TKCC/Garvan Cancer Biology Seminars Melanoma & Cancer Immunotherapy

Transcription

1 TKCC/Garvan Cancer Biology Seminars Melanoma & Cancer Immunotherapy 19/02/2016 A/Prof Anthony Joshua Head, Dept of Medical Oncology St Vincent s Hospital, Sydney

2 Immunotherapy Progress: A Long Time Coming Joost W et al. Nature Reviews Drug Discovery;10: , 2011.

3 Three Requirements for Spontaneous or Therapeu;c Immune Response Immunization T-cell response Overcome Immune Suppression Mellman, Coukos, Dranoff. Nature 2011;480:

4 Immunotherapy Balance Tumor Promoting Lymphocytes (T reg) Cytokines: TGF-beta, IL-10, IDO Suppressive macrophage CTLA-4, PD1, LAG3, TIM3 Anti-Cancer Lymphocytes (CD8 T cells) Cytokines: IFN-γ, IL2 Dendritic cells (DC) CD40, OX40, TLR

5 Tumor An;gens Tissue associated antigens MART1, gp100, tyrosinase; PSA, her2/neu, mesothelin, CEA, folate receptor-α Oncofetal/cancer-testis MAGE family BAGE family GAGE family NY-ESO-1 Universal Antigens Survivin, htert Neo-antigens CDK4, β-catenin, mutated introns New sequences resulting from mutations

6 Tumors with a High Muta;onal Load Soma>c muta>on frequencies observed in exomes from 3,083 tumor-normal pairs. MS Lawrence et al. Nature 000, 1-5 (2013) doi: /nature12213

7 [TITLE] Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

8 Immune Checkpoint Pathways Central Loca;on An;gen- Presen;ng Cell CTLA-4 Blockade (ipilimumab) PD-1 Blockade PD-1 Blockade (nivolumab) (pembrolizumab, nivolumab) Presented By Jedd D. Wolchok, MD, PhD at 2013 ASCO Annual Meeting

9 1 st Generation Agents

10 Improved Survival with Ipilimumab (An;-CTLA-4) Stage IV or unresectable Stage III Melanoma Now Health Canada approved 1 st line

11 Long-term Survival in 4846 Metasta;c Melanoma Pa;ents Treated with Ipilimumab 1.0 Propor;on Alive Median OS, months (95% CI): 9.5 ( ) Pooled Data: Phase II, III, EAP 3-year OS rate, % (95% CI): 21 (20 22) Ipilimumab CENSORED Months Pa;ents at Risk Ipilimumab Schadendorf, Hodi FS, Robert et al. ESMO 2013

12 Adop;ve Cell Therapy (ACT) with TIL NCI Strategy! Highly selected TIL! Rapid expansion protocol! Lymphodepletion: Cytoxan/ Fludarabine! - Increase IL2, IL7, IL15 availability! - Reduce regulatory T cells! Administration of high dose IL-2! - Toxic, but fewer doses given! Gattinoni et al. Nature Reviews Immunology 6: , 2006.

13 Rosenberg, AACR Annual Mee>ng, 2014

14 TIL Therapy Across the World 1) Dudley/Rosenberg % response rates, 22% complete responses (years) 2) Besser/Schacter 40-50% response rates (57, 5 CR 18, PR) 10% CR 3) Radyvani/Hwu 48% response rates (15/31, 2 CR) 4) Ellebaek/Svane 30% response rates (2/6, 2 CR) 5) Pilon-Thomas/Sarnaik 38% response rates (13 patients; 2 CR, 3 PR 6) Princess Margaret Canadian trials initiated

15 2nd Generation Agents

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21 Original Article Nivolumab in Previously Untreated Melanoma without BRAF Mutation Robert C et al. N Engl J Med UPDATE - the 2-year OS rate with frontline nivolumab was 57.7% compared with 26.7% for 2015;372: dacarbazine.

22 Characteristics of Response. Robert C et al. N Engl J Med 2015;372:

23 Case

24 Presentation 41 year old previously well Irregular lesion on right thigh for approximately 12 months Shave biopsy 3.2mm, ulcerated, mitotic rate 3/mm2, followed by WLE and SNB (0/2) Determined to be BRAF Neg, NRAS +ve

25 Metastatic Presentation Initial CTs clear 1 year post diagnosis noted to have new metastatic infrahilar node (1.4cm), 6mm RLL nodule Referred for PET scan/ EBUS - +ve for melanoma

26 Moving towards therapy Short interval CT demonstrated right hilar node (15mm), right fissural nodule, RLL nodule all increasing in size Also new right inguinal node (16mm)

27 TIL pa;ent 1: Clinical response Partial Response (78% decrease in index 2 months): Pretreatment Other 2 months: Pulmonary nodules - stable Right hilar nodes absent Subcut lesion Rt upper thigh - absent 2 Months After TIL infusion: Disease 6 months. Ipilimumab (progression). Pembrolizumab (response).

28 Clinical Experience With NIVO Plus IPI Combination Phase I study of NIVO plus IPI in advanced melanoma: 1,2 ORR up to 53% (CR rate of 18%) 2-year OS rate up to 88% Phase II study of NIVO plus IPI in untreated melanoma: 3 ORR of 61% with the combination vs. 11% for IPI alone; CR rate of 22% with the combination Treatment-related grade 3 4 adverse events (AEs): 54% for the combination vs. 24% for IPI In the above studies, response rates were similar regardless of PD-L1 expression Wolchok et al. N Engl J Med 2013;369:122-33; 2. Oral presentation by Dr. Mario Sznol at the ASCO 2014 Annual Meeting; 3. Postow et al. N Engl J Med 2015;372:

29 CA : Study Design Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Stratify by: PD-L1 expression* BRAF status AJCC M stage N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression** or unacceptable toxicity *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. N=315 **Patients could have been treated beyond progression under protocol-defined circumstances. IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo 29

30 PFS (Intent-to-Treat) 1.0 NIVO + IPI (N=314) NIVO (N=316) IPI (N=315 ) Proportion alive and progression-free NIVO + IPI NIVO Median PFS, months (95% CI) HR (99.5% CI) vs. IPI HR (95% CI) vs. NIVO 11.5 ( ) 0.42 ( )* 0.74 ( )** 6.9 ( ) 0.57 ( )* 2.9 ( ) -- *Stratified log-rank P< vs. IPI **Exploratory endpoint IPI 0.0 No. at Risk Months NIVO + IPI NIVO IPI

31 Response to Treatment ORR, % (95% CI)* Two-sided P value vs IPI Best overall response % NIVO + IPI (N=314) 57.6 ( ) NIVO (N=316) 43.7 ( ) IPI (N=315) 19.0 ( ) <0.001 < Complete response Partial response Stable disease Progressive disease Unknown Duration of response (months) *By RECIST v1.1. NR, not reached. Median (95% CI) NR (13.1, NR) 31 NR (11.7, NR) NR (6.9, NR)

32 Tumor Burden Change From Baseline Baseline reduction from baseline in target lesions (%) Baseline reduction from baseline in target lesions (%) NIVO + IPI Median change: -51.9% NIVO Median change: -34.5% Baseline reduction from baseline in target lesions (%) IPI Median change: +5.9% Confirmed responder 30% reduction in tumor burden by RECIST v1.1 32

33 PFS by PD-L1 Expression Level (1%) PD-L1 1%* PD-L1 <1%* 1.0 mpf S HR 1.0 mpf S HR Proportion alive and progression-free NIVO + IPI NIVO IPI NIVO + IPI 12.4 NIVO IPI Proportion alive and progression-free NIVO + IPI NIVO IPI NIVO + IPI 11.2 NIVO IPI Months Months No. at Risk NIVO + IPI NIVO IPI No. at Risk NIVO + IPI NIVO IPI *Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells. 33

34 Safety Summary Patients Reporting Event, % Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation NIVO + IPI (N=313) Any Grade Grade 3 4 NIVO (N=313) Any Grade Grade 3 4 IPI (N=311) Any Grade Grade Treatment-related death* *One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest). 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs developed a response 34

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36 Adoptive T cell therapy Underwent Resection of inguinal node Underwent Apharesis Admitted for Treatment 6 weeks later for TIL therapy Fludarabine/ Cyclophosphamide thereafter subcutaneous IL2

37 Recovery Recovered well, playing hockey Remains on pneumocystis prophylaxis CT scans show significant improvement 3 months post treatment

38 Relpase Restaging MRI also demonstrates a 1.1cm precentral brain lesion Treated with SRS 9 months from TILS therapy

39 Relapse 2 Restaging demonstrated a 4.9 X 1.8 cm right diaphragmatic mass along with growth in the RLL nodule

40 RESPONSE

41 Vb13.1 CD8 T Cell Popula;on Increased with Clinical Responses Infusion Product % of CD Vb Vb5.3 Vb9 Vb18 Vb13.1 Vb5.2 Vb23 Vb11 Vb13.2 Vb7.1 Vb17 Vb5.1 Vb13.6 Vb2 Vb1 Vb22 Vb4 Vb3 Vb16 Vb20 Vb8 Vb12 Vb21.3 Vb14 Vb7.2 Unknown Peripheral Blood Baseline 1W Response to TILs 4W 16W 28W % of CD % of CD Vb5.3 Vb9 Vb18 Vb13.1 Vb5.2 Vb23 Vb11 Vb13.2 Vb7.1 Vb17 Vb5.1 Vb13.6 Vb2 Vb1 Vb22 Vb4 Vb3 Vb16 Vb20 Vb8 Vb12 Vb21.3 Vb14 Vb7.2 Unknown 0 Vb5.3 Vb9 Vb18 Vb13.1 Vb5.2 Vb23 Vb11 Vb13.2 Vb7.1 Vb17 Vb5.1 Vb13.6 Vb2 Vb1 Vb22 Vb4 Vb3 Vb16 Vb20 Vb8 Vb12 Vb21.3 Vb14 Vb7.2 Unknown Response to Pembrolizumab 40W 50W 59W 65W % of CD % of CD Vb5.3 Vb9 Vb18 Vb13.1 Vb5.2 Vb23 Vb11 Vb13.2 Vb7.1 Vb17 Vb5.1 Vb13.6 Vb2 Vb1 Vb22 Vb4 Vb3 Vb16 Vb20 Vb8 Vb12 Vb21.3 Vb14 Vb7.2 Unknown 0 Vb5.3 Vb9 Vb18 Vb13.1 Vb5.2 Vb23 Vb11 Vb13.2 Vb7.1 Vb17 Vb5.1 Vb13.6 Vb2 Vb1 Vb22 Vb4 Vb3 Vb16 Vb20 Vb8 Vb12 Vb21.3 Vb14 Vb7.2 Unknown

42 Other points

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44 Progression versus Pseudo-progression Ribas 2009 by A American et al. Clin Association Cancer for Res Cancer 2009;15: Research

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46 iraes Observed with Novel Immuno-oncology Therapy Skin Skin rash or pruritus Endocrine Headache Visual changes Fever Fatigue/weakness Confusion Hepatic Abnormal LFTs (eg, AST, ALT, total bilirubin) Gastrointestinal (GI) Diarrhea Stomach pain Nausea/vomiting/pain Blood in stool Constipation Neurologic Sensory or motor neuropathy Muscle weakness Fatigue Difficulty waking up ALT: alanine aminotransferase AST: aspartate aminotransferase irae: immune-related adverse event If not vigilant, may result in more serious immune-related adverse events

47 Combining immunotherapy and targeted therapy for melanoma? Immunotherapy Targeted therapy Combination Percent alive Percent alive Percent alive Years Years Years