Download - Advances for Non Small cell Lung Cancer
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New and Improved Targeted Therapies for NSCLCs
William N. William Jr.
Assistant ProfessorChief, Head and Neck Section
Department of Thoracic / Head and Neck Medical OncologyM. D. Anderson Cancer Center
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• Adenocarcinomas
• Squamous Cell Carcinomas
Outline
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• Adenocarcinomas
• Squamous Cell Carcinomas
Outline
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Selective EGFR TKIs
Sequist et al., ASCO 2014
CO-1686
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Selective EGFR TKIs
Janne et al., ASCO 2014
AZD-9298
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Selective EGFR TKIs
Lynch et al., ASCO 2014
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Selective EGFR TKIs: Conclusions• High response rates and extended PFS after failure
of first-generation EGFR TKIs• Higher response rates in T790M+• Toxicity patterns consistent with selectivity to
mutant receptors
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Crizotinib
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Crizotinib
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PROFILE 1007Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007
Shaw A et al. NEJM 2013
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PROFILE 1007Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007
Shaw A et al. NEJM 2013
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PROFILE 1007Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007
Shaw A et al. NEJM 2013
Crossover rate of 64% in the chemotherapy arm
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PROFILE 1007Crizotinib versus Pemetrexed / Platinum – PROFILE 1014
Mok T et al. ASCO 2014
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Ceritinib in ALK+ Patients
Shaw A et al. NEJM 2014
Response rates:• 56% crizotinib-treated patients• 62% crizotinib-naïve patients
Response rates:• 86% ALK-dependant resistance• 59% non ALK-dependant resistance
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ALK Inhibitors: Conclusions• Crizotinib improves PFS over pemetrexed/platinum in
treatment-naïve ALK+ patients• Crizotinib improves response rates, PFS and QoL over
pemetrexed or docetaxel in previously treated ALK+ patients. No improvements on premature analysis of OS, in the setting of high crossover rate (64%)
• Pemetrexed has better response rates and PFS compared to docetaxel in ALK+ patients
• Second generation ALK inhibitors have high response rates in crizotinib-naïve and crizotinib-treated patients, including responses in the brains
• Best strategy as regards to sequencing of ALK inhibitors and chemotherapy to be determined
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Crizotinib in ROS1-rearranged NSCLCs
Ou et al. ASCO 2013
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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[TITLE]
Presented By David Planchard, MD, PhD at 2013 ASCO Annual Meeting
Dabrafenib in NSCLCs with V600E BRAF Mutation
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[TITLE]
Presented By David Planchard, MD, PhD at 2013 ASCO Annual Meeting
Dabrafenib in NSCLCs with V600E BRAF Mutation
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Dasatinib in NSCLCs with BRAF Inactivating Mutation
Sen et al. Sci Transl Med 2012
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Docetaxel plus Selumetinib vs. Placebo in NSCLCs with KRAS Mutations
Response ratesPFS
OS
Janni et al. ASCO 2012
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Docetaxel vs. Trametinib in NSCLCs with KRAS Mutations
Blumenschein et al. ASCO 2013
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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HER-2 Targeted Therapies in NSCLCs with HER2 Mutations
Patient
First-Line Treatment Second-Line Treatment Third-Line Treatment Fourth-Line Treatment
Treatment Best Disease Response Treatment Best Disease
Response Treatment Best Disease Response Treatment Best Disease
Response
11 VIN-TRAS PR
15 CAR-PAC-TRAS SD
19 TXT-MASA PD
24 VIN-TRAS PR
26 CAR-PAC-TRAS PR
27 VIN-TRAS PR28 VIN-TRAS SD30 LAP PD31 NVB-TRAS PR32 LAP PD TRAS-VIN PR AFA SD CAR-TRAS SD37 VIN-TRAS PD41 DOC-TRAS PR43 VIN-TRAS PR AFA PR44 VIN-TRAS PR AFA SD45 VIN-TRAS SD PAC-TRAS SD47 TRAS PR
Mazières et al. JCO 2013
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HER-2 Targeted Therapies in NSCLCs with HER2 Mutations
Patient
First-Line Treatment Second-Line Treatment Third-Line Treatment Fourth-Line Treatment
Treatment Best Disease Response Treatment Best Disease
Response Treatment Best Disease Response Treatment Best Disease
Response
11 VIN-TRAS PR
15 CAR-PAC-TRAS SD
19 TXT-MASA PD
24 VIN-TRAS PR
26 CAR-PAC-TRAS PR
27 VIN-TRAS PR28 VIN-TRAS SD30 LAP PD31 NVB-TRAS PR32 LAP PD TRAS-VIN PR AFA SD CAR-TRAS SD37 VIN-TRAS PD41 DOC-TRAS PR43 VIN-TRAS PR AFA PR44 VIN-TRAS PR AFA SD45 VIN-TRAS SD PAC-TRAS SD47 TRAS PR
Mazières et al. JCO 2013
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HER-2 Targeted Therapies in NSCLCs with HER2 Mutations
Patient
First-Line Treatment Second-Line Treatment Third-Line Treatment Fourth-Line Treatment
Treatment Best Disease Response Treatment Best Disease
Response Treatment Best Disease Response Treatment Best Disease
Response
11 VIN-TRAS PR
15 CAR-PAC-TRAS SD
19 TXT-MASA PD
24 VIN-TRAS PR
26 CAR-PAC-TRAS PR
27 VIN-TRAS PR28 VIN-TRAS SD30 LAP PD31 NVB-TRAS PR32 LAP PD TRAS-VIN PR AFA SD CAR-TRAS SD37 VIN-TRAS PD41 DOC-TRAS PR43 VIN-TRAS PR AFA PR44 VIN-TRAS PR AFA SD45 VIN-TRAS SD PAC-TRAS SD47 TRAS PR
Mazières et al. JCO 2013
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HER-2 Targeted Therapies in NSCLCs with HER2 Mutations
Patient
First-Line Treatment Second-Line Treatment Third-Line Treatment Fourth-Line Treatment
Treatment Best Disease Response Treatment Best Disease
Response Treatment Best Disease Response Treatment Best Disease
Response
11 VIN-TRAS PR
15 CAR-PAC-TRAS SD
19 TXT-MASA PD
24 VIN-TRAS PR
26 CAR-PAC-TRAS PR
27 VIN-TRAS PR28 VIN-TRAS SD30 LAP PD31 NVB-TRAS PR32 LAP PD TRAS-VIN PR AFA SD CAR-TRAS SD37 VIN-TRAS PD41 DOC-TRAS PR43 VIN-TRAS PR AFA PR44 VIN-TRAS PR AFA SD45 VIN-TRAS SD PAC-TRAS SD47 TRAS PR
Mazières et al. JCO 2013
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Cabozantinib in NSCLCs with RET Fusions
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasCrizotinib for MET-amplified NSCLCs
Camidge et al., ASCO 2014
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Shepherd et al. N Engl J Med. 2005;353:123.
Adenocarcinomas
Selumetinib / TrametinibErlotinib / Gefitinib / Afatinib / selective
EGFR TKIsCrizotinib / Ceritinib / Alectinib
CabozantinibVemurafenib / Dabrafenib
Trastuzumab...
Targeted agents for driver molecular alterations
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Targeted Agents for Driver Molecular Alterations
• Crizotinib is active in ROS-1 positive tumors• Dabrafenib is active in patients with a BRAF V600E activating
mutation• Dasatinib may be active in patients with a BRAF inactivating
mutation• MEK inhibitors with modest activity in difficult to treat, KRAS
positive patients• Preliminary evidence of activity of HER-2 targeting with
trastuzumab, afatinib, but not lapatinib, in HER-2 mutant tumors
• Cabozantinib may be active in RET positive tumors• Metmab + erlotinib may improve PFS and OS comapred to
erlotinib in MET positive patients. Phase III results pending.
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• Adenocarcinomas
• Squamous Cell Carcinomas
Outline
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Shepherd et al. N Engl J Med. 2005;353:123.
Squamous Cell CarcinomasTargeted agents for driver molecular alterations
Paik et al. ASCO 2013
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Take Home Messages
• Treatment with agents targeting driver alterations may result in promising activity for molecularly-defined subgroups of patients
• Targetable mutations more frequently identified in adenocarcinomas, compared to squamous cell carcinomas
• Precision medicine for NSCLC treatment is here to stay