Background

Department of Thoracic/Head & Neck Medical Oncology

Combined Modality Therapy for NSCLC

Anne S. Tsao, M.D.

Associate Professor

Director, Mesothelioma Program

Director, Chemoradiation Program

TheUniversityofTexasMDANDERSONCANCER CENTER

BackgroundStaging

Standard of Care(RTOG 9410, LAMP)

Outline: Stage III NSCLC

Induction chemo (CALGB 39-801)Consolidation (SWOG 9504)

(SWOG 0023)

Unresectable IIIA/B

Resectable IIIAInduction chemo

Induction chemoXRT (INT 0139)

Inhibitors EGFR, VEGF RTOG 1306/Alliance 31101 Novel Therapies

Lung Cancer

• During 2013, ~228,190 new cases and ~159,480 deaths are expected in the United States

• Second most common cancer and leading cause of cancer death

American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer Society; 2013; Siegel. CA Cancer J Clin. 61(4):212.

Stage at Diagnosis

Localized

(stage I/II)

15%

Distant

(stage IV)

56%

Regional

(stage III)

22%

5-Year Relative Survival Rate

by Stage at Diagnosis

Su

rviv

al (

%)

Localized DistantRegional

53%

24%

4%0

10

2030

40

50

60

70

80

90100

New Staging Stage III

Detterbeck F C et al. Chest 2009;136:260-271

Classic Stage IIIA Patient Presentations

• Early clinical stage Surgery – find microscopic disease in N2 Lymph nodes so pathologic stage IIIA Radiation then adjuvant

chemotherapy

• Multi-station N2 lymph nodes Induction chemo then

chemoXRT Induction chemo then surgery

then XRT Induction chemoXRT then

surgery ChemoXRT

• T3-4 chest wall invasion

(superior sulcus tumors) Induction chemo then

chemoXRT ChemoXRT Induction chemoXRT then

surgery

• Single station N2 lymph nodes Induction chemo then chemoXRT Induction chemo then surgery then

XRT Induction chemoXRT then surgery ChemoXRT

Stage III NSCLC TreatmentThe optimal regimen has not been defined yet although stage III

patients require multi-modality therapy to achieve long-term survival.

Concurrent chemo-radiation is better than XRT alone and sequential chemo-radiation in unresectable stage III NSCLC

10

12

14

16

18

20

22

24

Sequential Concurrent

WJLCG

GLOT

CZECH

LAMP

RTOG 9410

BROCAT

14 (n=716)

17 (n=709)

P < 0.05 (Kruskal-Wallis Test)Choy, ASCO 2003

Med

ian

OS

Stage III NSCLC Treatment

• ASCO Guidelines

Patients with a good performance status (FEV1 > 800 cm3 ) should receive 2-4 cycles of platinum-based chemotherapy and should receive no less than the biologic equivalent of 60 Gy XRT in 1.8 –2.0 fractions

Pfister et al. JCO 22 (2): 330-353, 2004

Stage III NSCLC

Unanswered questions:

Optimal chemotherapy, dosing, timing

Induction regimen

Consolidation

Sequencing Tri-modality Therapy

Biologic therapies

BackgroundStaging

Standard of Care


Induction chemo (CALGB 39-801)Consolidation (SWOG 9504)

(SWOG 0023)

Unresectable IIIA/B




Phase III Induction Chemo-surgery Trials for IIIA

Trial Therapy nMedian survival (months)

Survival

(%)P-value

NCIPE +Surg

Surg+XRT

13

14

28.7

15.6

42 (3-yr)

12 (3-yr)0.095

RossellMIC+Surg

Surg (XRT)

30

30

26

8

30 (3-yr)

0 (3-yr)<0.005

RothCEP+Surg

Surg

28

32

21

14

36 (5-yr)

15 (5-yr)0.048

DepierreMIC+Surg+MIC

Surg

187

186

37

26

52 (3-yr)

41 (3-yr)0.15

Pass et al Ann Thor Surg 1992, Rosell et al NEJM 1994, Roth JNCI 1994, Depierre JCO 2002

PE = cisplatin, etoposide

MIC = mitomycin, ifosfamide, cisplatin

CEP = cisplatin, etoposide, cyclophosphamide

Depierre et al. found that the benefit of chemo was in N0-1 disease (RR 0.68) and not in N2 disease (RR 1.04)

Induction Chemotherapy Trials

• Bimodality Lung Oncology (BLOT) (carboplatin,taxol)

• French Thoracic Cooperative Group (gemcitabine, cisplatin vs. carboplatin, taxol)

• Medical research Council LU-22 (MIC vs. mitomycin, vinblastine, and cisplatin)

• NATCH (carboplatin, taxol)

• CLINCH (carboplatin, taxol)

• CHEST(gemcitabine, cisplatin)

The role of surgery in IIIA patients after neoadjuvant chemotherapy remains controversial.

Prognostic Factors for Improved Survival to Surgery after Neoadjuvant

Chemo

• Response to chemotherapy

• Down-stage N2 disease

• Single-station N2 is better than multi-station N2 disease

• R0 resection

• Pathologic CR

Resectable IIIA – Induction Chemo

• Limited Data - Conflicting for pN2 patients

• Reasonable to offer induction chemotherapy (ideally on protocol)

• Patients with objective response should be offered surgery

• Positive subcarinal nodes or multiple level involvement portends a poor prognosis Definitive chemoradiation may be better for the patient

INT 0139 Phase III Trial of CT/RT vs. CT/RT/S

Albain K, et al Lancet 374: 379-386, 2009

Chemotherapy (PE)Cisplatin 50 mg/m2 d1, 8, 29, 36

Etoposide 50 mg/m2 d1-5, d29-33

RadiationThoracic Radiation 45 Gy

starting on Day 1 (1.8 Gy/day)

InductionPE x 2 + XRT

Surgery

XRT to 61 Gy + PE x 2

Stage IIIA

T1-3pN2

Surgery Feasible

Predicted post-

surgery FEV1 > 800cc

Medically fit

*RANDOMIZE

*Stratified by KPS, T-stage Primary endpoint: overall survival in ITT

INT 0139 PFS Favors Tri-modality Arm

Months from Randomization

0

25

50

75

100

0 12 24 36 48 60

/

/ /// / // / / / // / // / / / / / / // / /

0

25

50

75

100

0 12 24 36 48 60

/

/ /// / // / / / // / // / / / / / / // / /

% A

live

wit

ho

ut

Pro

gre

ssio

n

CT/RT/S CT/RT

5-yr Median PFS (mo) 12.8 10.5

5-yr PFS Rate 22.4% 11.1%

CT/RT/SN=202

CT/RTN=194

HR 0.77, p=0.017


INT 0139 Overall Survival%

Aliv

e

0

25

50

75

100


0 12 24 36 48 60

HR 0.87 p=0.24

% A

live

0

25

50

75

100


0 12 24 36 48 60

CT/RT/S CT/RT

5-yr Median OS (mo) 23.6 22.2

5-yr OS Rate 27.2% 20.3%

CT/RT/SN=202

CT/RTN=194


Chemo-XRT

(n=179)

ChemoXRT-Surgery

(n=177)

Induction ChemoXRT 0 0

30 days Post-operative period

- 10 (5%)

Consolidation

ChemoRT4 (2%) -

Other 0 6 (3%)

Total 4 (2%) 16 (8%)

INT 0139 Deaths

Deaths on surgery arm mostly occurred in pneumonectomy patients (14 of the 16 pts).

26% (n=14/54) of all pneumonectomy cases died; mostly from ARDs and respiratory failure.



% A

live

0

25

50

75

100

0 12 24 36 48 60

/

//

/ // /

/

/

/

CT/RT/SN=38

CT/RTN= 42

p = NS

INT 0139 OS by Pneumonectomy vs CT/RT

CT/RT/S CT/RT

Median OS (mo) 18.9 29.4

3 yr OS 36% 45%

5 yr OS 22% 24%


INT 0139 OS by Lobectomy vs CT/RT %

Aliv

e

0

25

50

75

100

Months from Randomization0 12 24 36 48 60

///

// / / / / / / / /// / / /

/ / // /

CT/RT/SN=57

CT/RTN=74 p = 0.002

CT/RT/S CT/RT

Median OS (mo) 33.6 21.7

5 yr OS 36% 18%


Summary: INT 0139

• Neoadjuvant chemo-radiation before surgery improves PFS but not OS over definitive chemo-radiation in stage IIIA (T1-3 pN2) NSCLC patients.

• There was a trend towards increased 5-year OS rates with the tri-modality arm.

• N0 status at surgery predicts for greater 5-yr survival; i.e. down-staging is associated with improved survival.


Summary: INT 0139

• No significant differences in toxicity beyond increased esophagitis in the chemo-radiation alone arm.

• In patients that require a pneumonectomy, neoadjuvant chemo-radiation is associated with a high risk of post-operative death (26%).

• At this time, can safely consider neoadjuvant chemo-radiation in very good PS patients who can receive a lobectomy.

Future Issues

How to determine which patient should receive aggressive tri-modality?

• Develop prognostic molecular models to help guide treatment decisions

How to optimize down-staging?

• Improve systemic therapies

• Personalize medicine to molecular genotype

BackgroundStaging



Consolidation (SWOG 9504)(SWOG 0023)

Unresectable IIIA/B




Consolidation Chemotherapy

S9019, n= 50

pStage IIIB

Cisplatin/VP-16XRT

Cisplatin/VP-16

pStage IIIB

Cisplatin/VP-16XRT

Docetaxel

SWOG Phase II Trials

S9504, n=83

SWOG 9504

Cisplatin

50 mg/m2 d1, 8, 29, 36

Etoposide

50 mg/m2 d1-5, d29-33

+

Thoracic Radiation 61 Gy

45Gy (1.8 Gy/fx),

16 Gy boost (2Gy/fx)

Docetaxel

Cycle 1: 75 mg/m2

Cycle 2-3: 100 mg/m2

NSCLC

Stage IIIB

(T4N0-2, TanyN3)

Cytology negative pleural

effusion

PS 0-2

Gandara D, et al. (SWOG 9504), Abstract # 7059, ASCO 2005

StudyMST

(mo)2 yr 3 yr 4 yr 5 yr

SWOG 9504

(PE/RT) -> D26 54% 37% 29% 29%

SWOG 9019

(PE/RT)-> PE15 34% 17% 17% 17%

PE: cisplatin/etoposide; RT: 61 Gy Radiotherapy; D: docetaxel


SWOG 9504 Overall Survival

SWOG 9504

• Long-term survival results are impressive for stage IIIB NSCLC.

• Certain subsets of stage IIIB can have survival range of 20-37%.

• However, confirmatory randomized trials are needed.

• Cisplatin/Etoposide given concurrently with radiation followed by docetaxel for 3 cycles is an appropriate regimen to use in stage IIIB NSCLC.


Hoosier Oncology Group

LUN01-24

RANDOMIZE

PE/XRT

PE/XRT

Docetaxel

Confirmatory Consolidation Trials

SWOG 0023

PE/RT -> Docetaxel

RANDOMIZE

Gefitinib

Placebo

ChemoRT InductionCisplatin 50 mg/m2 d 1,8,29,36

Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy

Unresectable, Stage IIIA-IIIB NSCLC;ECOG PS 0-1; <5% Weight Loss in Prior 3 mo

HOG LUN 01-24(Closed to Accrual 7/06, n=244/259)

CR, PR, or SD;ECOG PS 0-2

Docetaxel 75 mg/m2 q 3 wk 3 Observation

Randomize

There was no difference in

outcome between the two arms

SWOG 0023

Kelly K, et al. (SWOG 0023), Abstract # 7058, ASCO 2005

Cisplatin

50 mg/m2 d1, 8, 29, 36

Etoposide

50 mg/m2 d1-5, d29-33

+

Thoracic Radiation 61 Gy

Docetaxel

Cycle 1-3: 75 mg/m2

NSCLC

Unresect IIIA, or IIIB

Cytology negative pleural

effusion

PS 0-1

Predicted post-

surgery FEV1 > 800cc

Gefitinib250 mg

or500 mgdaily

Placebo

SWOG 9504SWOG 0023 PFS


Gefitinib

SWOG 0023: Overall Survival

P-value for alternative hypothesis 33% improvement with gefitinib was p= 0.0015

0%

20%

40%

60%

80%

100%

0 12 24 36Months After Randomization

Gefitinib Placebo

N 124 131

Events4332

Medianin Months

1929

P=0.09 2-sided stratified

Log-rank


SWOG 0023

• Gefinitib maintenance after concurrent chemoradiation and docetaxel consolidation does not improve progression-free nor overall survival.


• In fact, it is possible that gefitinib may have a detrimental effect. This remains under investigation.

• SWOG 9504 regimen has favorable survival and can be used as a standard regimen for unresectable stage IIIB NSCLC.

BackgroundStaging



Consolidation (SWOG 9504)(SWOG 0023)

Unresectable IIIA/B




Systemic Therapy

• Clear survival benefit seen in stage III with down-staging

• Distant relapse remains a significant cause of death in stage III patients

• Improving systemic therapies would potentially improve survival outcomes

NSCLC PATIENT

Non-SCC

Neuroendocrine

Platinum-etoposide;

Switch Maintenance: pemetrexed, erlotinib

Adenocarcinoma

EGFR mutation EGFR wild-type

EGFR TKI

1st or 2nd line

Maintenance

(IPASS, BR.21, SATURN)

EML 4 ALK, ROS1

crizotinib

Platinum-doublet-bevacizumab

Platinum-pemetrexed + bevacizumab

Non-platinum or platinum based doublet


(E4599, AVAiL, Pointbreak, SATURN, JMEN)

SCC

Avoid pemetrexed or bevacizumab

Consider 2nd line EGFR TKI or maintenance erlotinib

(BR.21, SATURN)

Tsao Stage IV Algorithm: Histology and Molecular Profiling

Cetuximab

IgG1 chimerized antibody to EGFRBlocks ligand binding of EGF/TGF to EGFR

• Potentiates apoptosis

• Inhibits cell cycle progression

• Decreases production of angiogenic factors

• Inhibits invasion and metastasis

1o Endpoint: Feasibility/Safety

20 Endpoint: 1 year survival, TTP, Overall Survival

N=84

RTOG 0324 Treatment Schema

Blumenschein et al. JCO 2011


RTOG 0324 - Response Rate

Efficacy

Median OS time 22.7 months

2-year survival rate 49.3%


Median PFS 12 months

2-year progression-failure rate 55.2%

RTOG 0324 Conclusions

• The addition of cetuximab to chemo-radiation is feasible. Radiotherapy was delivered per protocol or within acceptable

variation for 86% of patients. Incidence of Grade ≥ 3 non-hematologic AE rate of 68% was

similar to historical control • LAMP/ ACR 427 – 68%• Most common toxicities: skin, GI, pulmonary, and metabolic

or laboratory abnormalities• There were six grade 5 events with the addition of

cetuximab; 3 were in cases where > 20 Gy was administered to a significant volume of lung

• A confirmatory phase III trial RTOG 0617 has completed accrual on May 12, 2011. Additional trials have also used cetuximab with other chemotherapy backbones.

RTOG 0617: Conventional vs. High Dose RT +/- C225

R

A

N

D

O

M

I

Z

E

XRT: 60 Gy

Carbo-paclitaxel

+/- cetuximab

XRT: 74 Gy

Carbo-paclitaxel

+/- cetuximab

Carbo-paclitaxel

X 2 cycles

The high-dose XRT 74 Gy arms were closed due to lack of OS benefit on May

2011.

Weekly carboplatin AUC 2, paclitaxel 45 mg/m2, cetuximab 400 mg/m2 LD then weekly 250 mg/m2

Primary endpoint: OS

N=464

Bradley et al. ASCO 2013 Abstract 7501

RTOG 0617 Results

OutcomeN=419

Standard dose XRT

High-dose XRT P-value

18-month OS 28.7 months 19.5 months 0.0007

18-month Local failure rate

35.3% 44% 0.04

• There was no difference in distant metastases rate.

• Multivariate analysis for Poor prognostic factors: higher XRT dose, higher esophagitis/dysphagia rate, greater tumor volume, and heart volume > 5 Gy.

• Data on effects of cetuximab were presented IASLC 2013.

Bradley et al. ASCO 2013 Abstract 7501

RTOG 0617 Cetuximab Effects• 237 patients received cetuximab

• No significant benefit in overall or progression-free survival with cetuximab. Higher overall grade 3-5 toxicity (85% vs 69%, p<0.0001). Higher non-hematologic grade 3-5 toxicities (70.5% vs 50.7%,

p<0.0001)

• Patients with EGFR IHC H-score > 200 may have more benefit with cetuximab.

Pemetrexed

• Pemetrexed inhibits thymidylate synthase and other folate-dependent enzymes (GARFT, TS, DHTR)

• Preclinical data indicate that high expression of TS correlates with reduced sensitivity to Pemetrexed.

• SCC have higher baseline TS gene and protein expression compared to adenocarcinomas

• Cells with MTAP deletions may be particularly sensitive to agents that reduce de-novo purine synthesis.

Ceppi et al. Cancer 2006; Sigmond et al. Biochem. Pharmacol. 2003; Giovannetti et al. Mol. Pharmacol. 2005, Schmid et al. Oncogene, 1998

Abstract #7505 Phase II CALGB 30407

Primary endpoint: Overall Survival

Secondary endpoint: FFS, RR, toxicity, tissue EGFR expression and mutation

Stats: 90% power to detect whether median survival is 20.9 months or more compared to historical control (CALGB 39801) 13.9 months

Govindan et al. ASCO abstract #7505

Eligible Patients: Untreated stage III, PS 0-1, No pleural effusions

CALGB 30407 RR and FFS

Carbo-Pem(n=48)

Carbo-Pem-C225(n=51)

CR/PR 6%/64% 2%/68%

SD 25% 24%

ORR 73% 71%

Median FFS 13 months 12 months

18 month FFS 28% 34%


FFS by Histology


Median FFS 18-month FFS

SCC 12 months 25%

Non-SCC 13 months 36%

CALGB 30407 by OS


Carbo-Pem(n=48)

Carbo-Pem-C225(n=51)

Median OS (months) 22 22

18-month OS 57% 50%

CALGB 30407 OS by Histology


Median OS 18-month OS

SCC 18 months 48%

Non-SCC 22 months 56%

Implications for Practice

• In summary, the addition of cetuximab to chemo-radiation did not have any new safety signals.

• Use of cetuximab in combination with chemotherapy and radiation for local-regionally advanced NSCLC remains investigational.

• Identification of a predictive biomarker would be beneficial.

BEVACIZUMAB in NSCLC Recombinant Humanized Monoclonal Antibody to

VEGF-A

• Phase II NSCLC trial Pulmonary hemorrhage

in squamous histology

• E4599 (Phase III)

carbo/paclitaxel + bevacizumab

RR, PFS, OS

in non-SCC NSCLC

Johnson et al. JCO 22 (11): 2184-2191, Jun 2004; Sandler et al. NEJM 355 (24): 2542-2550, Dec 2006

SWOG 0533Concurrent Chemoradiation

PE: Cisplatin 50 mg/m2 IV d 1, 8, 29, 36Etoposide 50 mg/m2 IV d 1-5, 29-33

RT: 1.8 Gy X 36 Fractions

COHORT 1: No concurrent bevacizumab

COHORT 2: Bevacizumab d 15, 36, 57

COHORT 3: Bevacizumab d 1, 22, 43

Consolidation (4-8 weeks)Docetaxel 75 mg/m2 IV Q21 days x 3All COHORTS: Bevacizumab Q21 x 3

SWOG 0533

• The first cohort enrolled 12 patients but due to slow accrual, and emerging safety data from SCLC, the trial was closed.

• In SCLC, chemo-bevacizumab given concurrently with radiation led to increased morbidity and mortality from TE fistulas.

AE-941

• Æ-941 is a standardized cartilage extract (dogfish shark)

• Preclinical data support antiangiogenic and antitumoral activity

• Well-tolerated in Phase I/II studies; nausea-11%, diarrhea-5%, vomiting-3% ; <1% withdrew due to drug-related AEs

• Inhibition of endothelial cell proliferation via apoptosis (induction of caspase-3, 8)

• Inhibition of VEGF receptor signaling (Flk-1/KDR)

• Inhibition of MMP activity (MMP-2, 9, 12)Clinical Lung Cancer 4:231, 2003, Annals of

Oncology 13:1259, 2002, Lu et al. ASCO 2007

A Phase III Study Of Æ-941 with Induction Chemotherapy and Concomitant Chemoradiotherapy for Stage III NSCLC

(NCI T99-0046, RTOG 02-70, MDA 99-303)

Æ-941 or Placebo 120 ml PO bid, starting day 1

Day: 1 8 15 22 29 50 57 64 71 78 85

P: X X X X X X X XC: X X X X X X X X

OR**

Cis: X X X XV: X X X X X X X X

Chest RT: xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx

P = Paclitaxel 200 mg/m2 IV days 1, 22; 45 mg/m2 IV days 50, 57, 64, 71, 78, 85C = Carboplatin AUC 6 days 1, 22; AUC 2 days 50, 57, 64, 71, 78, 85

OR**Cis = Cisplatin 75 mg/m2 IV days 1, 22, 50, 71V = Vinorelbine 30 mg/m2 IV days 1, 8, 22, 29; 15 mg/m2 days 50, 57, 71, 78** Chemotherapy regimen decided by each site

XRT: 60 Gy in 30 fx over 6 weeks

Lu et al. ASCO 2007

AE-941 Efficacy

Endpoint

(Total N=379)Chemo+ AE-341

(N=188)

Chemo + Placebo

(N=191)P-value

Response Rate 39% 48% P=0.12

Median PFS (months)

11.3 [9.0-16.8]

10.7

[9.5-21.6]P=0.65

Median OS

(months)

14.4

[12.6-17.9]

15.6

[13.8-18.1]P=0.73

Multivariate Cox proportional hazards analysis incorporating treatment arm and prespecified stratification factors (stage, gender, chemotherapy regimen) showed no significant associations with OS or PFS.

Lu et al. ASCO 2007

Time (Years)

Pro

babi

lity

of S

urvi

val

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

P-value= 0.73

AE-941 ( E / N = 135 / 188 )

Placebo ( E / N = 148 / 191 )

Lu et al. ASCO 2007

Overall Survival

The addition of Æ-941 to induction chemotherapy and concomitant chemoradiotherapy does not improve overall survival in patients with unresectable stage III NSCLC

NSCLC PATIENT

Non-SCC

Neuroendocrine

Platinum-etoposide;


Adenocarcinoma

EGFR mutation EGFR wild-type

EGFR TKI

1st or 2nd line

Maintenance

(IPASS, BR.21, SATURN)

EML 4 ALK, ROS1

crizotinib

Platinum-doublet-bevacizumab

Platinum-pemetrexed + bevacizumab

Non-platinum or platinum based doublet


(E4599, AVAiL, Pointbreak, SATURN, JMEN)

SCC

Avoid pemetrexed or bevacizumab

Consider 2nd line EGFR TKI or maintenance erlotinib

(BR.21, SATURN)

Tsao Algorithm: Histology and Molecular Profiling

ALK – anaplastic lymphoma kinase

EML 4 – echinoderm microtubule associated protein like 4

• Found Primarily in adenocarcinoma patients who are never- or light former smokers, EGFR and KRAS WT, and younger

All adenocarcinomas: 9% EML4-ALK

If EGFR WT, Caucasian never-smoker, adenocarcinoma: ~10-20% EML4-ALK

•EML4-ALK-positive tumors are a distinct entity among lung adenocarcinomas and usually do not respond to EGFR TKIs.

•EML 4 ALK is a negative prognostic factor

ALK (+) NSCLC treated with 2nd/3rd line crizotinib have longer OS than those who are not treated with crizotinib.

EML4-ALK Fusion Gene

Koivunen et al. CCR 14 (13): 2008; Shaw et al. ASCO 2011 Abstract 7507; Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506

Crino et al. ASCO 2011 Abstract 7514

Phase II crizotinib in ALK-positive NSCLC

Crino et al. ASCO 2011 Abstract 7514

Best response

ORR 51.1%

SD 34%

DCR week 6 85%

week 12 74%

PD 7.5%

Tumor Response

Crizotinib was FDA approved for use

in pre-treated EML4 ALK patients.

Individualized Combined Modality Therapy for Stage III Non-small Cell Lung Cancer (NSCLC) RTOG 1306/Alliance 31101

NSCLC stage III

Stratification

Weight loss

IIIA vs IIIB

Chemo choice

Arm 1: induction erlotinib x 12 wk

Arm 2: Concurrent chemoXRT, 60 Gy

Concurrent chemoXRT (IMRT or

3D-CRT), 60 Gy

Arm 3: Induction crizotinib x 12 wk

Concurrent chemoXRT (IMRT or

3D-CRT), 60 Gy

Arm 4: Concurrent ChemoXRT, 60 Gy

Sensitive EGFR

mutation

ALK translocation

Primary endpoint: PFS

Secondary endpoints: RR, toxicity, OS, NGS of tumor tissue and correlation to clinical outcomes

• Median PFS from 12 months 19.8 months

(65% improvement in median PFS)

• A design with 90% power one-sided,15% type I error rate

89 progression events to detect the hazard ratio.

• Sample size: 156 EGFR mutation patients (78 per arm)

• Accrual time: 52 months of patient accrual (3/month)




89 progression events to detect the hazard ratio.

• Sample size: 156 EGFR mutation patients (78 per arm)

• Accrual time: 52 months of patient accrual (3/month)




• Sample size: 78 ALK+ translocation patients (39 per arm)

• Accrual time: 52 months of patient accrual (1.5/month)




• Sample size: 78 ALK+ translocation patients (39 per arm)

• Accrual time: 52 months of patient accrual (1.5/month)

Sample Size for the EGFR Mutation Cohort

Sample Size for the ALK Cohort

Novel Therapies Summary• Targeted Agents have a different side effect profile than

chemotherapy but may have equivalent or additional efficacy when combined with chemo-radiation.

• Biomarkers have unclear prognostic significance and will be under investigation for clinical trials. EGFR mutation – erlotinib (RTOG 1306/Alliance 31101)

EML-4 ALK – crizotinib (RTOG 1306/Alliance 31101)

Met IHC (+) – onartuzumab

• Trials using erlotinib, cetuximab, bevacizumab, pemetrexed, vandetanib, celecoxib, immunotherapy are ongoing.

Conclusion: Resectable IIIA

Consider XRT after surgical resection for improved local-regional control. Then

adjuvant cisplatin-doublet based chemo.

Microscopic pN2

Surgery after chemoradiation improves PFS but not OS in excellent PS patients.

DO NOT consider pre-op chemoradiation in patients who require a pneumonectomy.

ChemoXRT + Surgery

Unclear whether preoperative chemo or adjuvant is better. Recommend multi-

modality Tx.Clinical N2

Conclusion: Unresectable III

Stage IIIA/IIIB

Concurrent chemo-radiation is standard of care. Chemo regimen should be platinum-doublet based.

Role of induction chemo versus conslidation chemo is unclear.

-SWOG 9504 had high survival results in IIIB pts; yet, HOG LUN phase III study did not show a survival benefit for consolidation docetaxel .

• Maintenance gefitinib following SWOG 9504 regimen is not appropriate and may be harmful in unselected stage III NSCLC. (SWOG 0023)

• Await final results from RTOG 0617 to define a role for cetuximab.

• Pemetrexed based therapy should not be given in SCC.

• Bevacizumab + chemoXRT led to high rate of morbidity. SWOG 0533 closed early.

• Trials using predictive biomarkers will reshape the future for stage III NSCLC. RTOG1306/Alliance 31101

Novel therapies

Conclusion: Unresectable III

Documents

Background