Anthony Chalmers University of Glasgow

Transcription

1 Radiotherapy-drug combinations for NSCLC: current and potential UK collaborative initiatives Anthony Chalmers University of Glasgow UK SABR Consortium 25th November 2016

2 Increase tumour control and cure rates by combining molecular targeted agents with precision radiotherapy

3 Surviving fraction 66 Gy in Gy in 20 SABR Radiation dose per (Gy)

4 Why combine drugs with SABR? Improve local control

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6 Why combine drugs with SABR? Improve local control Large tumours? Adverse dosimetry? Adverse biology?? Systemic effects Only if SABR will enhance systemic effects Immunomodulators Bystander effects? Reduce normal tissue toxicity

7 Which drugs to combine with RT and/or SABR? Improve local control Systemic effects Reduce normal tissue toxicity

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10 Late responding normal tissues Base Excision Repair PARP ATM, ATR Chk1, Chk2 Tumour G 1 S G 2 M Nonhomologous end-joining ATM Homologous recombination

11 s u rv iv in g fra c tio n E 2 C S C E 2 C S C P A R P i E 2 C S C A T R i E 2 C S C A T M i E 2 C S C C h k 1 i E2 primary GBM stem cell cultures Ahmed SU, Carruthers R et al Cancer Research G y Calu6 lung adenocarcinoma subcutaneous xenografts Andy Ryan, Oxford unpublished data

12 Immune checkpoint inhibitors Courtesy: Inge Verbrugge Larson et al. Nat Rev Cancer 2015

13 Why have so few radiotherapy-drug combinations been approved?

14 Commercial gain from drug Additional factors: Slow trial set-up and recruitment Fear of exacerbating normal tissue toxicities Lack of consensus over RT standard of care Uncertainties over route to registration and regulatory approval processes Commercial gain from drug-rt combination

15 What can we do about it?

16 CTRad: Clinical and Translational Radiotherapy Research Working Group CTRad Executive Group WS1 (science base) WS2 (phase I/II) WS3 (phase III/ methodology) WS4 (new technology, physics, QA) Consumers RaDCom Biomarker Support Network Preclinical QA group RADCAS Advanced RT Trials proposals meetings RTTQA Protons Molecular RT Database development Academic work force development

17 Strength in numbers: 82 members Diversity, knowledge and expertise to make a difference

18 CTRad: How to get involved 1. Pass the limbo test 2. Perform a solo dance routine

19 Strength in numbers: 82 members Diversity, knowledge and expertise to make a difference

20 CTRad: Other ways to get involved 1. Clinical trials methodology workshops Annual event jointly run with RCR 2. Trials sandpit days For junior clinicians and investigators Convert a study idea into a research proposal 3. Proposals guidance meetings Twice yearly events (June, November) Obtain expert feedback and advice on clinical trial proposals Prepare for funding applications 58 clinical trials successfully funded to date

21 CTRad: Clinical and Translational Radiotherapy Research Working Group CTRad Executive Group WS1 (science base) WS2 (phase I/II) WS3 (phase III/ methodology) WS4 (new technology, physics, QA) Consumers RaDCom Biomarker Support Network Preclinical QA group RADCAS Advanced RT Trials proposals meetings RTTQA Protons Molecular RT Database development Academic work force development

22 Radiotherapy-Drug Combinations Consortium: RaDCom Providing preclinical evidence for early phase clinical trials Collaborative network of labs delivering quality preclinical efficacy data Partnership with industry, CRUK and other funding bodies Key point of contact for industrial partners seeking appropriate expertise Chair: Kaye Williams Co-chairs Workstream 1 Nicola Curtin (Newcastle) Susan Short* (Leeds) Co-chairs Workstream 2 Richard Adams* (Cardiff) Ricky Sharma* (Oxford) Theme Leads DNA damage response: Anthony Chalmers* (Glasgow) Signalling pathways: Anderson Ryan (Oxford) Tumour microenvironment: Kaye Williams (Manchester) Tumour metabolism: JSC Prioritisation Immunotherapy: Biological therapies: Patient representative: Ian Stratford (Manchester) Tim Illidge* (Manchester) Susan Short* (Leeds) Helen Bulbeck * clinician

23 Working with Industry EXPERTISE AND ADVICE Industry often have limited internal expertise in radiation therapy Require advice on normal tissue toxicity and experimental design ACTIVE COLLABORATIONS PRELIMINARY DISCUSSIONS Encouraging and facilitating evaluation of radiotherapy-drug combinations earlier in drug development pipeline

24 Quantifying normal tissue toxicity Radiation induced lung fibrosis Oesophagitis Skin erythema Andy Ryan, Oxford; unpublished data

25 CTRad: Clinical and Translational Radiotherapy Research Working Group CTRad Executive Group WS1 (science base) WS2 (phase I/II) WS3 (phase III/ methodology) WS4 (new technology, physics, QA) Consumers RaDCom Biomarker Support Network Preclinical QA group RADCAS SABR Trials proposals meetings RTTQA Protons Molecular RT Database development Academic work force development

26 Sharma et al, Nature Reviews Clinical Oncology, 2016

27 PRIMING: Pembrolizumab with SBRT for Advanced NSCLC Primary Endpoint: PI: Dr McDonald To establish MTD and RP2D that can be safely combined with ablative 3# thoracic SBRT. Week Run-in Phase of Pembrolizumab RT Phase: 54 Gy in 3 # over 1 week Post-RT Phase: Pembrolizumab D1 100 mg / D2 200 mg q3w 200mg q3w Pembrolizumab

28 MESO-PRIME: Pembrolizumab with SBRT for Malignant Mesothelioma Primary Endpoint: PI: Dr McDonald & Dr Harrow To establish MTD and RP2D that can be safely combined with ablative 5# thoracic SBRT. Week Run-in Phase of Pembrolizumab RT Phase: 55 Gy in 5 # over 2 week Post-RT Phase: Pembrolizumab D1 100 mg / D2 200 mg q3w 200mg q3w Pembrolizumab

29 PARIS: Pembrolizumab with Radical Radiotherapy for LA NSCLC Primary Endpoint: PI: Prof Faivre-Finn To establish MTD and RP2D that can be safely combined with conventional radical RT following chemotherapy. Week Platinum Chemotherapy Phase Run-in Phase of Pembrolizumab RT Phase: Gy in # w Post-RT Phase: Pembrolizumab D mg / D1 200 mg q3w 200mg q3w Pembrolizumab

30 SABR PARP- A phase I study of rucaparib and stereotactic ablative body radiotherapy (SABR) to the lung in the treatment of oligometastatic disease Improve local control Particularly if defects in BRCA, FA or HR pathways Protect normal lung tissue Reduction in normal lung tissue toxicity Improve distant control Enhanced bystander/ abscopal effects Extensive in vitro and in vivo data showing radiosensitising effects of PARPi Phase 1 trials ongoing combining PARPi & conventional external beam XRT

31 Separate phase I trials testing single RT-drug combinations are highly inefficient

32 Multiple overlapping and/or competing proposals submitted to CTRad for RT-drug combinations in non-small cell lung cancer Lack of consensus over radiotherapy backbone regime Fragmented approach Two day workshop in Glasgow, February 2016 Clinicians, statisticians, scientists, consumers, pharma

33 Phase I multi-arm drug dose escalation study of DNA repair inhibitors in combination with radical RT for stage III NSCLC Trial Development Group Lead Scientist (Lung CSG SLWG) Clinical Oncology CI Medical Oncology CI Clinical Trials Unit Lead Statistician Drug A Gy CI Drug B Gy CI Drug C Gy CI Drug D Gy CI Gy control arm CI s Gerry Hanna (Belfast), Alistair Greystoke (Newcastle) Leeds Clinical Trials Unit, Sarah Brown lead statistician

34 Stage III study design Patients fit for radical RT but not concomitant chemort (sequential chemo permitted but not required) Performance status 0-2 RT dose in 30# determined by normal tissue constraints Initially, drugs from AZ DDRi portfolio (olaparib, Wee1i, ATRi, ATMi); additional drugs could be added Initally, patients randomly allocated to each arm If biomarkers become available, enrich relevant arm(s) with biomarker+ patients

35 Phase II multi-arm study of immunomodulatory agents in combination with RT for stage IV NSCLC Trial Development Group Lead Scientist (Lung CSG SLWG) Clinical Oncology CI Medical Oncology CI Standard chemotherapy Clinical Trials Unit Lead Statistician Palliative RT indicated Palliative RT not indicated Drug A + RT Drug B + RT Drug C + RT RT alone Drug X alone Drug X + RT Drug Y alone Drug Y + RT CI s Fiona McDonald (RMH), Martin Forster (UCLH) ICR Clinical Trials Unit, Emma Hall lead statistician

36 Stage IV study design Patients with stage IV NSCLC (include stage III patients ineligible for radical treatment?) Standard chemotherapy followed by stratification based on indication for palliative RT Immunomodulatory drugs; phase I RT combination data will be available for several; emeging agents can be added Opportunity to compare different RT dose and fractionation schedules

37 Summary Compelling rationale to combine new drugs with RT Different issues but still valid for SABR Historically, pharma reluctant to support RT-drug combinations CTRad and UK clinical oncology community have become world leaders in this area Pre-clinical expertise and organisation RaDCom Route to Registration Consensus Guidelines Strong relationships with some pharma companies, supported by Combinations Alliance Consortium based approach to optimise efficiency, increase engagement and access, maximise scientific and clinical outputs