Beyond EGFR and ALK: Targeting ROS1, RET, and BRAF in ... Drilon (DL... · Lim et al ESMO 2016...
Transcript of Beyond EGFR and ALK: Targeting ROS1, RET, and BRAF in ... Drilon (DL... · Lim et al ESMO 2016...
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Beyond EGFR and ALK:
Targeting ROS1, RET, and BRAFin Advanced Lung Cancers
Alexander Drilon MD
Clinical Director, Developmental Therapeutics
Assistant Attending Physician, Thoracic Oncology Service
Memorial Sloan Kettering Cancer Center
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1999
2004
2009
2014
Driver discovery over time
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Targets identified today
Jordan et al, ASCO Annual Meeting 2016; NCCN Guidelines NSCLC Version 2.2017, 10/26/16
833 tumor samples from patients with lung adenocarcinoma
sequenced on MSK-IMPACTTM
FDA-approved therapiesEGFR mutations: erlotinib, gefitinib, afatinib, osimertinibALK fusions: crizotinib, alectinib, ceritinibROS1 fusions: crizotinib
Refer to:NCCN Guidelines Version 2.2017Non-Small Cell Lung CancerEmerging targeted agents for patients with genetic alterations
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• Recurrent gene rearrangements– ROS1 rearrangements
– RET rearrangements
• Mutations– BRAF V600E
Outline
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ROS1-RearrangedLung Cancers
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Rikova et al, Cell 2007; Bergethon et al JCO 2012
• ROS1 rearrangements
– Late 1980s: identified in GBM
– 2007: identified in NSCLC• HCC78 cell line (SCL34A2-ROS1)
• tumor biopsy (CD74-ROS1)
– Multiple partners:• TPM3-ROS1 t(1;6)
• SDC4-ROS1 t(6;20)
• SLC34A2-ROS1 t(4;6)
• CD74-ROS1 t(5;6)
• EZR-ROS1 inv(6)
• LRIG3-ROS1 t(6;12)
ROS1-rearranged lung cancers
ROS1 tyrosine Kinase domain
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Bergethon et al JCO 2012; Rimkunas et al CCR 2012; FISH image courtesy of Lu Wang, MSKCC
• ROS1-rearranged lung cancers
– 1-2% of NSCLCs
– young never or former light smokers
– Adenocarcinomas
• Diagnosis
– IHC
– FISH
– DNA-based NGS
– RNA sequencing
– Plasma assays
ROS1-rearranged lung cancers
response to crizotinib
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Crizotinib in ROS1-rearranged lung cancers
Shaw et al NEJM 2014
Multicenter phase 1 expansion cohortCrizotinib 250 mg twice dailyPrimary endpoint: overall response
overall response 72% [95% CI 58-84]33 responses in 50 ROS1-rearranged patients
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Crizotinib in ROS1-rearranged lung cancers
Shaw et al NEJM 2014 ; NCCN Guidelines NSCLC Version 2.2017, 10/26/16
Median PFS 19.2 mos [95% CI 14.4-NR]Median DoR 17.6 mos [95% CI 14.5-NR]
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Ceritinib in ROS1-rearranged lung cancers
Lim et al ESMO 2016
Korean phase 2 trialCeritinib 750 mg daily
Primary endpoint: overall response
All (n=32) Crizotinib-naïve(n=30)
Overall response 67% 62%
CR 1 1
PR 19 19
Median PFS 10 months(95% CI 2.5-17.4)
20.7 months(95%CI 4.7-NR)
Median DoR 18.4 months (95%CI 8.0-18.4)
Intracranial response (CR/PR) 2 of 5 evaluable patients with brain metastases at baseline
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Drilon et al, Clin Cancer Res 2015; Davare et al PNAS 2015
Cabozantinib in ROS1-rearranged lung cancers
ALK inhibition does not always equate to ROS1 inhibitor
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• ROS1 rearrangements– Actionable drivers that can be identified in the clinic
– Crizotinib is FDA-approved
– Acquired resistance to crizotinib can be mediated by the acquisition of ROS1 mutations
– Other active drugs: ceritinib, cabozantinib, lorlatinib• not all ALK inhibitors are ROS1 inhibitors!!
Summary
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RET-RearrangedLung Cancers
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Drilon et al Cancer Disc 2013; Suehara et al Clin Cancer Res 2012; Kohno et al Nature 2012, Takeuchi et al Nature 2012, Lipson et al Nature 2012; Ju et al Genome Res 2012
• RET rearrangements
– Papillary thyroid CAs
– 2011: identified in NSCLCs
– Multiple partners:• KIF5B-RET
• CCDC6-RET
• NCOA4-RET
• TRIM33-RET
• KIAA1468-RET
• CUX1-RET
• Diagnosis
– FISH, DNA-based NGS, RNA sequencing, Plasma assays (IHC - not useful)
RET-rearranged lung cancers
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• Incidence
– 1-2% in unselected NSCLCs
– mutually exclusive with other major lung cancer drivers
• Clinical Features
– common in young (≤60 years), never/former light smokers with lung adenocarcinomas
• Pathologic Features
– described largely in lung adenocarcinomas• solid subtype in ~2/3 of cases
• >10% signet ring cells ~1/3 of cases
Wang et al JCO 2012, Cai et al Cancer 2013, Yokota et al Oncol Reports 2012, Seung et al Korean Med 2013, Drilon et al ASCO 2012
Never-SmokersPan-Negative
Lung AdenoCAs
Pan-NegativeNSCLCs
Unselected NSCLCs
RETFusions
6%
15%
95% CI [3-27%]n = 5/34
Lipson et al5
Nature 2012Wang et al6
CCR 2012
2%
solid subtype ≥10% signet ring cells
RET-rearranged lung cancers
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RET-rearranged lung cancers
Outcomes of RET-Rearranged Lung Cancers with Pemetrexed-Based Chemotherapy
Drilon et al. Ann Oncol 2016;27:1286-1291
Patients ORR (PR)
RET-rearranged 45% (n = 5/11)
ROS1-rearranged 78% (n = 7/9)
ALK-rearranged 50% (n = 14/28)
KRAS-mutant 26% (n = 9/35)
P value 0.02
• Durable clinical benefits were observed with pemetrexed-based chemotherapy in RET-rearranged lung cancers.
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Drilon et al Cancer Disc 2013; Drilon et al Lancet Oncology 2016 (In Press)
• RET Inhibitors
– all currently available drugs are multikinaseinhibitors
– cabozantinib
– vandetanib
– ponatinib
– lenvatinib
– sunitnib
– sorafenib
– alectinib
BASELINE 4 WEEKS
RET-rearranged lung cancers
Kinase IC50
MET 1.8
VEGFR2 0.035
RET 5.2
KIT 4.6
AXL 7.0
TIE2 14
FLT3 14
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-100%
-80%
-60%
-40%
-20%
0%
20%
40%
Max
imu
m re
du
ctio
n fr
om
bas
elin
e m
eas
ure
men
t(%
)
Best confirmed responsePartial responseStable disease
A
Drilon et al Lancet Oncology 2016
Median PFS 5.5 months (95% CI: 3.8 to 8.4)
Median DoR 4·7 months (IQR 3·1–8·4)
Median OS 9.9 months (95% CI: 8.1 to NR)
Best Response
% (n)
PR 28% (7/25)
SD 72% (18/25)
ORR 28%, 95% CI 12–49
Cabozantinib in RET-rearranged lung cancers
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Global RET-Rearranged Lung Cancer Registry
Best response*
(n=35)
CR = 1 (3%)
PR = 7 (20%)
SD = 12 (34%)
PD = 14 (40%)
NA = 1 (3%)
ORR = 23%
DCR = 57%
*unconfirmed and locally
assessed by RECIST1.1
• Rate of any response to therapy
– Cabozantinib: 31% (4/13)
– Vandetanib: 18% (2/11)
– Sunitinib: 22% (2/9)
Gautschi, Drilon, et al ASCO 2016
• 132 patients with RET-rearranged lung cancer from Europe, the USA, and Asia were identified
– 41 patients were treated with single-agent RET TKI therapy outside the context of a clinical trial
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Multicenter phase 2 trialPrimary endpoint: response
Lenvatinib ORR 16%
Multikinase inhibitors in RET-rearranged lung cancers
Korean phase 2 trialPrimary endpoint: response
Vandetanib ORR 18%
Velcheti et al ESMO 2016, Lee et al Annals Oncol 2016, Yoh Lancet Oncology 2016
Japanese phase 2 trialPrimary endpoint: response
Vandetanib ORR 53%
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Multikinase inhibitors in RET-rearranged lung cancers
Drilon et al ASCO 2015, Velcheti et al ESMO 2016, Lee et al Annals Oncol 2016, Yoh et al ASCO 2016
Multikinaseinhibitor with
anti-RET activity
Dose Reduction
Rate
HTN(any grade)
Rash(any grade)
Diarrhea(any grade)
Cabozantinib 69% 16% 44% (PPE) 63%
VandetanibKorean phase 2Japanese phase 2
22%53%
89%84%
72%63%
44%79%
Lenvatinib 64% 68% not reported 60%
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• RET rearrangements– Actionable drivers that can be identified in the clinic
– No FDA-approved therapies thus far
– Active drugs: cabozantinib, vandetanib, lenvatinib, in addition to other multikinase inhibitors• Response rates comparable to other driver-positive lung cancers
(i.e. BRAF V600E-mutant lung cancers)
• Tolerability in the face of chronic dosing is an important concern
– May require better drugs (i.e. RET-specific inhibitors) or combination therapy
Summary
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BRAF V600E-MutantLung Cancers
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• Incidence
– 1-4% of NSCLCs
– 2% of lung adenocarcinomas
• Features
– former/current smokers• V600E-mutant: more likely to
be light/never smokers
– mutually exclusive with other oncogenic drivers in most cases
Paik et al JCO 2011; 29:2046. Kris MG, Johnson BE, et al. JAMA. 2014;311(19):1998-2006; Litvak and Riely, et al JTO 2014
BRAF-Mutant Lung Cancers
NRAS 1%
Lung Cancer Mutation Consortium(n = 733 lungadenocarcinomas)
EGFR
(sensitizing)
17%
HER2 3%
ALK 8%MEK1 <1%
MET 1%
Mut >1 gene 3%
No oncogenic
driver detected
36%
PIK3CA 1%
KRAS 25%
EGFR (other)
4%
BRAF 2%(V600E 1.6%)
MSKCC(n=63 BRAF-mutant lung adenocarcinomas)
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• Prognosis
– V600E mutations confer improved survival (compared to non-V600E mutations)
Litvak and Riely, et al JTO 2014
BRAF-Mutant Lung Cancers
Stage IIIB-IV (BRAF V600 vs. EGFR: p=0.25; BRAF V600 vs. KRAS: p=0.12; EGFR vs. KRAS: p <0.001)
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Multicenter phase 2 basket studyVemurafenib 960 mg twice dailyPrimary endpoint: response at week 8
overall response 42% [95% CI 20-67]8 PRs of 19 BRAF V600E-mutant patients
Vemurafenib in BRAF V600E-Mutant Lung Cancers
Hyman, et al. NEJM 2016
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Multicenter single-arm phase 2 studyDabrafenib 150mg twice dailyPrimary endpoint: overall response
overall response 33% [95% CI 23–45]26 PRs of 78 BRAF V600E-mutant patients
Dabrafenib in BRAF V600E-Mutant Lung Cancers
Planchard et al. Lancet Oncol 2016
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Multicenter single-arm phase 2 studyDabrafenib 150mg twice daily + Trametinib 2 mg dailyPrimary endpoint: overall response
Dabrafenib+Trametinib in BRAF V600E-Mutant Lung Cancers
Planchard et al. Lancet Oncol 2016
overall response 63·2% [95% CI 49·3-75·6]36 PRs of 57 BRAF V600E-mutant patients
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Median PFS 9·7 months (95% CI 6·9–19·6)
Dabrafenib+Trametinib in BRAF V600E-Mutant Lung Cancers
Planchard et al. Lancet Oncol 2016
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Dabrafenib+Trametinib in BRAF V600E-Mutant Lung Cancers
Planchard et al. Lancet Oncol 2016
Median duration of treatment10·6 months (IQR 4·2–12·2 months)
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ORR Median PFS Median OS
Vemurafenib 42%[95% CI 20-67]
7.3 months (95% CI 3.5-10.8)
Not reached
Dabrafenib 33% [95% CI 23–45]
5·5 months(95%CI 3·4–7·3)
12·7 months (95% CI 7·3–16·9
Dabrafenib + Trametinib
63% [95% CI 49·3–75·6]
9·7 months (95% CI 6·9–19·6)
Not reached
Targeted Therapy in BRAF V600E-Mutant Lung Cancers
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• BRAF mutations– Actionable drivers that can be identified in the clinic
– Active drugs for BRAF V600E: vemurafenib, dabrafenib, dabrafenib and trametinib
– Dabrafenib + Trametinib with breakthrough designation by the FDA
Summary
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• Recurrent gene rearrangements– ROS1 rearrangements
• Crizotinib, Ceritinib, Cabozantinib
– RET rearrangements• Cabozantinib, Vandetanib,
Lenvatinib
• Mutations– BRAF V600E
• Vemurafenib, Dabrafenib, Dabrafenib + Trametinib