2010; 65: 765-73.
8 Barlaskar FM, Spalding AC, Heaton JH, et al. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab 2009; 94: 204-12.
9 Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol 2015; published online March 18. http://dx.doi.org/10.1016/S1470-2045(15)70081-1.
10 Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385-94.
Old drugs, new tricks for triple-negative breast cancer
In The Lancet Oncology, Xi-Chun Hu and colleagues1 report results of the CBCSG006 trial, which assessed the non-inferiority and possible superiority of a cisplatin plus gemcitabine regimen versus a paclitaxel plus gemcitabine regimen in patients with metastatic triple-negative breast cancer. Cancer therapeutics can generally be divided into so-called “smart” drugs and “dumb” drugs. The perfect smart cancer drug is tumour- specific, targeted, highly effective, and has little toxicity,
whereas cytotoxic chemotherapeutics are generally the representative dumb drugs. However, evidence in triple-negative breast cancer calls this aphorism into question-chemotherapy could be targeted therapy. Even our dumb drugs might not be that dumb.
The prototype targeted breast cancer therapy is endocrine therapy plus HER2-targeted drugs. However, chemotherapy cannot yet be removed from breast cancer therapy. HER2-targeted drugs
Published Online March 18, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70108-7 See Article page 436