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Rosario García Campelo Servicio de Oncología Médica

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Presentation on theme: "Rosario García Campelo Servicio de Oncología Médica"— Presentation transcript:

Rosario García Campelo Servicio de Oncología Médica Hospital Universitario A Coruña

2 NSCLC care 21st century “Don Quixotes”
“ Aquel loco caballero que tenía por cordura su escudero”

3 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 Mar 1;10(2):

5 The State of Cancer Care in America 2014
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. Progress in 5-year survival As a result of this progress, more people are surviving cancer than ever before

6 Responses in ALK+ patients
Drug discovery EML4-ALK discovery First clinical tests Responses in ALK+ patients NEJM publiction PHASE III TRIAL 2007 2005 2006 2008 2009 2010 ASCO ALK+ COHORT Lovly CM et al. Clin Cancer Res 2014

7 Anaplastic Lymphoma Kinase
ALK: One of 58 transmembrane receptor tyrosine kinases (RTKs) 1,620 amino acids Kinase domain between aa 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 LDLa ***Drexler ref still needed?**** Figure from Palmer, Biochem J ALK: Located on chromosome 2p23 29 exons, 6,223 bp cDNA, 4.9 kB Morris SW, et al. Oncogene 1997; 14: Stoica GE, et al. J Biol Chem 2001; 276: Stoica Gem et al. J Biol Chem 2002; 277: Palmer RH, et al. J Biochem. 2009;4201:345–61. Mehlen P, Bredesen DE. Sci Signaling 4 (157) mr2

8 Transforming Activity of EML4-ALK: a potent oncogenic fusion
Soda M. Nature 2007;448:

9 ALK oncogenic pathway ALK 2p23 Proliferación Diferenciación

WHY SHOULD WE TEST FOR ALK? CRIZOTINIB CLINICAL ACTIVITY Profile 1001, Since 2009…. 2009 N: 19 2010 N: 82 2011 N: 119 2012 N: 149 N 261 2013 N 347 2014 N 343 Patients could be tested by any FISH test in any lab, but ALK positivity had to be confirmed by FISH in a central lab. Brain mets were allowed if treated and stable 1. Kwak EL et al. J Clin Oncol 2009;27:15S abstract 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– Camidge DR et al. J Clin Oncol 2011;29:18S abstract Camidge DR et al. Lancet Oncol 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

11 Phase 1 Crizotinib Study PROFILE 1001
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 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 ALK-enriched cohort ALK translocations or gene amplification Patients with NSCLC MET-enriched cohort Met amplification or activating mutations SoC; standard of care NCT

n (N=149) % Median Age 52.0 (21–86) Men/Women 73/76 49/51 Ethnic White Asian Otther Smoking status Never Former Present 71 28 <1 Histology Adenocarcinoma Large-cell carcinoma Squamous-cell carcinoma Other 97 <1 1 1 ECOG: ≥2 Number of previous advanced metastatic treatment regimens ≥4 Camidge DR et al. Lancet Oncol (10):1011-9 We always gave data on 119 patients which was cohort presented by Camidge at ASCO 2011 During one of the poster discussions some emphasis was put on the wide age range, which here is 21 to 86, Don’t remember that we do not only have never smokers. Approx one third is former smoker and this will also be emphasized in 1005 Esst adenocarcinoma, but in a poster from East Asia fe on 392 tissue samples using RT-PCR and validation with sequencing, they found overall 6.1% ALK pos but this in 5 pts with squamous cell CA and 5 pts with adenosquamous CA. (14 were pure adeno) Updated info shows now 24 pts in first line, which is more than the 13 pts reported by Camidge at ASCO last year However, till approx one third has 3 or more previous treatment lines ECOG; Estado funcional del Eastern Cooperative Oncology Group performance status.

13 An impressive RR and Progression free survival
100 PFS: 9.7 months (IC 95%: 7.7–12.8) RR: 60.8% 80 60 Progression-free survival (%) 40 20 No. en riesgo Time (months) Camidge DR et al. Lancet Oncol 2012

14 administered continuously
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 Crizotinib 250 mg BID administered continuously (21-day cycle) 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

15 Survival Distribution Function Progression Free Survival time (months)
PROFILE 1005: Progression-free survival in the mature population (n=261) 1.0 Median PFS 8.1 months (95% CI: 6.8–9.7) 28% patients in follow-up for progression + Censored 95% Hall-Wellner Band 0.8 ORR: 59.8% Mature population, n=259 response-evaluable patients 0.6 Survival Distribution Function 0.4 0.2 Progression Free Survival time (months) n at risk Kim et al. Ann Oncol 2012; 23 (suppl 9); Abstr 1225O

16 Study Design of PROFILE 1007
Endpoints Primary PFS (RECIST 1.1, independent radiology review) Secondary ORR, DCR, DR OS Safety Patient reported outcomes (EORTC QLQ-C30, LC13) Key entry criteria ALK+ by central FISH testinga Stage IIIB/IV NSCLC 1 prior chemotherapy (platinum-based) ECOG PS 0−2 Measurable disease Treated brain metastases allowed Crizotinib 250 mg BID PO, 21-day cycle (n=159) R A N D O M I Z E Pemetrexed 500 mg/m2 or Docetaxel 75 mg/m2 IV, day 1, 21-day cycle (n=159) b Say it is validated lung cancer symptom and QOL questionnaire. N=318 CROSSOVER TO CRIZOTINIB ON PROFILE 1005 aALK status determined using standard ALK break-apart FISH assay bStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no) PROFILE 1007: NCT

17 ORRa by independent radiologic review
ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.0001 100 Crizotinib (n=173b) 65.7 29.3 6.9 Crizotinib (n=172c) Pemetrexed (n=99c) Docetaxel (n=72c) 40 Chemotherapy (n=174c) 65.3 80 60 ORR (%) 40 19.5 20 aRECIST; bIntent-to-treat population; cAs treated population; ORR=overall response rate Shaw A, et al. Ann Oncol 2012;23(Suppl9):Abstract 440O aRECIST v1.1; bITT population; cas-treated population

18 PROFILE 1007 Phase III trial: Crizotinib vs chemotherapy in ALK-positive patients
Events, n (%) 100 (58) 127 (73) Median, mo 7.7 3.0 HR (95% CI) 0.49 (0.37–0.64) P <0.0001 Crizotinib (n=173) PEM/DOCa (n=174) Events, n (%) 49 (28) 47 (27) Median, mo 20.3 22.8 HR (95% CI) 1.02 (0.68 –1.54)b P 0.539 aIntent-to-treat population; bHR 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

19 The relevance of QoL Time to deterioration with respect to a composite lung cancer symptom endpoint Overall change from baseline in symptoms and global QoL QoL=quality of life; CI=confidence interval Shaw A, et al. N Engl J Med 2013;368:2385–2389

20 PFS (RECIST 1.1, independent radiology review)
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) Endpoints Primary PFS (RECIST 1.1, independent radiology review) Secondary ORR, DCR, DR OS Safety Patient reported outcomes (EORTC QLQ-C30, LC13) 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 . Crizotinib 250 mg BID PO, 21-day cycle R A N D O M I Z E Pemetrexed 500 mg/m2 + Cisplatin75 mg/m2 or Carboplatin AUC 5-6 IV, day 1, 21-day cycle b N=334 Estimated Enrollment:334 Study Start Date:January 2011 Estimated Study Completion Date:February 2015 Primary Completion Date:November 2013 Identifier: NCT

21 PROFILE 1014: RR 74% 45% Crizotinib Chemotherapy
Median time to response (months) 1.4 2.8 Median duration of response (months) 11.3 5.3 Mok et al. J Clin Oncol 2014, Abst 8002

22 PROFILE 1014: PFS (ITT Population)
10.9 vs 7 m Solomon et al. NEJM 2014

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

24 TOXICITY PROFILE Solomon et al NEJM 2014 Shaw A et al. NEJM 2013

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 therapy Any line 32 % 2nd line 2nd and beyond 6,6 % 2nd line 2nd line 1st line ORR % 60.8 59.8 65,3 74 Median duration of response 48.1 wks 41.9 wks 36 wks 49 wks Median duration of treatment 43.1 weeks 48 weeks 30 weeks NR Median PFS 9.7months 8.1 months 7.7 months 10.9 months Survival probability At 12 months 81% NA 70% 84%





30 My challenges today… Are we playing in The Champions League?

31 Is there a role for a 3rd line ALK inhibitor? • Resistance mechanism
How should we integrate genetic and clinical information? 1L 2L 3L Is there a role for a 3rd line ALK inhibitor? • CNS disease • Resistance mechanism Crizotinib Ceritinib, alectinib etc or platinum/pem 1L 2L Which ALK inhibitor? • CNS efficacy • Tolerability • Resistance mechanism Novel ALK inh Shaw A. ESMO 2014

32 MIS RETOS.. Mi día a día…y supondo que el de muchos de vosotros…
Mujer 24 años, dx el pasado 31/10/2014 Adenocarcinoma pulmón estadio IV, M1 hepáticas, cerebrales, pulmonares, óseas, DP bilateral, pericárdico.. EML4-ALK+ 9 Septiembre 2011 Aprobación FDA 23 Octubre 2012 Aprobación EMA AEMPS 12 Noviembre 2012 Mayo 2014 CF farmacia CHUAC Comisión uso medicamentos de alto impacto Noviembre 2014 Febrero 2015 Comisión Central Autonómica pendiente CRIZOTINIB REGULATORY TIMELINE





37 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

38 Mechanisms of therapeutic resistance to kinase inhibitors.
Mechanisms of therapeutic resistance to kinase inhibitors. Resistance to targeted therapies can be classified as primary resistance or acquired resistance. Primary resistance is defined as a de novo lack of treatment response and can be mediated by tumor intrinsic factors, such as concurrent genetic alterations within the drug target or within other signaling molecules, and by patient-specific factors, such as drug–drug interactions. Conversely, acquired resistance refers to disease progression after an initial response to the targeted therapy. Acquired resistance develops while the patient is still receiving the targeted therapy, implying that the tumor has developed an “escape” mechanism to evade continuous blockade of the target. These “escape” mechanisms include target modification (gene amplification, second-site mutations, splice variants), the emergence of bypass signaling tracks, histologic transformation, as well as other less well-characterized mechanisms such as increased growth factor production. Examples of strategies to overcome acquired resistance, which are discussed in more detail within the text, include alternative doses or schedules of the targeted inhibitor, development of more potent “next-generation” inhibitors, dual blockade of the initial target with two or more target-specific agents, and combination drug strategies designed to suppress compensatory signaling loops. Lovly C M , and Shaw A T Clin Cancer Res 2014

39 Novel potent HSP90 inhibitors
HSPs are a family of chaperone proteins that shepherd the aberrantly expressed EML4-ALK proteins to their subcellular location and substrates1 Ipi-504 have demonstrated a RR of 67% in ALK+ NSCLC patients2 Ganestepib in ALK+: PFS 8.1 m3 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 (NCT ) Crizotinib+AT13387 (NCT ) LDK378+AUY922 (NCT ) 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 39

40 Acquired and intrinsic Resistance in ALK+ NSCLC
Most patients develop resistance to crizotinib4,5 Usually within 1–2 years CNS relapses are common6 Mechanisms of resistance are diverse4,5 ALK resistance mutations Alternative signaling pathways Refs: Kim, S., et al., JTO 2013 Apr 8:415-22 Huang, D et al., Genomics 2013 Feb 20 Katayama R et al., Sci Translational Med 4 120ra17 (2012) Doebele et al., Clin CA Research 2012 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.

41 Presented By Scott Gettinger at 2014 ASCO Annual Meeting
Slide 30 Presented By Scott Gettinger at 2014 ASCO Annual Meeting

IS CRIZOTINIB ACTIVE BEYOND PROGRESSION? Clinical outcome of patients who continued Crizotinib Beyond Progressive Disease in PROFILE 1001 and 1005: 174 P 29.6m 10.8m Ou et al. Lancet Oncol 2014


44 Brain mets at any point in course of disease Brain mets on treatment
THE BRAIN: A Sanctuary site in ALK+ NSCLC Brain mets at any point in course of disease Shaw et al, TLO 2011 52% ALK+ crizotinib naive 47% 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 2012 46% as site of first progression (85% had CNS as sole site of first progresson) Costa et al, JCO 2011 At CNS progression CSF: plasma ratio= (<0.3% gets into brain)

45 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

46 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

47 PROFILE 1014: Higher Intracranial DCR with Crizotinib in Patients with Previously Treated Brain Metastases Crizotinib (n=39) Chemotherapy (n=40) Difference: 40% (95% CI: 21–59) Pa=0.0003 Difference: 31% (95% CI: 11–52) Pa=0.006 100 80 60 DCR (95% exact CI; %) 40 20 12 weeks 24 weeks DCR, disease control rate (% CR + PR + SD) aPearson χ2 test Solomon et al. Ann Oncol 2014; Abst 1225O

48 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

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