Stefania Canova UO Oncologia Medica Ospedale San Gerardo
Monza
NSCLC:
La personalizzazione del trattamento
Pisa, 13 Novembre 2015
NSCLC Heterogeneity
Kris MG et al. JAMA 2014;311(19):1998-2006
Gower A et al. J Mol Med 2014;92:697-707
EGFR TKI
Exon 19 deletions
L858R
Kuan F-C et al. BJC 2015; 356:1-10
Mechanisms of acquired resistance to EGFR TKIs
Ohashi K et al. JCO 2013; Feb11:1-11
T790M
Overcoming Acquired Resistance in EGFR
T790M+Rociletinib
AZD9291
Sequist L NEJM 2015
Janne P, NEJM 2015
Osimertinib
Best response to rociletinib in 243 centrally confirmed T790M+ patients
Sequist L, et al. ASCO 2015
PFS in 270 centrally confirmed T790M+ patients
Sequist L, et al. ASCO 2015
Best response to rociletinib in plasma T790M+
patients
Sequist L, et al. ASCO 2015
T790M plasma testing is a viable alternative to tissue testing
Sequist L, et al. ASCO 2015
Rociletinib activity observed in central T790M negative patients
Sequist L, et al. ASCO 2015
AZD9291, a Mutant-selective EGFR Inhibitor, as First-line Treatment for EGFR Mutation-positive Advanced Non-small Cell Lung Cancer: Results From a Phase I Expansion Cohort
Ramalingam S, et al. ASCO 2015
Phase I Dose Escalation / Expansion Global Study Design
Ramalingam S, et al. , ASCO 2015
AZD9291: expansion cohort data in first-line setting
at two different dose levels
Response Rate in First-line Cohorts by Dose
Ramalingam S, et al. , ASCO 2015
Response to AZD9291 in first-line patients
Progression-free Survival
Ramalingam S, et al. , ASCO 2015
PFS to AZD9291 in first-line patients
FLAURA Study Design
Ramalingam S, et al. , ASCO 2015
Preliminary data support phase III trial against
standard of care
Novel ALK inhibitors in early phase clinical studies
Drug Target Trials PFS in
Crizotinib resistant months
ORR in Crizotinib resistant
Efficacy in CNS
ASP3026
No longer in clinical development
L1196M Ph I/II
Maitland et al. 2014
5.5 50% -
Entrectinib
FDA orphan drug designation for TrkA, TrkB, TrkC, ROS1- and ALK-positive NSCLC
ALK, ROS1, TrK-A,B,C
Ph I
De Braud et al. 2014
ONGOING
STARTRK-1 Ph I/II NCT02097810
ONGOING
ALK, ROS1 and TRK A, B and C positive neoplasms PF-06463922 ALK G1202R,
ROS1
Ph I/II NCT01970865
ONGOING ALK/ROS1 positive
NSCLC
Good SNC penetration in preclinical models
TSR-011 ALK L1196M, TrK-A,B, C
Ph I/IIa NCT02048488
NA 60% -
X-396 ALK
MET
Ph I/II NCT01625234
NA 55%
CEP-37440 ALK FAK
Ph I NCT01922752
ONGOING
Ceritinib or alectinib in ALK+ NSCLC
Alectinib
crizotinib pretreated
Ceritinib
pretreated Naive
Felip E, et al. ESMO 2014, Gandhi, et al. ASCO 2015; Ou S-H, et al. ASCO 2015; Mok T, et al. ASCO 2015
Abstract 8008<br />Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: an open-label, single-arm, global phase 2 study (NP28673)
Ou S-H, et al. ASCO 2015
Marked activity of alectinib in ALK+ NSCLC patients with measurable CNS metastases
Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting
ALEX phase III study design
Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting
Mechanisms of acquired resistance to ALK inhibitors
Unknown (ALK -)
6%
EGFR Muta on 12%
KRAS Muta on 19%
ALK CNG
ALK 13%
Muta on + CNG
6%
ALK Muta on 31%
Unknown (ALK +)
13%
Takezawa K. et al, Cancer Discovery 2012
ROS1
02/11/15
Sadiq AA et al. JCO 2013;Feb11
MET can be activated by:
• Binding to its ligand HGF
• Overexpression/amplification
• Mutation
• Decreased degradation
Randomized, double-blind phase II study MetMab (onartuzumab) 15 mg/kg iv 1 q21
137 pts NSCLC Second- third-line
Erlotinib + placebo
Erlotinib + Onartuzumab
Intent-to-treat population
MET pos
MET neg
Spigel DR et al. J Clin Oncol 2013;31(32):4105-14
OS 3.8 vs 12.6m p= .002
OS 15.3 vs 8.1m p= .16
Efficacy and safety of crizotinib in <br />patients with advanced MET-amplified <br />non-small-cell lung cancer (NSCLC)
Presented By D. Camidge at 2014 ASCO Annual Meeting
BRAF
Dabrafenib + Trametinib
Multicenter open-label phase II trial in pts with BRAF-V600E mutated NSCLC
Primary objective:ORR
Okudela et al. Cancer Res 2008, Weiss et al. Sci Transl Med 2010 Hammerman et al. Cancer Discovery 2011, TCGA Nature 2012
ORR 63% and DCR 88%
RET
Kohno T et al. Nature Med 2012;18:375-7 Kohno T et al. Cancer Sci 2013;104(11):1396-400
Song M et al. Arch Pharm Res 2015, Sep 16
RAS
Garraway LA. J Clin Oncol 2013;31(15): 1806-14.
Selumetinib
Roberts PJ and Stinchcombe TE. J Clin Oncol 2013;31:1112-21
OS 9.4 vs 5.2 months
PFS 5.3 vs 2.1 months
Janne PA et al. Lancet Oncol 2013;14:38-47
• Serious adverse events (febrile neutropenia, neutropenia, pneumonia)
• Primary endpoint was changed from PFS to OS
• The sample size was not changed (n=87) !!!
• HR 0.57, power 80%
• Additional genetic alterations
• Differential sensitivity of the various KRAS mutations to selumetinib
Pitfalls
Roberts PJ and Stinchcombe TE. J Clin Oncol 2013;31:1112-21 Janne PA et al. Lancet Oncol 2013;14:38-47
Chen Z et al. Nature 2012;483:613-17.
SELECT-01 Randomized III Study
Advanced NSCLC
• KRAS mut+
• Second-line treatment
• PS 0-1
R A N D O M I Z E
Selumetinib 75 mg bid Docetaxel 75 mg/m2
Placebo 75 mg bid Docetaxel 75 mg/m2 1
1 N = 634 patients
Primary endpoint:
PFS
NCT01933932
Pre- and Post-treatment biopsies
Next generation sequencing (NGS)
Separate individual strands spatially Amplify all strands in parallel
Capture amplification products locally Sequence-by-sinthesis in parallel
Enables:
- assessment of many different targets in one test - identification of sub-populations
- analysis of heterogeneous very small samples - relative quantitation of mutations
Oxnard GR et al. Clin Cancer Res 2014;20:1698-1705
Serial monitoring for EGFR activating and EGFR T790M resistance mutation in erlotinib treated EGFR mutant patients
Circulating tumor DNA
• Noninvasive technique
• Highly sensitive genotyping assay
• Monitoring of residual disease after surgery
• Identification of genetic determinants for targeted therapy (point
mutations EGFR, rearrangements EML4/ALK, amplification MET, etc)
• Monitoring of tumor burden during treatment
• Early detection of resistance
Diaz LA et Bardelli A. J Clin Oncol 2014;32:579-86 Oxnard GR et al. Clin Cancer Res 2014;20:1698-1705
Conclusions
Targeted therapies for well targeted populations
Improved survival
In increasingly selected populations, it will be difficult to run large phase III trials
Co-clinical trials
Basket and umbrella trials
Fast timeline are admissible in selected populations
New technologies
Costs of drugs and technologies