How to address tumour heterogeneity in next generation oncology trials

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1 How to address tumour heterogeneity in next generation oncology trials Cihangir YANDIM, PhD Research Associate in Cancer Therapeutics and Clinical Sciences Dr. Cihangir Yandim - CTIP 2016, Hamburg 1

2 Founded in 1909, one of the leading cancer research centres in the world and repeatedly ranked as the top research institute in the United Kingdom. The very first discovery regarding the link between DNA damage and cancer has been made (1952 and 1964) First lines of chemotherapy drugs discovered: busulphan, chlorambucil and melphalan (1950s). And involved in the development of Carboplatin. BRCA2 and RAS oncogenes discovered at the ICR. Appx. 100 million pounds profit per year from the drugs discovered at the ICR. At the moment, many compounds are under development and 2 trials in set up and 18 trials under recruitment and more than 20 trials in follow-up period. New focus on targeted therapies. Dr. Cihangir Yandim - CTIP 2016, Hamburg 2

3 Repeatedly ranked within top 3 universities in Europe together with Cambridge and Oxford. Penicillin was discovered by Alexander Fleming in Number one university in setting up collaborations with industry and has a huge impact on translational medicine. Division of Experimental medicine and Clinical Sciences Centre lead the development of new drugs and targeted therapies. Around 20 clinical trials are running at the moment. Dr. Cihangir Yandim - CTIP 2016, Hamburg 3

4 Cancer is a disease of DNA Ciriello et al. 2013, Nat Genetics Dr. Cihangir Yandim - CTIP 2016, Hamburg 4

5 Tumour Heterogeneity Dick et al. 2009, Nature Dr. Cihangir Yandim - CTIP 2016, Hamburg 5

6 Clonality of Tumour Evolution Alizadeh et al., 2015, Nat Medicine Dr. Cihangir Yandim - CTIP 2016, Hamburg 6

7 Levels of Tumour Heterogeneity Inter-tumour variation Fox and Loeb, 2014, Nature Dr. Cihangir Yandim - CTIP 2016, Hamburg 7

8 Current biomarker tests used in oncology for decision making Bedard et al. 2013, Nature Dr. Cihangir Yandim - CTIP 2016, Hamburg 8

9 Targeted Therapies in Oncology Dr. Cihangir Yandim - CTIP 2016, Hamburg Whadwa et al. 2013, 9 Nat Clin Onc Rev

10 Strategies to measure tumour heterogeneity Next generation sequencing from various parts of the tumour or metastases. Sequencing of circulating tumour DNA Proteomics and Phospho-proteomics SNP / mutation analysis arrays Fluoroscence In Situ Hybridization Main challenges Limited amount of tissue/biopsy samples : Sampling bias Formalin and paraffin fixations (to preserve histology) interfere with sequencing. The cost of genome wide techniques Verification of mutation may delay the result but the treatment needs to be done immediately. Targeting critical hubs / oncogene addiction Dr. Cihangir Yandim - CTIP 2016, Hamburg 10

11 Timing of the targeted treatment Most oncologists prefer general cytotoxic drugs (e.g. cisplatin) as first line treatment Tumour evolution still takes place during the first line of treatments. Targeted therapies are less likely to work after tumour has evolved up to a certain level. The revolutionary ABL inhibitor imatinib (Gleevec ) failed to be effective until it had been moved to the front line of the therapy. It is usually difficult to get ethics approval and also attract patients to an experimental drug at early stage cancer. Real time monitoring of the tumuors are needed for treatment regimen, however, multiple biopsies are not feasible. ctdna could be an important tool. Dr. Cihangir Yandim - CTIP 2016, Hamburg 11

12 Clinical Trial Design Frameworks addressing Tumour Heterogeneity Bedard et al. 2013, Nature Dr. Cihangir Yandim - CTIP 2016, Hamburg 12

13 Next Generation Clinical Trial Design Frameworks BATTLE and I-SPY trials Ideal to assist in identifying the best molecular subset for a drug, if this is previously unknown, in phase I-IIb trials Adaptive statistical design to confirm early efficacy signals in later stages of the trial Requires very high numbers of patients for adequate power from start to FDA approval of a drug Difficult to accrue for follow up large phase III trials if biomarker is rare. Catenacci. 2010, Mol Oncology Dr. Cihangir Yandim - CTIP 2016, Hamburg 13

14 Next Generation Clinical Trial Design Frameworks FOCUS-4 trial Umbrella biomarker enrichment that addresses inter-patient heterogeneity with efficient molecular profiling and treatment assignment Ideal if biomarker-drug association is already established Assumes drug is only useful for a certain biomarker, or at least best suited for that biomarker Can test defined biomarker subsets within a cancer with a drug (or drug combination) thought best matched to that biomarker cohort in an organized global approach for that specific tumor type Catenacci. 2010, Mol Oncology Dr. Cihangir Yandim - CTIP 2016, Hamburg Very high number of patients required 14

15 Next Generation Clinical Trial Design Frameworks NCI-MATCH and Novartis Signature trials Can test defined biomarker subsets in any tumor type with a drug (or drug combination) thought best matched to that biomarker cohort in an organized global approach for that specific tumor type Each biomarker cohort is run as its own phase IIa or b trial (compartmentalized) with a separate principal investigator There is not a treatment algorithm and therefore tumors with multiple mutations are randomly selected to one of many possible biomarker groups High patient numbers Catenacci. 2010, Mol Oncology Dr. Cihangir Yandim - CTIP 2016, Hamburg 15

16 Next Generation Clinical Trial Design Frameworks PANGEA-BBP The only biomarker-driven trial to address intra-patient tumor heterogeneity over time due to resistance in sequential fashion Sequential nature of BBP allows for less confounding of post-protocol therapies for overall survival endpoint, and also less selection bias at second or third line setting A randomized phase IIb can evaluate overall survival of a personalized holistic approach compared to standard therapy Those positive phase IIb trials can move to the phase III setting to test the Holistic approach OR positive cohorts within the phase IIb can spin-off to their own phase III Multiple biopsies are required, a potential deterrent for some patients/physicians FDA approval of such designs are still uncertain. Catenacci. 2010, Mol Oncology Dr. Cihangir Yandim - CTIP 2016, Hamburg 16

17 PANGEA: Personalised Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma Catenacci et al. 2014, Mol Oncology Dr. Cihangir Yandim - CTIP 2016, Hamburg 17

18 CONCLUSIONS and FUTURE DIRECTIONS Tumour heterogeneity brings an even further complex level to personalised medicine. Thorough understanding of molecular genetics and oncology as well as statistics is needed. A paradigm shift from one-size-fits-all to next generation designs and diagnostics. Better methods should be delivered in terms of multiple biopsies and regulatory bodies should recognise this. Drug screens on cultured patient tumour cells could be implemented but this highly complex approach has not been recognised well by the regulatory bodies. There has to be better mechanisms to learn more from negative results, such as increased biomarker testing even in simpler designs and these should be published. Dr. Cihangir Yandim - CTIP 2016, Hamburg 18

19 THANK YOU Cihangir YANDIM, PhD Dr. Cihangir Yandim - CTIP 2016, Hamburg 19