Presentation on theme: "NUEVOS AVANCES DE CRIZOTINIB EN EL TRATAMIENTO PERSONALIZADO DE LOS PACIENTES CON CPNM ALK+ AVANZADO Rosario García Campelo Servicio de Oncología Médica."— Presentation transcript:
NUEVOS AVANCES DE CRIZOTINIB EN EL TRATAMIENTO PERSONALIZADO DE LOS PACIENTES CON CPNM ALK+ AVANZADO Rosario García Campelo Servicio de Oncología Médica Hospital Universitario A Coruña
NSCLC care 21 st century “Don Quixotes” “ Aquel loco caballero que tenía por cordura su escudero”
Many important needs in Oncology… We need to know how we got here… We need to determine how to move forward…
The cancer revolution is a result of long investment in research to understand cancer’s biology, together with advances in the way care is delivered to patients every day. Today’s patients benefit from a range of important advances, such as a growing number of approved cancer drugs, more precise and effective surgical techniques, and comprehensive supportive care measures. American Society of Clinical Oncology. J Oncol Pract. 2014 Mar 1;10(2):119-42.
Progress in 5-year survival As a result of this progress, more people are surviving cancer than ever before NEW SCIENTIFIC, TECHNICAL AND ECONOMIC TRENDS ARE LIKELY TO ALTER ONCOLOGY CARE DELIVERY MORE SIGNIFICANTLY IN THE NEXT 20 YEARS THAN IN THE LAST 50.
Drug discovery EML4-ALK discovery First clinical tests Responses in ALK+ patients NEJM publiction PHASE III TRIAL 200720052006200820092010 ASCO ALK+ COHORT Lovly CM et al. Clin Cancer Res 2014
● ALK: – One of 58 transmembrane receptor tyrosine kinases (RTKs) – 1,620 amino acids – Kinase domain between aa 1123-1392 – 177 kDa (calculated MW) – Primarily expressed in nervous system during development – Major ligands: midkine, pleiotrophin – “Dependence receptor” Pro-apoptotic absence of ligand Anti-apoptotic: ligand binding ● ALK: – Located on chromosome 2p23 – 29 exons, 6,223 bp cDNA, 4.9 kB LDLa Anaplastic Lymphoma Kinase Morris SW, et al. Oncogene 1997; 14: 2175-2188 Stoica GE, et al. J Biol Chem 2001; 276: 16772-16779 Stoica Gem et al. J Biol Chem 2002; 277: 35990-35999 Palmer RH, et al. J Biochem. 2009;4201:345–61. Mehlen P, Bredesen DE. Sci Signaling 4 (157) mr2
Transforming Activity of EML4-ALK: a potent oncogenic fusion Soda M. et.al. Nature 2007;448:561-567
WHY SHOULD WE TEST FOR ALK? CRIZOTINIB CLINICAL ACTIVITY Profile 1001, Since 2009…. 1. Kwak EL et al. J Clin Oncol 2009;27:15S abstract 3509 2. Bang Y-J et al. J Clin Oncol 2010;28:18S abstract 3 3. Kwak EL et al. N Engl J Med 2010;363:1693–1703 4. Camidge DR et al. J Clin Oncol 2011;29:18S abstract 2501 5.Camidge DR et al. Lancet Oncol. 2012 Epub ahead of print 6.Kim et al.. Ann Oncol 2012; 23 (suppl 9); Abstr 1225º 7.Shaw A et al. N Engl J Med 2013;368:2385–9 8.Mok T et al. J Clin Oncol 2014; Abstr 8002
Phase 1 Crizotinib Study PROFILE 1001 SoC; standard of care Part 2: Crizotinib 250 mg BID Patients: Molecularly defined No limit on prior regimens Midazolam drug-drug interaction sub-study Efficacy and single-/multi-dose PK data collected Part 2: Crizotinib 250 mg BID Patients: Molecularly defined No limit on prior regimens Midazolam drug-drug interaction sub-study Efficacy and single-/multi-dose PK data collected Part 1: MTD determination Patients: Clinically selected Advanced solid malignancies Refractory to SoC or no SoC available MTD determined as 250 mg BID PK data collected ALK-enriched cohort ALK translocations or gene amplification Patients with NSCLC ALK-enriched cohort ALK translocations or gene amplification Patients with NSCLC MET-enriched cohort Met amplification or activating mutations MET-enriched cohort Met amplification or activating mutations NCT00585195
PATIENTS CHARACTERISTICS: PROFILE 1001 Camidge DR et al. Lancet Oncol 201213(10):1011-9 n (N=149)% Median Age52.0(21–86) Men/Women73/7649/51 Ethnic White Asian Otther 95 41 13 64 28 9 Smoking status Never Former Present 106 42 1 71 28 <1 Histology Adenocarcinoma Large-cell carcinoma Squamous-cell carcinoma Other 144 1 2 2 97 <1 1 1 ECOG: 0 1 ≥2 56 75 18 38 50 12 Number of previous advanced metastatic treatment regimens 1 2 3 ≥4 24 47 31 19 28 16 32 21 13 19 ECOG; Estado funcional del Eastern Cooperative Oncology Group performance status.
No. en riesgo14954110 An impressive RR and Progression free survival Progression-free survival (%) 100 80 0 60 40 20 Time (months) 051015202530 PFS: 9.7 months (IC 95%: 7.7–12.8) RR: 60.8% Camidge DR et al. Lancet Oncol 2012
Open-label, Multicenter, Phase II Study of Crizotinib in Advanced ALK-positive Non-Small Cell Lung Cancer ALK+ NSCLC by central review ECOG PS: 0–3 ≥1 prior line of chemotherapy Brain metastases that were stable/controlled were allowed Not eligible for Phase 3 study Primary endpoints: Response rate, safety, and tolerability Secondary endpoints: OS, TTR, duration of response, disease control rate, PK, biomarkers, PRO/HRQoL (EORTC QLQ-C30 and LC-13) N=400 (planned) Kim et al. Ann Oncol 2012; 23 (suppl 9); Abstr 1225O
PROFILE 1005: Progression-free survival in the mature population (n=261) 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 Survival Distribution Function 05101520 Progression Free Survival time (months) + Censored 95% Hall-Wellner Band n at risk 26117595262 Kim et al. Ann Oncol 2012; 23 (suppl 9); Abstr 1225O ORR: 59.8% Mature population, n=259 response-evaluable patients
Study Design of PROFILE 1007 Key entry criteria ●ALK+ by central FISH testing a ●Stage IIIB/IV NSCLC ●1 prior chemotherapy (platinum-based) ●ECOG PS 0−2 ●Measurable disease ●Treated brain metastases allowed N=318 Crizotinib 250 mg BID PO, 21-day cycle (n=159) Pemetrexed 500 mg/m 2 or Docetaxel 75 mg/m 2 IV, day 1, 21-day cycle (n=159) PROFILE 1007: NCT00932893 Endpoints ●Primary –PFS (RECIST 1.1, independent radiology review) ●Secondary –ORR, DCR, DR –OS –Safety –Patient reported outcomes (EORTC QLQ- C30, LC13) RANDOMIZERANDOMIZE CROSSOVER TO CRIZOTINIB ON PROFILE 1005 a ALK status determined using standard ALK break-apart FISH assay b Stratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no) b
a RECIST v1.1; b ITT population; c as-treated population ORR a by independent radiologic review a RECIST; b Intent-to-treat population; c As treated population; ORR=overall response rate Shaw A, et al. Ann Oncol 2012;23(Suppl9):Abstract 440O 65.3 19.5 ORR (%) ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.0001 Crizotinib (n=173 b ) Chemotherapy (n=174 c ) 80 60 40 20 0 65.7 29.3 6.9 Crizotinib (n=172 c ) Pemetrexed (n=99 c ) Docetaxel (n=72 c ) 40 0 100
PROFILE 1007 Phase III trial: Crizotinib vs chemotherapy in ALK-positive patients a Intent-to-treat population; b HR for death in the crizotinib group; QT=chemotherapy; HR=hazard ratio; PEM/DOC=pemetraxed/docetaxel Shaw A, et al. N Engl J Med 2013;368:2385–2389 Crizotinib (n=173) Chemotherapy (n=174) Events, n (%) 100 (58)127 (73) Median, mo 7.73.0 HR (95% CI) 0.49 (0.37–0.64) P <0.0001 Crizotinib (n=173) PEM/DOC a (n=174) Events, n (%) 49 (28)47 (27) Median, mo 20.322.8 HR (95% CI) 1.02 (0.68 –1.54) b P 0.539
The relevance of QoL QoL=quality of life; CI=confidence interval Shaw A, et al. N Engl J Med 2013;368:2385–2389 Overall change from baseline in symptoms and global QoL Time to deterioration with respect to a composite lung cancer symptom endpoint
A Clinical Trial Testing The Efficacy of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin or Carboplatin in Patients With ALK Positive Non Squamous Cancer of The Lung ( PROFILE 1014 ) Key entry criteria ●ALK+ ●Stage IIIB/IV NSCLC ●First line treatment ●ECOG PS 0−2 ●Measurable disease ●Patients with brain metastases only if treated and neurologically stable. N=334 Crizotinib 250 mg BID PO, 21-day cycle Pemetrexed 500 mg/m 2 + Cisplatin75 mg/m 2 or Carboplatin AUC 5-6 IV, day 1, 21-day cycle Endpoints ●Primary –PFS (RECIST 1.1, independent radiology review) ●Secondary –ORR, DCR, DR –OS –Safety –Patient reported outcomes (EORTC QLQ-C30, LC13) RANDOMIZERANDOMIZE Estimated Enrollment:334 Study Start Date:January 2011 Estimated Study Completion Date:February 2015 Primary Completion Date:November 2013 b ClinicalTrials.gov Identifier: NCT01154140
PROFILE 1014: RR CrizotinibChemotherapy Median time to response (months) 1.42.8 Median duration of response (months) 11.35.3 74% 45% Mok et al. J Clin Oncol 2014, Abst 8002
PROFILE 1014: PFS (ITT Population) Solomon et al. NEJM 2014 10.9 vs 7 m
2 YEARS SURVIVAL RATE NSCLC Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al. Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi et al. Ann Oncol 2014
TOXICITY PROFILE Solomon et al NEJM 2014 Shaw A et al. NEJM 2013
THE REASON FOR ALK TESTING SEEMS QUITE CLEAR… Ph I (1001) n = 149 Ph II (1005) n=261 Ph III (1007) n= 172 (crizo arm) Ph III (1014) N=172 (crizo arm) Line of therapyAny line 32 % 2 nd line 2 nd and beyond 6,6 % 2 nd line 2 nd line1 st line ORR %60.859.865,374 Median duration of response 48.1 wks41.9 wks36 wks49 wks Median duration of treatment 43.1 weeks48 weeks30 weeksNR Median PFS9.7months8.1 months7.7 months10.9 months Survival probability At 12 months 81%NA70%84%
My challenges today… Are we playing in The Champions League?
How should we integrate genetic and clinical information? Crizotinib Ceritinib, alectinib etc or platinum/pem 1L2L Which ALK inhibitor? CNS efficacy Tolerability Resistance mechanism 3L Is there a role for a 3 rd line ALK inhibitor? CNS disease Resistance mechanism Shaw A. ESMO 2014 Novel ALK inh 1L
MIS RETOS.. Mi día a día…y supondo que el de muchos de vosotros… CRIZOTINIB REGULATORY TIMELINE
CELL BLOCK BAL: CITOCENTRIFUGADO BLOQUE CITOLOGICO DE BAL
Beyong first line… SOME KEY QUESTIONS Why did 26% of the patients who received crizotinib in PROFILE 1014 not have a response? Are there combinations of agents that might convert good partial responses to durable complete responses? Is crizotinib still active after PD? Brain mets management
Mechanisms of therapeutic resistance to kinase inhibitors. Lovly C M, and Shaw A T Clin Cancer Res 2014
Novel potent HSP90 inhibitors HSPs are a family of chaperone proteins that shepherd the aberrantly expressed EML4-ALK proteins to their subcellular location and substrates 1 Ipi-504 have demonstrated a RR of 67% in ALK+ NSCLC patients 2 Ganestepib in ALK+: PFS 8.1 m 3 AUY 922 in ALK+: RR 32% (previously treated; 50% in crizotinib-naïve) HSP90 inhibitors alone or in combination with other therapy have the potential to overcome acquired resistance to crizotinib: Crizotinib+Ganetespib (NCT01579994) Crizotinib+AT13387 (NCT01712217) LDK378+AUY922 (NCT01772797) RR=response rate; PFS=progression free survival 1. Crystal A and Shaw A. Clin Cancer Res 2012;18:4479–4481; 2. Sequist LV, et al. J Clin Oncol 2010;28:4953—4960; 3. Socinski MA, et al. Clin Cancer Res 2013;19:3068—3077; 4. Felip E, et al. Ann Oncol 2012;23(Suppl 9):Abstract 4380
Acquired and intrinsic Resistance in ALK+ NSCLC Most patients develop resistance to crizotinib 4,5 Usually within 1–2 years CNS relapses are common 6 Mechanisms of resistance are diverse 4,5 ALK resistance mutations Alternative signaling pathways 1. Camidge DR, et al. Lancet Oncol 2012;13:1011–1019; 2. Kim D-W, et al. ESMO 2012 (Abstr 1230PD); 3. Shaw AT, et al. ESMO 2012 (Abstr LBA1_PR); 4. Katayama R, et al. Sci Transl Med 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res 2012;18:1472–1482; 6. Takeda M, et al. J Thorac Oncol 2013;8:654–657.
Slide 30 Presented By Scott Gettinger at 2014 ASCO Annual Meeting
29.6m 10.8m Ou et al. Lancet Oncol 2014 IS CRIZOTINIB ACTIVE BEYOND PROGRESSION? Clinical outcome of patients who continued Crizotinib Beyond Progressive Disease in PROFILE 1001 and 1005: 174 P
THE BRAIN: A Sanctuary site in ALK+ NSCLC Brain mets at any point in course of disease Shaw et al, TLO 201152% ALK+ crizotinib naive47% ALK+ crizotinib treated Shaw et al, NEJM 2013 PROFILE 1007 35% ALK + crizotinib naive Solomon et al, NEJM 2014 PROFILE 1014 45% ALK+ crizotinib naive Brain mets on treatment Weickhardt et al, ASCO 201246% as site of first progression (85% had CNS as sole site of first progresson) Costa et al, JCO 2011At CNS progression CSF: plasma ratio=0.0026 (<0.3% gets into brain)
Crizotinib in PROFILE 1005 and PROFILE 1007 275 p with asymptomatic BM Intracranial DCR at 12 weeks: 56% if untreated BM 62% if previously treated BM Intracranial ORR (only 40 patients with BM identified as a target lesion at the basal moment) 18% if untreated BM 33% if previously treated BM Costa D, et al. J Clin Oncol 2015
Systemic progression-free survival (PFS) by presence or absence of brain metastases (BM) at baseline (BL) The presence of BM at BL does not significantly affect systemic PFS to crizotinib Costa D, et al. J Clin Oncol 2015
PROFILE 1014: Higher Intracranial DCR with Crizotinib in Patients with Previously Treated Brain Metastases Crizotinib (n=39)Chemotherapy (n=40) DCR, disease control rate (% CR + PR + SD) a Pearson χ 2 test 12 weeks24 weeks DCR (95% exact CI; %) Difference: 40% (95% CI: 21–59) P a =0.0003 Difference: 31% (95% CI: 11–52) P a =0.006 100 80 60 40 20 0 Solomon et al. Ann Oncol 2014; Abst 1225O
I have never accepted the incurability of cancer. And I have remained hopeful, not because of wishful thinking –that´s not progress– but because for the factual evidence of progress Sidney Farber, MD