OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Una Visión Actualizada Dolores Isla Servicio de Oncología Médica HCU Lozano Besa de Zaragoza

Targeted NO Therapies with Molecular Selection YES

1st-LINE

NECITUMUMAB Targeted Therapies NO

NINTEDANIB with 2ND-3RD- Molecular LINE YES Selection AFATINIB BEVACIZUMAB

st Targeted 1 -LINE Therapies NO 2ND-3RD- with LINE Molecular YES Selection OS

PFS

Soria JC, Ann Oncol 2013 SQUIRE Study

EGFR IHC >0 (95,2%) as a Biomarker

Paz-Ares L, ELCC 2016

Thatcher N, Lancet Oncol 2015 1st-LINE Targeted ERLOTINIB NO Therapies 2ND-3RD- LINE with RAMUCIRUMAB Molecular YES Selection AFATINIB BR.21 Study

• Erlotinib significantly 1.00

prolongs survival,

improves QoL and 0.75 symptom control in relapsed advanced 0.50 HR=0.73, p<0.001 NSCLC

0.25 Erlotinib

rd function distribution Survival • Also indicated in 3 - Placebo Line and PS=3 0 0 5 10 15 20 25 30 Survival time (months)

Shepherd F, N Engl J Med 2005 Bezjak A, J Clin Oncol 2005 LUME-LUNG 1 Study

HR=0.79, p=0.0019 Median 3,4 vs 2,7 m

Reck M, Lancet Oncol 2014 REVEL Study

Garon EB, Lancet 2014 LUX-LUNG 8 Study

Soria JC, Lancet Oncol 2015 Targeted NO

Therapies with EGFR Molecular Selection YES ALK

OTHERS Frequency of Molecular Aberrations in Lung Adenocarcinomas and Drugs against these oncogenic proteins

Tsao A, JTO 2016

Targeted ERLOTINIB NO Therapies AFATINIB with EGFR Molecular YES ALK Selection OTHERS HM61713 Phase III studies with EGFR-TKI vs Platinum based-CT in 1st-L EGFR mutated p.

PFS Group Study N TKI Control HR

WJTOG 3405 177 gefitinib cis + doc 0.48

NEJ 002 230 gefitinib carbo + pac 0.30

China OPTIMAL 165 erlotinib carbo + gem 0.16

platinum-based SLCG EURTAC 174 erlotinib 0.37 doublets

Asia ENSURE 217 erlotinib cis + gem 0.37

Asia / LUX-Lung 3 345 afatinib cis + pem 0.58 Non-Asia

Asia LUX-Lung 6 364 afatinib cis + gem 0.28 Park K, Lancet Oncol 2016 Phase II 1st-line , an irreversible pan-HER TKI in EGFR+ p.

ARCHER 1050 Phase III Study: Dacomitinib vs Gefitinib

74% of pts with EGFR exon 19 or 21 mutant lung cancers experienced PR with first-line dacomitinib

Janne P, Lancet Oncol 2014 REVIEWS

Acquired resistance to TKIs in solid tumours: REVIEWSlearning from lung cancer D. Ross Camidge, William Pa o and Lecia V. Sequist

Abstract | The use of advanced molecular profiling to direct the use of , such as inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to atargeted therapies inevitably occurs. This Review explores breakthroughs in the undNoers identitandingf cationand treatment therapeutic strategies to combat bypass track-mediated of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangemenARt-po smechanismitive disease, which may be relevant across multipleEMT ~1–2% different solid malignancies with oncogene-addicted subtypes. Mechanisms of acquired resistance may be pharmacologicalRe (that-Biopsy is, failure of delivery of the drug~15–20% to its target) or biological, acquired resistance indicates that inhibition of both the resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches can maintain coHER2ntrol of amplithe disfecationase in the acquired resistance setting, including the use of radiation to bypass track and the original oncogene-addicted pathway treat isolated areas of progre~8–13%ssion and adding or switching to cytotoxic . Furthermore, novel 46,47 approaches that have already proven successful include the development of second-generation and third- is necessary for cell death. Consequently, clinical generation inhibitors and the combination of some of these inhibitors with antibodies directed against the Bypasssame target. With our incrBRAFeased ~1%understanding of the spectrum of acquired resistance, major changes in how studies assessing combinations of drugs targeting both we conduct clinical research in this setting are now underway. T790M tracks alone Camidge, D. R.MET et al. ampliNat. Rev.f Clin.cation Oncol. a~5%dvance online publication 1 July 2014; doi:10.1038/ nrclinonc.2014.104 the original and the bypass pathways, such as EGFR and ~20% ~40–55% Introduction Liquid Biopsy ?? In the past decade, PIK3CA ~1–2%the treatment of advanced non- PFS compared to chemotherapy (7.7 months versus MET, are now being explored in this setting. small-cell lung cancer (NSCLC) has witnessed two major 3.0 months, HR 0.49, P <0.001).5–7 Multiple otherEGFR exam- breakthroughs that haSCLCve trans aloneformed ~6% patient care. The ples of genotype-directedT790M therapy producing dramatic Patients with ALK-rearranged NSCLC with acquired first was the recognition that distinct somatic molecular responses in molecular withsubty pEGFRes of lung cantargetcer are aberrations in tumour genes correlated with dramatic al so emergi ng, including ROS1 rearrangementsalteration, MET resistance to can also manifest bypass tracks, and durable clinical benSCLCefit fro withm spe PI3Kcific ty r~4%osine kinase amplification, BRAF mutampliations,f HER2cation mutations and inhibitor (TKI) therapies. 1–12 The second was that pro- RET rearrangements.8–12 ~10% ~60% including the development of EGFR mutat ions or activa- spective molecular profiling of lung cancers to find such Despite these advancements, clinically-apparent ‘driver’ abnormalities became feasible in clinical prac- acquired resistance to such TKIs devel ops in most cases 43,44,53 tice, allowing for routine genPanotype-directe-d rinhibitorsather than af ter 1–2 year s, reg ar??dlessOther of the EGFRline of therapy.2–7 For tion of wild-type EGFR, HER2 or KIT. The rare emer- empiric ther apy. EGFR mutant disease, formal criteria to define acquired point mutations13 University of Colorado To date, the best characterized examples are somatic resistance were published some years ago. These cri- gence of clones with an independent driver mutation, such Comprehensive Cancer mutations in the gene encoding the EGFR and fusions teria, referred to as the ‘J1–2%ackman’ criteria, specifically Center, Mailstop F704, involving the gene encoding the anaplastic propose that an acquired resistance state can be defined Anschutz Cancer as an EGFR or KRAS mutation, with the disappearance of Pavilion Room 5327, kinase, ALK. Activating EGFR mutations occur in when a tumour either harbours a known EGFR muta- Anschutz Medical b10–20% of patients with NSCLC in North American tion associated withNat drug sRevensiti vClinity (suc Oncolh as L858R 2014 Campus, Aurora, the original ALK rearrangement has been observed in some andNo Eu ridentiopeanf pcationopulat ioARns mechanismand in up to 60% among or exon 19 deletions) or has demonstrated objective CO 80045, USA ALK mutations (D.R.C.). Asians populations.1 Treatment of EGFR~25%-mutant lung clinical benefit from treatment with an EGFR TKI; Vanderbilt-Ingram cancer with specific TKIs that target EGFR, such as there has been systemic p~22–33%rogression of disease while ALK rearranged patients with acquired resistance to crizo- Cancer Center, 2220 Pierce Avenue, gefitinib, erlotinib or afatinib, has led to remarkable on continuous treatmen■t wL1196Mith an EGFR TKI within 44,54 Nashville, TN 37232, tumour shrinkage and improvement in progression-f ree 30 days; and there has been no intervening systemic tinib. To date, such a finding has not been described in USA (W.P.). KIT amplif cation Massachusetts survival (PFS) and quality of life compared to standard therapy between cessation■ oG1202Rf the EGFR TKI and initia- General Hospital chemotherapy.2–4 Similarly, ~10%ALK gene rearrange ments tion of new therapy. These criteria specifically propose Cancer Center and ■ S1206Y patients with a primary EGFR-mutant tumour. Harvard Medical have been reported in 3–7% of NSCLC and such using Response Evaluat ion Criteria in Solid Tumours School, 55 Fruit Street, Changeaberratio nsin sdriverhow i mmutationspressive responses to the ALK- (RECIST) or WHO cr iteri■a foG1269Ar defini ng disease pALKrogres- Boston, MA 02114, directed TKI crizotinib (with objective response rates sion on therapy. However, in routine clinical practice USA (L.V.S.). ~5% target of approximately 60%) and significantly improved and for the purposes of■ u 1151Tinsnderstanding the under- Correspondence to: lying range of mechanisms, acquired resistanalterationce can Phenotypic changes D. R.C. be defined much more pr■a gOthermaticaslly as any evidence ross.camidge@ Competing interests ~28–49% ucdenver.edu The authors declare no completing interests. of clinical progression after initial clinical benefit. Another observation during acquired resistance in EGFR- mutant cases is a clinical change in the overall morpho- NATURE REV IEWS | CLINICALIncreased ONCOLOGY EGFR signalling ADVAALKNCE ONLINE PUBLICATION | 1 ~30–35%© 2014 Macmillan Publishers Limited. All rights reserved amplif cation logy of the cancer cells. Specifically, phenotypic change to ~6–16% either small-cell lung cancer or to NSCLC with evidence Figure 2 | Mechanisms of biological acquired resistance. a | EGFR-mutant NSCLC of epithelial-to-mesenchymal transformation (EMT) have resistant to erlotinib and gefitinib. Note that frequencies are approximate, and data been observed at the time of acquired resistance.31,51,55 are compiled from multiple series.31,36,37,39–41,46,49–51,55,56 b | ALK-rearranged NSCLC How frequently this occurs is under investigation because resistant to crizotinib. Note that frequencies are approximate, and data are of the relatively small size of the re-biopsy series available compiled from two studies.43,44 for anal ysis. Estimates of transition to a small cell pheno- type in EGFR-mutant disease range from 3–10%.31,51 with chronic myeloid leukaemia, which, like ALK, is also How the phenotypic changes mediate resistance is cur- activated by a primary gene rearrangement rather than a rently unclear, but might reflect the induction of multiple primary kinase mutation.45 Some patients with acquired phenotype-associated bypass signalling tracks. Because resistance to crizotinib demonstrate amplification of the the same EGFR mutation has been consistently observed rearranged ALK, although not always with an accompany- in the baseline cells and the phenotypically-transformed ing ALK mutation.43,44 Collectivel y, ALK mutations and cells, this is believed to be a resistance phenomenon and ALK copy number gain are referred to as ‘ALK dominant’ not coexistence of a second cancer diagnosis. The EMT mechanisms of crizotinib acquired resistance, in that both shift might be related to activation of AXL, either through drive resistance by reinstituting ALK signalling in the increased expression of the receptor or via its ligand, presence of the inhibitor. ALK dominant acquired resis- GAS6.56 Although small cell transition of EGFR-mutant tance mecha nisms have been described in approximately disease may be sensitive to st andard small cell-directed 30–45% of crizotinib-resistant cases to date.43,44 chemotherapy regimens, specific targeted mechanisms of addressing phenotypic change as a mechanism of Bypass track signalling pathways acquired r esistance remain elusi ve.31 The other common mechanism of acquired resistance observed in patients with EGFR-mutant and ALK- Downstream signalling rearranged tumours is activation of bypass tracks that Inhibiting an oncogenic receptor with a TKI com- render ongoing inhibition of the drug target alone insuffi- monly leads to decreased signalling of pathways affect- cient to preserve tumour control. The first bypass track ing prolifer ation and increased pro-apoptotic signalling. resistance mechanism described was MET amplification Factors that modulate these downstream effects could in EGFR-mutant lung cancer.46,47 Activation of MET influence resistance to TKIs, in both the acquired and through its ligand HGF can also yield a similar effect.48 de novo setting. For example, specific baseline poly- Several other bypass tracks in patients with EGFR-mutant morphisms in BIM, a pro-apoptotic mediator, have been tumours and acquired resistance to gefitinib and erlotinib associated with modulation of initial responsiveness have also been identified, including PI K3CA mutation, to EGFR TKIs in EGFR-mutant cell lines and also in BRAF mutat ion and HER2 amplification that always patients, al though acquired variations in BIM on therapy occur within the context of the original drug-sensitive have not been described in patients to date.15–18 Similarly, EGFR mutation.31,49–51 Other putative bypass tracks have direct activation of downst ream proliferative signalling been described in EGFR mutant cell line models, such as through MAPK1 amplification has been described as a induction of an FGFR1 autocrine signalling loop, but the mechanism of acquired resistance to EGFR inhibitors in findings await clinical confirmation.52 Early research on preclinical EGFR-mutant NSCLC models. 57

4 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved EGFR-TKIs beyond RECIST disease progression: ASPIRATION study

Park K, JAMA Oncology 2015 3rd-generation EGFR-TKI

• Osimertinib • Rociletinib • HM61713 Maybe • EGF816 • WZ4002 differents ?? • ASP8273 • PF-06747775 • (AP26113) • AZD3759 N= 253 p. ORR= 51% 9.6 m.

ORR= 61%

2.8 m.

ORR= 21% AURA P1: AURA P2 (80 mg):

N: 63 p. N: 411 p. ORR: 71% ORR: 66% PFS: 9,7 m. PFS: 11 m.

Yang J, ELCC 2016

Re-biopsy

Ramalingam S, ELCC 2016:

N: 60 p. ORR: 77% PFS: 19,3 m. ADAURA Study N= 130 p.

ORR= 59%

ORR= 29% 2015 PFS: - T790M +: 13.1 m - T790M -: 5.6 m

ELUXA 2 Phase III Study ongoing in 2nd-Line vs QT (T790M +)

ELUXA 3 Phase III Study ongoing in 1st-Line vs EGFR-TKI (T790M + or -)

ELCC 2016 Mechanisms of Resistance to 3rd-generation EGFR TKIs

Many resistances are the same of 1st-2nd gen. EGFR-TKI: de novo or adquired ?

Tan C, Lung Cancer 2016 Sensitivity of different combinations of Primary, Secondary or Tertiary EGFR mutations

Primary

Secondary

Tertiary    

Ayeni D, Cancer Res 2015 Study Design

Chemotherapy-naïve EB combination Stage IIIB/IV NSCLC or Erlotinib 150mg qd + postoperative recurrence PD bevacizumab 15mg/kg q3w Non-squamous (n = 75) Activating EGFR mutations* Exon 19 deletion R Exon 21 L858R 1:1 E monotherapy Phase II Erlotinib 150mg qd PD PS 0–1 (n = 75) No brain metastasis Primary endpoint: *T790M excluded PFS (RECIST v1.1, independent review) Stratification factors: sex, smoking status, Secondary endpoints: clinical stage, OS, tumor response, QoL, safety EGFR mutation type Exploratory endpoint: BELIEF Studybiomarker: assessm ent Kato T, et al. J Clin Oncol. 2014;32(Suppl): Abstract 8005.

Primary Endpoint: PFS bBevacizumaby Independent Review + Erlotinib betterEB E with T790M+ Median, Months 1.0 HR 0.54 (95%(Stahel CI: 0.36–0.79) R, ESMO 2015) P value* 0.8

*log-rank test, two-sided

y

t

i

l

i b

a 0.6

b EB

o r

P E

0.4

S

F P 0.2

9.7 16.0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Number at risk Time, Months EB 75 72 69 64 60 53 49 38 30 20 13 8 4 4 0 Seto, Lancet Oncol 2014 E 77 66 57 44 39 29 24 21 18 12 10 5 2 1 0

Kato T, et al. J Clin Oncol. 2014;32(Suppl): Abstract 8005. RELAY Study

T790M- BOOSTER Study ETOP Targeted NO Therapies CRIZOTINIB with EGFR Molecular YES ALK Selection OTHERS OTHERS Current Therapeutic Landscape for ALK-Rearranged NSCLC HR 0.49 0.45 REVIEWS

a No identif cation therapeutic strategies to combat bypass track-mediated AR mechanism EMT ~1–2% ~15–20% acquired resistance indicates that inhibition of both the HER2 amplif cation bypass track and the original oncogene-addicted pathway ~8–13% is necessary for cell death.46,47 Consequently, clinical Bypass BRAF ~1% T790M studies assessing combinations of drugs targeting both tracks MET amplif cation ~5% alone the original and the bypass pathways, such as EGFR and ~20% ~40–55% PIK3CA ~1–2% MET, are now being explored in this setting. EGFR SCLC alone ~6% REVIEWST790M Patients with ALK-rearranged NSCLC with acquired with EGFR target resistance to crizotinib can also manifest bypass tracks, SCLC with PI3K ~4% amplif cation alteration Acquired resistance to TKIs in solid tumours: ~60% learning from lung cancer ~10% including the development of EGFR mutat ions or activa- 43,44,53 D. Ross Camidge, William Pa o and Lecia V. Sequist Other EGFR tion of wild-type EGFR, HER2 or KIT. The r are emer- Abstract | The use of advanced molecular profiling to direct the use of targeted therapy,point such a smutations tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized gence of clones with an independent driver mutation, such the treatment of this disease. However, acquired resistance, defined as progression aft1–2%er initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment as an EGFR or KRAS mutation, with the disappearance of of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which b No maidentiy be relef cationvant across AR mechanismmultiple different solid malignancies with oncogene-addicted subtypes. Mechanisms the original ALK rearrangement has been observed in some of acquired resistance may be pharmacological (that is, failure of delivery of the drug toALK its target) mutations or biological, resulting from evolutionary selec~25%tion on molecularly diverse tumours. A number of clinical approaches can maintain control of the disease in the acquired resistance setting, including the us~22–33%e of radiation to ALK rearranged patients with acquired resistance to crizo- treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. ■Fu rL1196Mthermore, novel 44,54 approachesKIT thatampli havef alreadycation proven successful include the development of second-generation and third- tinib. To date, such a finding has not been described in generation inhibitors an~10%d the combination of some of these inhibitors with antibodies d■ir eG1202Rcted against the same target. With our increased understanding of the spectrum of acquired resistance, major changes in how patients with a primary EGFR-mutant tumour. we conduct clinical research in this setting are now underway. ■ S1206Y Change in driver mutations ALK Camidge, D. R. et al. Nat. Rev. Clin. Oncol. advance online publication 1 July 2014; doi:10.1038/ nrclinonc.2014.104■ G1269A ~5% target Introduction ■ 1151Tins In the past decade, the treatment of advanced non- PFS compared to chemotherapy (7.7 months versusalteration Phenotypic changes small-cell lung cancer (NSCLC) has witnessed two major 3.0 months, HR 0.49, P <0.001).■ 5–7Other Multipsle other exam- breakthroughs that have transformed patient care. The ples of genotype-directed therapy producing dramatic~28–49% first was the recognition that distinct somatic molecular responses in molecular subtypes of lung cancer are Another observation during acquired resistance in EGFR- aberrations in tumour genes correlated with dramatic al so emergi ng, including ROS1 rearrangements, MET Increasedand dura bEGFRle clinic asignallingl benefit from specific tyrosine kinase amplification, BRAF mutations, HER2 mutations and mutant cases is a clinical change in the overall morpho- inhibitor (TKI) therapies. 1–12 The second was that pro- RET rearrangements.8–12 ALK spective molecular~30–35% profiling of lung cancers to find such Despite these advancemenamplits, clinficcationally-apparent ‘driver’ abnormalities became feasible in clinical prac- acquired resistance to such TKIs devel ops in most cases logy of the cancer cells. Specifically, phenotypic change to tice, allowing for routine genotype-directed rather than af ter 1–2 year s, regar dless of t~6–16%he line of therapy.2–7 For empiric ther apy. EGFR mutant disease, formal criteria to define acquired either small-cell lung cancer or to NSCLC with evidence 13 University of Colorado To date, the best characterized examples are somatic resistance were published some years ago. These cri- Comprehensive CaFincegr urem ut2a ti|on Mechanismss in the gene encodi nofg th biologicale EGFR and fus iacquiredons teria, r eresistance.ferred to as the ‘J acak m| aEGFRn’ criteri-am, spuetciafincatll yN SCLC Center, Mailstop F704, involving the gene encoding the anaplastic lymphoma propose that an acquired resistance state can be defined of epithelial-to-mesenchymal transformation (EMT) have Anschutz Cancer Pavilion Room 532r7e, sistkiannatse t, oA LeKr. lAocttivnaitbin ga EGFRnd g meuftiattiinonisb o.c Ncuor itne thwahten f ar etuqmuouer neicthieer sha raboruer sa a pknpowronx EGFRima mteut,a -and data 31,51,55 Anschutz Medical 10–20% of patients with NSCLC in North American tion associated withNat drug sRevensiti vClinity (suc Oncolh as L858R 2014 been observed at the time of acquired resistance. Campus, Aurora, CO 80045, USA and European populations and in up to 60% a31,36,37,39–41,46,49–51,55,56mong or exon 19 deletions) or has demonstrated objective (D.R.C.). are compiledAsians popu lafromtions.1 Tmultiplereatment of EGFR series.-mutant lung clinical benefit from t rbea t|m AenLtK w-irthe anr EraGnFRg TeKdI; NSCLC Vanderbilt-Ingram cancer with specific TKIs that target EGFR, such as there has been systemic progression of disease while How frequently this occurs is under investigation because Cancer Center, 2220 Pierce Avenue,re sistgaefnititn itbo, e crlortiiznoibt oinr aibfat.i nNibo, htaes ltedh taot r efmrearqkaublee ncioens co antrienu oaups ptreraotmxiemnt awitteh ,a na EnGdF Rd TaKtIa w iathrien Nashville, TN 37232, tumour shrinkage and improvement in progression-f ree 30 days; and there has been no intervening systemic of the relatively small size of the re-biopsy series available USA (W.P.). 43,44 Massachusetts compiledsurviv afroml (PFS) atwond qu astudies.lity of life compared to standard therapy between cessation of the EGFR TKI and initia- General Hospital chemotherapy.2–4 Similarly, ALK gene rearrange ments tion of new therapy. These criteria specifically propose Cancer Center and for anal ysis. Estimates of transition to a small cell pheno- Harvard Medical have been reported in 3–7% of NSCLC and such using Response Evaluat ion Criteria in Solid Tumours School, 55 Fruit Street, aberrations show impressive responses to the ALK- (RECIST) or WHO cr iteria for defini ng disease progres- 31,51 Boston, MA 02114, directed TKI crizotinib (with objective response rates sion on therapy. However, in routine clinical practice type in EGFR-mutant disease range from 3–10%. USA (L.V.S.). of approximately 60%) and significantly improved and for the purposes of understanding the under- Correspondence to: lying range of mechanisms, acquired resistance can D. R.C. with chronic myeloid leukaemia, which, like ALK, is also How the phenotypic changes mediate resistance is cur- ross.camidge@ Competing interests be defined much more pragmatically as any evidence ucdenver.edu The authors declare no completing interests.activated by a priomf clainricyal gpreongrees srioena arftrear ningitiealm clienincatl breantehfite. r than a rently unclear, but might reflect the induction of multiple 45 NATURE REV IEWS | CLINICAL ONCOLOGY primary kinase mutation. SAoDVmANeCE pONaLtINiEe PnUBtLsIC wATIOitNh | 1acquired phenotype-associated bypass signalling tracks. Because © 2014 Macmillan Publishers Limited. All rights reserved resistance to crizotinib demonstrate amplification of the the same EGFR mutation has been consistently observed rearranged ALK, although not always with an accompany- in the baseline cells and the phenotypically-transformed ing ALK mutation.43,44 Collectivel y, ALK mutations and cells, this is believed to be a resistance phenomenon and ALK copy number gain are referred to as ‘ALK dominant’ not coexistence of a second cancer diagnosis. The EMT mechanisms of crizotinib acquired resistance, in that both shift might be related to activation of AXL, either through drive resistance by reinstituting ALK signalling in the increased expression of the receptor or via its ligand, presence of the inhibitor. ALK dominant acquired resis- GAS6.56 Although small cell transition of EGFR-mutant tance mecha nisms have been described in approximately disease may be sensitive to st andard small cell-directed 30–45% of crizotinib-resistant cases to date.43,44 chemotherapy regimens, specific targeted mechanisms of addressing phenotypic change as a mechanism of Bypass track signalling pathways acquired r esistance remain el usive.31 The other common mechanism of acquired resistance observed in patients with EGFR-mutant and ALK- Downstream signalling rearranged tumours is activation of bypass tracks that Inhibiting an oncogenic receptor with a TKI com- render ongoing inhibition of the drug target alone insuffi- monly leads to decreased signalling of pathways affect- cient to preserve tumour control. The first bypass track ing prolifer ation and increased pro-apoptotic signalling. resistance mechanism described was MET amplification Factors that modulate these downstream effects could in EGFR-mutant lung cancer.46,47 Activation of MET influence resistance to TKIs, in both the acquired and through its ligand HGF can also yield a similar effect.48 de novo setting. For example, specific baseline poly- Several other bypass tracks in patients with EGFR-mutant morphisms in BIM, a pro-apoptotic mediator, have been tumours and acquired resistance to gefitinib and erlotinib associated with modulation of initial responsiveness have also been identified, including PI K3CA mutation, to EGFR TKIs in EGFR-mutant cell lines and also in BRAF mutat ion and HER2 amplification that always patients, al though acquired variations in BIM on therapy occur within the context of the original drug-sensitive have not been described in patients to date.15–18 Similarly, EGFR mutation.31,49–51 Other putative bypass tracks have direct activation of downst ream proliferative signalling been described in EGFR mutant cell line models, such as through MAPK1 amplification has been described as a induction of an FGFR1 autocrine signalling loop, but the mechanism of acquired resistance to EGFR inhibitors in findings await clinical confirmation.52 Early research on preclinical EGFR-mutant NSCLC models. 57

4 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved • N= 130 patients • ORR: • 58% • 80 patients who had received crizotinib previously: 56% • PFS: 7 m. Ceritinib activity in ASCEND-1

Kim DW, Lancet Oncol 2016 CLOSED PHASE III STUDY in 1st-LINE (ASCEND 4): CERITINIB vs QT

Felip E, ELCC 2016 N= 87 p. ORR= 48%

ORR= 75%

Lancet Oncol 2016 Ou SI, JCO 2016 Phase III studies of 1L Alectinib vs Crizotinib in ALK+ disease ALEX (BO28984)1,2 Primary endpoint • PFS (investigator • Stage IIIB/IV NSCLC assessed) Alectinib 600mg BID • ALK+ disease according Innovative features to IHC test* • Regularly scheduled 1:1 • Treatment-naïve R brain MRI to assess time to CNS • ECOG PS 0–2 Crizotinib 250mg BID progression (n=286) • QoL measured post-progression J-ALEX3 • Stage IIIB/IV NSCLC Alectinib 300mg BID • ALK+ disease according Primary endpoint to IHC, FISH or RT-PCRNokihara H, ASCO 2016: • PFS (independent • Treatment-naïve or R 1:1 review) received 1L chemo PFS HR = 0.34, p<0.0001, • ECOG PS 0–2 Median NRCrizotinib vs 10.4 250mg m.BID (n=200)

*IHC test is being developed by Ventana as a CDx to alectinib. Sufficient tumour tissue is required to test for ALK+ disease via IHC and FISH 1. NCT02075840 Alectinib is not approved in Malaysia for the treatment of patients with ALK+ NSCLC 2. Peters, et al. ESMO 2014; 3. JapicCTI-132316

ORR: 44%

Bauer TM, WCLC 2015

Activity of Next-Generation ALK inh in P with Brain Metastases Mechanisms of Progression in ALK- Rearranged NSCLC and ALK inh. Activity

Current Treatment Paradigm for ALK + NSCLC Targeted NO Therapies with EGFR Molecular ROS-1 ALK Selection YES BRAF OTHERS MET

RET

…...

Crizotinib in ROS-1+ NSCLC

Shaw A, NEJM 2014 BRAF V600E-mutant NSCLC

Dabrafenib +

ORR= 33%

Planchard D, Lancet Oncol 2016 Planchard D, ASCO 2015 ASCO 2014

Therapies to increase Response to Immune Checkpoint Inhibitors Ongoing & Planned Combination Studies Ongoing & Planned Combination Studies

ELCC 2016

ELCC 2016 JAMA Oncology 2016 Heterogeneity and Molecular Techniques in Cancer

Le Tourneau C, JNCI 2016 2016 Looking for Mutations and Therapies: MASTER PROTOCOLS LUNG MASTER PROTOCOL: Lung-MAP SAFIR02 LUNG MATCH Trial

[email protected]