OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Selección del … · 2017-05-24 · OTRAS TERAPIAS BIOLÓGICAS...

OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Selección del Tratamiento

Dolores Isla Servicio de Oncología Médica HCU Lozano Besa de Zaragoza

Pillars of Lung Cancer Therapy

Current Algorithm Sq NSCLC Non-Sq NSCLC

EGFR Mutation

ALK Rearrangement

ROS1 Rearrangement

Others

First-Line

PLATINUM DOUBLET

PEMBROLIZUMAB

(PD-L1+≥50%)

GEFITINIB ERLOTINIB

+/- BEVACIZUMAB

AFATINIB

CRIZOTINIB CRIZOTINIB

PLATINUM DOUBLET

(PEM/BEV) PEMBROLIZUMAB

(PD-L1+≥50%)

Maintenance - - - - PEM/BEV

Second-Line

DOCETAXEL

ERLOTINIB

NIVOLUMAB PEMBROLIZUMAB

(PD-L1+≥1%)

OSIMERTINIB (T790M+)

CT

ALECTINIB CERITINIB

DOCETAXEL

+/- NINTEDANIB

PEMETREXED

ERLOTINIB


(PD-L1+≥1%)

Advanced NSCLC Therapies

LUME-LUNG 1 Study

Reck M, Lancet Oncol 2014

HR=0.79, p=0.0019

Median 3,4 vs 2,7 m

Frequency of Genetic Alterations

in NSCLC

Barlesi F, Lancet 2016

Molecular Aberrations in Lung

Adenocarcinomas and Drugs

Tsao A, JTO 2016


EGFR Mutation

ALK Rearrangement

ROS1 Rearrangement

Others

First-Line

PLATINUM DOUBLET

PEMBROLIZUMAB

(PD-L1+≥50%)

GEFITINIB ERLOTINIB

+/- BEVACIZUMAB

AFATINIB


PLATINUM DOUBLET


(PD-L1+≥50%)

Maintenance GEM - - - PEM/BEV

Second-Line

DOCETAXEL

ERLOTINIB AFATINIB


(PD-L1+≥1%)


CT

ALECTINIB CERITINIB

DOCETAXEL

+/- NINTEDANIB

PEMETREXED

ERLOTINIB


(PD-L1+≥1%)


EGFR-TKI 1L Studies

x

Urata Y, JCO 2016

Erlotinib vs Gefitinib:

WJOG 5108L Study

Park K, Lancet Oncol 2016

Paz-Ares L, Ann Oncol 2017

Afatinib vs Gefitinib: LUX-Lung 8 Study

Erlotinib + Bevacizumab

Seto T, Lancet Oncol 2014

Rosell R, Lancet Resp Med 2017

RELAY Study

T790M-

PD after 1st-Line EGFR-TKI

x x

NATURE REVIEWS | CLINICAL ONCOLOGY ADVANCE ONLINE PUBLICATION | 1

University of Colorado

Comprehensive Cancer

Center, Mailstop F704,

Anschutz Cancer

Pavilion Room 5327,

Anschutz Medical

Campus, Aurora,

CO 80045, USA

(D.R.C.).

Vanderbilt-Ingram

Cancer Center,

2220 Pierce Avenue,

Nashville, TN 37232,

USA (W.P.).

Massachusetts

General Hospital

Cancer Center and

Harvard Medical

School, 55 Fruit Street,

Boston, MA 02114,

USA (L.V.S.).

Correspondence to:

D.R.C.

ross.camidge@

ucdenver.edu

Acquired resistance to TKIs in solid tumours: learning from lung cancerD. Ross Camidge, William Pao and Lecia V. Sequist

Abstract | The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine

kinase 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

targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment

of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which

may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms

of acquired resistance may be pharmacological (that is, failure of delivery of the drug to its target) or biological,

resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches

can maintain control of the disease in the acquired resistance setting, including the use of radiation to

treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel

approaches that have already proven successful include the development of second-generation and third-

generation inhibitors and the combination of some of these inhibitors with antibodies directed against the

same target. With our increased understanding of the spectrum of acquired resistance, major changes in how

we conduct clinical research in this setting are now underway.

Camidge, D. R. et al. Nat. Rev. Clin. Oncol. advance online publication 1 July 2014; doi:10.1038/ nrclinonc.2014.104

Introduct ionIn the past decade, the treatment of advanced non-

small-cell lung cancer (NSCLC) has witnessed two major

breakthroughs that have transformed patient care. The

first was the recognition that distinct somatic molecular

aberrations in tumour genes correlated with dramatic

and durable clinical benefit from specific tyrosine kinase

inhibitor (TKI) therapies.1–12 The second was that pro-

spective molecular profiling of lung cancers to find such

‘driver’ abnormalities became feasible in clinical prac-

tice, allowing for routine genotype-directed rather than

empiric therapy.

To date, the best characterized examples are somatic

mutations in the gene encoding the EGFR and fusions

involving the gene encoding the anaplastic lymphoma

kinase, ALK. Activating EGFR mutations occur in

10–20% of patients with NSCLC in North American

and European populations and in up to 60% among

Asians populations.1 Treatment of EGFR-mutant lung

cancer with specific TKIs that target EGFR, such as

gefitinib, erlotinib or afatinib, has led to remarkable

tumour shrinkage and improvement in progression- free

survival (PFS) and quality of life compared to standard

chemotherapy.2–4 Similarly, ALK gene rearrange ments

have been reported in 3–7% of NSCLC and such

aberrations show impressive responses to the ALK-

directed TKI crizotinib (with objective response rates

of approximately 60%) and significantly improved

PFS compared to chemotherapy (7.7 months versus

3.0 months, HR 0.49, P <0.001).5–7 Multiple other exam-

ples of genotype-directed therapy producing dramatic

responses in molecular subtypes of lung cancer are

also emerging, including ROS1 rearrangements, MET

amplification, BRAF mutations, HER2 mutations and

RET rearrangements.8–12

Despite these advancements, clinically-apparent

acquired resistance to such TKIs develops in most cases

after 1–2 years, regardless of the line of therapy.2–7 For

EGFR mutant disease, formal criteria to define acquired

resistance were published some years ago.13 These cri-

teria, referred to as the ‘Jackman’ criteria, specifically

propose that an acquired resistance state can be defined

when a tumour either harbours a known EGFR muta-

tion associated with drug sensitivity (such as L858R

or exon 19 deletions) or has demonstrated objective

clinical benefit from treatment with an EGFR TKI;

there has been systemic progression of disease while

on continuous treatment with an EGFR TKI within

30 days; and there has been no intervening systemic

therapy between cessation of the EGFR TKI and initia-

tion of new therapy. These criteria specifically propose

using Response Evaluation Criteria in Solid Tumours

(RECIST) or WHO criteria for defi ning disease progres-

sion on therapy. However, in routine clinical practice

and for the purposes of understanding the under-

lying range of mechanisms, acquired resistance can

be defined much more pragmatically as any evidence

of clinical progression after initial clinical benefit. Competing interests

The authors declare no completing interests.

REVIEWS

© 2014 Macmillan Publishers Limited. All rights reserved

Nat Rev Clin Oncol 2014

4 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc

with chronic myeloid leukaemia, which, like ALK, is also

activated by a primary gene rearrangement rather than a

primary kinase mutation.45 Some patients with acquired

resistance to crizotinib demonstrate amplification of the

rearranged ALK, although not always with an accompany-

ing ALK mutation.43,44 Collectively, ALK mutations and

ALK copy number gain are referred to as ‘ALK dominant’

mechanisms of crizotinib acquired resistance, in that both

drive resistance by reinstituting ALK signalling in the

presence of the inhibitor. ALK dominant acquired resis-

tance mecha nisms have been described in approximately

30–45% of crizotinib-resistant cases to date.43,44

Bypass track signalling pathways

The other common mechanism of acquired resistance

observed in patients with EGFR-mutant and ALK-

rearranged tumours is activation of bypass tracks that

render ongoing inhibition of the drug target alone insuffi-

cient to preserve tumour control. The first bypass track

resistance mechanism described was MET amplification

in EGFR-mutant lung cancer.46,47 Activation of MET

through its ligand HGF can also yield a similar effect.48

Several other bypass tracks in patients with EGFR-mutant

tumours and acquired resistance to gefitinib and erlotinib

have also been identified, including PIK3CA mutation,

BRAF mutation and HER2 amplification that always

occur within the context of the original drug-sensitive

EGFR mutation.31,49–51 Other putative bypass tracks have

been described in EGFR mutant cell line models, such as

induction of an FGFR1 autocrine signalling loop, but the

findings await clinical confirmation.52 Early research on

therapeutic strategies to combat bypass track-mediated

acquired resistance indicates that inhibition of both the

bypass track and the original oncogene-addicted pathway

is necessary for cell death.46,47 Consequently, clinical

studies assessing combinations of drugs targeting both

the original and the bypass pathways, such as EGFR and

MET, are now being explored in this setting.

Patients with ALK-rearranged NSCLC with acquired

resistance to crizotinib can also manifest bypass tracks,

including the development of EGFR mutations or activa-

tion of wild-type EGFR, HER2 or KIT.43,44,53 The rare emer-

gence of clones with an independent driver mutation, such

as an EGFR or KRAS mutation, with the disappearance of

the original ALK rearrangement has been observed in some

ALK rearranged patients with acquired resistance to crizo-

tinib.44,54 To date, such a finding has not been described in

patients with a primary EGFR-mutant tumour.

Phenotypic changes

Another observation during acquired resistance in EGFR-

mutant cases is a clinical change in the overall morpho-

logy of the cancer cells. Specifically, phenotypic change to

either small-cell lung cancer or to NSCLC with evidence

of epithelial-to-mesenchymal transformation (EMT) have

been observed at the time of acquired resistance.31,51,55

How frequently this occurs is under investigation because

of the relatively small size of the re-biopsy series available

for analysis. Estimates of transition to a small cell pheno-

type in EGFR-mutant disease range from 3–10%.31,51

How the phenotypic changes mediate resistance is cur-

rently unclear, but might reflect the induction of multiple

phenotype-associated bypass signalling tracks. Because

the same EGFR mutation has been consistently observed

in the baseline cells and the phenotypically-transformed

cells, this is believed to be a resistance phenomenon and

not coexistence of a second cancer diagnosis. The EMT

shift might be related to activation of AXL, either through

increased expression of the receptor or via its ligand,

GAS6.56 Although small cell transition of EGFR-mutant

disease may be sensitive to standard small cell-directed

chemotherapy regimens, specific targeted mechanisms

of addressing phenotypic change as a mechanism of

acquired r esistance remain elusive.31

Downstream signalling

Inhibiting an oncogenic receptor with a TKI com-

monly leads to decreased signalling of pathways affect-

ing prolifer ation and increased pro-apoptotic signalling.

Factors that modulate these downstream effects could

influence resistance to TKIs, in both the acquired and

de novo setting. For example, specific baseline poly-

morphisms in BIM, a pro-apoptotic mediator, have been

associated with modulation of initial responsiveness

to EGFR TKIs in EGFR-mutant cell lines and also in

patients, although acquired variations in BIM on therapy

have not been described in patients to date.15–18 Similarly,

direct activation of downstream proliferative signalling

through MAPK1 amplification has been described as a

mechanism of acquired resistance to EGFR inhibitors in

preclinical EGFR-mutant NSCLC models.57

a

b

Other EGFRpoint mutations1–2%

EGFRtargetalteration~60%

T790Malone~40–55%

T790Mwith EGFRamplif cation~10%

SCLC alone ~6%

SCLC with PI3K ~4%

PIK3CA ~1–2%

Bypasstracks~20% MET amplif cation ~5%

BRAF ~1%

HER2 amplif cation~8–13%

EMT ~1–2%

No identif cationAR mechanism~15–20%

No identif cation AR mechanism~25%

ALKtargetalteration~28–49%

ALK mutations~22–33%■ L1196M■ G1202R■ S1206Y■ G1269A■ 1151Tins■ Others

ALKamplif cation~6–16%

Change in driver mutations~5%

Increased EGFR signalling~30–35%

KIT amplif cation~10%

Figure 2 | Mechanisms of biological acquired resistance. a | EGFR-mutant NSCLC

resistant to erlotinib and gefitinib. Note that frequencies are approximate, and data

are compiled from multiple series.31,36,37,39–41,46,49–51,55,56 b | ALK-rearranged NSCLC

resistant to crizotinib. Note that frequencies are approximate, and data are

compiled from two studies.43,44

REVIEWS


Liquid Biopsy

Pan-inhibitors ??

Re-Biopsy

Re-biopsy

AURA 3 Study

AURA 3 Study

BOOSTER Study ETOP

ADAURA Study

Mechanisms of Resistance to

3rd-generation EGFR TKIs

Tan C, Lung Cancer 2016

JAMA Oncol 2016

EGFR + NSCLC

Novello S, Ann Oncol 2016


EGFR Mutation

ALK Rearrangement

ROS1 Rearrangement

Others

First-Line

PLATINUM DOUBLET

PEMBROLIZUMAB

(PD-L1+≥50%)

GEFITINIB ERLOTINIB

+/- BEVACIZUMAB

AFATINIB


PLATINUM DOUBLET


(PD-L1+≥50%)

Maintenance GEM - - - PEM/BEV

Second-Line

DOCETAXEL

ERLOTINIB AFATINIB


(PD-L1+≥1%)


CT

ALECTINIB CERITINIB

DOCETAXEL

+/- NINTEDANIB

PEMETREXED

ERLOTINIB


(PD-L1+≥1%)


Crizotinib 1L: PROFILE 1014 Study

Median 10,9 vs 7 m

ALK-TKI 2nd/3rd gen. naive p.

Ceritinib Alectinib Brigatinib Ensartinib

Trial ASCEND-1 (Kim et al. Lancet Oncol 2016)

ASCEND-3 (Felip et al. ESMO 2016)

ASCEND-4 (G De Castro et al. WCLC 2016)

AF001JP (Seto et al. Lancet Oncol 2013)

Phase I/II (Gettinger et al.

Lancet Oncol 2016)

Phase I/II Horn et al. ESMO 2016

N 83 124 189 46 8 14

RR 72 % 63.7 % 72.5 % 94 % 100 % 71 %

DCR 74 % 77 % 84.8 % 79.1 % 100 % 85.7 %

PFS 18.4 m 18.4 m 16.6 m 27.7 m NR -

Alectinib 1L: J-ALEX Study

Hida T, Lancet 2017

ALK-TKI 2nd/3rd gen. resistant p.

Ceritinib Alectinib Brigatinib

Trial ASCEND-1 (All)

ASCEND-2 (measurable, active)

Measurable *

Non measurable *

Phase I/II (measurable)

Phase I/II (Non

measurable)

ALTA (measurable)

180 mg

ALTA (All)

180mg

N 75 20 50 136 15 31 18 72

RR 19 45 64 42.6 67 42 67 31

CRR 5 10 22 27.2 7 42 0 14

DCR 65 80 90 85.3 87 94 83 86

PFS 6 - - - 15.6 NR NR

Ou SH-I, et al. WCLC 2016; Kim D, JCO 2017

CNS activity in Crizotinib

Resistant p.

Lorlatinib

NATURE REVIEWS | CLINICAL ONCOLOGY ADVANCE ONLINE PUBLICATION | 1

University of Colorado

Comprehensive Cancer

Center, Mailstop F704,

Anschutz Cancer

Pavilion Room 5327,

Anschutz Medical

Campus, Aurora,

CO 80045, USA

(D.R.C.).

Vanderbilt-Ingram

Cancer Center,

2220 Pierce Avenue,

Nashville, TN 37232,

USA (W.P.).

Massachusetts

General Hospital

Cancer Center and

Harvard Medical

School, 55 Fruit Street,

Boston, MA 02114,

USA (L.V.S.).

Correspondence to:

D.R.C.

ross.camidge@

ucdenver.edu

Acquired resistance to TKIs in solid tumours: learning from lung cancerD. Ross Camidge, William Pao and Lecia V. Sequist

Abstract | The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine

kinase 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

targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment

of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which

may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms

of acquired resistance may be pharmacological (that is, failure of delivery of the drug to its target) or biological,

resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches

can maintain control of the disease in the acquired resistance setting, including the use of radiation to

treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel

approaches that have already proven successful include the development of second-generation and third-

generation inhibitors and the combination of some of these inhibitors with antibodies directed against the

same target. With our increased understanding of the spectrum of acquired resistance, major changes in how

we conduct clinical research in this setting are now underway.

Camidge, D. R. et al. Nat. Rev. Clin. Oncol. advance online publication 1 July 2014; doi:10.1038/ nrclinonc.2014.104

Introduct ionIn the past decade, the treatment of advanced non-

small-cell lung cancer (NSCLC) has witnessed two major

breakthroughs that have transformed patient care. The

first was the recognition that distinct somatic molecular

aberrations in tumour genes correlated with dramatic

and durable clinical benefit from specific tyrosine kinase

inhibitor (TKI) therapies.1–12 The second was that pro-

spective molecular profiling of lung cancers to find such

‘driver’ abnormalities became feasible in clinical prac-

tice, allowing for routine genotype-directed rather than

empiric therapy.

To date, the best characterized examples are somatic

mutations in the gene encoding the EGFR and fusions

involving the gene encoding the anaplastic lymphoma

kinase, ALK. Activating EGFR mutations occur in

10–20% of patients with NSCLC in North American

and European populations and in up to 60% among

Asians populations.1 Treatment of EGFR-mutant lung

cancer with specific TKIs that target EGFR, such as

gefitinib, erlotinib or afatinib, has led to remarkable

tumour shrinkage and improvement in progression- free

survival (PFS) and quality of life compared to standard

chemotherapy.2–4 Similarly, ALK gene rearrange ments

have been reported in 3–7% of NSCLC and such

aberrations show impressive responses to the ALK-

directed TKI crizotinib (with objective response rates

of approximately 60%) and significantly improved

PFS compared to chemotherapy (7.7 months versus

3.0 months, HR 0.49, P <0.001).5–7 Multiple other exam-

ples of genotype-directed therapy producing dramatic

responses in molecular subtypes of lung cancer are

also emerging, including ROS1 rearrangements, MET

amplification, BRAF mutations, HER2 mutations and

RET rearrangements.8–12

Despite these advancements, clinically-apparent

acquired resistance to such TKIs develops in most cases

after 1–2 years, regardless of the line of therapy.2–7 For

EGFR mutant disease, formal criteria to define acquired

resistance were published some years ago.13 These cri-

teria, referred to as the ‘Jackman’ criteria, specifically

propose that an acquired resistance state can be defined

when a tumour either harbours a known EGFR muta-

tion associated with drug sensitivity (such as L858R

or exon 19 deletions) or has demonstrated objective

clinical benefit from treatment with an EGFR TKI;

there has been systemic progression of disease while

on continuous treatment with an EGFR TKI within

30 days; and there has been no intervening systemic

therapy between cessation of the EGFR TKI and initia-

tion of new therapy. These criteria specifically propose

using Response Evaluation Criteria in Solid Tumours

(RECIST) or WHO criteria for defi ning disease progres-

sion on therapy. However, in routine clinical practice

and for the purposes of understanding the under-

lying range of mechanisms, acquired resistance can

be defined much more pragmatically as any evidence

of clinical progression after initial clinical benefit. Competing interests

The authors declare no completing interests.

REVIEWS


Nat Rev Clin Oncol 2014

4 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc

with chronic myeloid leukaemia, which, like ALK, is also

activated by a primary gene rearrangement rather than a

primary kinase mutation.45 Some patients with acquired

resistance to crizotinib demonstrate amplification of the

rearranged ALK, although not always with an accompany-

ing ALK mutation.43,44 Collectively, ALK mutations and

ALK copy number gain are referred to as ‘ALK dominant’

mechanisms of crizotinib acquired resistance, in that both

drive resistance by reinstituting ALK signalling in the

presence of the inhibitor. ALK dominant acquired resis-

tance mecha nisms have been described in approximately

30–45% of crizotinib-resistant cases to date.43,44

Bypass track signalling pathways

The other common mechanism of acquired resistance

observed in patients with EGFR-mutant and ALK-

rearranged tumours is activation of bypass tracks that

render ongoing inhibition of the drug target alone insuffi-

cient to preserve tumour control. The first bypass track

resistance mechanism described was MET amplification

in EGFR-mutant lung cancer.46,47 Activation of MET

through its ligand HGF can also yield a similar effect.48

Several other bypass tracks in patients with EGFR-mutant

tumours and acquired resistance to gefitinib and erlotinib

have also been identified, including PIK3CA mutation,

BRAF mutation and HER2 amplification that always

occur within the context of the original drug-sensitive

EGFR mutation.31,49–51 Other putative bypass tracks have

been described in EGFR mutant cell line models, such as

induction of an FGFR1 autocrine signalling loop, but the

findings await clinical confirmation.52 Early research on

therapeutic strategies to combat bypass track-mediated

acquired resistance indicates that inhibition of both the

bypass track and the original oncogene-addicted pathway

is necessary for cell death.46,47 Consequently, clinical

studies assessing combinations of drugs targeting both

the original and the bypass pathways, such as EGFR and

MET, are now being explored in this setting.

Patients with ALK-rearranged NSCLC with acquired

resistance to crizotinib can also manifest bypass tracks,

including the development of EGFR mutations or activa-

tion of wild-type EGFR, HER2 or KIT.43,44,53 The rare emer-

gence of clones with an independent driver mutation, such

as an EGFR or KRAS mutation, with the disappearance of

the original ALK rearrangement has been observed in some

ALK rearranged patients with acquired resistance to crizo-

tinib.44,54 To date, such a finding has not been described in

patients with a primary EGFR-mutant tumour.

Phenotypic changes

Another observation during acquired resistance in EGFR-

mutant cases is a clinical change in the overall morpho-

logy of the cancer cells. Specifically, phenotypic change to

either small-cell lung cancer or to NSCLC with evidence

of epithelial-to-mesenchymal transformation (EMT) have

been observed at the time of acquired resistance.31,51,55

How frequently this occurs is under investigation because

of the relatively small size of the re-biopsy series available

for analysis. Estimates of transition to a small cell pheno-

type in EGFR-mutant disease range from 3–10%.31,51

How the phenotypic changes mediate resistance is cur-

rently unclear, but might reflect the induction of multiple

phenotype-associated bypass signalling tracks. Because

the same EGFR mutation has been consistently observed

in the baseline cells and the phenotypically-transformed

cells, this is believed to be a resistance phenomenon and

not coexistence of a second cancer diagnosis. The EMT

shift might be related to activation of AXL, either through

increased expression of the receptor or via its ligand,

GAS6.56 Although small cell transition of EGFR-mutant

disease may be sensitive to standard small cell-directed

chemotherapy regimens, specific targeted mechanisms

of addressing phenotypic change as a mechanism of

acquired r esistance remain elusive.31

Downstream signalling

Inhibiting an oncogenic receptor with a TKI com-

monly leads to decreased signalling of pathways affect-

ing prolifer ation and increased pro-apoptotic signalling.

Factors that modulate these downstream effects could

influence resistance to TKIs, in both the acquired and

de novo setting. For example, specific baseline poly-

morphisms in BIM, a pro-apoptotic mediator, have been

associated with modulation of initial responsiveness

to EGFR TKIs in EGFR-mutant cell lines and also in

patients, although acquired variations in BIM on therapy

have not been described in patients to date.15–18 Similarly,

direct activation of downstream proliferative signalling

through MAPK1 amplification has been described as a

mechanism of acquired resistance to EGFR inhibitors in

preclinical EGFR-mutant NSCLC models.57

a

b

Other EGFRpoint mutations1–2%

EGFRtargetalteration~60%

T790Malone~40–55%

T790Mwith EGFRamplif cation~10%

SCLC alone ~6%

SCLC with PI3K ~4%

PIK3CA ~1–2%

Bypasstracks~20% MET amplif cation ~5%

BRAF ~1%

HER2 amplif cation~8–13%

EMT ~1–2%

No identif cationAR mechanism~15–20%

No identi f cation AR mechanism~25%

ALKtargetalteration~28–49%

ALK mutations~22–33%■ L1196M■ G1202R■ S1206Y■ G1269A■ 1151Tins■ Others

ALKamplif cation~6–16%

Change in driver mutations~5%

Increased EGFR signalling~30–35%

KIT amplif cation~10%

Figure 2 | Mechanisms of biological acquired resistance. a | EGFR-mutant NSCLC

resistant to erlotinib and gefitinib. Note that frequencies are approximate, and data

are compiled from multiple series.31,36,37,39–41,46,49–51,55,56 b | ALK-rearranged NSCLC

resistant to crizotinib. Note that frequencies are approximate, and data are

compiled from two studies.43,44

REVIEWS


Mechanisms of Progression in ALK-

Rearranged NSCLC and ALK inh. Activity

Gainor et al. Cancer Discov 2016

Acquired Resistance to 2nd/3rd gen. TKIs

Future

• Sequence vs 2nd/3rd gen. ALK TKIs front line?:

Phase III trials vs Crizotinib: • Alectinib (J-ALEX: positive, ALEX trial: closed, positive)

• Brigatinib (ALTA 1L: recruiting)

• Lorlatinib, Ensartinib (eXalt3: recruiting)

• Mechanism of Resistance

Gainor E, Cancer Discov 2016

ALK + NSCLC

Novello S, Ann Oncol 2016

• Actionable mutations are relevant, no matter how rare they

are

• Smokers can also have NSCLC with actionable mutations

• Patients with rare mutations should be enrolled in clinical

trials

• Registries can provide complementary “real world” data

First line: ROS1 rearrangements: crizotinib

Second line: BRAF V600E: dabrafenib or vemurafenib + MEKi

MET ex14: crizotinib or cabozantinib

RET rearrangements: cabozantinib or vandetanib

HER2 ins20: afatinib or trastuzumab+vino/doce or TD-M1

Other Mutations

Crizotinib in ROS-1+ NSCLC

Shaw A, NEJM 2014

EUCROSS Study

CERITINIB (Cho BC, WCLC 2016)

LORLATINIB (Felip E, WCLC 2016)

BRAF

N= 59 P. ORR= 63%, PFS= 9,7 m

Hyman et al. NEJM 2015;

Planchard D,et al. Lancet Oncol 2016; Gautschi at al. JTO 2015

Planchard D, et al. Lancet Oncol 2016

BRAF v600e: Monotherapy BRAF v600e: Combo DABRAFENIB + TRAMETINIB

MET: PROFILE 1001 Study

RET Author Drug Test N RR PFS

Drilon Cabozantinib FISH or NGS 26 28% 5.5 mo

Yoh Vandetanib RTPCR+FISH 19 47% 4.7 mo

Lee Vandetanib FISH 18 18% 4.5 mo

Velcheti Lenvatinib NGS 25 16% 7.3 mo

Drilon A, JTO 2016

RET Registry

Gautschi O, J Clin Oncol 2017

PFS= 2.3 m.

OS= 6.8 m.

EUHER Registry HER2 mut exon 20

Mazieres J, Ann Oncol 2016

HER2Lung Study

(HER2 IHC 2-3+):

ASCO 2017

NTRK1: Entrectinib

Drilon, AACR 2016

Therapies to increase Response to Immune Checkpoint Inhibitors

De S, Ann Oncol 2016

Comprehensive Analyses of

Cancer Genome Sequencing Data

NGS Work Flow

Tumour T790M-positive Plasma T790M-positive

No. at risk

Osimertinib

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18

Months

279

140

240

93

162

44

88

17

50

7

13

1

0

0

No. at risk

Osimertinib

Platinum-

pemetrexed Platinum-

pemetrexed

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18

116

56

95

39

63

13

35

5

20

2

5

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AURA 3: T790M plasma vs tissue

Wu Y-L, et al. WCLC 2016

PFS=10.1 vs 4.4 m (HR=0,30) ORR= 71% vs 31%

8.2 vs 4.2 m (HR=0,42)

ORR= 77% vs 39%

Sensitivity 51%; Specificity 77%

30% False Negative

• Randomized clinical trial (all comers) – All patients are randomized

– Prospective/retrospective biomarker characterization

• Trial in marker-positive patients (enrichment strategy)

• Marker-based strategy design

• Marker-by-treatment-interaction design

• Master protocol

• Adaptive design

Novel Clinical Trial Designs

Biankin AV et al. Nature 2015

• BATTLE

• I-SPY2

• LUNG-MAP

• MATRIX

• Imatinib

Basket

• BRAF+

• NCI MATCH

Umbrella, Basket & Adaptive studies

LUNG CANCER THERAPY:

The Last ….

GRACIAS [email protected]

OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Selección del … · 2017-05-24 · OTRAS TERAPIAS BIOLÓGICAS...

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