Advances and Emerging Therapy for Lung Cancer Rachel E. Sanborn, M.D. Providence Cancer Center.

Advances and Emerging Therapy for Lung Cancer

Rachel E. Sanborn, M.D.

Providence Cancer Center

Early-Stage Disease

Definitive Therapy

• Surgical resection is preferred

• Survival with resection alone:– Stage I: 60-85%– Stage II: 50%

Adjuvant Therapy for Resected Disease

Adjuvant Chemotherapy, 1

• 4 cycles of Cisplatin-based therapy– Improves 5-year survival 4-17%– Benefit in patients with nodal or later-stage

disease– Less benefit in stage I tumors

Adjuvant Chemotherapy, 2

• Carboplatin-based therapy– No survival benefit

Adjuvant Chemotherapy, Questions

• Will addition of targeted agents improve survival?

• Will predictive markers help to guide who needs or benefits from adjuvant therapy?

Adjuvant Therapy--Questions

• Which agents?

• Stage I disease?

• How far out to treat before “window of opportunity” is lost?

Locally-Advanced Disease:Mediastinal Nodal Involvement

or Invasive Tumors

Neoadjuvant Therapy

Neoadjuvant Therapy

• Smaller phase III trials (60 pts), both stopped early

• Stage IIIA• Survival advantage with neoadjuvant

chemotherapy• Med survival 26 mo vs 8 mo; P<0.001• 64 mo vs 11 mo; P<0.008

Rosell et al, NEJM 1994; Roth et al, JNCI 1994

SWOG 9900

R ANDOM I Z E

Resectable NSCLC,

354/600 Planned Patients

Arm B:Surgery Alone

Arm A:Carboplatin/PaclitaxelX3 cycles

Surgery

Pisters et al, ASCO 2005; abstr 7012

SWOG 9900, Early Results

Chemo + Surgery Surgery P

Med PFS 31 mo 20 mo 0.26

Overall Survival 47 mo 40 mo 0.47

Pisters et al, ASCO 2005; abstr 7012

Neoadjuvant Therapy

• For patients with advanced but potentially resectable disease, possible benefit to survival

• Possible increase in surgical resectability rate

• Some trial interpretation confounded by adjuvant therapy, adjuvant radiation

• Is benefit equivalent to adjuvant therapy?

Definitive Therapy for Unresectable Disease:

Combined Modality Therapy

Initial Combination Trial

• Randomized to Radiation vs

Chemo Radiation• Increased median survival from

9.7 months to 13.8 months• Increased 3-Y OS from 11% to 26%

Dillman et al, NEJM 1990

Chemo/RT Combinations

• Chemo/RT combination shown better than sequential (Cisplatin-based combination)

• Median survival increased from 13.3 mo to 16.5 mo

• 5-Y OS increased from 8.9% to 15.8%

Furuse et al, JCO 1999

Copyright © American Society of Clinical Oncology

Furuse, K. et al. J Clin Oncol; 17:2692 1999

Fig 1. Overall survival in patients with NSCLC according to treatment group

Concurrent vs Sequential Tx

SWOG 9019

• Stage IIIB only, 50 patients

• Cisplatin/Etoposide/Concurrent TRT

• Median OS 15 months

• 5-Y OS 15%

Albain et al, JCO 2002

Carboplatin-based chemo/RT

• Median survival 11.4 months with concurrent treatment

• Median survival 14 months with induction followed by concurrent treatment

• P=0.154

• Results consistently inferior to cisplatin

Vokes et al, PASCO 2004

Consolidation:Chemo After Chemo/RT

SWOG 9504Med Surv

3-Y OS 4-Y OS 5-Y OS

PE/RT DocetaxelS9504

26m 40% 29% 29%

PE/RT PES9019

15m 17% 17% 17%

Gandara et al, ASCO 2005, abstr 7059

SWOG 0023

R ANDOM I Z E

Cis/EtopConcurrent RT

Kelly et al, ASCO 2007; abstr 7513

ConsolidationDocetaxel

Gefitinib

Placebo

Overall Survival From Randomization

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60Months After RANDOMIZATION

Gefitinib

Placebo

N

118

125

Events

71

54

Median

in Months

23

35

P = .01

1 YR OS

2 YR OS

73% 46%

59%81%

Median FU time: 27 months


SWOG 0023

• Closed after DSMB interim analysis


Gefitinib Placebo P

Median PFS 11m 10m NS

Dead from Cancer 86% 80%

Dead from Toxicity 3% 0%

Overall Survival 23m 35m 0.013

HOG Phase III;Replicating SWOG 9504

R ANDOM I Z E

IIIA/B243/259Patients randomized

Hanna et al, ASCO 2007; abstr 7512

Cis/EtopConcurrent RT

ConsolidationDocetaxel

Observation

Months since registration

0 10 20 30 40 50 60

Per

cent

of p

atie

nts

surv

ivin

g

0%

25%

50%

75%

100%

ObservationDocetaxel Consolidation

Overall Survival (ITT)Randomized Patients (n=147)

Observation: Median: 24.1 months (18.0-34.2)

3 year survival rate: 27.6%

Docetaxel: Median: 21.5 months (17.-34.8)

3 year survival rate: 27.2%

P-value: 0.940

Hanna et al, ASCO 2007; abstr 7512

HOG, Phase III Results

• DSMB interim analysis• Closed after 203 pts due to futility

Hanna et al, ASCO 2007; Mina et al, ASCO 2008

Docetaxel Observation P

Median PFS 12.3m 12.9m 0.94

Median Survival 24.3m 26m 0.75

Hospitalizations 28.8% 8.1%

Toxic Death 5.5%

Metastatic Disease

Chemo or Hospice?

• Median survival with Best Supportive Care: 5 months– Spiro et al, Thorax 2004

• BMJ Meta-Analysis, 1995– Detriment with long-term alkylating agents

suggested (AKA: Old Chemo)– Cisplatin-Based Trials– 10% absolute improvement in 1-Y OS, (5%

to 15%)– Increased median survival 6 weeks

Chemo or Hospice?

• Median survival with Best Supportive Care: 5 months– Spiro et al, Thorax 2004

• BMJ Meta-Analysis, 1995– Detriment with long-term alkylating agents

suggested– Cisplatin-Based Trials– 10% absolute improvement in 1-Y OS, (5%

to 15%)– Increased median survival 6 weeks

ChemotherapyFirst-Line

Comparison Trial

• Cisplatin/Paclitaxel

• Cisplatin/Gemcitabine

• Cisplatin/Docetaxel

• Carboplatin/Paclitaxel

Schiller et al, NEJM 2002

Schiller et al, NEJM 2002

Median Survival:

8 mo

1-Y Survival:

34%

2-Y Survival:

12%

Targeted Agents—Bevacizumab

Why Target VEGF?• Actively proliferating tumor cells express more

Vascular endothelial growth factor (VEGF) than nonproliferating cells1

– VEGF may act as an autocrine growth factor1

• VEGF expression is upregulated in many cancer types, including NSCLC2-4

• Elevated serum VEGF levels have been associated with poorer outcomes in limited- or early-stage disease2,5-7

1. Mattern et al. Br J Cancer. 1996;73:931–934. 2. Yuan A et al. Int J Cancer Pred Oncol. 2000;89:475–483.3. Lantuejoul et al. J Pathol. 2003;200:336–347. 4. Ravindranath et al. J Androl. 2001; 22:432–443. 5. Shimanuki et al. Lung. 2005;183:29–42.6. Hasegawa et al. Intern Med. 2005;44:26–34. 7. Mineo et al. J Clin Pathol. 2004;57:591–597.

VEGF: A Key Mediator of Angiogenesis

Binding and activation of VEGFR

Environmental factors

(Hypoxia, pH)Growth factors

Hormones (EGF, bFGF, PDGF,

IGF-1, IL-1, IL-6, estrogen)

Genes involved in tumorigenesis(p53, p73, src, ras,

vHL, bcr-abl)

PP

PP

ANGIOGENESIS

ProliferationSurvival

Migration

Endothelial cellactivation

Increased VEGF levels

bFGF, basic fibroblastic growth factor; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor.1. Dvorak. J Clin Oncol. 2002;20:4368–4380; 2. Ebos et al. Mol Cancer Res. 2002;1:89–95; 3. Ferrara et al. Nat Med. 2003;9:669–676.

Summary of Anti-VEGF Proposed Mechanisms of Action Based on Preclinical Models

May regress existing microvasculature1,2

May normalize surviving mature vasculature3-5

May inhibit vessel regrowth and neovascularization2,3,6

1

2

3

1. Lee et al. Cancer Res. 2000;60:5565–5570; 2. Inai et al. Am J Pathol. 2004;165:35–52; 3. Gerber et al. Cancer Res. 2005;65:671–680; 4. Jain Science. 2005;307:58–62; 5. Tong et al. Cancer Res. 2004;64:3731–3736; 6. Hicklin et al. J Clin Oncol. 2005;23:1011–1027.

Avastin® (bevacizumab)

• Recombinant humanized monoclonal IgG1 antibody

• Recognizes all isoforms of VEGF-A and blocks VEGF function

• Half-life is approximately 20 days (range, 11 to 50 days)

Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.

Randomized Phase II/III

R ANDOM I Z E

Advanced Non-Squamous NSCLC,

855 PatientsArm B:Carboplatin/Paclitaxel+Bevacizumab

Arm A:Carboplatin/Paclitaxel+Placebo

Bev until progression

Sandler et al, NEJM 2006

Exclusion

• Squamous cell carcinoma• Central tumors• Brain mets (Actively screened for prior to

enrollment)• Hemoptysis• Anticoagulation (Except ASA 81mg)


Phase III: Overall Survival

HR: 0.80, P = .013

BV/PC 51.0% 22.0% 12.3 mo

PC 44.4% 15.4% 10.3 mo

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

surv

ivin

g

0 6 42 4818 30

12 mo 24 mo Median

12 24 36

444 318 1 0104 9190 36 5

434 340 3 0127 25216 54 8

PC

BV/PC

Months

Patients at risk

Median 12.3 mo

Median 10.3 mo

Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.

Carbo/Tax/Bevacizumab:Toxicities

• HTN• Neutropenia• Hemorrhage• Proteinuria• Thromboembolism

PCB Conclusions

• Significant gains in survival for patients treated with bevacizumab

• Carboplatin/Paclitaxel/Bevacizumab has become new treatment standard for many cooperative groups– (For this patient population)


Targeted Agents—Cetuximab

The HER Family of Receptors

HER1erb-b1EGFR

HER2 erb-b2neu

HER3 erb-b3

HER4erb-b4

Tyrosinekinase

domain

Ligand-bindingdomain

Transmembrane

EGFTGF

AmphiregulinBetacellulin

HB-EGFEpiregulin

NRG2NRG3

HeregulinsBetacellulin

Heregulins

Roskoski. Biochem Biophys Res Commun. 2004;319:1.Rowinsky. Annu Rev Med. 2004;55:433.

Potential Consequences ofEGFR Dysregulation

Signaling cascades

EGFR

PI3K MAPK

NucleusGene activation

Cell cycle progression

M G1

SG2

MycFos

Jun

PP

MAPK = mitogen-activated protein kinase.Roskoski. Biochem Biophys Res Commun. 2004;319:1.Rowinsky. Annu Rev Med. 2004;55:433.

Survival

Proliferation

AngiogenesisInvasion

Apoptosis

Metastasis

Epidermal Growth Factor Receptor

• EGFR expression upregulated in a number of cancers

• Most NSCLC found to express EGFR

• Inhibition of EGFR can induce apoptosis and reduce tumor proliferation

EGFR-Targeted Approaches

Anti-EGFRblocking

antibodies

Antiligandblocking

antibodies

Tyrosinekinase

inhibitors Ligand-toxin

conjugates

HER dimerizationinhibitors

TOXIN

Adapted from Noonberg and Benz. Drugs. 2000;59:753.

Cisplatin/Vinorelbine/Cetuximab

• Randomized Phase III trial

• Cis/Vinorelbine

• With or without Cetuximab

• Cetuximab till disease progression

Pirker et al, PASCO 2008

Cetuximab Toxicity with Chemo

• Rash

• Febrile neutropenia

• No difference in treatment-related mortality

Pirker et al, PASCO 2008

Conclusions• Cetuximab added to first line chemotherapy with

CV demonstrated superior survival over CV alone in patients with EGFR detectable advanced NSCLC– Would other platin-based combinations have a more

acceptable toxicity profile?

Conclusions• Cetuximab added to first line chemotherapy with

CV demonstrated superior survival over CV alone in patients with EGFR detectable advanced NSCLC– Would other platin-based combinations have a more

acceptable toxicity profile?

• Further refining patient selection may increase the current modest survival benefit– EGFR FISH– KRAS mutation

ChemotherapySecond-Line

Second-Line Therapy

• Chemotherapy with newer agents (docetaxel) given second-line:

• Improved survival from 4.6 months (Best supportive care)

• To 5.9 months• 1-Y survival from 11% to 19%

Shepherd et al, JCO 2000

Docetaxel Survival Curve

Shepherd et al, JCO 2000

Improvement in overall QOL, pain, appetite, and fatigue with Docetaxel compared with BSC

Pemetrexed

R ANDOM I Z E

Recurrent NSCLC,

571 Patients

Arm B:Docetaxel

Arm A:Pemetrexed

Hanna et al, JCO 2004

Median Survival:

8.3 months

1-Y Survival:

29.7%

Median Survival:

7.9 months

1-Y Survival:

29.7%

Targeted Agents—Erlotinib

Proposed Mechanism of Action of EGFR-Targeted TKIs

P P

P

P

M G1

SG2

Arteaga. Semin Oncol. 2003;30(suppl 7):3.

Tumor cell survival Tumor cell

proliferation

Apoptosis G1 arrest

No signaling

MAPK

BAXBCL2

PI3K

Inhibit EGFR kinase activity

TKIs

Phosphorylation

Erlotinib single agent trial

R ANDOM I Z E

Advanced NSCLC,

731 Patients

1-2 Prior Chemo Regimens

Arm B:Placebo

Arm A:Erlotinib

Shepherd et al, PASCO 2004

Erlotinib single agent trial

R ANDOM I Z E

Advanced NSCLC,

731 Patients

1-2 Prior Chemo Regimens

Arm B:Placebo

Arm A:Erlotinib


Overall Survival

Erlotinib 6.7 mo

Placebo 4.7 mo

P<0.001

Erlotinib Single Agent Survival


Erlotinib in Combination

Study Patients Median Survival

Median TTP

TALENT1 (Gem/Cis with Erlotinib or placebo)

1172 301 days v 309 days

167 days v 179 days

TRIBUTE2 (Carbo/Tax with Erlotinib or placebo)

1059 10.8m v 10.6m

5.1m v 4.9m

1. Gatzmeier et al, PASCO 2004 2. Herbst et al, PASCO 2004

Chemotherapy for Metastatic Disease

• First, second, third-line therapy:

• Improves survival

• Improves quality of life

What next?

• Histology-derived treatment selection

• Treatment/Prognosis driven by molecular profiles

• Ongoing efforts to understand interactions between targeted agents and chemo

Small Cell Lung Cancer

Small Cell Lung Cancer

• 10-15% new lung cancers are SCLC

• Decreasing proportion over time

• ~32,000 cases yearly

SCLC--Staging

• Limited stage– Involving the ipsilateral hemithorax within a

single radiation port– May encompass contralateral hilar nodes– “Not metastatic”, no malignant effusion

• Extensive stage– Presence of obvious metastases– Malignant effusion

Survival

• Limited Stage– Median survival 3 months without treatment– Median survival 14-16 months with treatment– ~25% 5-year survival*

*Turrisi et al, NEJM, 1999

Survival

• Limited Stage– Median survival 3 months without treatment– Median survival 14-16 months with treatment– ~25% 5-year survival*

• Extensive Stage– Median survival 6 weeks without treatment**– Median survival with treatment 8-11 months***– <5% 2-year survival

*Turrisi et al, NEJM, 1999; **Green et al, Am J Med 1969; ***Aisner et al, JCO 1996

Conclusions, SCLC

• SCLC is a highly aggressive and rapidly fatal disease

• Significant gains in life expectancy and QOL have been made with chemotherapy and radiation

• Despite previous gains, plateaus in survival have been reached, and further gains with conventional therapy will be modest at best

Lung Cancer:So are we crazy?

• Despite pessimism, advances HAVE been made in survival and QOL in treatment of lung cancer

• Further advances will require rationally-designed agents and careful monitoring for efficacy

Clinical Trials Help to Provide Answers

Advances and Emerging Therapy for Lung Cancer Rachel E. Sanborn, M.D. Providence Cancer Center.

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Transcript of Advances and Emerging Therapy for Lung Cancer Rachel E. Sanborn, M.D. Providence Cancer Center.