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NSCLC: La personalizzazione del trattamento

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Stefania Canova UO Oncologia Medica Ospedale San Gerardo

Monza

NSCLC:

La personalizzazione del trattamento

Pisa, 13 Novembre 2015

(2)

NSCLC Heterogeneity

(3)

Kris MG et al. JAMA 2014;311(19):1998-2006

(4)

Gower A et al. J Mol Med 2014;92:697-707

(5)

EGFR TKI

(6)

Exon 19 deletions

(7)

L858R

Kuan F-C et al. BJC 2015; 356:1-10

(8)

Mechanisms of acquired resistance to EGFR TKIs

Ohashi K et al. JCO 2013; Feb11:1-11

T790M

(9)

Overcoming Acquired Resistance in EGFR

T790M+

Rociletinib

AZD9291

Sequist L NEJM 2015

Janne P, NEJM 2015

Osimertinib

(10)

Best response to rociletinib in 243 centrally confirmed T790M+ patients

Sequist L, et al. ASCO 2015

(11)

PFS in 270 centrally confirmed T790M+ patients

Sequist L, et al. ASCO 2015

(12)

Best response to rociletinib in plasma T790M+

patients

Sequist L, et al. ASCO 2015

(13)

T790M plasma testing is a viable alternative to tissue testing

Sequist L, et al. ASCO 2015

(14)

Rociletinib activity observed in central T790M negative patients

Sequist L, et al. ASCO 2015

(15)

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

(16)

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

(17)

Response Rate in First-line Cohorts by Dose

Ramalingam S, et al. , ASCO 2015

Response to AZD9291 in first-line patients

(18)

Progression-free Survival

Ramalingam S, et al. , ASCO 2015

PFS to AZD9291 in first-line patients

(19)

FLAURA Study Design

Ramalingam S, et al. , ASCO 2015

Preliminary data support phase III trial against

standard of care

(20)
(21)
(22)

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

(23)

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

(24)

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

(25)

Marked activity of alectinib in ALK+ NSCLC patients with measurable CNS metastases

Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

(26)

ALEX phase III study design

Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

(27)

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

(28)

ROS1

(29)

02/11/15

(30)
(31)
(32)
(33)
(34)
(35)
(36)

Sadiq AA et al. JCO 2013;Feb11

(37)

MET can be activated by:

• Binding to its ligand HGF

• Overexpression/amplification

• Mutation

• Decreased degradation

(38)

Randomized, double-blind phase II study MetMab (onartuzumab) 15 mg/kg iv 1 q21

137 pts NSCLC Second- third-line

Erlotinib + placebo

Erlotinib + Onartuzumab

(39)

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

(40)
(41)
(42)
(43)
(44)

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

(45)
(46)
(47)

BRAF

(48)
(49)
(50)

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%

(51)

RET

(52)

Kohno T et al. Nature Med 2012;18:375-7 Kohno T et al. Cancer Sci 2013;104(11):1396-400

(53)

Song M et al. Arch Pharm Res 2015, Sep 16

(54)

RAS

(55)

Garraway LA. J Clin Oncol 2013;31(15): 1806-14.

(56)

Selumetinib

Roberts PJ and Stinchcombe TE. J Clin Oncol 2013;31:1112-21

(57)

OS 9.4 vs 5.2 months

PFS 5.3 vs 2.1 months

Janne PA et al. Lancet Oncol 2013;14:38-47

(58)

• 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

(59)

Chen Z et al. Nature 2012;483:613-17.

(60)

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

(61)

Pre- and Post-treatment biopsies

(62)

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

(63)

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

(64)

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

(65)

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

(66)

Grazie per l’attenzione!

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