Download Advances in Lung Cancer 2016: a year in review

CLOSING LECTURE
Avanços no Câncer de Pulmão 2016:
um ano em análise
(Advances in Lung Cancer 2016:
a year in review)
Daniel B. Costa, MD, PhD, MMSc
Associate Professor of Medicine
Harvard Medical School
Thoracic Oncology Group Leader
Division of Hematology/Oncology
Beth Israel Deaconess Medical Center
2013-2016:
A Golden Era For Approval of Anti-Cancer Therapies for
Advanced Non-Small-Cell-Lung Cancer
(EGFR, ALK, ROS1 TKIs, VEGF inhibitors, EGFR antibody, anti-PD-1, PD-L1 antibodies)
crizotinib
reg. approval ALK+
ramucirumab ceritinib
2ndline NSCLC
ALK+
2013
erlotinib
approved EGFR+
necitumumab
osimertinib
approved squ. EGFR-T790M+
2014
afatinib
EGFR+
crizotinib
ROS1+
2015
gefitinib
EGFR+
nivolumab pembrolizumab
PD-1
approved PD-L1+
alectinib
ALK+
2016
atezolizumab
PD-L1
? 2017
Small cell lung cancer (no approvals for close to a decade)
[the final frontier for novel anti-cancer compound approvals]
2013
2014
2015
? 2017-2018 DLL3 target
rovalpituzumab tesirine (Rova-T)
? 2017-2018 immune checkpoint inhibitors
pembrolizumab or nivolumab
2016
My personal thoughts about upcoming drug
approvals for ES-SCLC:
SCLC stem cell markers (DLL3)
rovalpituzumab tesirine (Rova-T) – likely by 2017/2018
Immune checkpoint inhibitors (anti-PD-1 agents)
nivolumab (off-label use since 2015)
pembrolizumab (off-label use since 2015)
- likely FDA approval of anti-PD-1 by 2017/2018
1st, 2nd and 3rd generation EGFR tyrosine kinase inhibitors (TKIs)
osimertinib
EGFR-T790M+
2013
erlotinib
approved EGFR+
2014
afatinib
EGFR+
2015
gefitinib
EGFR+
2016
EGFR mutations, ALK and ROS1 rearrangements in
lung adenocarcinomas (minimal testing required)
Lung Cancer Mutation Consortium
(LCMC)
n=733
CAP,
IASLC
and
AMP
recommend rapid testing for
EGFR mutations and ALK
rearrangements (plus add ROS1
rearrangement in 2016) in all
patients with advanced stage
adenocarcinoma, regardless of
sex, race, smoking history or
other clinical risk factors
LCMC frequency:
EGFR mutations 14-20%
ALK rearrangements 6-10%
ROS1 rearrangements 1-2%
(Lindeman NI, et al. J Thorac Oncol 8:823 [2013])
(adapted from Kris MG, et al. JAMA 311:1998 [2014])
Palliative therapies for advanced EGFR mutated NSCLC:
(November 2016)
“SM” = sensitizing mutation. “X” in G719X = substitution for several different amino acids and is not a stop codon.
Approved doses of TKIs are: gefitinib 250mg daily, erlotinib 150mg daily (1st generation TKIs); afatinib 40mg daily (2nd
generation TKI); osimertinib 80mg daily (3rd generation TKI). #Most common exon 19 deletion is delE746_A750 (LREA
motif). *Cause of acquired resistance to gefitinib, erlotinib and afatinib in >50%. ^Cause of osimertinib resistance in 30%.
Evidence-based use of EGFR TKIs (gefitinib, erlotinib and
afatinib) for EGFR-L858R or exon 19 deletions mutated
advanced NSCLCs as first line systemic therapy
April 23rd, 2009 (European Medicines Agency) and 2015 (US):
Gefitinib (Iressa) approved by for the treatment of NSCLC with EGFR
mutations (mostly exon 19 deletions and L858R)
September 1st, 2011 (European Medicines Agency):
Erlotinib (Tarceva) approved by European Union for the treatment of
NSCLC with EGFR mutations (mostly exon 19 deletions and L858R)
May 14th, 2013 (Food and Drug Administration/US):
Erlotinib (Tarceva) approved by FDA for the treatment of NSCLC with
EGFR mutations (exon 19 deletions and L858R)
July 12th, 2013 (Food and Drug Administration/US):
Afatinib (Gilotrif) approved by FDA for the treatment of NSCLC with
EGFR mutations (exon 19 deletions and L858R)
What is the best 1st line EGFR TKI for EGFR mutant NSCLC:
LUX-Lung 7 clinical trial of afatinib vs gefitinib
EGFR TKIs and EGFR mutated NSCLC:
mechanisms of resistance to 1st/2nd gen. EGFR TKIs
neuroendocrine
transformation
NSCLC
SCLC
LCNEC
H&E
Chromogranin
Synaptophysin
Kobayashi S. N Engl J Med;352:786. (2005)
Yun CH. Proc Natl Acad Sci;
105:2070. (2008)
Engelman JA. Science: 316:1039. (2007)
Pao W. Proc Natl Acad Sci; 104: 20932. (2007)
Therapies for acquired resistance to EGFR TKIs in
EGFR mutated NSCLC (covalent EGFR TKI, osimetinib)
Phase I study of osimertinib/AZD9291 (clinicaltrials.gov - NCT01802632)
The AURA Study – FDA approval Nov. 13th, 2015
Courtesy of Pasi Jänne – Santa Monica Conference (2014)
Ranson M. European Cancer Congress: abstr33LBA. (2013)
Ranson M. 15th WCLC: abstract.11-034. (2013)
Cross. AACR-NCI-EORTC: abstract A109. (2013)
Janne PA. N Engl J Med;372:1689. (2015)
FDA approval of 3rd gen. EGFR TKI osimertinib for EGFR-T790M
advanced NSCLC (AURA2 clinical trial)
AURA2
The Lancet Oncology 2016
osimertinib – EGFR-T790M positive (rebiopsy)
ORR 70%
duration response 11.4 months
median PFS 9.9 months
1-yr OS 81%
only 3% participants required dose reductions and 5% discontinued drug from adverse event
Whack-a-mole paradigm for EGFR TKI monotherapies
1st/2nd generation EGFR TKIs
(gefitinib, erlotinib or afatinib)
T790M(clinical assay)
3rd generation EGFR TKI
(osimertinib)
T790M+
(clinical assay)
12-16 months
T790M+ / C797S+
(clinical assay)
9-12 months
EGFR mutated cells sensitive to
1st/2nd generation EGFR TKIs
T790M+
T790M- (other resistant mechanisms)
T790M+ / C797S+
T790M(clinical assay)
T790M+ or - / C797S(clinical assay)
T790M± / C797S(other resistant mechanisms)
Adapted from Costa DB, Kobayashi S.
Trans Lung Cancer Research (2015)
1st and 2nd gen. ALK TKIs
1st generation ROS1 TKI
upcoming inhibitors for other genomic cohorts (BRAF-V600E, MET)
crizotinib
reg. approval ALK+
2013
ceritinib
ALK+
2014
crizotinib
ROS1+
2015
alectinib
ALK+
2016
? 2016-2017 BRAF-V600E
dabrafenib + trametinib
? 2018 MET-exon 14 skip.
crizotinib (other MET TKI)
ALK inhibitors (multitargeted TKIs) in clinical
development in late 2007 - early 2010: crizotinib
A549
H3122
(KRAS G12S) (EML4–ALK E13;A20)
crizotinib
(µM)
0
0.1 1.0 0
0.1 1.0
pALK
ALK
120kDa
pAKT
AKT
60kDa
actin
45kDa
RR (CR+PR) = 57% (95% CI: 46–68%)
DCR (CR+PR+SD) = 87% (71/82)
crizotinib 250 mg BID
Yasuda et al. J Thorac Oncol. 2012 Jul;7(7):1086-90.
Kwak, E. et al. N Engl J Med 2010 Oct28; 363(18):1693-703.
ALK TKI crizotinib as first line therapy for ALK
rearranged NSCLC: PROFILE1014 – results
Solomon BJ et al N Engl J Med 2014;371:2167
Crizotinib as an ALK TKI versus 1st line
chemotherapy for CNS disease after radiotherapy
platinum-based
Acquired resistance to crizotinib
(pharmacokinetic or biologic)
- crizotinib pharmacokinetic issues (major component):
low serum conc., poor CNS penetration, p-glycoprotein
- crizotinib biological resistance: ALK kinase domain mutations or bypass oncogenes
ALK mutations:
L1196M
1151Tins
C1156Y
F1174L
G1202R
S1206Y
G1269A
(crizotinib resistant)
Activated
oncogenes:
G1202R
F1174C/L
(ceritinib resistant)
P2Y/PKC
G1202R
I1171T/N/S
(alectinib resistant)
EGFR
KIT
IGF-1R
Initial results of the second generation
ALK/ROS1 kinase inhibitor ceritinib
(750 mg once daily)
-
114 patients with NSCLC received at least 400mg/day
of ceritinib;
-
Overall response rate (RR) was 58% (95%CI, 48-67);
-
Among 80 patients who had received crizotinib
previously, the RR was 56% (95% CI, 45-67);
-
Among patients with NSCLC who received at least
400mg/day of ceritinib, the median progression-free
survival (PFS) was 7.0 months (95% CI, 5.6-9.5).
Shaw AT et al. N Engl J Med 2014; 370:1189
Initial results of the second generation
ALK kinase inhibitor alectinib
(600 mg twice daily)
-
138 patients with NSCLC received 600 mg/twice day of
alectinib;
-
Overall response rate (RR) was 50% (95%CI, 41-59);
-
The median progression-free survival (PFS) was 8.9
months (95% CI, 5.6-11.3).
-
Adverse events were mild (grade 1 or 2) with
constipation, fatigue and edema the most common
Ou SH et al. JCO 2016; 34:661
What is the best 1st line ALK TKI for ALK rearranged NSCLC
J-ALEX clinical trial of alectinib vs crizotinib
Summary of mechanisms of ALK inhibitor resistance and
therapeutic strategies for ALK rearranged NSCLC (2016)
ROS1 rearrangements define a novel actionable oncogene in
NSCLC: clinical activity of crizotinib (PROFILE 1001 trial)
~ 1-2% of all NSCLC
~ 6% of never smokers
sensitive to crizotinib
Stumpfova M , and Jänne P A Clin Cancer Res 2012;18:4222
crizotinib 250 mg BID (PROFILE1001)
RR 72% (95%CI 58-84%) [n=50]
median PFS 19.2 months (95%CI: 14.4-NR)
overall survival (OS) 85% at 12 months
Shaw AT et al. N Engl J Med 2014; 371:1963
MET amplification as an actionable oncogene in NSCLC
responsive to crizotinib
- High grade MET amplification present in 1-2%
NSCLCs
(smokers and never smokers)
(adenocarcinoma histology)
- Ongoing clinical trials of MET TKIs
(example: crizotinib)
Adapted from: Camidge et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8001)
Adapted from: Christine Lovly et al. MyCancerGenome.org 2014
MET exon 14 skipping mutations as actionable
oncogenes in NSCLC responsive to crizotinib
- MET exon 14 skipping mutations
present in 4% NSCLCs
(smokers and never smokers)
(adenocarcinoma histology)
- Ongoing clinical trials of MET TKIs
(example: crizotinib)
TCGA. Nature 511:543 (2014)
Kong-Beltran Can Research (2006)
Jenkins RW Clin Lung Cancer (2015) Shea M, Costa DB JTO (2016)
BRAF mutations as actionable oncogenes in NSCLC (1)
-somatic mutations in BRAF have been found in 1–3% of all NSCLC
(smokers and never smokers);
(adenocarcinoma histology)
- BRAF V600E (~50% of cases)
Adapted from: Planchard et al. J Clin Oncol 31, 2013 (suppl; abstr 8009)
Adapted from Christine Lovly et al. MyCancerGenome.org 2013
Driver oncogene genotypes with kinase inhibitor
approval/development (lung adenocarcinoma) in 2016/2017
EGFR mutations
gefitinib
erlotinib
afatinib
osimertinib
none/other
approved
ALK rearrangements
crizotinib
ceritinib
alectinib
NF1 mutations
emerging
RIT1 mutations
evolving
HRAS mutations
NRAS mutations
future
ROS1 rearrangements
crizotinib
BRAF-V600E mut.
dabrafenib+trametinib
MET amplification
(high)
MET exon 14 skipping
mutation
ERBB2 mutations
MAP2K1 mutations
RET rearrangements
FGFR2/3/4 mutations/
rearrangements
KRAS mutations
NTRK1 rearrangements
Adapted from: Shea M. Ther Adv Respir Dis. 2016
Immune checkpoint inhibitors for NSCLC
(squamous cell carcinomas and adenocarcinomas)
anti-PD-1 pembrolizumab (1st line PD-L1 IHC ≥50%, 2nd line PD-L1 IHC >1%)
anti-PD-1 nivolumab (2nd line, irrespective of biomarker PD-L1 IHC)
anti-PD-L1 atezolizumab (2nd line, irrespective of biomarker PD-L1 IHC)
2015
nivolumab pembrolizumab
PD-1
approved PD-L1+
2016
atezolizumab
PD-L1
Harnessing the immune system to treat lung cancer
(PD-1 and PD-L1 antibodies [remove the breaks of the immune system])
Ribas A., et al. N Engl J Med 2012; 366:2417-2519.
Harnessing the immune system to treat lung cancer
(PD-1 and PD-L1 antibodies: early activity in NSCLC since 2012)
effects of the anti-PD-L1 antibody BMS-936559 (example, drug discontinued)
anti-PD-1 and anti-PD-L1 antibodies with FDA approval for NSCLC:
Nivolumab (phase III trials – “positive” survival/FDA approved 2015)
Pembrolizumab (phase III trials - “positive PD-L1-survival”/FDA approved 2015)
Atezolizumab (phase III trial – “positive” survival/FDA approved 2016)
Brahmer JR, et al. N Engl J Med 2012; 366:2455-2465.
FDA approval of anti-PD-L1 atezolizumab for second line therapy
of advanced NSCLC (POPLAR clinical trial)
POPLAR
The Lancet April 30 2016
atezolizumab – PD-L1 IHC score predictive of improved outcomes (not mandatory for selection)
ORR 15% duration response 14.3 months
median PFS 2.7 months median OS 12.6 months
OS
FDA approval of anti-PD-1 nivolumab for second line therapy of
advanced NSCLC (CheckMate-057 clinical trial)
CheckMate
-057
Borghaei H NEJM 2015
nivolumab – PD-L1 IHC score predictive of improved outcomes (not mandatory for selection)
ORR 19%
duration response 17.2 months
median PFS 2.3 months
12-month OS 51%
OS
FDA approval of anti-PD-1 pembrolizumab for second line therapy
of advanced NSCLC (KEYNOTE-010 clinical trial)
KEYNOTE
-010
Herbst R et al. The Lancet 2016
pembrolizumab - PD-L1 >1% expression using the clone 22C3 pharmDx kit
ORR 18% duration response NR (> 10-12 mths)
median PFS 3.9 months
PFS
median OS 10.4 months
OS
FDA approval of anti-PD-1 pembrolizumab for first line therapy of
advanced NSCLC (KEYNOTE-024 clinical trial)
KEYNOTE
-024
Reck M et al. NEJM 2016
pembrolizumab - PD-L1 ≥50% expression using the clone 22C3 pharmDx kit
ORR 44.8% duration response NR (1.9-14.5 mths)
median PFS 10.3 months
PFS
6-month survival 80.2%
OS
New view of NSCLC (lung adenocarcinoma) in 2016-2017
(oncogene driven, immune evasion enhanced or none) [1]
PD-L1 <50%
EGFR or ALK or
ROS1 positive
PD-L1 <50%
EGFR/ALK/ROS1 neg.
[~20%]
TKI 1st line
[~50%]
cytotoxic
chemotherapy
1st line
PD-L1 ≥50%
EGFR/ALK/ROS1 neg.
[~30%]
anti-PD-1
pembrolizumab
1st line
Adapted from Costa DB, et al. 2016 (manuscript in preparation)
New view of NSCLC (lung adenocarcinoma) in 2016-2017
(oncogene driven, immune evasion enhanced or none) [2]
advanced lung
adenocarcinoma
subtype
classic driver oncogene
enriched
(EGFR/ALK/ROS1 pos.)
immune checkpoint
inhibitor
enriched
1st line therapy
2nd line therapy
3rd line therapy
approved TKI
approved matched
TKI
(EGFR-T790M+ or ALK)
(EGFR-T790M- or ROS1)
cytotoxic
chemotherapy
or anti PD-1
or anti-PD-L1
cytotoxic
chemotherapy
cytotoxic
chemotherapy
anti-PD-1
(pembrolizumab)
or cytotoxic
chemotherapy
(PD-L1 ≥50%)
non-oncogene
non-immune
enriched
(EGFR/ALK/ROS1 neg.)
(PD-L1 <50%)
cytotoxic
chemotherapy
anti-PD-1
(nivolumab or pembrolizumab)
or anti-PD-L1
cytotoxic
chemotherapy
(atezolizumab)
Adapted from Costa DB, et al. 2016 (manuscript in preparation)
Avanços 2016: um ano em análise