Thoracic Committee Corey Langer Director of Thoracic Oncology - - PowerPoint PPT Presentation

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Corey Langer Director of Thoracic Oncology Abramson Cancer Center University of Pennsylvania Philadelphia, PA 19104 On behalf of Joan Schiller

ECOG Thoracic Committee

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Specific Aims

 Investigate novel therapeutic agents for lung cancer and other thoracic malignancies [treatment and prevention]  Develop and incorporate novel chemotherapy regimens and combined modality approaches into the treatment of lung cancer and other thoracic malignancies  Identify hypothesis-driven, prognostic and predictive biomarkers, so as to identify groups of patients most likely to benefit from novel, molecularly targeted agents.

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Specific Aims

 Investigate novel therapeutic agents for lung cancer and other thoracic malignancies [treatment and prevention]  Develop and incorporate novel chemotherapy regimens and combined modality approaches into the treatment of lung cancer and other thoracic malignancies  Identify hypothesis-driven, prognostic and predictive biomarkers, so as to identify groups of patients most likely to benefit from novel, molecularly targeted agents.

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Specific Aims

 Investigate novel therapeutic agents for lung cancer and other thoracic malignancies  Selenium: Trace Mineral as Chemoprevention  Angiogenesis

• Hypothesis: anti-angiogenic drugs have activity in

lung cancer, and can improve the outcome of patients, either as single agents, or in combination with chemotherapy

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Stage I NSCLC: Chemoprevention

 E-91025: phase III randomized, placebo-controlled evaluation of cRA in pathologically proven T1N0, T2N0 NSCLC; accrual (n=1482) completed ~ 4/97; no benefit (except in never smokers)…Lippman SM, Journal of the National Cancer

Institute, Vol. 93, No. 8, 605-618, April 18, 2001

 E5597: Placebo controlled trial evaluating selenium in stage I disease (featured at ASCO ‘10)

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ASCO 2010

E5597: Phase III Chemoprevention Trial of Selenium Supplementation in Persons with Resected Stage I Non-Small Cell Lung Cancer

Daniel D. Karp, Sandra Lee, Gail Shaw Wright, David Johnson, Michael Johnston, Gary Goodman, Gerald Clayman, Gordon Okawara, Randolph Marks, Jack Ruckdeschel Eastern Cooperative Oncology Group Together with Cancer and Acute Leukemia Group B NCI Canada Treatment Group North Central Cancer Treatment Group Radiation Therapy Oncology Group Southwest Oncology Group Enrollment from Oct. 2000 – Nov. 2009

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Selenium Intergroup Prevention Study in Resected Stage I NSCLC

 Objectives

 Reduce incidence of second primary tumors (SPTs)  Evaluate safety and toxicity of L-Seleno-methionine  Compare overall and organ specific cancer mortality

• Selenium 200 microgms/day for

48 months

• Monitor for safety, SPTs and

recurrence

• Placebo daily for 48 months
• Monitor for safety, SPTs, and

recurrence ELIGIBILITY** 1. Stage pT1N0 and pT2N0 2. 6 – 36mo. post-op 3. Adjuvant Chemo allowed^ 4. Normal organ function 5. ECOG PS 0 or 1 6. Compliance with 4 wk “run-in” 7. No dietary supplements 8. No synchronous cancers **Stratify by smoking status and gender ^ Based on subsequent amendment

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Stratifications

• 1. Smoking Status
• Active (within 1 yr)
• Former (> 1 year)
• Never smoked (< 100 cigarettes)
• 2. Gender
• Male
• Female
• 3. Stage /Previous Therapy
• Ia
• Ib no chemotherapy
• Ib prior chemotherapy

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Selenium and Lung Cancer: A Quantitative Analysis of the Current Epidemiological Literature

Hanjing Zhuo, Allan H. Smith, and Craig Steinmaus. Cancer Epidemiology, Biomarkers & Prevention 2004; 13(5). May 2004

 Clark et al: 30% reduction in prostate and lung cancer with Se enrichment  Meta-analysis of 16 studies

 5 as Relative Risk (RR)  3 as Mean Differences (MD)  8 both RR & MD

 Overall pooled RR is 0.74 (95% CI 0.57-0.97) c2 = 28.9 p<0.01)  Protective effects greater in low Se areas  Hypothesis: Threshold effect

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 Stimulation of glutathione peroxidase thereby lowering tissue peroxides.  Alterations in carcinogen metabolism.  Production of cytotoxic selenium metabolites.  Inhibition of protein synthesis.  Inhibition of specific enzymes.  Stimulation of apoptosis.

Selenium: Proposed MOAs

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 Evaluate the efficacy of Selenium in

 Preventing second primary cancers in patients who have had a curative resection for Stage I NSCLC  Assess Toxicity

 Lab Correlates

 Steve Belinsky, Lovelace Institute, Albuquerque, NM  Determine prevalence of

• methylation of p16
• O6-methylguanine-DNA methyltransferase (MGMT)

 Longitundinal determination of methylation profile.  Assessment of DNA Oxidation Products

• 5- Hydroxymethyldeoxyuridine (5-HETE)
• Lipoxygenase (LTB4)

Objects of E5597

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Selenium Intergroup Prevention Study in Resected Stage I NSCLC

 Objectives

 Reduce incidence of second primary tumors (SPTs)  Evaluate safety and toxicity of L-Seleno-methionine  Compare overall and organ specific cancer mortality

• Selenium 200 microgms/day for

48 months

• Monitor for safety, SPTs and

recurrence

• Placebo daily for 48 months
• Monitor for safety, SPTs, and

recurrence ELIGIBILITY** 1. Stage pT1N0 and pT2N0 2. 6 – 36mo. post-op 3. Adjuvant Chemo allowed 4. Normal organ function 5. ECOG PS => 0 or 1 6. Compliance with “run-in” 7. No dietary supplements 8. No synchronous cancers **Stratify by smoking status and gender

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Daniel Karp, MD UT M. D. Anderson Cancer Center

Results 1. E5597 Selenium Prevention of Second Primary Lung Cancers in Resected Stage I Non Small Cell Lung Cancer

 STUDY DURATION

 Opened Oct 6, 2000 – Closed Nov 5, 2009  1772 pts enrolled 1561 randomized Step 2 (211 too early)  Planned: 1960 participants to detect a 40% decrease in SPTs [80% power]

 SECOND PRIMARY TUMOR INCIDENCE (as of 26 Aug ’09)

 216 second primary tumors (from 190 cases).



84 lung cancers in 83 patients ( 46.7% of anticipated 180)  Placebo: 1.36 per 100 person yrs  Selenium: 1.91 (2-sided p-value=.150, NS)

 FUTILITY ANALYSIS

 Ratio (Selenium/Placebo): 1.40, 95% CI (.65, 3.04)  Conditional power calculation made a positive effect extremely unlikely.

 OVERALL SECOND PRIMARY TUMORS

 Placebo: 3.66 per 100 person yrs followed  Selenium: 4.11 per 100 person yrs followed

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Daniel Karp, MD UT M. D. Anderson Cancer Center

Results 2. E5597 Selenium Prevention Study: Progression Free Survival (PFS) Better for The Control Group

Control Group: 78% PFS at 5 yrs Divergence at

• approx. 28 months

Selenium Group: 72% PFS at 5 yrs p = 0.15)

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Daniel Karp, MD UT M. D. Anderson Cancer Center

Results 3. ECOG 5597 Selenium in Resected Stage I NSCLC. Overall Survival.

90% 85% 80% 75% The selenium group had approximately 5% lower survival at 3 and 5 years. (p = 0.15, NS)

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E5597: Results

 Stopped b/o futility:  Interim analysis occurred in Oct ’09 after 1561/1772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken).  216 SPTs developed of which 84 (38.9%) were lung cancer.

SPTs/ 100 person years Placebo Selenium P values Lung 1.36 1.91 Overall 3.66 4.11 5 yr PFS 78% 72% 0.15 5 yr OS 80% 75% 0.15 Gr 3 toxicity 3% 1% Compliance at 2 yrs > 95% > 95%

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E5597: Conclusions

 No benefit for Selenium wrt to SPTs, recurrence, or Overall Survival  No increase in diabetes or skin cancer detected.  Never smokers: slight benefit [NSS]  Selenium was safe, but conferred no benefit over placebo.

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ECOG 5597: Is there anything salvageable?

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ECOG 5597: Is there anything salvageable?

 Vital data on natural history of stage IA and IB pts in the post PET era  Will ultimately “mine” patterns of recurrence  Crucial bio-correlates regarding methylation, etc

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ECOG 5597: Is there anything salvageable?

 Vital data on natural history of stage IA and IB pts in the post PET era  Will ultimately “mine” patterns of recurrence  Crucial bio-correlates regarding methylation, etc  Should give us and our patients pause when they graft supplements and nutriceuticals onto standard Tx  Future studies will need to focus on molecular signaling pathways, not epidemiologic extrapolation

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Thalidomide

Diverse Properties  Anti-angiogenic  Inhibits expression of a number of angiogenic cytokines: VEGF, bFGF, COX2, TGF beta expression  Immunomodulatory  T cell/NK stimulation  Induces expression of immunomodulatory cytokines (IL-12, gamma IFN)  Anti-proliferative

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E3598: Chemo/RT +/- Thalidomide

Amended Schema

Stage IIIA, B NSCLC R A N D O M I Z E Carboplatin Paclitaxel

2 cycles

Carboplatin Paclitaxel Thalidomide

2 cycles

Wkly carbo/paclitaxel RT (60 Gy/6

weeks)

Wkly carbo/paclitaxel RT (60 Gy/6

weeks) +

Thalidomide PR, CR, Stable Thalidomide:

total of 2 years

• Amended 6/04/2003 after 288 patients had been registered
• Weekly concurrent carboplatin/paclitaxel added

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Outcomes

Progression Free Survival Survival

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Phase III Trial of Carbo/paclitaxel +/- Bevacizumab in Non-Squamous NSCLC

E4599 Schema R A N D O M I Z E Eligibility:

• No prior Rx
• Stage IIIB or IV
• Non-Squamous Ca
• ECOG PS 0-1
• No CNS mets
• No Tx anticoagulation

Carbo: AUC=6 Paclitaxel: 200 mg/m2 Carbo: AUC=6 Paclitaxel: 200 mg/m2 Bevacizumab: 15 mg/kg

• No cross over on progression
• 855 pts entered
• Primary objective: survival

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0.0 0.2 0.4 0.6 0.8 1.0

Progression-Free Survival by Treatment

Probability PC PCB P < 0.0001 6 12 18 24 30 36 Months Medians: 4.5, 6.4

6 mo. 12 mo.

32.6% 6.4% 55.0% 14.6%

HR: 0.62 (0.53, 0.72) 0.0 0.2 0.4 0.6 0.8 1.0

Survival by Treatment

Probability PC PCB P = 0.007 6 12 18 24 30 36 Months Medians: 10.2, 12.5

12mo 24 mo.

43.7% 16.9% 51.9% 22.1% HR: 0.77 (0.65, 0.93)

PC PCB Overall RR% 15% 35% P<0.001

ECOG 4599: Outcomes

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HTN Analysis Background

 Antagonism of VEGF decreases nitric oxide production  Leads to constriction of the vasculature and a reduction in sodium ion renal excretion  Causing increased blood pressure  Hypertension may also be a consequence a depletion of the arterioles and capillaries, caused by the inhibition of angiogenic growth factors

26

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Adjusted hazard ratios

 PCB, High Blood pressure by the end of cycle 1  OS: 0.65 (0.51-0.82), p=0.0002  PFS: 0.60 (0.48-0.75), p<0.0001  PCB, No High Blood pressure by the end of cycle 1  OS: 0.85 (0.72-1.00), p=0.05  PFS: 0.68 (0.58-0.80), p<0.0001

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Landmark analysis: overall survival

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0.0 0.2 0.4 0.6 0.8 1.0 Time in Months from End of Cycle 1 Probability 6 12 18 24 30 36 42 48 PC, High BP (92 events/ 95 cases) PC, No High BP (263 events/ 276 cases) PCB, High BP (93 events/ 107 cases) PCB, No High BP (242 events/ 263 cases) Medians: 10.1, 10.3, 11.5, 15.9

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Median Survival (mos) by Sex and Age -/+ BEV on E4599: 3 age cut-points

Age in Years < 45 45-59  60 Women Control 5.8 12.5 13.8 Women + BEV 16.8 15.5 12.8 Men Control 3.4 9.5 8.5 Men + BEV 12.6 12.3 11.0 Wakelee, H et al IASLC/ASTRO 2008

Conclusion: Only group that failed to have a conclusive benefit were women over 60.

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Wakelee, H et al IASLC/ASTRO 2008

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Wakelee, H et al IASLC/ASTRO 2008

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Stratification:

• Stage
• Histology
• Gender
• Type of Chemo

Eligibility:

Resected IB (>4 cm) -IIIA Lobectomy No prior chemo No planned XRT No h/o CVA/TIA No ATE w/in 12 mo R A N D O M I Z E Chemotherapy X 4 cycles

Cis/gem Cis/docetaxel Cis/vinorelbine Cis/pemetrexed

Chemo x 4 cycles Plus Bevacizumab X 1 year

• Intergroup study
• 1500 patients; 85% power, 2.5% significance level - one-sided test
• Detect 26.5% difference in median OS; from median of 66 mo to 83.5 mo
• Blood, tissue being banked;6/09: over 400 patients accrued
• Accrual: 690 as of 07/03/10; 963 as of 8/11 [projected to complete 5/21/13 08/04/13]

Specific Aim 1: Anti-angiogenesis

Example: Development of Bevacizumab in Earlier Stage NSCLC

E1505: Adjuvant Phase III Study of Chemotherapy +/- Bevacizumab In IB - IIIA NSCLC

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Stage IIIA/B non- squamous NSCLC Concurrent Chemo/XRT Paclitaxel 45 mg/m2 /wk x 6 Carboplatin AUC 2/wk x 6 TRT 66 Gy Consolidation ChemoRx Paclitaxel 200 mg/m2 Carbo AUC 6 2 cycles

E V A L U A T E E V A L U A T E

LBLP vaccine q21 days up to 34 cycles + Bevacizumab 15 mg/kg q 21 d up to 34 cycles

PD Off study PD Off study

• Primary Endpoint

Safety

• Secondary Endpoints

PFS, OS Determination of fraction of circulating immature dendritic cells, and their ability to induce an allo-MLR response in vitro

~55

4 as of 8/11

~30 E6508: Phase II Study of Maintenance Bevacizumab & L- BLP25 in Unresectable Stage IIIA/B Non-Squamous NSCLC

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BLP25 Vaccine

 Liposome based MUC1 vaccine  MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC  In preclinical studies, vaccination produced a proliferative T- cell response to the MUC1 antigen and production of INF g, indicating a T-helper type 1 response

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Randomized Phase IIB Study of BLP25 Liposome Vaccine in Stage IIIB and IV NSCLC

 171 patients who achieved at least SD after chemotherapy  Randomized to BSC vs BLP25  No significant adverse effects  Median survival

 BLP25 17.2 mos  BSC 13.0 mos (p=0.066)

Butts, JCO 2005; 23(27):6674-81

65 pts with Stage IIIB locoregional disease 85% of pts with IIIB LR received RT Phase III study in Stage III LR is ongoing

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Dendritic Cell Function and Tumor Vaccine Development  Inadequate function of dendritic cells is one mechanism of tumor escape  VEGF can inhibit the maturation of dendritic cells  Bevacizumab can reverse important mechanisms of immunoresistance, namely T cell defects and antigen presentation defects

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BLP25 + Bevacizumab in Stage III NSCLC

 Primary Endpoint  Determine the safety of this regimen  Secondary Endpoints  Progression Free Survival  Overall Survival  Determination of fraction of circulating immature dendritic cells, and their ability to induce an allo-MLR response in vitro

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BLP25 + Bevacizumab in Stage III NSCLC  2-stage safety study  Halt accrual if >2/10, >5/30 patients develop gr 4/5 hemorrhagic, esophageal, or fistula events during BLP25+bevacizumab treatment  ~55 patients total accrued for chemoradiation30 will go

• n to BLP25+bevacizumab

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Specific Aim 1

 Investigate novel therapeutic agents for lung cancer and other thoracic malignancies  Angiogenesis

• Hypothesis: anti-angiogenic drugs have activity

in lung cancer, and can improve the outcome of patients, either as single agents, or in combination with cytotoxic agents

 Inhibition of signaling pathways

• Hypothesis: inhibition of signaling pathways in

will be most effective in the appropriately selected patient population

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TRIBUTE Never smokers: overall survival

1.0 0.8 0.6 0.4 0.2

5 10 15 20 25 Survival rate Erlotinib Placebo Months on study

TRIBUTE

Miller et al. Poster discussion #7061; poster #12 Median survival (months)

• No. of patients

Erlotinib 22.5 64 Placebo p-value 10.1 41 .01 Median survival (months)

• No. of patients

Erlotinib 22.5 64 Placebo p-value 10.1 41 .01

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Specific AIM 1: Inhibition of Signaling Pathways

Example: EGFR

• TRIBUTE data suggested significant

benefit of carbo/paclitaxel/erlotinib in never smokers (22.5 mo compared to 10.1 mo in smokers)

• Standard first line therapy in

Western never-smokers still chemo

• Bev added to patients who are bev

eligible

• EGFr mutation and expression data

will be collected

• PCO integral

E2508: Role of Erlotinib in Never-Smoking Patients with Advanced NSCLC

R A N D O M I Z E Carbo/paclitaxel (+/- bevacizumab) Carbo/paclitaxel + erlotinib (+/- bevacizumab)

• Endpoint: PFS
• Stats: 35% reduction in HR with 91% power

( median PFS from 5.5 to 8.5 mo)

• 170 pts
• Terminated b/o poor accrual 3/11

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E3508 Schema

Chemonaive Bev eligible Advanced NSCLC ECOG 0-1

R A N D O M I Z E

Carboplatin AUC 6 IV day 1 Paclitaxel 200 mg/m2 IV day 1 Bevacizumab 15 mg/Kg day 1 IMC-A12 6 mg/kg IV days 1,8,15 Every 21 days

Maximum of 6 cycles of chemotherapy Bevacizumab and IMC-A12 will continue until progression

E4599 regimen Carboplatin AUC 6 IV day 1 Paclitaxel 200 mg/m2 IV day 1 Bevacizumab 15 mg/Kg day 1 Every 21 days

Primary endpoint: PFS, N=180 (n=2) as of 7/10; n=47 as of 8/11; projected completion 9/10/16

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Specific Aim 1: Inhibition of Signaling Pathways

Example: EGFR + IGF-1R Inhibition

E4508: Randomized Phase II of Chemotherapy + Cetuximab, IMC-A12 or Both in First Line NSCLC

R A N D O M I Z E Carbo/Paclitaxel + Cetuximab Carbo/Paclitaxel + A12 Carbo/Paclitaxel + Cetuximab + A12

Every 3 weeks X 4 cycles

• EGFR & IGF-1R pathways interact to

regulate proliferation, migration, and apoptosis

• Pick the winner design
• Lab studies:
• IHC for EGFR, IGF-1R, and AKT
• Circulating IGF-1R
• Primary Endpoint: PFS
• PCO integral

Stats: 60 pts/arm; 88% power to detect a 60% increase in PFS HR; corresponds to an improvement in median PFS from 3.5 to 5.6 months

Accrual: 66 of 200 projected [projected completion 9/03/11]

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Specific Aim 1: Inhibition of Signaling Pathways

Example: EGFR + IGF-1R Inhibition

E4508: Randomized Phase II of Chemotherapy + Cetuximab, IMC-A12 or Both in First Line NSCLC

R A N D O M I Z E Carbo/Paclitaxel + Cetuximab Carbo/Paclitaxel + A12 Carbo/Paclitaxel + Cetuximab + A12

Every 3 weeks X 4 cycles

• EGFR & IGF-1R pathways interact to

regulate proliferation, migration, and apoptosis

• Pick the winner design
• Lab studies:
• IHC for EGFR, IGF-1R, and AKT
• Circulating IGF-1R
• Primary Endpoint: PFS
• PCO integral

Stats: 60 pts/arm; 88% power to detect a 60% increase in PFS HR; corresponds to an improvement in median PFS from 3.5 to 5.6 months

Accrual: 66 of 200 projected [projected completion 9/03/11]

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Specific Aim 1: Inhibition of Signaling Pathways

Example: HedgeHog or IGF-1R Inhibitors

E1508: Randomized Phase II of GDC-049 or IMC-A12 in Extensive Stage Small Cell Carcinoma

R A N D O M I Z E Cis/Etoposide Cis/Etoposide + GDC-409 Cis/Etoposide + IMC-A12

Every 3 weeks X 4 cycles

• Pathways active in many cancer types
• First study of HedgeHog inhibitor or

IGF-1R inhibitor plus chemo in SCLC

• Pick the winner design
• Lab studies:
• IHC for hedgehog ligand

expression and IGF-1R

• Circulating tumor cells
• Primary Endpoint: PFS
• PCO integral

Stats: 74 pts/arm; 85% power to detect a 33% reduction in PFS HR; corresponds to a 50% improvement in median PFS from 5 to 7.5 months

Accrual: 7/10 -35 out of 222 [projected completion 06/05/13] 8/11 -164/170 [projected completion 08/22/11]

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Specific Aims

 Investigate novel therapeutic agents for lung cancer and

• ther thoracic malignancies

 Develop and incorporate novel chemotherapy regimens and combined modality approaches into the treatment of lung cancer and other thoracic malignancies  Identify hypothesis-driven, prognostic and predictive biomarkers, so as to identify groups of patients most likely to benefit from novel, molecularly targeted agents.

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Maintenance Chemotherapy for NSCLC

Survival

Maintenance Docetaxel

Fidias, JCO, 2008 Immediate: 11.9 mos Delayed: 9.1 mos P= 0.071

Meta-analysis of Extended Duration Chemotherapy

Soon, et al. JCO published on line, 2009 HR 0.92; 95% CI 0.86 to 0.99. p= 0.03

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3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Pemetrexed 15.5 mos Placebo 10.3 mos

Maintenance Pemetrexed: Non-Squamous Cell

Belani, ASCO, 2009

HR=0.70 (95% CI: 0.56-0.88) p =0.002

Survival Probability

Maintenance Chemotherapy for NSCLC

Survival

R A N D O M I Z E Pemetrexed Placebo 4 cycles gem/paclitaxel/docetaxel + platin

Every 3 weeks until PD

Stable or responding dx

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Histology Groups Median OS, mos Median PFS, mos Pem Plac P-value (HR) Pem Plac P-value (HR) Non-squamous (n=481) 15.5 10.3 0.002 (0.70) 4.4 1.8 <0.00001 (0.47)

Adeno (n=329) 16.8 11.5 0.026 (0.73) 4.6 2.7 <0.00001 (0.51)

Large cell (n=20) 8.4 7.9 0.964 (0.98) 4.5 1.5 0.104 (0.40) Other (n=133) 11.3 7.7 0.025 (0.61) 4.1 1.6 0.0002 (0.44)

Squamous (n=182) 9.9 10.8 0.678 (1.07) 2.4 2.5 0.896 (1.03)

Efficacy by Histologic Groups

There was a statistically significant treatment-by-histology interaction with both PFS (P=0·036) and OS (P=0·033)

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Questions

 Can these results be confirmed or extended?  Is it the pemetrexed?  Is it the maintenance?  “More chemotherapy?”  Is it the “consolidation?”  Non-cross resistant therapy?  Is it the non-squamous histology?  Is it the absence of mandatory crossover?  How do we incorporate these results into our standard of care?

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Aim 2: Optomize Chemotherapy

E5508: Phase III Trial of Maintenance Chemotherapy for NSCLC

R A N D O M I Z E Bevacizumab Pemetrexed Carbo/paclitaxel/ Bevacizumab x 4 cycles R E G I S T E R Bevacizumab + pemetrexed CR, PR, stable PD Off study

Eligibility:

• Wet IIIB, IV,

recurrent dx

• PS 0,1
• Non Squams
• Treated brain

mets allowed

• No hemoptysis

Maintenance

Primary endpoint: OS, Targeted accrual: 1282 N = 105 as of 8/11 [projected completion – 7/30/18]

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Specific Aims

 Investigate novel therapeutic agents for lung cancer and other thoracic malignancies  Develop and incorporate novel chemotherapy regimens and combined modality approaches into the treatment of lung cancer and other thoracic malignancies  Identify hypothesis-driven, prognostic and predictive biomarkers, so as to identify groups of patients most likely to benefit from novel, molecularly targeted agents.

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Specific Aim 3: Accomplishments

The Biology of Lung Cancer

• Proteomic signature identified

by MALDI-TOF

• Proteomic profile identified

which predicts response to erlotinib

• Not a prognostic marker
• To be validated in randomized

European 2nd line

• Taguchi, et al. JNCI: 99: 838,

2007

E3503: Single Agent Erlotinib in First Line NSCLC

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SNP Basics

 Single nucleotide polymorphisms – SNPs  DNA sequence variation  SNPs can be found in coding sequences or non- coding sequences  Only about 3-5% of a person’s DNA codes for proteins  Challenges – Genome is so large that patterns could be found by chance

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HYPOTHESIS & CANDIDATE GENE POLYMORPHISMS

 Angiogenesis pathway: VEGF C+936T, VEGF G-634C, VEGF C-1498T, VEGF G-1154A, ICAM1 T469C, FGFR4 G388A, EGF A-61G, EGFR G497A, IL8 T- 251A, CXCR2 C+785T, COX2 G-765C  DNA repair pathway: ERCC1 C118T, ERCC1 3'UTR C/A, XPD A751C, XPD C156A, XRCC1 G-399A, GSTP1 A105G, KDR T/A  WNK1 rs11064560 T/G; WNK1 rs2158501 G/A

Clinical Outcome for pts with advanced NSCLC may be predicted by SNPs

easte stern rn coopera rati tive oncolo logy gro roup

10 20 30 40 50 60 0.0 0.2 0.4 0.6 0.8 1.0

OS, PC only

Months Probability Good SNP Profile Bad SNP Profile 10 20 30 40 50 60 70 0.0 0.2 0.4 0.6 0.8 1.0

OS, PC+Bevacizumab

Months Probability Good SNP Profile Bad SNP Profile

Median survival Good SNP profile 16.8 mo

• Bad SNP

profile 10.2 mo Median survival Good SNP profile 8.5 mo

• Bad SNP

profile 10.7 mo

Carbo/Paclitaxel + Bev Carbo/Paclitaxel

4599 Survival by SNP profile

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• ncolo

logy gro roup

Thanks for your attention!