Efficacy of anti-pd-1 therapy in patients with melanoma brain metastases

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Efficacy of anti-pd-1 therapy in patients with melanoma brain metastases John J.

Grant McArthur 7, Andrew Haydon 5, Miles C. Andrews 2,3,4, Jonathan Cebon 5, Alex Guminski 6,8,9, Richard F. Kefford 1,10, Georgina V.

Crown Princess Mary Cancer Centre, Westmead Hospital, NSW, Australia 2.

Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia 4.

1 Efficacy of anti-pd-1 therapy in patients with melanoma brain metastases John J. Park 1, Sagun Parakh 2,3,4, Shehara Mendis 5, Rajat Rai 6, Wen Xu 7, Serigne Lo 6, Martin Drummond 6, Catherine Rowe 7, Annie Wong 7, Grant McArthur 7, Andrew Haydon 5, Miles C. Andrews 2,3,4, Jonathan Cebon 5, Alex Guminski 6,8,9, Richard F. Kefford 1,10, Georgina V. Long 6,8,9, Alexander M. Menzies 6,8,9, Oliver Klein 2,3 and Matteo S. Carlino 1,6 1. Crown Princess Mary Cancer Centre, Westmead Hospital, NSW, Australia 2. Medical Oncology Unit, Austin Health, Heidelberg, VIC, Australia 3. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia 4. La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia 5. Medical Oncology Unit, Alfred Hospital, VIC, Australia 6. Melanoma Institute Australia, Sydney, NSW, Australia 7. Pater MacCallum Cancer Centre, VIC, Australia 8. The University of Sydney, Sydney, NSW, Australia 9. Royal rth Shore and Mater Hospitals, Sydney, Australia 10. Medical Oncology Department, Macquarie University Hospital, NSW, Australia

2 Background Brain metastases (BM) occur in approximately 40-50% of patients (pts) with metastatic melanoma Melanoma pts with BMs have a poor prognosis with a median survival of 4 6 months (mths) Anti-PD-1 agents such as pembrolizumab and nivolumab improve response and survival in metastatic melanoma Most clinical trials exclude pts with untreated or symptomatic BMs requiring corticosteroid use There is limited data describing activity of anti-pd-1 therapy in BMs

3 Objectives To describe efficacy of anti-pd-1 therapy in real world melanoma pts with BMs, including symptomatic BMs and pts on corticosteroids Study end-points Intracranial (IC) response rate (RR) Disease control rate (DCR) of IC lesions Progression Free Survival (PFS) Overall survival (OS) Impact of corticosteroids and symptoms on PFS and OS

4 Methods Retrospective analysis of metastatic melanoma pts with BMs treated with anti-pd-1 therapies between October 2012 to March centres across Australia Key inclusion criteria 1 brain metastasis measuring 5 mm Up to 5 IC lesions were measured for IC RR Key exclusion criteria Uveal melanoma Leptomeningeal disease Prior anti-pd-1 therapy

5 Baseline Characteristics Characteristic Total (N=66) Characteristic Total (N=66) Age at PD-1 start, median yrs (range) 62 (19 85) Male n (%) 45 (68) BM at stage IV diagnosis n (%) ECOG PS n (%) LDH n (%) < ULN > ULN Unknown Local therapy to BMs prior to anti- PD-1 n (%) Nil Surgery (Sx) SRS WBRT Combination 38 (58) 28 (42) 45 (68) 19 (29) 2 (3) 30 (45) 33 (50) 3 (5) 24 (36) 3 (5) 9 (14) 12 (18) 18 (27) SRS stereotactic radiosurgery, WBRT whole brain radiotherpay ~1pt concurrent use with bevacizumab, 1 pt concurrent use with dabrafenib and trametinib Mutational status n (%) BRAF V600* Other Type of anti-pd-1 therapy n (%) Nivolumab Pembrolizumab~ # lines of prior systemic Tx n (%) Total no. of IC metastases n (%) >10 Symptomatic BMs n (%) On steroids for symptomatic BMs at start of anti-pd-1 therapy n (%) * 30 (45) 36 (55) 6 (9) 60 (91) 14 (21) 33 (50) 15 (23) 4 (6) 7 (10) 34 (52) 19 (29) 6 (9) 47 (71) 19 (29) 46 (70) 14 (21)

Results 66 pts with median F/U of 7.0 mths (range 0.8 24.

6 Results 66 pts with median F/U of 7.0 mths (range mths) ORR 13/66 = 20% DCR 37/66 = 56% Best IC RR All pts (n=66) Symptomatic BMs (n=19) Steroids for BM (n=14) ORR (CR/PR) 13 (20) 2 (11) 2 (14) DCR (CR/PR/SD) 37 (56) 9 (47) 6 (44) CR 5 (8) 0 (0) 0 (0) PR 8 (12) 2 (11) 2 (14) SD 24 (36) 7 (37) 4 (28) PD 16 (24) 6 (31) 6 (44) Clinical PD 13 (20) 4 (21) 2 (14)

7 Examples of Responders Pt with PR, who had symptoms and on steroids at the start of anti-pd-1 therapy Pt with PR, anti-pd-1 therapy alone without any local Tx

8 Results Intracranial progression free survival Time (months) Overall survival Time (months) Intracranial PFS 5.3 mths (95% CI ) Median OS 9.9 mths (95% CI )

9 Impact of symptomatic BMs and use of corticosteroids on IC PFS Probability of Overall Survival Intracranial progression- CNS symptoms Time (months) Probability of Overall Survival Intracranial progression- Steroids Time (months) IC PFS N Median time (95% CI) Hazard Ratio (95% CI) P-value CNS symptoms Corticosteroids ( ) 2.66 ( ) 2.33 ( ) ( ) 2.53 ( ) 2.03 ( )

10 Conclusion Anti-PD-1 therapy is effective in metastatic melanoma with BMs Clinicians should consider anti-pd-1 therapy in pts on corticosteroids or with symptomatic BMs Symptomatic BMs and/or on corticosteroid for BMs have significantly shorter PFS and OS Prospective studies are awaited to further elucidate the efficacy in this population

Summary... 2 MELANOMA AND OTHER SKIN TUMOURS... 3

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