Molecular Targeted Agents for Stage III NSCLC

Bilal Piperdi, MD

Associate Professor of Clinical Medicine

Director, Thoracic Medical Oncology Program

Montefiore Einstein Center for Cancer Care

Bronx, NY 10461

Case

• 69 y old AA female, former smoker with

2 months history of persistent cough

• PET/CT showed left lung mass, hilar

LN and mildly enlarged subcarinal LN.

No evidence of distant metastasis

• ECOG PS: 1

• Brain MRI: negative.

• PFTs : excellent

• The patient underwent mediastinoscopy

• Path: 2/3 left level 4 LN positive for

poorly differentiated adenocarcinoma

Your recommendation for treatment ?

A. Concurrent chemoRT with 60 Gy RT and two cycles of

cisplatin and etoposide

B. Concurrent chemoRT with 60 Gy RT and weekly

carboplatin/paclitaxel followed by two cycles of carboplatin and

paclitaxel

C. ChemoRT up to 45 Gy followed by surgery

D. Neoadjuvant chemotherapy with 3 cycles of platinum doublet

followed by surgery

E. Surgery followed by adjuvant chemotherapy.

The patient tested positive for exon 19 deletion in EGFR. Your recommendation for treatment ?

A. My treatment recommendation will not change

B. Concurrent chemoRT followed by EGFR-TKI for 1 year

C. EGFR TKI alone

D. EGFR TKI followed by chemoRT

E. EGFR TKI followed by surgery

F. A clinical trial if available

Stage III NSCLC

• Locally advanced disease

• Requires combined modality approach

• Median survival: 14-22 months

• 5 yr survival: 19-24% (IIIA) and 5-10% (IIIB)

• Stage III A : – T1a,b T2a,b N2 M0

– T3 N1 or N2

– T4 N0 or N1

• Stage III B : – T4 N2

– Any T N3

Stage III NSCLC

Resectable

Non-resectable

Practical Classification of stage III disease

Resectability depends on location of tumor and patient’s

characteristics (age, comorbidities, PFT etc..)

Menu for treatment for stage III disease

Surgery Chemotherapy

Radiation Targeted Therapies

Local Systemic

Definitive Concurrent chemoRT

Neoadjuvant chemotx

Neoadjuvant chemoRT

Surgery

Surgery

Surgery

Adjuvant chemotx.

Treatment paradigms in stage III NSCLC

Outcomes from clinical trials

• EGFRTKI after chemoRT no benefit in unselected patients (SWOG 0023)

• Adding Cetuximab to chemoRT did not improve survival (RTOG 9410; CALGB 30407)

• Platium doublets as neoadj tx.

• Concurrent ChemoRT better than sequential chemo.

• No benefit from additional chemo before (CALGB 39801) or after chemoRT (HOG)

• Surgery not better than RT after neoadj chemo (EORTC)

• Survival same for definitive chemoRT vs chemoRT+S (INT 0139)

• Best outcome in patient with mediastinal downstaging

• Concurrent ChemoRT prolongs survival over sequential (RTOG 9410)

• No added benefit from RT or chemoRT after neoadj chemo (GLCCG; SAKK)

• More is not better ; 60 vs 74Gy (RTOG 0617)

Radiation Surgery

Targeted Therapy

Chemotherapy

INT 0139 trial

• Patients with N2 disease were treated with chemoRT

and then randomized to surgery or further chemoRT

• 5yr PFS: surgery 22% vs chemo/RT 11%;

• 5yr OS: surgery 27% vs chemoRT 20%

• In the surgical group, the best outcome was seen in

patients who had mediastinal down staging

• The 5yr survival rates: anyT,N0 : 41% vs anyT,N1-3:

24%

Targeted Agents in Stage III NSCLC

• MAbs

– Bevacizumab

– Cetuximab

• TKI

– Gefitinib

– Erlotinib

• Immunotherapy

– L-BLP25

• Failed Agents

– Thalidomide (ECOG

3598)

– AE 941 (Shark

Cartilage)

– Bortezomib

– Doranidazole

(radiosensitizer)

Bevacizumab

• Phase I/II study ( Socinski et al. J Clin Oncol. 2012 Nov 10;30(32):3953-9)

– In combination with erlotinib and concurrent chemoRT

– High rate of pulmonary hemorrhage in squamous

– Tracehoesophageal fistula and other toxicities

– Use with chemoRT strongly discouraged outside the setting

of properly designed clinical trial

• E1505

– Chemo +/- bev in resected NSCLC

– Includes a good subset of resected stage IIIA patients.

Cetuximab

• N0422 trial

– Phase II trial; n=57; age >65; PS=2

– Cetuximab +RT (60Gy)

– TTP: 7.2 m; median OS 15.1 m

• RTOG 0324 trial

– Phase II trial; n=87

– Cetuximab with carbo/paclitaxel and RT (63 Gy) followed by

consolidation chemotx

– RR: 62%; median OS 22.7 months

CALGB 30407

Pem/Carbo +/- cetuximab with RT

Govindan R et al. JCO 2011;29:3120-3125

©2011 by American Society of Clinical Oncology

EGFR-TKI in unselected patients

SWOG 0023

SWOG 0023

Kelly K et al. JCO 2008;26:2450-2456

©2008 by American Society of Clinical Oncology

Failed trial designs for targeted therapies

• No prior selection by molecular markers or early imaging

• Adding to chemoRT

• Increase toxicity; No synergy or too synergistic and toxic; best strategy?

• Quality control for radiation in clinical trials

• As maintenance tx after chemoRT

• Very heterogeneous group

• The patients are usually beat out after chemoRT

• Purpose: To perform a systematic review and meta-

analysis of published reports assessing the impact of

radiotherapy quality assurance results on outcomes in

clinical trials.

• 8 trials across different disease sites that have QA and

survival data

• # of patients with protocol deviations across the trials

~20-30%

Overall Survival Random Effects Model

HR = 1.74

95% CI = [1.28, 2.35]

p < 0.001

Better trial designs for targeted therapies

• Selection by molecular markers?

• Early imaging modalities for response prediction?

• In a selected group of patients, give the drug with best response in stage IV disease upfront?

• Better RT techniques?

• Better patient selection for maintenance therapy?

• Question the best local therapy

Bilal Piperdi, MD

Steven Keller, MD

Montefiore Medical Center

Albert Einstein College of Medicine

E3512

Molecular and Image guided Neoadjuvant Therapy

for Resectable Stage III (N2) NSCLC (MINT study)

Eirc Rohren, MD, Ph.D

MD Anderson Cancer Center

Caroline Chiles, MD

Wake Forest Baptist Medical Center

MINT study schema: pilot single arm

phase II study

Stage III NSCLC

N2 disease confirmed (EUS/EBUS/mediastinoscopy)

3 cycles of neoadjuvant chemotherapy

SURGERY

mediastinal nodal clearance rate

PET/CT scan

After 1 cycle (t1)

PET/CT scan

Baseline (t0)

PET/CT scan

After 3 cycles (t2)

ERCC-1

determination (Response Genetics; RT/PCR)

ERCC-1 negative

(<1.7)

Chemo Regimens

Cisplatin/gemcitabine

Cisplatin/docetaxel

Cisplatin/pemtrexed

Better RT techniques?

PET-adjusted IMRT for stage III NSCLC

patients (PAINT study)

Dose based on metabolic tumor volume

PET reveals large RUL tumor, small hilar/mediastinal LNs

LNs (red) are close to organs at risk (OARs, heart and esophagus, yellow)

65 Gy to large tumor, 57 Gy to small LNs, sparing OARs from high-dose RT

NO MUTATION DETECTED

EML4-ALK7%

DOUBLE MUTANTS 3%

BRAF 2%

PIK3CA

HER2

MET AMP

MEK1

NRAS

AKT1

KRAS22%

EGFR17%

Lung cancer is no longer one disease

Lung Cancer Mutation Consortium

Incidence of Single Driver Mutations

in Adenocarcinoma of the Lung

Kris MG et al. J Clin Oncol. 2011(suppl);29. Abstract CRA7506. 37

Riely GJ, et al. Clin Cancer Res. 2006;12(3 Pt 1):839-844.

Mutations Identified in EGFR Gene

Exons 1–16

Exons 18–24

Exons 25–28

EGFR transcript

Exon 17

Extracellular

domain

Trans-

membrane

domain

Tyrosine-

kinase

domain

Regulatory

domain

Confer sensitivity/resistance to

EGFR TKIs

Unclear effect on

sensitivity to

EGFR TKIs

18

18

19

20

21

Deletions

L858R

G719A/S

L861X

P694X

V700D

E709X

G735S

V738F

V742A

T751I

S752Y

D761N A763V

N765A

S768I

T783A

L792P

L798F

G810S

N826S

L838V

T847I

I853T

A859T

E866K

L833V

H835L

H850N

V851X

G863D

A864T

L730F P733L

E746K

L688P

V689M

I715S

L718P

S720X

D761Y

D770_N771 insNPG

T790M

EGFR

Chro

mosom

e 7

EGFR mutation and EGFR-TKI’s

• Subsets of NSCLC patients with activating mutations in EGFR kinase domian (deletion in exon 19 and L858R point mutation in exon 21) are exquisitely sensitive to EGFR-TKI including erlotinib and afatinib

• 15-20% of adenocarcinoma in Western patient population have EGFR mutation Rosell et al NEJM

• Similar incidence in early stage (I-IIIA) (20%) versus late stage (IIIB/IV) 27% D’Angelo et al JCO May 20 2011

EURTAC: Objective Response Rate

40

65%

16%

0

10

20

30

40

50

60

70

Ob

jecti

ve R

esp

on

se R

ate

, %

ORR in the EURTAC Intent-to-Treat Population

Erlotinib

(n=86)

Chemotherapy

(n=88)

• The objective response rate was 65% (95% CI, 54.1%-75.1%) for patients treated with erlotinib

tablets and 16% (95% CI, 9.0%-25.3%) for patients treated with chemotherapy

ALK Rearrangement in Cancer

1. Mossé YP et al. Clin Cancer Res. 2009;15:5609-5614.

2. Chiane R et al. Nat Rev Cancer. 2008;8:11-24. 41

Or

Inversion

Translocation

ALK-positive cancers: • NSCLC: EML4-ALK, KIF5B-ALK, TFG-ALK

(3%-5%)1

• Anaplastic large cell lymphoma: NPM-ALK1

• Inflammatory myo-fibroblastic tumor: TPM3-

ALK, TPM4-ALK2

• Other solid tumors2

Tumor Responses to Crizotinib for

Patients With ALK-Positive NSCLC

*Partial response patients with 100% change have nontarget disease present.

Kwak EL et al. N Engl J Med. 2010;363:1693-1703. Copyright © 2010 Massachusetts Medical Society.

All rights reserved. 42

Progressive disease

Stable disease

Confirmed partial response

Confirmed complete response

Max

imu

m C

ha

ng

e

in T

um

or

Siz

e (

%)

-30%

60

40

20

0

-20

-40

-60

-80

-100

RTOG 1308/A 31101 study

Screen patients with Stage III

NSCLC for EGFR mutation and

EML4-alk fusion

EGFR mutated tumors

Arm 1:

Erlotinib for 12 wks followed by chemoRT

Arm 2:

ChemoRT

EML4-alk fusion positive tumors

Arm 3:

Crizotinib for 12 wks followed by

chemoRT

Arm 4:

Chemo RT

Concurrent chemoradiation:

64 Gy thoracic RT with either cisplatin-etoposide or carboplatin-paclitaxel

EVENT trial EValuation of Erlotinib as a Neoadjuvant

Therapy in stage III NSCLC patients with EGFR mutations (EVENT trial)

Multi-institutional pilot phase II study

Stage III NSCLC; EGFR mutation positive

Stage III NSCLC (N2 node confirmed by mediastinoscopy or EUS)

PET/CT and MRI brain negative

EGFR mutation testing

EGFR mutation positive

Erlotinib 150mg PO daily for 2 months

Re-staging by PET/CT +/- mediastinal restaging (*) and evaluation for surgery

Surgically resectable

surgery

Chemotherapy +/- radiation (at investigator’s discretion)

Unresectable

Chemotherapy +/- RT or erlotinib

(at investigator’s discretion)

Progressive disease

Chemotherapy +/- RT (at investigator’s discretion)

EGFR mutation negative

* Patient with non-progressive disease who are not going for

surgery should have mediastinal restaging done by either

EUS/EBUS or mediastinoscopy

Objectives

• Primary

– To estimate the rate of mediastinal downstaging (N0 disease

in final pathology) after neoadjuvant erlotinib in patients with

EGFR mutated stage III NSCLC

– To estimate the complete pathological response rate after

neoadjuvant erlotinib in patients with EGFR mutated stage III

NSCLC

Statistics

• The primary objective is to estimate the rate of mediastinal downstaging (path N0 disease) after neoadjuvant erlotinib

• Based on neoadj chemo trials, the path N0 rate of 30% or higher will justify the further study of neoadjuvant erlotinib and the rate of 15% or less will be considered ineffective.

• An optimal two-stage phase II study

• Nineteen (19) patients will be accrued in the first stage of phase II. If 3 or fewer responses are observed during the first stage then the treatment will be concluded early for lack of efficacy. Otherwise, 36 additional patients will be accrued for the second stage. If 12 or fewer responses among 55 patients are observed by the end of this phase II study, no further investigation of this treatment regimen iswarranted.

• The power under this design is 80% and the type I error is 0.05. The probability of early stopping at the first stage is 68.4% if the true response rate is 15%. If the true response rate is 30%, the probability of early stopping at the first stage is 13.3%.

National Cancer Center Korea: phase II

Stage III NSCLC Stratified by

EGFR mutation

Arm 1:

Erlotinib X 3 cycles -> CCRT with Erlotinib (-

> continue Erlotinib (X 6 cycles)

Arm 2: Erlotinib X 3 cycles -> CCRT

with IP -> recurrence ->

Erlotinib (until PD)

Arm 3 IP X 3 cycles -> CCRT with IP (X

2 cycles)

Arm 4 : CCRT with IP (X 2 cycles) ->

consolidation IP (X 3 cycles)

Irinotecan 65mg/m2 + Cisplatin 30mg/m2 IV on D1,D8 every 3 weeks X 3 cycles

Drug: CCRT with IP chemotherapy Irinotecan (60mg/m2) + cisplatin (30mg/m2) IV on D1 & 8 every 3 weeks X 2 cycles

Radiation: CCRT CCRT :Concurrent Thoracic Radiotherapy (2.4 Gy/fr, Total 60 Gy, 25fr over 5 weeks)

Conclusion

• Progress is needed in treatment of stage III NSCLC

• We have reached a plateau with concurrent

chemoRT

• More novel trial designs with better patient selection

for targeted therapy is needed

• Signals from immunotherapy trial needs confirmation