Virtual Journal Club: Front-Line Therapy and Beyond Recent Perspectives on ALK-Positive Non-Small Cell Lung Cancer Reference Slides
ALK Rearrangement in NSCLC ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase In NSCLC, ALK is activated by chromosomal rearrangement, leading to constitutive kinase activation and oncogene addiction ALK rearrangements are identified in 3%-7% of lung adenocarcinomas, commonly from younger never smoking patients Inversion Translocation or
ALK-Positive NSCLC ALK translocation in NSCLC oncogenic activation Adenocarcinomas Never or light smokers Median age 5 years No sex differences Break-apart FISH assay for ALK-fusion genes Telomere 2p23 region 3 5 Centromere t(2;5) ALK gene breakpoint region ~25 kb ~3 kb Shaw AT, et al. Lancet Oncol. 211;12(11):14-112. Camidge DR, et al. Lancet Oncol. 212;13(1):111-119. Wellstein A, et al. Nat Med. 211;17(3):29-291.
Current Approach to Diagnosis and Management of ALK-Positive NSCLC Screen all patients with advanced non-squamous NSCLC Screen select patients with advanced squamous cell lung carcinoma Screen at the time of metastatic diagnosis Treat patients with advanced, ALK-positive NSCLC with crizotinib in the first-line setting (and beyond) Treat patients who relapse on crizotinib with ceritinib, a next generation ALK inhibitor
Lung cancer Small cell An ALK-Testing Algorithm Not small cell Squamous Probably squamous Adenocarcinoma NSCLC Are there strong clinicopathologic indicators for oncogene addiction? YES TEST! FISH, fluorescence in situ hybridization; IHC, immunohistochemistry ALK rearrangement IHC screening If positive, confirmation by FISH
First Generation ALK Kinase Inhibitor Crizotinib, an oral receptor tyrosine kinase inhibitor (TKI), including ALK, HGFR, c-met and RON Change in DNA Sequence ALK Translocation Transcription ALK Fusion Gene mrna Transcript Translation ALK PROTEIN Biologic Activity Oncogenesis Drug Target Sahu A, et al. South Asian J Cancer. 213;2(2):91-97. Crystal AS, et al. Clin Cancer Res. 212;18(17):4479-4481
Crizotinib Studies in ALK-Positive NSCLC 1. Camidge DR, et al. Lancet Oncol. 212;13(1):111-119. 2. Kim D-W, et al. J Clin Oncol. 212;3(15S): Abstract 7533. 3. Shaw AT, et al. N Engl J Med. 213;368(25):2385-2394. 4. Mok T, et al. N Engl J Med, 214; 371 (23):2167-2177
Crizotinib in ALK-Positive Patients PROFILE 17: PFS Shaw AT, et al. Ann Oncol. 212;23(Suppl 9): Abstract LBA1.
Study Design PROFILE 114 Crizotinib Versus Chemotherapy Key entry criteria ALK-positive by central FISH testing a Locally advanced, recurrent, or metastatic nonsquamous NSCLC No prior systemic treatment for advanced disease ECOG PS -2 Measurable disease Stable treated brain metastases allowed R A N D O M I Z E b N = 343 Crizotinib 25 mg BID PO, continuous dosing (n = 172) Pemetrexed 5 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC 5-6 q3w for 6 cycles (n = 171) Endpoints Primary PFS (RECIST 1.1, IRR) Secondary ORR OS Safety Patient-reported outcomes (EORTC QLQ-C3, LC13) CROSSOVER TO CRIZOTINIB PERMITTED AFTER PROGRESSION c a ALK status determined using standard ALK break-apart FISH assay; b Stratification factors: ECOG PS (/1 vs 2), Asian vs non-asian race, and brain metastases (present vs absent); c Assessed by IRR ECOG PS, Eastern Cooperative Oncology Group performance status; EORTC QLQ-C3, European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C3; IRR, independent radiologic review; PFS, progression-free survival; IRR, independent radiologic review; ORR, overall response rate; OS, overall survival Solomon BJ, et al. N Engl J Med. 214;371(23):2167-2177.
PFS Probability, % PROFILE 114: Progression-Free Survival 1 8 6 4 2 No. at risk Crizotinib Chemotherapy 5 1 15 2 25 3 35 Time, Months 172 12 65 38 19 7 1 171 15 36 12 2 1 Solomon BJ, et al. N Engl J Med. 214;371(23):2167-2177.
OS, % PROFILE 114: Overall Survival 1 Crizotinib 8 6 Chemotherapy 4 2 No. at risk Crizotinib Chemotherapy 5 1 15 2 25 3 35 Time, Months 172 152 123 8 44 24 3 171 146 112 74 47 21 4 Solomon BJ, et al. N Engl J Med. 214;371(23):2167-2177.
Common Crizotinib Toxicities (PROFILE 114) Crizotinib (n = 171), n (%) Any Grade Grade 3/4 Vision disorder c 122 (71) 1 (1) Diarrhea 15 (61) 4 (2) Edema c 83 (49) 1 (1) Vomiting 78 (46) 3 (2) Constipation 74 (43) 3 (2) Elevated transaminases c 61 (36) 24 (14) Abdominal pain c 45 (26) Dysgeusia 45 (26) Headache 37 (22) 2 (1) Permanent treatment discontinuations due to treatment-related AEs: 5% and 8%, respectively b No grade 5 AEs were reported to be related to treatment; 1 patient in the chemotherapy arm had grade 5 pneumonitis after crossover to crizotinib, considered to be treatment-related a Not adjusted for differential treatment duration; b Before crossover to crizotinib; c clustered term Solomon BJ, et al. N Engl J Med. 214;371(23):2167-2177.
Subgroup Analyses of PROFILE 114: Intracranial Efficacy of First-Line Crizotinib vs Chemotherapy in ALK- Positive NSCLC Solomon BJ, et al. Presented at: 16 th World Conference on Lung Cancer; September 6-9 215; Denver, Colorado; Abstract MINI31.4.
Management of CNS Relapses in the era of crizotinib 1. Surgical resection 2. Whole brain radiation therapy 3. Stereotactic radiosurgery 4. Chemotherapy, eg, pemetrexed AND continue crizotinib
Probability of No Progression, % Probability of No Progression, % Intracranial TTP a in Patients With/Without Brain Metastases at Baseline Brain Metastases Present Brain Metastases Absent 1 1 8 8 6 6 4 4 2 2 No. at risk Crizotinib Chemotherapy 5 1 15 2 25 3 35 39 4 26 15 Time, Months 9 7 7 3 1 1 No. at risk Crizotinib Chemotherapy 132 131 5 1 15 2 25 3 35 93 92 Time, Months 56 32 33 11 2 3 7 1 1 NR, not reached; a Time from randomization to first documentation of intracranial tumor progression by IRR; b Two-sided log-rank test Solomon BJ, et al. Presented at: 16 th World Conference on Lung Cancer; September 6-9 215; Denver, Colorado; Abstract MINI31.4.
Intracranial DCR (95% Exact CI; %) Intracranial DCR a in Patients With Brain Metastases at Baseline Crizotinib (n = 39) Chemotherapy (n = 4) 1 Difference: 4% (95% CI: 21-59) P<.1 b Difference: 31% (95% CI: 11-52) P =.6 b 8 6 4 2 12 Weeks 24 Weeks DCR, disease control rate (% CR + PR + SD); a By IRR; b Two-sided Pearson χ 2 test Solomon BJ, et al. Presented at: 16 th World Conference on Lung Cancer; September 6-9 215; Denver, CO; Abstract MINI31.4.
Duration of Treatment Before/After Intracranial PD in Patients Randomized to Crizotinib * * * * BM at baseline No BM at baseline Radiotherapy after intracranial PD On treatment at data cutoff Had intracranial PD in existing lesion -1-9 -8-7 -6-5 -4-3 -2-1 1 2 3 4 5 6 7 8 9 1 Treatment Duration, Weeks Duration of treatment beyond intracranial PD a : Median 2.4 weeks (range: 3.3-84.4) a Among the 22 patients receiving crizotinib for 3 weeks beyond intracranial PD PD, progression of disease; BM, brain metastases Solomon BJ, et al. Presented at: 16 th World Conference on Lung Cancer; September 6-9 215; Denver, Colorado; Abstract MINI31.4.
Management of CNS Relapses with the advent of new ALK inhibitors 1. Surgical resection 2. Whole brain radiation therapy 3. Stereotactic radiosurgery 4. Chemotherapy, eg, pemetrexed 5. Next generation ALK inhibitors
Sequencing for Patients With ALK-Positive NSCLC Based on Current Paradigm 1 st Line Crizotinib Based on PROFILE 114 trial Progression Disease Rebiopsy No mutation ALK G122R mutation * 2 nd Line Second Generation TKI (eg, ceritinib, alectinib) Chemotherapy? ALK G122R mutation, a new aquired secondary mutation in the ALK gene who is resistant to both ceritinib and alectenib* Verbal communication Tony Mok. Solomon BJ, et al. N Engl J Med. 214;371(23):2167-2177. Gainor JF, et al. Clin Cancer Res. 215;21(12):2745-2752. Friboulet L, et al. Cancer Discov. 214;4(6):662-667. * Ignatius Ou SH, et al. J Thorac Oncol. 214;9(4):549-553.
Activity of Other ALK TKIs ALK TKI RR, % (n) Crizotinib Naïve RR, % (n) Crizotinib Resistant mpfs Ceritinib LDK378 6% (35) 57% (79) 8.6 m Alectinib CH542582 93.5% (46) 6% (47) >14 m Brigatinib AP26113 2/2 (2) 76% (13/17) AUY922 5% (8) 21% (14) N=16 Felipe E, et al. Ann Oncol. 212; Abstract 438. Shaw AT, et al. N Engl J Med. 214;37(26):2537-2539. Gadgeel SM, et al. Lancet Oncol. 214;15(1):1119-1128. Nakagawa K, et al. J Clin Oncol. 213;31(Suppl): Abstract 833.
Next Generation ALK TKIs 5% maximal inhibitory concentration (IC5) values of Ba/F3 cells dependent on expression of EML4-ALK (native) or kinase domain mutated EML4-ALK variants (n = 1). Data for each cell line are derived from at least 4 independent experiments (error bars = standard deviation). Dashed horizontal lines indicate the mean steady-state exposure concentrations of each drug corrected for the functional effects of protein binding at the recommended phase 2 doses: a Crizotinib: 25 mg BID, 259 nm 9 ; AP26113: b 18 mg QD, 899 nm and c 9 mg QD, 264 nm 1 ; d Ceritinib: 75 mg QD, 456 nm 11 ; e Alectinib: 6 mg BID, 277 nm 12 ; f n = 2 Ou SH. Drug Des Devel Ther. 211;5:471-485. Shaw AT, et al. N Engl J Med. 214;37(13):1189-1197. Ou S, et al. Eur J Cancer. 213;49(Suppl 2): Abstract 44.
Next Generation ALK Inhibitors in Crizotinib Resistance 1. Kim D-W, et al. J Clin Oncol 214;32(5S): Abstract 83; 2. Ou S-H, et al. J Clin Oncol 215;33(Suppl): Abstract 88; 3. Camidge DR, et al. J Clin Oncol 215;33(Suppl): Abstract 862; 4. Shaw AT, et al. J Clin Oncol. 215;33(Suppl): Abstract 818.
Ongoing Trials in ALK+ NSCLC ASCEND-4 trial A randomized phase III trial of oral ceritinib versus standard chemotherapy in previously untreated patients with ALK+ NSCLC ALEX trial A randomized phase III trial of alectenib versus crizotinib in previously untreated patients with advanced ALK+ NSCLC ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/nct182899. Accessed 15 October 215. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/nct27584. Accessed 15 October 215