Response and resistance in melanoma. Helen Rizos

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1 Response and resistance in melanoma Helen Rizos

2 RESISTANCE: Kinase inhibitors PI3K only 5% MAPK+PI3K 20% Unknown 38% MAPK 37% BRAF amplification 15% 111 pati ents 100 BRA F inhibitor 11 BRAF+MEK inhibitor 148 progression biopsies BRAF Splice 14% MEK1/2 8% Johnson et al Eur J Cancer Long et al Nat Commun

3 RESISTANCE: MAPK activity Transcriptome data from 37 patients 37 pre-treatment tumours 16 early on therapy tumours 55 progressing tumours Single sample gene set enrichment score represents the activity level of a gene signature in each tumour sample MAPK reactivation 57% using genomic data 93% using transcriptome data

4 RESISTANCE: MAPK activity Pre-existing MEK2 F57C PFS 107 days Lesion grew on therapy PFS 119 days Shi et al Cancer Discovery

5 MAPK activity and response MAPK signalling pre-therapy does not reflect response MAPK activity early on therapy does not reflect response

6 Redundancy of MAPK signaling Redundancy of MAPK signalling may correlate with response Mitosis is closely associated with MAPK in melanoma This association is disrupted on therapy in a subset of tumours

7 Summary Inhibition of MAPK activity is required, but is not sufficient, for response to MAPK inhibitors in melanoma Exploratory analysis suggests that MAPK may not be the sole dominant pathway in some tumours and pathway redundancy may influence degree and duration of patient response Compensation favours MAPK reactivation

8 RESPONSE to immunotherapy 76 patients with metastatic melanoma treated with anti-ctla4 and anti-pd1 NRAS Q61R 15% NRAS Q61K 12% BRAF V600K 13% Others NRAS Q61L 5% NRAS Q61H 1% C-Kit K642E 3% BRAF Non-V600E/K 5% BRAF V600E 47% Dr Jenny Lee

9 ctdna - digital droplet PCR Circulating tumour DNA can be detected in patients with cancer 1 Most circulating DNA fragments measure between base pairs with a half life of a few minutes to a few hours Little is known about the predictive utility of ctdna in patients treated with immunotherapy 2. Ascierto et al, J Clin Oncol Gray et al, Oncotarget Diaz et al, J Clin Oncol 2014

10 Longitudinal liquid biopsy samples 76 melanoma patients on immunotherapy Always undetectable Detectable undetectable Always detectable Dr Jenny Lee

11 ctdna and clinical correlates Characteristics Variable Group A Group B Group C P value ECOG no. % (75) 9 (25) 14 (64) 8 (36) 4 (22) 14 (78) < AJCC tumour stage no. % M1a or M1b M1c 14 (39) 22 (61) 4 (18) 18 (82) 2 (11) 16 (89) 0.05 Prior therapy no. (%) No Yes 16 (44) 20 (56) 11 (50) 11 (50) 3 (17) 15 (83) NS Treatment type no. (%) Single agent Combination 22 (61) 14 (39) 10 (45) 12 (55) 16 (89) 2 (11) 0.02 LDH no. (5) ULN* >ULN 29 (81) 7 (19) 14 (64) 8 (36) 9 (50) 9 (50) NS Disease volume no. (%) SPOD** 1000 SPOD > (67) 12 (33) 6 (27) 14 (73) 1 (6) 17 (94) < Brain metastases no. % No yes 27 (75) 9 (25) 17 (77) 5 (23) 14 (78) 4 (22) NS *ULN: Upper limit of normal **SPOD: sum of product of diameters, European Collaborative Oncology Group Performance Status

12 Response CR/PR SD/PD Group A (always undetectable) Group B (detectable undetectable) Group C (always detectable) 28% 23% 6% 72% 77% 94% ORR = 72% ORR = 77% ORR = 6% 12

13 Extra-cranial response CR/PR SD/PD Group A (always undetectable) Group B (detectable undetectable) Group C (always detectable) 13% 15% 6% 89% 86% 94% ORR = 89% ORR = 86% ORR = 6% 13

14 Progression free survival Group A No. at risk Progression free survival (% of patients) Group C Group B Group A Group B Group C Death or disease progression No. of patients/total no. Median PFS Months Group A 3/36 NR Group B 7/22 NR Group C 16/ Hazard ratio (95% CI) p value Group A vs C 0.09 ( ) < Group B vs C 0.16 ( ) <

15 Overall survival Group A Overall survival (% of patients) Group B Group C Death from disease Median OS No. of patients/total no. Months Group A 1/36 NR Group B 2/22 NR Group C 9/ No. at risk Group A Group B Group C Hazard ratio (95% CI) p value Group A vs C 0.04 ( ) < Group B vs C 0.14 ( ) <

16 Multivariate analysis Characteristics Variable Progression Free Survival Overall Survival Hazard ratio (95% CI) ctdna Groups A and B 0.10 ( ) LDH Baseline normal 0.39 ( ) ECOG ( ) Stage M1a or M1b 0.63 ( ) Disease volume SPOD < 1000mm ( ) p value Hazard ratio (95% CI) < ( ) ( ) ( ) ( ) ( ) p value

17 ctdna predictive value Isolated intracranial progression Extra-cranial response only Sensitivity = 79% = 79% 91% Specificity = 94% CR (n = 3) PR (n = 44) SD (n = 8) POD (n = 21) Group A/B: 100% Group C: 0% Group A/B: 98% Group C: 2% Group A/B: 50% Group C: 50% Group A/B: 39% Group C: 61% 17

18 Conclusions Digital droplet PCR is quick, cheap, reproducible and minimally invasive predictive biomarker ctdna profiles in patients with predominant brain metastases were not accurate predictors of objective response Optimal timing for on therapy liquid biopsies in patients who had detectable ctdna at baseline is 5-8 weeks following the first infusion

19 Acknowledgements Patients and Families PCT team Rick Kefford, Esther Lim, Zsuzsi Nagy, Mariana Brocardo, Mal Irvine, Ashleigh Stewart, Bernadette Pedersen, Carina Fung, Suzanah Boyd, Jenny Lee, Jen Ming, Sara Alavi National and International Colleagues and Scientists working in Melanoma Georgina Long, Richard Scolyer, Matteo Carlino, Alex Menzies, Ric Villain, Graham Mann, Hojabr Kakavand, Jason Madore, James Wilmott, Sarah Welsh, Rebecca Dean, Michelle Peranec, Gulietta Pupo, Varsha Tembe, Valarie Jakrot Melanoma Institute Australia and Trials Team Maria Gonzales, Tracy Liaw, Maria Cruzado, Denise Mcaleer, Kate, Sarah Fitzpatrick, Libby Emmett, Monika Keczkowska, Elizabeth Liniker, Sangeetha Ramanujam, Anna Hoadley, Georgia Cairns, John Thompson, Robyn Saw, Jonathon Stretch, Andrew Spillane, Kerwin, Shannon, Omgo Nieweg, Ken Lee

20 Translational Research Gulietta Pupo Ric Villain Jason Madore Georgina Long Graham Mann Richard Scolyer James Wilmott Nick Hayward Alex Menzies

21 Methods Patients with metastatic melanoma receiving treatment with anti-pd1 antibody ± anti-ctla4 antibody Mutation in tumour tissue identified using commercially available tests (Oncocarta, oncofocus, V600 AMOY, VE1 IHC, Cobas) Baseline and during therapy samples collected (up to 12 weeks post therapy initiation) ctdna quantification with Digital droplet PCR Patient outcome - Response evaluation criteria in solid tumors (RECIST) response at first re-staging - Progression free survival (PFS) - Overall survival (OS) Clinical characteristics - Eastern Cooperative Oncology Group (ECOG) performance status - Lactate dehydrogenase (LDH) level - Disease volume: sum of product of diameters (SPOD) - American Joint Committee on Cancer (AJCC) tumour Stage

22 Optimal timing of progress biopsy Predictive window Weeks