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.
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Advances and Emerging Therapy for Lung Cancer
Rachel E. Sanborn, M.D.
Providence Cancer Center
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Early-Stage Disease
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Definitive Therapy
• Surgical resection is preferred
• Survival with resection alone:– Stage I: 60-85%– Stage II: 50%
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Adjuvant Therapy for Resected Disease
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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
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Adjuvant Chemotherapy, 2
• Carboplatin-based therapy– No survival benefit
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Adjuvant Chemotherapy, Questions
• Will addition of targeted agents improve survival?
• Will predictive markers help to guide who needs or benefits from adjuvant therapy?
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Adjuvant Therapy--Questions
• Which agents?
• Stage I disease?
• How far out to treat before “window of opportunity” is lost?
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Locally-Advanced Disease:Mediastinal Nodal Involvement
or Invasive Tumors
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Neoadjuvant Therapy
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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
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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
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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
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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?
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Definitive Therapy for Unresectable Disease:
Combined Modality Therapy
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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
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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
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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
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SWOG 9019
• Stage IIIB only, 50 patients
• Cisplatin/Etoposide/Concurrent TRT
• Median OS 15 months
• 5-Y OS 15%
Albain et al, JCO 2002
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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
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Consolidation:Chemo After Chemo/RT
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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
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SWOG 0023
R ANDOM I Z E
Cis/EtopConcurrent RT
Kelly et al, ASCO 2007; abstr 7513
ConsolidationDocetaxel
Gefitinib
Placebo
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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
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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
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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
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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
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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%
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Metastatic Disease
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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
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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
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ChemotherapyFirst-Line
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Comparison Trial
• Cisplatin/Paclitaxel
• Cisplatin/Gemcitabine
• Cisplatin/Docetaxel
• Carboplatin/Paclitaxel
Schiller et al, NEJM 2002
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Schiller et al, NEJM 2002
Median Survival:
8 mo
1-Y Survival:
34%
2-Y Survival:
12%
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Schiller et al, NEJM 2002
Median Survival:
8 mo
1-Y Survival:
34%
2-Y Survival:
12%
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Targeted Agents—Bevacizumab
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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.
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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.
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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.
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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.
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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
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Exclusion
• Squamous cell carcinoma• Central tumors• Brain mets (Actively screened for prior to
enrollment)• Hemoptysis• Anticoagulation (Except ASA 81mg)
Sandler et al, NEJM 2006
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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.
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Carbo/Tax/Bevacizumab:Toxicities
• HTN• Neutropenia• Hemorrhage• Proteinuria• Thromboembolism
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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
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Targeted Agents—Cetuximab
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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.
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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
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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
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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.
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Cisplatin/Vinorelbine/Cetuximab
• Randomized Phase III trial
• Cis/Vinorelbine
• With or without Cetuximab
• Cetuximab till disease progression
Pirker et al, PASCO 2008
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Cetuximab Toxicity with Chemo
• Rash
• Febrile neutropenia
• No difference in treatment-related mortality
Pirker et al, PASCO 2008
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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?
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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
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ChemotherapySecond-Line
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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
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Docetaxel Survival Curve
Shepherd et al, JCO 2000
Improvement in overall QOL, pain, appetite, and fatigue with Docetaxel compared with BSC
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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%
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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%
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Targeted Agents—Erlotinib
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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
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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
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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
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Erlotinib Single Agent Survival
Shepherd et al, PASCO 2004
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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
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Chemotherapy for Metastatic Disease
• First, second, third-line therapy:
• Improves survival
• Improves quality of life
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What next?
• Histology-derived treatment selection
• Treatment/Prognosis driven by molecular profiles
• Ongoing efforts to understand interactions between targeted agents and chemo
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Small Cell Lung Cancer
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Small Cell Lung Cancer
• 10-15% new lung cancers are SCLC
• Decreasing proportion over time
• ~32,000 cases yearly
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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
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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
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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
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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
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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
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Clinical Trials Help to Provide Answers
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