advances for non small cell lung cancer

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