Cancer de Pulmón ALK+: Nueva generación de inhibidores. Incremento de supervivencia

Transcription

1 Cancer de Pulmón ALK+: Nueva generación de inhibidores. Incremento de supervivencia Carlos Camps Jefe Servicio Oncología Médica Hospital General Universitario Valencia Profesor Titular Medicina Lab Oncologia Molecular Fundación de Investigación News Drivers

2 Lung Cancer. What do we need to do? Improve habits and decrease incidence. Earlier diagnosis Optimize therapy more effective therapies. Oncogenic addiction

3 Shaw, et al. N Engl J Med (25): ; Solomon, et al. N Engl J Med (23): Crizotinib has changed the paradigm of NSCLC treatment

4 Crizotinib 2 on Line Crizotinib 1st Line Previously treated Shaw et al. NEJM 2013 Salomon et al. NEJM 2014 First line Lancet Oncol 2017 NEJM 2017

5 SOME CONTROVERSIES 1. Treatment with crizotinib beyond progression does it have any sense with the new ALKi? Should we use 2nd, 3rd ALKi from the very beginning? 2. How should we treat patients harboring brain mets?

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7 ACTIVITY OF ALK INHIBITORS IN CRIZOTINIB TREATED PATIENTS Drug Study RR mpfs Ceritinib 1,2,3 Phase I ASCEND-1 Phase II ASCEND-2 Phase III ASCEND-5 56% 38.6% 39.1% Alectinib 4--7 Phase I/II AF-001JP Phase II NP28761 Phase II NP28673 Phase III ALUR 55% 52% 50% 37.5% NA Brigatinib 8 Phase I/II 55% 15.6 Lorlatinib 9,10 Phase I Phase II 42-46% 69% Ensartinib 11 Phase I/II 64% Not Reached 1. Kim DW et al. Lancet Oncol Mok T et al. J Clin Oncol 2015 Abstr Shaw A et al. Lancet Oncol Seto T et al. Lancet Oncol Shaw A et al. Lancet Oncol Ou SH et al. J Clin Oncol Novello S, et al. ESMO Bazhenova et al. ESMO Shaw A, et al. Lancet Oncol Ahn W et al. WCLC Horn et al. ESMO 2016.

8 Activity of ALK inhibitors in crizo-naive ALK+ patients Drug Study ORR mpfs Crizotinib Phase I PROFILE 1001 Phase II PROFILE % 59.8% Ceritinib Phase I ASCEND-1 Phase II ASCEND-3 72% 63% Alectinib Phase I/II AF-001JP 93.5% NR Brigatinib Phase I/II 100% 34.2m Lorlatinib Phase II 90% NR Ensartinib Phase II 80% (FISH)- 92% NGS 23.8m Camidge DR, et al Lancet Oncol Kim DW, et al. ASCO 2012.Kim DW et al. Lancet Oncol Felip E et al. ESMO 2016; Tamura T, et al. J Clin Oncol Bazhenova L et al. ESMO Solomon et al WCLC Wakelee H et al. WCLC 2017

9 ASCEND-4: randomised, multicentre, phase III, open-label study of 1L ceritinib vs chemo in ALK+ NSCLC Newly diagnosed stage IIIB/IV or relapsed locally advanced or metastatic non-squamous NSCLC Ceritinib 750mg/day ALK+ disease according to IHC No previous treatment* R 1:1 1 measurable lesion as defined by RECIST 1.1 (n=348) Pemetrexed/cisplatin or pemetrexed/carboplati n i.v. q3w Pemetrexed maintenance Primary endpoint PFS (assessed by BIRC per RECIST 1.1) Secondary endpoints PFS (investigator) ORR DoR DCR Safety PROs Time to response OS OIRR DOIR ICBR *Exception of neo-adjuvant or adjuvant therapy Cycle = 21 days; Duration = four cycles of treatment (induction) followed by pemetrexed alone as single agent (maintenance) every 21 days in patients without blinded independent review committee (BIRC) progressive disease (PD) after induction chemotherapy DCR, disease control rate; DOIR, duration of intracranial response; DoR, duration of response; ICBR, intracranial clinical benefit rate; OIRR, overall intracranial response rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRO, patientreported outcomes Soria JC, et al. Lancet 2017;389:917 29

10 Soria JC, et al. Lancet 2017 ASCEND-4: PFS in patients with and without brain metastases at baseline Patients with brain metastases at baseline Patients without brain metastases at baseline

11 ALEX STUDY DESIGN Primary endpoint Secondary endpoints Investigator-assessed PFS in the ITT population Time to CNS progression, CNS ORR, CNS DoR (CNS endpoints were assessed by IRC) Stage IIIB/IV NSCLC ALK+ disease according to IHC test Treatment naïve ECOG PS 0 2 Brain metastases permitted if asymptomatic (n=303) R 1:1 Alectinib 600mg BID (n=152) All patients underwent restaging chest/abdominal CT scans and brain imaging every 8 weeks Crizotinib 250mg BID (n=151) Until PD*, toxicity, withdraw al or death Subseque nt therapy and survival follow-up mpfs: NR vs 11.1m mpfs (IRC): 25.7 VS 10.4 Peters, et al. NEJM 2017 RR 75.5 vs 82.9% 11

12 ALEX phase 3 study: Secondary endpoint PFS by CNS disease Patients WITH CNS metastases at baseline Patients WITHOUT CNS metastases at baseline 100 Alectinib (n=64) 100 Alectinib (n=88) 80 Crizotinib (n=58) 80 Crizotinib (n=93) PFS (%) NR (95% CI: 9.2 NR) PFS (%) NR (95% CI: ) (95% CI: ) 0 0 Day Day Duration of PFS (months) Duration of PFS (months) HR=0.40 p< HR=0.51 p= *Investigator assessed All patients with CNS metastases at baseline, irrespective of RT Shaw, et al. ASCO 2017 Gadgeel, Shaw A, ASCO et al. 2017; ESMO Peters 2017NEJM 2017

13 Patients frequently present with multiple brain metastases; approximately 50% of patients with brain metastases at diagnosis have 4 lesions CNS: a Sanctuary Site 40% of ALK+ have CNS metastases at diagnosis CNS is among the most common sites of relapse on crizotinib Among Crizotinib resistant patients entering trials of next-generation ALK inhibitors, rates CNS metastases approach 60%

14 Shaw A, et al. Lancet Oncol 2017 De Castro J, et al. ESMO 2017 Ahn W, et al. WCLC 2017 Solomon et al, WCLC Lancet Oncol 2017 ALK TKI CNS Disease activity Post-Crizotinib Drug/ TRIAL Objective response rate in CNS measurable disease CNS PFS Ceritinib ASCEND 5 Phase III Alectinib ALUR Phase III Brigatinib ALTA Phase II 90->180mg dose Lorlatinib Phase II (Multiple prior TKIs permissible) 35% mpfs 4.4m 54% mpfs % mpfs 18.4 m 48-68% NR

15 Summary Phase III 1 st line ALK inhibitors ALEX Alectinib J-ALEX Alectinib ASCEND-4 Ceritinib ALEX/ J-ALEX Crizotinib mpfs IRC (m) HR PFS NA ORR (%) mdor (m) NR NE Peters S, et al. NEJM Hida T, et al. Lancet Soria JC et al. Lancet 2017

16 1 st line Phase III trials: CNS activity ALEX Alectinib J-ALEX Alectinib ASCEND-4 Ceritinib ALEX J-ALEX Crizotinib PFS BM NR (> 27) NR (>21) CNS ORR 81% % 50% CNS DOR Peters S, et al. NEJM 2017 Hida T, et al. Lancet 2017 Soria JC et al. Lancet 2017

17 MAIN ELEMENTS FOR DECISSION EFFICACY PFS OS INTRACRANIAL EFFICACY RR, PFS, mdor Protective effect TOXICITY 15.3 months difference in PFS BRAIN ACTIVITY BRAIN METS PROTECTION!!! ALEX IS A WINNER

18 Toxicity can be an element for decission Hepatotoxicity Neutropenia Fatigue Diarrhoea Nausea Constipation Lipase Amylase ALKi Zhou Q et al. BMC Cancer 2017 MA 10 trial 1826 pts

19 Ongoing Phase III trials

20 ALTA phase II: Brigatinib OS in previously Crizo treated ALK NSCLC patients OS 27.6m Treatment Median OS (95% CI) HR (95% CI) Arm A: 90 mg qd (% events = 38) NR (20.2 NR) 0.67 Arm B: 90 mg 180 mg qd a (% events = 29) 27.6 (27.6 NR) ( ) Ahn W, et al. WCLC 2017

21 How can we optimize outcomes among TKI inh? Brigatinib Alectinib Ceritinib ALK+ Crizotinib Lorlatinib Sequential approach? Resistant mutations? Brain activity? Toxicity profile? Wakelee H, J Thorac Dis 2017 Perphaps selection of a first line agent is slightly more complex than meets the eye Perphaps..it may matter less what ALK inhibitor a patient sarts on, rather than how they are sequentially managed based on their evolving tumor biology

22 Sum of longest diameter, maximum decrease from baseline (%) Most Crizotinib-Resistant Patients Respond to More Potent, 2nd Generation ALK Inhibitors 140 Global Phase 2 Study of Alectinib Systemic BOR: PD (n=22) SD (n=35) PR (n=61) NE (n=1) Missing (n=3) * * * * * * ORR 50% Median PFS 8.9 mos Median DOR 11.2 mos * ** * ** * * * * * * ** * * * * Change in measurable disease size for all patients who received alectinib 600 mg BID *Chemotherapy naïve patients Ou et al., JCO 2016;34(7):661-8

23 No 2nd ALKi 28.2m 2nd ALKi and beyond 89.6m BSC post Crizo19.6m Defining the best sequence for every single patient OS 7.5 years Duruisseau M, et al. Oncotarget 2017

24 PROFILE 1014: Impact of Subsequent Therapy on OS: ALK TKI versus Treatment Other Than ALK TKI Overall Survival (%) NR 49.5m + Censored m m Months Crizotinib followed by any ALK TKI Crizotinib followed by any follow-up therapy other than ALK TKI Chemotherapy followed by any ALK TKI Chemotherapy followed by any follow-up therapy other than ALK TKI Mok T, et al. ESMO 2017

25 Figure 5 Journal of Thoracic Oncology , DOI: ( /j.jtho )

26 THE WHOLE PICTURE PFS1 + PFS2 + PFS3 (PROFILE ALTA + Lorlatinib Phase 2) OR PFS1 + PFS2 (ALEX + Lorlatinib Phase 2) Total PFS = 34.5 months!! PROFILE 1014 Phse III Crizotinib Median PFS = 10.9 m ALTA Phase II Brigatinib Median PFS = 16.7 m Lorlatinib Phase II Median PFS = 6.9 m Total PFS = 31.2 months! QT IO ALEX Phase III Alectinib Median PFS = 25.7 m Lorlatinib Phase II Median PFS = 5.5m Adapted from Ou I. WCLC 2017

27 Patrones moleculares de Resistencia a inhibidores ALK Unknown Alectinib mantiene la eficacia contra la mutacion de resistencia ALK L1196M ALK amp ALK+ ALK mut No ALK amp or mut Bypass tracks Katayama R, et al. Sci Transl Med 2012;4:120ra17; Doebele RC, et al. Clin Cancer Res 2012;18: ; Takeda M, et al. J Thorac Oncol 2013;8:

28 Different ALK TKIs Have Different Potencies Depending on the ALK Resistance Mutation Cellular ALK Phosphorylation Mean IC50 (nm) IC50 50 nm IC50 > 50 <200 nm IC nm Gainor et al., Cancer Discov 2016;6(10):

29 Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer ALK resistance mutations, G1202R, were more common with EML4-ALK variant 3. In third-generation TKI, progression-free survival was longer with EML4-ALK variant 3. Lin J et al. J Clin Oncol 2018

30 Lorlatinib is Effective Against ALK G1202R and Other Resistance Mutations (Phase 1) Best response Duration of treatment Shaw et al. Lancet Oncol,

31 Tailoring Selection of Third-Line ALK Targeted Strategies G1202R 3L Lorlatinib therapy 1L Crizotinib PD 2L 2 nd generation ALK TKI PD I1171 Ceritinib or Lorlatinib 1L 2 nd generation ALK TKI PD REBIOPSY L1196M F1174 L1198F compound WT Alectinib or Lorlatinib Crizotinib ALK-based combo

32 Allele fraction Clonal Evolution of Resistance in ALK+ NSCLC Plasma-Based Detection of Clinically Actionable ALK Resistance Mutations crizotinib alectinib ceritinib EML4-ALK ALK I1171N (resistant to alectinib, sensitive to ceritinib) Time (days) Dagogo-Jack et al., in press

33 La lesión de mandíbula aumenta de tamaño ALK + (EML4-ALK traslocation) PD ALK+ platelets 3 resistance mutation detected to Crizotinib & Brigatinib TKI (1st generation, Crizotinib) TKI(2nd generation, Brigatinib) Lorlatinib Guardant 360 Jantus & Camps Lab 2017

34 Crizotinib Resistance is Often Mediated by Secondary ROS1 Resistance Mutations WT 47% G2032R 41% S1986F 6% D2033N 6% Gainor et al., JCO precision oncol, Aug

35 MET mut+ NSCLC

36 Entrectinib in ROS1+ NSCLC Updated information IASLC 17 (abstract 8564) Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC Drilon Cancer Discov 17

37 Recent advances in targeting ROS1 in lung cancer Jessica J. Lin & Alice T. Shaw, JTO 2017

38 N Engl J Med 2017;377:849 1,070 patient samples were profiled using CGP 47 were found to harbour ALK rearrangements, of which 31 had prior FISH results available FISH testing missed 35% of ALK rearrangements identified by CGP ALK FISH false-negative patients can be targeted therapeutically and are clinically significant Ali, S.M., et al. (2016) The Oncologist 21:

39 Are we testing our whole population? En la mayoría de hospitales grandes el estudio de ALK está protocolizado Isla CD et al Congreso SEOM Madrid 2016

40 Optimizing treatment in ALK+ NSCLC New Ways to work.. Molecular Tumor Board Relevance of molecular testing and Brain mets management Next generation ALK inhibitors are active in Crizotinib resistant Two Phase III trials confirm the superiority of Alectinib vs Crizotinib in 1 st line setting in terms of PFS, with impressive results in BM control. Molecular mechanisms of resistance and toxicity profile may be relevant for patient selection and the answer for the best sequence. (NGS the solution)