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ALK IN LUNG CANCER: PAST, PRESENT, AND FUTURE. Gene Mutations in Lung Adenocarcinomas.

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Presentation on theme: "ALK IN LUNG CANCER: PAST, PRESENT, AND FUTURE. Gene Mutations in Lung Adenocarcinomas."— Presentation transcript:



3 Gene Mutations in Lung Adenocarcinomas

4 17 years ago…… 2;5 chromosomal translocation in most anaplastic large-cell non-Hodgkin's lymphomas, which fused the NPM gene on chromosome 5q35 to ALK, on chromosome 2p23. Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.

5 The Mechanism of Carcinogenesis


7 Discovery of the EML4-ALK fusion in NSCLC  Initially reported in 2007 as a result of an inversion in chromosome 2p, which results in the fusion of the N- terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) with the kinase domain of ALK. Soda et al., Nature 2007; 448:561-567

8 1 Soda M, et al. Nature. 2007;448:561–67. EML4–ALK Is an Oncogenic Driver 3T3 Nude mice tumour/ injection0/80/80/88/80/88/82/2 VectorEML4ALK EML4–ALKK589MNPM–ALKv-Ras Expression plasmids for WT, EML4, ALK, EML4-ALK, EML4-ALK K589M, and NPM-ALK were introduced into 3T3 fibroblasts. Subcutaneous injection of the transfected 3T3 cells into nude mice revealed those that formed tumors

9 Evidence for EML4-ALK as a Lung Cancer Oncogene Insertion of EML4-ALK into NIH 3T3 fibroblasts was tumorigenic when implanted subcutaneously into nude mice Engineered the specific expression of EML4-ALK fusion gene in lung progenitor cells using a surfactant protein C gene promoter 100% of EML4-ALK transgenic mice developed lung adenocarcinoma that were + for ALK by IHC. No other primary cancers were observed. Following IV injection of EML4-ALK/3T3 cells into nude mice, all developed lung cancer. Ten animals were treated with an ALK-specific TKI and 10 were observed: PNAS December 16, 2008 vol. 105 no. 50 19893–19897

10 Frequency of ALK Rearrangements AuthorTotal Number Pos%Notes Shaw ASCO 2009 1411913%More likely in adenocarcinoma, light or never smokers, didn’t overlap with EGFR or KRAS, younger patients Inamura, JTO 2008 14953%No overlap with EGFR or KRAS Takeuchi, CCR 2008 253114% Koivuner, CCR 2008 30583%More common in never or light smokers Wong, Cancer 2009 266135%Mostly adenocarcinoma, never smokers, younger Rodig, CCR 2009358206%More common in younger, never smokers, adenocarcinoma with signet ring features, no overlap with EGFR mutations Kris, ASCO 2011598437%Rare overlap with EGFR, BRAF, KRAS

11 ALK fusions occur in numerous tumors ALK fusionIncidence ALCL NPM-ALK60-80% TPM3-ALK12-18% TGF-ALKrare CLTC1-ALKrare ATIC-ALKrare TPM4-ALKrare MSN-ALKrare ALO17-ALKrare MYH9-ALKrare IMT TPM3-ALK50-60% TPM4-ALK50-60% CARS-ALKrare RANBP2-ALKrare CTLC1-ALKrare SEC 31L1-ALKrare ALK fusionIncidence Lung EML4-ALK3-5% KIF5B-ALKrare TGF-ALKrare BreastEML4-ALK0-2.4% ColorectalEML4-ALK0-2.4% DLBCL CTLC1-ALKrare NPM-ALKrare Esophageal TPM4-ALK- Renal VCL-ALK- NPC TBD14/51 (27.5%) Atypical myeloproliferative leukemia RANBP2-ALK- Grande et al., Mol Cancer Ther 2011; 10:569-579 Barreca et al., J Molec Endocrinol 2011; 47:R11-R23 Garber, J Natl Cancer Inst 2010; 102:672-675 Röttgers et al., Leukemia 2010; 24:1197-1200

12 Other ALK alterations (mutations, gene amplification) ALK alterationIncidence Thyroid Mutations (L1198F, G1201E) 11% Neuroblastoma Mutations (F1174L, R1275Q) 6-8% Amplification4% Glioblastoma ALK protein expression Growth factor PTN protein, mRNA expression - Murugan et al., Cancer Res 2011; 71:4403–4411 Grande et al., Mol Cancer Ther 2011; 10:569-579 Powers et al., J Biol Chem 2002; 277:14153-14158 Lu et al., J Biol Chem 2005; 280:26953-26964

13 How do we test for ALK rearrangments? Histology/IHC FISH/Cytogenetics PCR Sequencing

14 What can we do in ALK+ NSCLC patient?

15 Crizotinib: A Dual MET/ALK Tyrosine Kinase Inhibitor Kinase IC 50 (nM) mean* Selectivity ratio c-MET8– ALK40-605-8X ROS607X RON8010X Axl 29434X 32237X Tie-244852X Trk A58067X Trk B39946X Abl1,159166X IRK2,887334X Lck2,741283X Sky>10,000>1,000X VEGFR2>10,000>1,000X PDGFR  >10,000>1,000X Co-crystal structure of crizotinib (PF- 02341066) bound to c-MET Cui et al. J. Med. Chem. 2011;54:6342-63 and Pfizer data on file

16 Early-phase clinical trial of crizotinib (PF-02341066) N Engl J Med 2010;363:1693-703. Key entry criteria Positive for ALK by central laboratory Expanded from phase I dose escalation trial Most were previously treated N=82 Crizotinib 250mg bid for 28-day cycle 6-month PFS among crizotinib users was estimated at 72% (95% CI, 61–83%)

17 Lancet Oncol 2012; 13: 1011–19 Updated of the phase I study Common treatment-related grade 1/2 AE

18 Overview of ongoing trials ● ALK inhibition, NSCLC – PROFILE 1007 – Ph III 2nd line (NCT00932893) – PROFILE 1014 – Ph III frontline (NCT01154140) – PROFILE 1005 – Ph II pretreated (NCT00932451) – PROFILE 1001 – Ph II expansion cohort (NCT00585195) ● ALK inhibition, other tumor types – PROFILE 1013 – Ph I in non-NSCLC (NCT01121588) ● Met inhibition – Study 1002 – Ph I/II with erlotinib (NCT00965731) – Study 1006 – Ph I with PF-0299804 (dacomitinib), NSCLC (NCT01121575)

19 Key entry criteria Positive for ALK by central laboratory 1 prior chemotherapy (platinum-based) PROFILE 1007 – phase III Key entry criteria Positive for ALK by central laboratory Progressive disease in Arm B of study A8081007 >1 prior chemotherapy PROFILE 1005 – phase II Crizotinib 250 mg BID (n=159) administered on a continuous dosing schedule Pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 (n=159) infused on day 1 of a 21-day cycle Primary endpoint = PFS met Crizotinib 250 mg BID (N=250) administered on a continuous dosing schedule Primary endpoint = ORR PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451

20 100 80 60 40 20 0 –20 –40 –60 –80 –100 –120 Decrease or increase from baseline (%) *n=240 response-evaluable patients from the mature population, and excludes patients with early death, indeterminate response and non-measurable disease +Per RECIST 1.1, percent change from baseline for subjects with best overall response of CR can be less than 100% when lymph nodes are included as target lesions PD + + ++ Marked Activity of Crizotinib in ALK+ NSCLC Update of the Phase 2 Study SDPRCR Kim et al., ASCO 2012

21 Median PFS 8.1 months (95% CI: 6.8–9.7) 28% patients in follow-up for progression 1.0 0.8 0.6 0.4 0.2 0 Probability of survival without progression 05101520 Time (months) + Censored 95% Hall-Wellner Band n at risk 26117595262 Marked Activity of Crizotinib in ALK+ NSCLC Update of the Phase 2 Study Kim et al., ASCO 2012

22 PROFILE 1005: Any-Grade Treatment- Related AEs in ≥10% of Patients AE Mature population, n=261 n (%) Overall population, n=901 n (%) Any AE 245 (93.9)827 (91.8) Vision disorder*154 (59)468 (51.9) Nausea 148 (56.7)423 (46.9) Vomiting 116 (44.4)352 (39.1) Diarrhea 106 (40.6)369 (41.0) Constipation 86 (33.0)249 (27.6) Peripheral edema 72 (27.6)211 (23.4) Fatigue 64 (24.5)163 (18.1) Decreased appetite 59 (22.6)167 (18.5) Increased alanine aminotransferase 45 (17.2)146 (16.2) Dysguesia 43 (16.5)149 (16.5) Dizziness 40 (15.3) 95 (10.5) Neutropenia 36 (13.8)84 (9.3) Increased aspartate aminotransferase 33 (12.6)106 (11.8) *Includes visual impairment, photopsia, vision blurred, vitreous floaters, photophobia and diplopia Rare instances of fatal pneumonitis and fatal hepatotoxicity were reported in crizotinib clinical trial program

23 N Engl J Med 2013. DOI: 10.1056/NEJMoa1214886 Result of PROFILE 1007

24 1 st line setting (PROFILE 1014): Key entry criteria Positive for ALK by central laboratory No prior systemic therapy RANDOMIZERANDOMIZE Crizotinib 250 mg BID administered on a continuous dosing schedule Pemetrexed 500 mg/m 2 + Cisplatin 75mg/m2 OR Pemetrexed 500mg/m2 + Carboplatin AUC 5 or 6 infused on day 1 of a 21-day cycle Primary endpoint = PFS Study Start Date: January 2011 Estimated Study Completion Date: December 2013

25 The Future: Overcoming Crizotinib Resistance Resistance develops on average within the first year or two of TKI therapy…

26 Acquired Crizotinib Resistance  The target gene can be altered by mutation or by amplification, limiting the ability of the drug to inhibit the kinase. (like T790M in EGFR and T315I in BCR-ABL)  Alternative signaling pathways (bypass tracks) can be activated in resistant cells, bypassing the need for signaling from the target. Nat Rev Clin Oncol. 2012 Apr 3 Current Opinion in Pharmacology 2013

27 Acquired Crizotinib Resistance Mutation  Up to 1/3 of relapsing patients, crizotinib resistance is mediated by secondary resistance mutations located in the ALK TK domain. MutationMechanism L1196Mgatekeeper mutation, hinder TKI binding through steric hindrance Most common G1269Alies directly in the ATP-binding Pocket G1202R and S1206YLocate in solvent-exposed region of the kinase domain, decrease binding affinity of Crizotinib

28 Acquired Crizotinib Resistance Amplification  Amplification of the ALK fusion gene has also been reported in a small number of crizotinib-resistant tumors

29 Acquired Crizotinib Resistance Alternative Pathway  In crizotinib-resistant tumors, several distinct bypass tracks mediating resistance have been reported.  EGFR ½ cases with crizotinib resistance showed increased EGFR activity  c-KIT Confirmed by IHC, FISH, and c-Kit ligand Stem cell factor (SCF) Can be overcome by Imatinib combine with crizotinib  There may be more than 1 bypass pathway in 1 individual Sci Transl Med 2012 Cancer 2011 Sci Transl Med 2012

30 Mechanisms of resistance to crizotinib in ALK-positive NSCLC Camidge, D. R. Nat Rev Clin Oncol. 2012 Apr 3

31 What Can We Do?

32 Summary of Crizotinib Resistance

33 Novel Agents to Overcome Crizotinib- resistance ALK+ NSCLC  LDK378 (Novartis, Basel, Switzerland)  AP26113(ARIAD Pharmaceuticals, Cambridge, MA),  AF802(Chugai Pharmaceutical, Tokyo, Japan)  ASP3026 (Astellas Pharma, Tokyo, Japan)  STA-9090(Ganetespib)  AUY922  IPI-504  AT 13387  DS-2248 2 nd generation ALK inhibitors HSP90 inhibitors




37 The Possible Difficulties  There may be more than 1 bypass mechanisms in one patient, therefore combination therapy may be needed.  The mutation may be different in different tumor sites in the same patient. Biopsy in different site may be indicated  There may be other unknown bypass pathway  Frontline 2 nd ALK inhibitor, sequential use, or combine with other agent/CT (cocktail use)

38 1. Soda M, et al. Nature 2007; 448: 561-566. 2. McDermott U, et al. Cancer Res 2008; 68: 3389-3395. 3. Koivunen JP, et al. Clin Cancer Res 2008; 14: 4275-4283. 4. Shaw AT, et al. JCO 2009; 27: 4247-4253. 5. Kwak EL, et al. N Engl J Med. 2010; 363: 1693-1703. 6. US Food and Drug Administration. ALK-Positive Timeline 2007 2009 EML4-ALK chromosomal rearrangements reported in NSCLC [1] 2011 EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics [4] Preclinical studies document antitumor activity of ALK inhibitors in lung cancer cell lines and xenografts [2,3] 20082010 Crizotinib produces a response in 47/82 ALK+ patients and a 6-month PFS of 72% [5] FDA approves crizotinib for treatment of ALK+ NSCLC [6] ? 2012 ? 2 nd generation ALK inhibitor TKIs and hsp inhibitors

39 Take Home Message  EML4-ALK defines a new molecular subset of NSCLC  Patients are more likely to be young, never/light smokers with adenocarcinoma  Crizotinib results in a 6-month PFS of 72% and overall response rate of 57% at 6.4 months  2nd generation ALK TKIs and HSP90 inhibitors offer promise in patients with crizotinib resistance

40 Thanks for Your Attention!!

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