advances for non small cell lung cancer
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New and improved targeted therapies for NSCLC William William, MDTRANSCRIPT
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
• Adenocarcinomas
• Squamous Cell Carcinomas
Outline
• Adenocarcinomas
• Squamous Cell Carcinomas
Outline
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Selective EGFR TKIs
Sequist et al., ASCO 2014
CO-1686
Selective EGFR TKIs
Janne et al., ASCO 2014
AZD-9298
Selective EGFR TKIs
Lynch et al., ASCO 2014
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
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Crizotinib
Crizotinib
PROFILE 1007Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007
Shaw A et al. NEJM 2013
PROFILE 1007Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007
Shaw A et al. NEJM 2013
PROFILE 1007Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007
Shaw A et al. NEJM 2013
Crossover rate of 64% in the chemotherapy arm
PROFILE 1007Crizotinib versus Pemetrexed / Platinum – PROFILE 1014
Mok T et al. ASCO 2014
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
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
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Crizotinib in ROS1-rearranged NSCLCs
Ou et al. ASCO 2013
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
[TITLE]
Presented By David Planchard, MD, PhD at 2013 ASCO Annual Meeting
Dabrafenib in NSCLCs with V600E BRAF Mutation
[TITLE]
Presented By David Planchard, MD, PhD at 2013 ASCO Annual Meeting
Dabrafenib in NSCLCs with V600E BRAF Mutation
Dasatinib in NSCLCs with BRAF Inactivating Mutation
Sen et al. Sci Transl Med 2012
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Docetaxel plus Selumetinib vs. Placebo in NSCLCs with KRAS Mutations
Response ratesPFS
OS
Janni et al. ASCO 2012
Docetaxel vs. Trametinib in NSCLCs with KRAS Mutations
Blumenschein et al. ASCO 2013
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
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
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
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
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
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Cabozantinib in NSCLCs with RET Fusions
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasTargeted agents for driver molecular alterations
Shepherd et al. N Engl J Med. 2005;353:123.
AdenocarcinomasCrizotinib for MET-amplified NSCLCs
Camidge et al., ASCO 2014
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
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.
• Adenocarcinomas
• Squamous Cell Carcinomas
Outline
Shepherd et al. N Engl J Med. 2005;353:123.
Squamous Cell CarcinomasTargeted agents for driver molecular alterations
Paik et al. ASCO 2013
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