Download - 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
Kelly et al, ASCO 2007; abstr 7513
SWOG 0023
• Closed after DSMB interim analysis
Kelly et al, ASCO 2007; abstr 7513
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%
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)
Sandler et al, NEJM 2006
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)
Sandler et al, NEJM 2006
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%
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
Shepherd et al, PASCO 2004
Overall Survival
Erlotinib 6.7 mo
Placebo 4.7 mo
P<0.001
Erlotinib Single Agent Survival
Shepherd et al, PASCO 2004
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