ALK positive Lung Cancer. Shirish M. Gadgeel, MD. Director of the Thoracic Oncology program University of Michigan

Transcription

1 ALK positive Lung Cancer Shirish M. Gadgeel, MD. Director of the Thoracic Oncology program University of Michigan

2 Objectives What is ALK translocation? What drugs are used in what sequence? How many times should a patient be treated with ALK inhibitor? Should I get immune therapy? What about chemotherapy? I have stage III ALK positive NSCLC. Should I receive ALK inhibitor?

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6 EML4-ALK Echinoderm microtubule associated protein like 4 (EML4) Anaplastic Lymphoma Kinase (ALK)

7 Schematic of ALK fusion oncogenes and important downstream signaling pathways. Alice T. Shaw, and Benjamin Solomon Clin Cancer Res 2011;17:

8 Testing for Rearrangements: ALK Chromosome Normal 2p21 EML4 ALK Kinase Domain FISH Probes 2p23 Camidge et al, Clin Cancer Res 2010.

9 Testing for Rearrangements: ALK Chromosome Normal Inversion Break Apart 2p21 EML4 FISH Probes ALK Kinase Domain 2p23 Camidge et al, Clin Cancer Res 2010.

10 Ventana ALK (D5F3) CDx Assay 1 Ventana ALK (D5F3) CDx Assay is intended for the qualitative detection of the ALK protein in FFPE NSCLC tissue stained with a BenchMark XT automated staining instrument Indicated as an aid in identifying patients eligible for treatment with Xalkori (crizotinib) D5F3 is a rabbit monoclonal primary antibody that binds to ALK Samples with strong granular cytoplasmic staining in tumor cells (any percentage of positive tumor cells) are interpreted as positive The Clinical Outcomes Study was based on PROFILE 1014 (Phase III crizotinib vs first-line chemo (pem/cis or pem/carbo) in previously untreated ALK+ advanced non-squamous NSCLC) The Vysis ALK Break Apart FISH Probe Kit was used to determine ALK positivity and trial eligibility Tissue specimens were retrospectively tested with the Ventana ALK (D5F3) CDx Assay Test is being validated in alectinib phase III trial (ALEX) Approved by the US FDA in June Ventana ALK (D5F3) CDx Assay. Tucson, AZ: Ventana Medical Systems, Inc.; 06/ Accessed 10/05/15.

11 Median age Is younger Clinical and Demographic Features of 30% smokers Patients With ALK-positive NSCLC N=149 N = 136 Median (range) age, years 52 (21 86) 52 (29-82) Gender, male/female 49/51 47/53 Race, n (%) White 95 (64) 87 (64) Asian 41 (28) 43 (32) Others 13 (9) 6 (4) Smoking history, n (%) Never smoker 106 (71) 92 (68) Former smoker 42(28) 39 (29) Current smoker 1 (1) 5 (4) Histology, n (%) Adenocarcinoma 144 (97) 130 (96) Squamous 2 (1) 0 (0) Other 3 (2) 6 (4) Prior treatment regimens, n (%) 0 24 (6) 1 47 (33) 2 31 (18) 3 47 (41) 1. Camidge DR, et al. Lancet Oncol. 2012;13: Crino D, et al. J Clin Oncol. 2011;29(suppl. Abstract 7514).

12 Incidence of ALK+ NCSLC is Relatively Uniform across Ethnicities Although the incidence of EGFR mutations varies by ethnicity (Asian vs Caucasian), the incidence of ALK+ disease is relatively uniform across ethnicities Europe 1 All histology US 2 Adenocarcinoma East Asia 3 Adenocarcinoma, never smokers (n=9,911) (n=733) (n=52) 1. Barlesi, et al. ASCO 2013; 2. Johnson, et al. ASCO 2013; 3. Sun, et al. J Clin Oncol 2010

13 Crizotinib: First-in-Human/Patient Trial Part 1: Dose escalation Cohort 5 (n=6) 300 mg BID Cohort 4 (n=7) 200 mg BID 2 DLTs: grade 3 fatigue Cohort 6 (n=9) 250 mg BID MTD/RP2D Cohort 3 (n=8) 200 mg QD Cohort 2 (n=4) 100 mg QD Cohort 1 (n=3) 50 mg QD ALT = alanine aminotransferase 1 DLT: grade 3 ALT elevation Part 2: Molecularly enriched cohorts (ALK and c-met) Enrolling patients with ALK-positive NSCLC after preliminary observation of impressive activity in a few patients Data from database April 7, 2010 Data presented for 82 patients Phase II target accrual (open): 400 With permission from Kwak EL et al. ASCO 2009;Abstract 3509.

14 2/26/2010 5/25/ year old never smoker- Gem+Pem+Bev, Carbo+Pac,erlotinib

15 Crizotinib in ALK positive NSCLC PROFILE Solomon B, NEJM 2014 PROFILE 1007 Shaw A, NEJM 2013

16 Common AEs of Any Cause in 15% of Patients 5% difference between groups Crizotinib (n=172) Chemotherapy (n=171) Visual disturbance a 103 (60) 16 (9) Diarrhea 103 (60) 33 (19) Nausea b 94 (55) 64 (37) Vomiting b 80 (47) 30 (18) Constipation 73 (42) 39 (23) Elevated transaminases a 66 (38) 25 (15) Edema a 54 (31) 27 (16) Upper respiratory infection a 44 (26) 22 (13) Dysgeusia 44 (26) 16 (9) Dizziness a 37 (22) 14 (8) Fatigue 46 (27) 57 (33) Alopecia 14 (8) 35 (21) Dyspnea a 23 (13) 32 (19) Rash 15 (9) 29 (17) a Clustered term; b antiemetic use significantly higher in chemotherapy arm compared with crizotinib arm (67% vs 20%); patients in chemotherapy arm also received more dexamethasone (94% vs 25%)

17 Grade 3/4 AEs of Any Cause in 3% of Patients Crizotinib (n=172) Chemotherapy (n=171) Elevated transaminases a 27 (16) 4 (2) Pulmonary embolism a 9 (5) 3 (2) Dyspnea a 7 (4) 5 (3) Pneumonia 6 (4) 3 (2) Hypokalemia 6 (4) 0 (0) ECG QTc prolonged 6 (4) 0 (0) b Neutropenia a,c 23 (13) 33 (19) Anemia a 4 (2) 9 (5) WBC decreased 2 (1) 8 (5) Fatigue 4 (2) 7 (4) a Clustered term; b no on-treatment assessments; c includes febrile neutropenia, reported in 1 patient treated with crizotinib and 16 patients treated with chemotherapy

18 Percentage of ALK+ NSCLC patients with brain metastasis in different studies 0.6 Brain metastssis percentage PROFILE 1014 PROFILE 1007 CBPD Ceritinib Phase 1 CBPD: Ou et al, Ann Oncol 2014

19 Response in Leptomeningeal Carcinomatosis Pre-Alectinib 6 weeks post-alectinib

20 Inhibitory Profiles of ALK Inhibitors in Cellular Models 1. Gettinger, et al. Presented at: ESMO (abstr 439O). 2. Squillace, et al. Presented at: AACR (abstr Kozuki TJSMO

21 Study design KEY ELIGIBILITY ALK+ by central IHC testing Advanced or metastatic ALK+ NSCLC Treatment-naïve ECOG PS 0 2 Measurable disease Asymptomatic brain metastases allowed R A N D O M I Z E Stratification factors: ECOG PS (0/1 vs 2) Race (Asian vs non-asian) Brain metastases (present vs absent) Alectinib 600 mg BID PO NO CROSSOVER per protocol Crizotinib 250 mg BID PO ENDPOINTS Primary PFS (RECIST 1.1), by investigator review Secondary PFS by IRC Time to CNS progression ORR, DOR OS Safety and tolerability Patient-reported outcomes ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; NSCLC, non-small-cell lung cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PO, by mouth; PFS, progression-free survival; IRC, independent review committee; CNS, central nervous system; ORR, objective response rate; DOR, duration of response; OS, overall survival Presented by: Alice T. Shaw

22 Primary endpoint: PFS, investigator-assessed Progression-free Survival (%) Alectinib Crizotinib Patients with events, n (%) Median PFS, months (95% CI) HR (95% CI) P-value (log-rank test) Crizotinib (N=151) Alectinib (N=152) 102 (68) 62 (41) 11.1 ( ) 0.47 ( ) P< NE (17.7 NE) Day Months No. at Risk Crizotinib Alectinib Presented by: Alice T. Shaw

23 PFS BY CNS METASTASES STATUS AT BASELINE* Patients with CNS metastases at baseline Patients without CNS metastases at baseline 100 Crizotinib (N=58) Alectinib (N=64) 100 Crizotinib (N=93) Alectinib (N=88) Progression-Free Survival Patients at Risk Crizotinib Alectinib 0 Day mo ( ) HR 0.40 (95% CI ) P< NR (9.2 NR) Duration of Progression-Free Survival (Months) Patients at Risk Crizotinib Alectinib *Investigator-assessed; All patients with CNS metastases at baseline, irrespective of radiotherapy NR = not reached Shaw, et al. ASCO 2017 Progression-Free Survival Day mo ( ) Duration of Progression-Free Survival (Months) HR 0.51 (95% CI ) P= NR 23

24 CUMULATIVE INCIDENCE RATE OF CNS PROGRESSION BY PRIOR RT A competing risk analysis with CNS progression, non-cns progression and death as competing events was conducted* Patients with prior RT Patients with no prior RT Cumulative Incidence (%) Crizotinib12 month CIR: 50.4% (95% CI, ) Alectinib 12 month CIR: 8.6% (95% CI, ) Cause-specific HR 0.11 (95% CI, ) P= Cumulative Incidence (%) Crizotinib12 month CIR: 62.5% (95% CI, ) Alectinib 12 month CIR: 20.5% (95% CI, ) Cause-specific HR 0.22 (95% CI, ) P< Months Months *For each patient, the first event of CNS progression, non-cns progression or death was counted RT= radiotherapy (includes both stereotactic radiosurgery and whole-brain radiotherapy) 24

25 This case study was selected by Dr Gadgeel. Roche had no input into the selection of the case used.

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27 April 2016 Baseline scans

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30 Pemetrexed in ALK positive NSCLC PROFILE 1007, Shaw A, NEJM 2013

31 Nivolumab Mechanism of Action PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function 11 Nivolumab binds PD-1 receptors on T cells and disrupts negative signaling triggered by PD-L1/PD-L2 to restore T-cell antitumor function IFNγ IFNγR T-cell receptor MHC T-cell receptor MHC Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 Nivolumab: PD-1 Receptor Blocking Ab Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody

32 Other treatment options Focus of the slide: Discuss the role that chemotherapy and immunotherapy in future. Chemotherapy Will continue to have role in the treatment of patients with ALK+ NSCLC As non-alk directed therapy, following two or more ALK inhibitors Challenges with access/reimbursement to ALK inhibitors Immunotherapy Immune checkpoint inhibitor pembrolizumab, is not indicated as monotherapy for ALK+ NSCLC in firstline (KeyNote-024) 1 The combination of ALK inhibitors and immunotherapeutic agents is currently being investigated in early phase clinical trials in ALK+ NSCLC Remains an option for disease progression on two ALK inhibitors if tumours are PDL-1 high and later if tumours are PDL-1 low or zero Phase 2 ATLANTIC study: durvalumab in third-line EGFR mutant/alk+, locally advanced or metastatic NSCLC: 12.2% ORR in PD-L1-high patients (n=74) 3.6% ORR in PD-L1-low/negative patients (n=28) 2 1. Pembrolizumab SmPC. Available at 2. Garassino et al. ELCC 2017

33 Agonist Antibody Blocking Antibody Ai M., Curran M. Immune checkpoint combinations from mouse to man. Cancer Immunology Immunotherapy, 2015.