Strategies to overcome resistance in NSCLCwith driver mutations

Federico CappuzzoIstituto Toscano Tumori

Ospedale CivileLivorno-Italy

First-line therapy for metastatic NSCLC in 2012

Stratification for EGFR, ALK and histology

EGFR mutated EGFR WT non-squamous

EGFR WT squamous

EGFR-TKIPlatinum +

pemetrexed+/-

bevacizumab

Platinum-based doublet

ALK+

Crizotinib

Mut+ NSCLC: EGFR-TKI Acquired Resistance

Baseline Tumor regression(RR up to 90%)

Progression(median 9 months)

Disease Flare: Hospitalization and/or death attributable to disease progression after discontinuation of gefitinib or erlotinib and before initiation of study drug

Risk of disease flare in EGFR mut+ NSCLC with acquired resistance: Chaft J et al. (O 19.05)

Characteristic: Total patients=61 N (% or range)

Male sex – N (%) 13 (21)

Age at diagnosis (years) Median (range) 58 (26-78)

EGFR mutation – N (%) Exon 19 deletion Exon 18 G719A Exon 21 L858R

41 (67)1 (2)

19 (31)

Time on gefitinib or erlotinib (months) Median (range)

19 (7-78)

Age in years - Median (Range) 61 (27-80)

Karnofsky Performance Status (%) 90% 80% 70%

13 (21)37 (61)11 (18)

• 14 of 61 patients (23%, 95% CI 14-35%) had a disease flare (hospitalization or death)

– Flare & no flare group – same 30 day pretrial hospitalization rate

• Median time from last TKI to flare was 8 days (range 3-21 days)

• 3 patients went on to trial treatment

Changes in Tumor Diameter (RECIST) After Discontinuation and Re-introduction of EGFR TKI

-30%

0%

20%

50%

EGFR TKIstop re-start

3 weeks 3 weeks

Chan

ge fr

om b

asel

ine

Riely et al, CCR 2007

Mechanisms responsible for EGFR-TKI resistance

Sequist et al, Science Transl Med 2011

EGFR-TKI resistance

A

B

T790M Mutation causes drug resistance by increasing affinity for ATP

Yun PNAS 2008

T790M mutations in EGFR-TKI naive NSCLC

• Present in up to 50% of NSCLC with EGFR-TKI acquired resistance

• Rare event in EGFR-TKI naive NSCLC (<3%) using low sensitive methods

• Detected in up to 40% of EGFR-TKI naive patients using high sensitive methods

Presence of T790M mutation predicts poor outcome to EGFR-TKI

Su et al. JCO 2012; Rosell et al. Clin Cancer Res 2011;

T790M mutation and acquired resistance to gefitinib therapy

Kobayashi et al. NEJM, 352, 786-792, 2005

Irreversible EGFR-TKI are still effective

Afatinib: Dual irreversible EGFR-HER2 inhibitor

• Orally bioavailable, small molecule tyrosine kinase inhibitor (TKI)• Designed to irreversibly bind to theATP binding pocket of EGFR and HER2• Highly specific for EGFR and HER2

EGFR IC50: 0.50 nM

HER2 IC50: 14 nM

EGFR or HER2 ATP binding pocket

Afatinib

+

Afatinib: active against resistance mutation

BIBW2992 but not erlotinib is active against cells expressing T790M EGFR mutation:

Li et al. Oncogene. 2008;27:4702–4711

NCI-H1975NCI-H1975

Afatinib + cetuximab as the best option in presence of EGFR T790M mutation

Regales et al. JCI 2009

Afatinib + cetuximab for metastatic NSCLC: Study Design

1EGFR G719X, exon 19 deletion, L858R, L861Q; 2Progression of disease (Response Evaluation Criteria in Solid Tumors v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 days; 3Amended from original 14-day interval; 4Acquisition of tumor tissue after the emergence of acquired resistance was mandated.i.v.=intravenous; MTD=maximum tolerated dose; NSCLC=non-small cell lung cancer; SD=stable disease.

Phase Ib, open-label, multicenter trial in the US and The Netherlands

Stop erlotinib/ gefitinib for ≥72 hours3

Disease progression2

NSCLC with EGFR mutation1

OR

SD 6 months with erlotinib/gefitinib

OR

Partial or complete response

to erlotinib/gefitinib

MTD cohort expanded up to 80 EGFR mutation-positive patients4:40 T790M+ and 40 T790M–

Dose escalation schema 3–6 patients per cohort

Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks

Dose levels starting at:afatinib 40 mg +cetuximab 250 mg/m2

Predefined maximum dose:afatinib 40 mg +cetuximab 500 mg/m2

Tumor Regression by T790M Mutation Statusat Recommended Dose

39 patients with proven EGFR T790M mutation: confirmed RR=31%

Acquired resistance to EGFR-TKIs

• Acquired drug resistance is almost inevitable (~10 months)

Mitsudomi, et al. Cancer Sci., 2007

• About 30% of resistant mechanisms are unknown.

Resistant mechanisms in 33 tumors from 6 patients with EGFR-TKI acquired resistance

Num

ber o

f Tum

ors

MET gene copy numbers (folds)

Tumors with T790M

Tumors without T790M

<2.0 2.0 - 4.0 < 4.0

93%

8%

80%

Suda et al. Clin Cancer Res 2010

Inhibition of both EGFR and MET is necessary for growth inhibition of HCC827 GR cells

• Irreversible EGFR inhibitors have no effect on HCC827 GR

• MET shRNA restores sensitivity to gefitinib

Engelman et al. Science 2007

0.01 0.1 1 1000

25

50

75

100

125GefitinibPHA665752Gefitinib/PHA665752

Drug Concentration ( μM)

% o

f con

trol

EML4-ALK fusion oncogene in NSCLC

3–7% of patients with NSCLC have an EML4-ALK gene fusion1

detection test available

mainly seen in adenocarcinomas(mutually exclusive with EGFR mutations)2

phase I/II trial of crizotinib, oral c-MET and ALK inhibitor in selected patients: DCR = 70%3

further potential for personalising therapy in NSCLC

1. Koivunen, et al. Clin Cancer Res 20082. Shaw, et al. ASCO 2009; 3. Bang, et al. ASCO 2010

ALK secondary mutations and crizotinib resistance

Sasaki et al. Cancer Res 2011

New ALK inhibitors TAE684 and AP26113 overcome crizotinib resistance in H3122 CR cell line

Katayama et al. PNAS 2011

Cell lines with ALK secondary mutation and ALK and EGFR co-dependency

Sasaki et al. Cancer Res 2011

ALK amplification or ALK FISH loss as mechanisms of crizotinib resistance

Katayama et al. PNAS 2011, Katayama et al Science Transl Med 2012, Doebele et al. Clin Cancer Res 2012

Several mechanisms responsible for crizotinib resistance: clinical implications

Doebele et al. Clin Cancer Res 2012

Conclusions

• Different mechanisms are responsible for acquired resistance to novel targeted therapies

• So far no proven efficacy of irreversible EGFR-TKIs in NSCLC with acquired resistance to reversible agents

• No clinically available strategies for crizotinib resistant patients

• New drugs and new strategies are under investigation