Academically led clinical trials: challenges and opportunities
Authors: S. Turajlic, J. Larkin, C. Swanton
Journal: Annals of Oncology (2015)

Highlights from ASCO 2015 demonstrate the impasse we face in solid tumour oncology: the compelling novel immune and targeted therapies are often associated with cost–benefit ratios significantly above the thresholds for reimbursement. This is at least in part a consequence of our incomplete understanding of the mechanisms of response and resistance to these agents. For example, ipilimumab is associated with durable clinical benefit in 15%–20% of unselected advanced melanoma patients (∼£75 000 per patient treated), and while the responses to single-agent targeted therapies such as vemurafenib are higher, they are often relatively short-lived (∼£42 000 per median PFS of 6–7 months). New trial design strategies such as basket and umbrella studies have improved upon patient selection, but have not yielded detailed biological understanding of the drug targets, nor polygenic mechanisms of resistance within or between patients. Academically led studies have the opportunity and the responsibility to prioritize biological insights as trial end points, maximising research gain, increasing patient benefit/safety and ultimately, improving cost-effectiveness. Collection of tumour material is fundamental to these aims but the timing, handling and sample analysis are of critical importance (Figure 1). Resistance to targeted therapies can be mediated by pre-existing rather than de novo alterations. High resolution tracking of cancer cells in vitro demonstrated that only 10% of resistant clones arise de novo [1.Bhang H.E. Ruddy D.A. Krishnamurthy Radhakrishna V. et al.Studying clonal dynamics in response to cancer therapy using high-complexity barcoding.Nat Med. 2015; 21: 440-448Crossref PubMed Scopus (286) Google Scholar], while mathematical models of tumour growth suggest that radiographically detectable lesions harbour at least 10 resistant sub-clones [2.Bozic I. Nowak M.A. Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers.Proc Natl Acad Sci U S A. 2014; 111: 15964-15968Crossref PubMed Scopus (70) Google Scholar]. Thus, comprehensive upfront tumour profiling could anticipate the genetic composition of such clone(s), while taking into account spatial and temporal tumour heterogeneity. Extensive sampling of metastatic sites at autopsy revealed 10 distinct PTEN alterations emerging under the selective pressure of PI(3)K&agr; inhibition [3.Juric D. Castel P. Griffith M. et al.Convergent loss of PTEN leads to clinical resistance to a PI(3)K&agr; inhibitor.Nature. 2015; 518: 240-244Crossref PubMed Scopus (374) Google Scholar], and five independent reversion events in a germline BRCA2 mutant carrier who progressed on olaparib and carboplatin [4.Patch A.M. Christie E.L. Etemadmoghadam D. et al.Whole-genome characterization of chemoresistant ovarian cancer.Nature. 2015; 521: 489-494Crossref PubMed Scopus (938) Google Scholar]. Distinct mechanisms of BRAF and EGFR inhibitor resistance were detected across multiple metastases within individual patients with melanoma [5.Kemper K. Krijgsman O. Cornelissen-Steijger P. et al.Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.EMBO Mol Med. 2015; 7: 1104-1118Crossref PubMed Scopus (104) Google Scholar] and colorectal cancer [6.Misale S. Arena S. Lamba S. et al.Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.Sci Transl Med. 2014; 6: 224ra26Crossref PubMed Scopus (219) Google Scholar], respectively. The benefit of combination strategies can be limited by excess toxicity (combined targeting of the PI3K and MAPK pathways [7.Shimizu T. Tolcher A.W. Papadopoulos K.P. et al.The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer.Clin Cancer Res. 2012; 18: 2316-2325Crossref PubMed Scopus (345) Google Scholar]), cross-resistance (BRAF and MEK inhibitors in melanoma [8.Moriceau G. Hugo W. Hong A. et al.Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.Cancer Cell. 2015; 27: 240-256Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar]) and the persistent role of intra-tumour heterogeneity (targeting of the T790M EGFR mutation in lung cancer [9.Piotrowska Z. Niederst M.J. Karlovich C.A. et al.Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor.Cancer Discov. 2015; 27: 240-256Google Scholar]). Informed by pre-clinical models, such as discontinuous dosing in BRAF-mutant melanoma [10.Das Thakur M. Salangsang F. Landman A.S. et al.Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.Nature. 2013; 494: 251-255Crossref PubMed Scopus (557) Google Scholar], academically led trials can address more finely tuned ways of managing treatment resistance. In colorectal cancer cell-free tumour DNA (cfDNA) shows pulsatile levels of mutant KRAS in response to intermittent EGFR inhibition [11.Siravegna G. Mussolin B. Buscarino M. et al.Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.Nat Med. 2015; 21: 795-801Crossref PubMed Scopus (632) Google Scholar], providing the molecular rationale for re-challenge with targeted therapy. Similar frameworks are required to prospectively evaluate alternative or sequential scheduling as well as the role of cfDNA in tracking tumour progression. PD-L1 expression, a putative predictive marker for PD1/PDL1 inhibition, is also spatially heterogeneous [12.Callea M. Albiges L. Gupta M. et al.Differential expression of PD-L1 between primary and metastatic sites in clear cell renal cell carcinoma.Cancer Immunol Res. 2015; (May 26 [epub ahead of print], doi: 10.1158/2326-6066)Crossref Scopus (223) Google Scholar]. Genomic data are a promising alternative biomarker in this area [13.Rizvi N.A. Hellmann M.D. Snyder A. et al.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science. 2015; 348: 124-128Crossref PubMed Scopus (5579) Google Scholar]. Mutational data, integrated with HLA typing, and tumour and peripheral T-cell profiling can define individual neo-antigenic repertoires. Academically led studies of immunotherapeutic agents must evaluate the ability of this approach to predict responses, inform immunotherapy/targeted combinations, and ultimately, facilitate adoptive T-cell therapy. Non-genetic causes of treatment resistance have been largely overlooked but studies that incorporate longitudinal biological sample collection and novel imaging techniques are well placed to examine tumour drug exposure (including heterogeneity of drug distribution [14.Fu F. Nowak M.A. Bonhoeffer S. Spatial heterogeneity in drug concentrations can facilitate the emergence of resistance to cancer therapy.PLoS Comput Biol. 2015; 11: e1004142Crossref PubMed Scopus (70) Google Scholar]) and individual variation in drug metabolising enzymes, receptors, and transporters. Patient-derived xenografts can provide a useful platform for investigating personalised therapy in co-clinical trials [15.Hidalgo M. Amant F. Biankin A.V. et al.Patient-derived xenograft models: an emerging platform for translational cancer research.Cancer Discov. 2014; 4: 998-1013Crossref PubMed Scopus (1085) Google Scholar], but only if robustly characterised and used in the full knowledge of their limitations (e.g. immunosuppressed host, mouse stroma and disparities in tumour burden between mouse and patient). There clearly are challenges to implementation of such complex studies but they can be overcome through close interdisciplinary work of academic/clinical consortia as illustrated by the Lung TRACERx programme [16.Jamal-Hanjani M. Hackshaw A. Ngai Y. et al.Tracking genomic cancer evolution for precision medicine: the lung TRACERx study.PLoS Biol. 2014; 12: e1001906Crossref PubMed Scopus (150) Google Scholar], the use of measures such as one-time consent [17.Dittrich C. Negrouk A. Casali P.G. Europea European Society for Medical Oncology S the European Organisation for R Treatment of Cancer B An ESMO-EORTC position paper on the EU clinical trials regulation and EMA's transparency policy: making European research more competitive again.Ann Oncol. 2015; 26: 829-832Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar], post-mortem studies and stakeholder engagement (patient and public). In summary, we argue for a change of emphasis in drug development from learning little from many patients towards biologically rich clinical studies focussed on gleaning the maximum amount of biological information that might inform drug response and resistance for every patient entered into academic trial protocols. The authors have declared no conflicts of interest.