OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Selección del … · 2017-05-24 · OTRAS TERAPIAS BIOLÓGICAS...
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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
NIVOLUMAB PEMBROLIZUMAB
(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
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 GEM - - - PEM/BEV
Second-Line
DOCETAXEL
ERLOTINIB AFATINIB
NIVOLUMAB PEMBROLIZUMAB
(PD-L1+≥1%)
OSIMERTINIB (T790M+)
CT
ALECTINIB CERITINIB
DOCETAXEL
+/- NINTEDANIB
PEMETREXED
ERLOTINIB
NIVOLUMAB PEMBROLIZUMAB
(PD-L1+≥1%)
Advanced NSCLC Therapies
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
© 2014 Macmillan Publishers Limited. All rights reserved
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
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 GEM - - - PEM/BEV
Second-Line
DOCETAXEL
ERLOTINIB AFATINIB
NIVOLUMAB PEMBROLIZUMAB
(PD-L1+≥1%)
OSIMERTINIB (T790M+)
CT
ALECTINIB CERITINIB
DOCETAXEL
+/- NINTEDANIB
PEMETREXED
ERLOTINIB
NIVOLUMAB PEMBROLIZUMAB
(PD-L1+≥1%)
Advanced NSCLC Therapies
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
© 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 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
© 2014 Macmillan Publishers Limited. All rights reserved
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
2016
Therapies to increase Response to Immune Checkpoint Inhibitors
De S, Ann Oncol 2016
Comprehensive Analyses of
Cancer Genome Sequencing Data
NGS Work Flow
2017
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
1
0
0
Months
Pro
ba
bil
ity o
f
pro
gre
ssio
n-f
ree s
urv
ival
Pro
ba
bil
ity o
f
pro
gre
ssio
n-f
ree s
urv
ival
Pro
ba
bil
ity o
f
pro
gre
ssio
n-f
ree s
urv
ival
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]