430 likes | 1.23k Views
Targeting ALK in Advanced NSCLC A New Treatment Paradigm. Alice T. Shaw, MD PhD Massachusetts General Hospital Cancer Center Harvard Medical School August 25, 2012. Oncogenic Drivers in NSCLC. KRAS 24% 1. EGFR 13% 1. PIK3CA 4% 1. RET ~1% 5. ALK 3% 2. M ET ~1% 4. HER2 2 % 3.
E N D
Targeting ALK in Advanced NSCLC A New Treatment Paradigm Alice T. Shaw, MD PhD Massachusetts General Hospital Cancer Center Harvard Medical School August 25, 2012
Oncogenic Drivers in NSCLC KRAS 24%1 EGFR 13%1 PIK3CA 4%1 RET ~1%5 ALK 3%2 MET ~1%4 HER2 2%3 1Sequist et al., Ann Oncol 22:2616, 2011 2Takeuchi et al., Nat Med, Feb 12 2012 3Shaw et al., NEJM 365:158, 2011 4Kris et al., WCLC 2011 5Takeuchi et al., Nat Med, Feb 12 2012 NRAS 1%1 BRAF 2%1 AKT ~1%3 ROS ~1%2
The Promise of Genotype-Directed Therapy Treatment B Treatment A NSCLC Treatment C Treatment D
The Promise of Genotype-Directed Therapy ALK (or ROS) Crizotinib, other ALK TKIs EGFR mutation Erlotinib or gefitinib NSCLC Treatment C Treatment D
Crizotinib an update
Crizotinib: A Dual MET/ALK Tyrosine Kinase Inhibitor 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
Marked Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase 1 Study ORR = 60.8%* in 143 evaluable patients (133 evaluable patients shown) Median response duration = 49.1 wks Median PFS = 9.7 mos *Higher ORR in Asians vs non-Asians -30 Camidge et al., Lancet Onc, in press
Phase 2 Study: PROFILE 1005 • Key entry criteria • Positive for ALK by central laboratory (local testing subsequently allowed on case-by-case basis) • Progressive disease in Arm B of PROFILE 1007 study • >1 prior chemotherapy • ECOG PS 0-3 • Stable/controlled brain mets allowed • Crizotinib250 mg BID • administered PO on a • continuous dosing • schedule N=250 >1000 NCT00932451
Marked Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase 2 Study 100 PD SD PR CR 80 60 40 20 0 Decrease or increase from baseline (%) –20 –40 –60 + + –80 –100 + + –120 *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 Kim et al., ASCO 2012
Marked Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase 2 Study 1.0 Median PFS 8.1 months (95% CI: 6.8–9.7) 28% patients in follow-up for progression 0.8 + Censored 95% Hall-Wellner Band 0.6 Probability of survival without progression 0.4 0.2 0 0 5 10 15 20 Time (months) n at risk 261 175 95 26 2 Kim et al., ASCO 2012
PROFILE 1005: Any-Grade Treatment-Related AEs in ≥10% of Patients *Includes visual impairment, photopsia, vision blurred, vitreous floaters, photophobia and diplopiaRare instances of fatal pneumonitis and fatal hepatotoxicitywere reported in crizotinib clinical trial program
Phase 3 Study: PROFILE 1007 • Crizotinib 250 mg BID • administered PO on • a continuous dosing • schedule • (N=159) • Endpoints • Primary • - PFS (RECIST 1.1, • independent review) • Secondary • - ORR, DR, DCR • - OS • - Safety • - Patient reported • outcomes (PROs) • Key entry criteria • Positive for ALK by central FISH testing • Stage IIIB/IV NSCLC • 1 prior chemotherapy (platinum-based) • ECOG PS0-2 • Measurable disease • Treated brain metastases allowed1 RANDOMIZE • Pemetrexed500 mg/m2 • or • Docetaxel 75 mg/m2 • infused IV on day 1 • of a 21-day cycle • (N=159) N=318 NCT00932893
Next Generation ALK TKIs LDK378
Mechanisms of Crizotinib Resistance Target gene alteration (28%) ?? No loss of ALK (26/26) No EGFR or KRAS mutations (21/21) * Bypass track activation (45%) *
LDK378: A Potent and Selective ALK Inhibitor • 2,4-diaminopyrimidine derivative. MW: 558.14 • Potent, ATP-competitive inhibitor of ALK Li et al., AACR-NCI-EORTC, 2011; Mehra et al., ASCO 2012
Preclinical Evaluation of LDK378 Activity NCI-H2228 sensitive xenograft models • LDK378 caused complete tumor regression after 14 days of treatment • No growth of tumors for >4 months in mice treated with LDK378 50 mg/kg/day Li et al., AACR-NCI-EORTC, 2011 • LDK378 caused complete tumor regression when dosed at 25 mg/kg/day or 50 mg/kg/day in mouse xenograft tumor model derived from NCI-H2228 (EML4-ALK, NSCLC) after 14 days of treatment. • Remission was maintained for more than 4 months after 14 days of treatment with LDK378 50 mg/kg/day.
Preclinical Evaluation of LDK378 Activity Crizotinib-resistant xenograft models ALK C1156Y mutation No ALK mutation • LDK378 at 50-100mg/kg/day has antitumor activity in different crizotinib-resistant models Li et al., AACR-NCI-EORTC, 2011
Phase I study of LDK378 ALK+ lung cancer Resistant to prior ALKi MTD ALK+ lung cancer Naive to prior ALKi Any ALK+ cancer Non-lung ALK+ tumors LDK378 continuous oral dosing Primary objective: Determine the MTD Secondary objectives: Safety, pharmacokinetics, and antitumor activity NCT01283516
Baseline Patient Characteristics Mehra et al., ASCO 2012
Adverse events associated with LDK378 • SAEs related to LDK378 have occurred in 5 patients • Transaminase elevation (400 mg), vomiting (500 mg), dehydration (600 mg), and interstitial lung disease (750 mg) • All SAEs were reversible upon cessation of LDK378 • Two patients resumed treatment with LDK378 a lower dose level • Two had simultaneous progressive disease • Common AEs included • Nausea (59%), vomiting (54%), and diarrhea (48%), fatigue (21%), and dyspnea (16%) • Only one patient has discontinued treatment because of an AE Mehra et al., ASCO 2012
Antitumor Activity of LDK378 in ALK+ NSCLC • Response rate 81% (21/26)in NSCLC patients treated at ≥400 mg who progressed following crizotinib • Responses include confirmed + unconfirmed per RECIST 1.0 (6 patients with PR awaiting confirmatory scans) Mehra et al., ASCO 2012
Typical Responses to LDK378 After 6 weeks on LDK378 Baseline Mehra et al., ASCO 2012
Typical Responses to LDK378 After 6 weeks on LDK378 Baseline Mehra et al., ASCO 2012
CNS Activity of LDK378 After 6 weeks on LDK378 Baseline Mehra et al., ASCO 2012
Summary of LDK378 • The MTD of LDK378 is 750 mg PO qd • The most common AEs are nausea, vomiting and diarrhea • LDK378 exhibits potent antitumor activity in patients with ALK+ NSCLC, particularly in those who have progressed following crizotinib • LDK378 is active in brain metastases
Other Next Generation ALK TKIs CH5424802 AP26113
CH5424802 is a Potent and Selective ALK TKI A C B Sakamoto et al., Cancer Cell 2011;19:679-90
AP26113 is a Potent and Selective ALK TKI Crizotinib AP26113 ALK-negative cells EML4-ALK -L1196M Relative Cell Viability EML4-ALK Drug Concentration (nM) • Ba/F3 cells (ALK-negative) engineered to express EML4-ALK or the L1196M mutant • AP26113, but not crizotinib, inhibits viability of the L1196M mutant with high selectivity • Similar results obtained with multiple other mutants, including G1269S, S1206R, C1156Y, F1174C, F1245C, I1174T and L1152V Zhang et al, AACR 2010
Phase I/ II Schema Phase 1/2 Study of AP26113 * Tissue must be obtained after development of resistance to ALK (cohort 2) or EGFR (cohort 3) TKI therapy
Summary • Crizotinib is now a standard therapy for patients with advanced, ALK+ NSCLC - ORR 60% - Median PFS 8-9 months - Phase 3 studies More potent ALK TKIs like LDK378 may be effective salvage therapies for the majority of patients who relapse on crizotinib •
Future Directions • Timing of next generation ALK TKIs Front-line use of next generation ALK TKIs Mechanism of action Overcoming resistance vs more potent target inhibition Resistance to next generation ALK TKIs Developing combination strategies - • - • •