Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Advances and Emerging Therapy for Lung Cancer Rachel E. Sanborn, M.D. Providence Cancer Center."— Presentation transcript:

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

2 Early-Stage Disease

3 Definitive Therapy Surgical resection is preferred Survival with resection alone: –Stage I: 60-85% –Stage II: 50%

4 Adjuvant Therapy for Resected Disease

5 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

6 Adjuvant Chemotherapy, 2 Carboplatin-based therapy –No survival benefit

7 Adjuvant Chemotherapy, Questions Will addition of targeted agents improve survival? Will predictive markers help to guide who needs or benefits from adjuvant therapy?

8 Adjuvant Therapy--Questions Which agents? Stage I disease? How far out to treat before “window of opportunity” is lost?

9 Locally-Advanced Disease: Mediastinal Nodal Involvement or Invasive Tumors

10 Neoadjuvant Therapy

11 Smaller phase III trials (60 pts), both stopped early Stage IIIA Survival advantage with neoadjuvant chemotherapy Med survival 26 mo vs 8 mo; P< mo vs 11 mo; P<0.008 Rosell et al, NEJM 1994; Roth et al, JNCI 1994

12 SWOG 9900 RANDOMIZERANDOMIZE Resectable NSCLC, 354/600 Planned Patients Arm B: Surgery Alone Arm A: Carboplatin/Paclitaxel X3 cycles Surgery Pisters et al, ASCO 2005; abstr 7012

13 SWOG 9900, Early Results Chemo + SurgerySurgeryP Med PFS31 mo20 mo0.26 Overall Survival47 mo40 mo0.47 Pisters et al, ASCO 2005; abstr 7012

14 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?

15 Definitive Therapy for Unresectable Disease: Combined Modality Therapy

16 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

17 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

18 Furuse, K. et al. J Clin Oncol; 17: Fig 1. Overall survival in patients with NSCLC according to treatment group Concurrent vs Sequential Tx

19 SWOG 9019 Stage IIIB only, 50 patients Cisplatin/Etoposide/Concurrent TRT Median OS 15 months 5-Y OS 15% Albain et al, JCO 2002

20 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

21 Consolidation: Chemo After Chemo/RT

22 SWOG 9504 Med Surv 3-Y OS4-Y OS5-Y OS PE/RT Docetaxel S m40%29% PE/RT PE S m17% Gandara et al, ASCO 2005, abstr 7059

23 SWOG 0023 RANDOMIZERANDOMIZE Cis/Etop Concurrent RT Kelly et al, ASCO 2007; abstr 7513 Consolidation Docetaxel Gefitinib Placebo

24 Overall Survival From Randomization 0% 20% 40% 60% 80% 100% Months After RANDOMIZATION Gefitinib Placebo N Events Median in Months P =.01 1 YR OS 2 YR OS 73%46% 59%81% Median FU time: 27 months Kelly et al, ASCO 2007; abstr 7513

25 SWOG 0023 Closed after DSMB interim analysis Kelly et al, ASCO 2007; abstr 7513 GefitinibPlaceboP Median PFS11m10mNS Dead from Cancer86%80% Dead from Toxicity3%0% Overall Survival23m35m 0.013

26 HOG Phase III; Replicating SWOG 9504 RANDOMIZERANDOMIZE IIIA/B 243/259 Patients randomized Hanna et al, ASCO 2007; abstr 7512 Cis/Etop Concurrent RT Consolidation Docetaxel Observation

27 Overall Survival (ITT) Randomized Patients (n=147) Observation: Median: 24.1 months ( ) 3 year survival rate: 27.6% Docetaxel: Median: 21.5 months ( ) 3 year survival rate: 27.2% P-value: Hanna et al, ASCO 2007; abstr 7512

28 HOG, Phase III Results DSMB interim analysis Closed after 203 pts due to futility Hanna et al, ASCO 2007; Mina et al, ASCO 2008 DocetaxelObservationP Median PFS12.3m12.9m0.94 Median Survival24.3m26m 0.75 Hospitalizations28.8%8.1% Toxic Death5.5%

29 Metastatic Disease

30 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

31 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

32 Chemotherapy First-Line

33 Comparison Trial Cisplatin/Paclitaxel Cisplatin/Gemcitabine Cisplatin/Docetaxel Carboplatin/Paclitaxel Schiller et al, NEJM 2002

34 Median Survival: 8 mo 1-Y Survival: 34% 2-Y Survival: 12%

35 Schiller et al, NEJM 2002 Median Survival: 8 mo 1-Y Survival: 34% 2-Y Survival: 12%

36 Targeted Agents— Bevacizumab

37 Why Target VEGF? Actively proliferating tumor cells express more Vascular endothelial growth factor (VEGF) than nonproliferating cells 1 –VEGF may act as an autocrine growth factor 1 VEGF expression is upregulated in many cancer types, including NSCLC 2-4 Elevated serum VEGF levels have been associated with poorer outcomes in limited- or early-stage disease 2, Mattern et al. Br J Cancer. 1996;73:931– Yuan A et al. Int J Cancer Pred Oncol. 2000;89:475– Lantuejoul et al. J Pathol. 2003;200:336– Ravindranath et al. J Androl. 2001; 22:432– Shimanuki et al. Lung. 2005;183:29– Hasegawa et al. Intern Med. 2005;44:26– Mineo et al. J Clin Pathol. 2004;57:591–597.

38 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) P P P P ANGIOGENESIS ProliferationSurvivalMigration Endothelial cell activation 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.

39 Summary of Anti-VEGF Proposed Mechanisms of Action Based on Preclinical Models May regress existing microvasculature 1,2 May normalize surviving mature vasculature 3-5 May inhibit vessel regrowth and neovascularization 2,3, 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.

40 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.

41 Randomized Phase II/III RANDOMIZERANDOMIZE Advanced Non- Squamous NSCLC, 855 Patients Arm B: Carboplatin/Paclitaxel +Bevacizumab Arm A: Carboplatin/Paclitaxel +Placebo Bev until progression Sandler et al, NEJM 2006

42 Exclusion Squamous cell carcinoma Central tumors Brain mets (Actively screened for prior to enrollment) Hemoptysis Anticoagulation (Except ASA 81mg) Sandler et al, NEJM 2006

43 Phase III: Overall Survival HR: 0.80, P =.013 BV/PC51.0%22.0% 12.3 mo PC44.4%15.4% 10.3 mo Proportion surviving mo24 mo Median 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.

44 Carbo/Tax/Bevacizumab: Toxicities HTN Neutropenia Hemorrhage Proteinuria Thromboembolism

45 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

46 Targeted Agents— Cetuximab

47 The HER Family of Receptors HER1 erb-b1 EGFR HER2 erb-b2 neu HER3 erb-b3 HER4 erb-b4 Tyrosine kinase domain Ligand-binding domain Transmembrane EGF TGF  Amphiregulin Betacellulin HB-EGF Epiregulin NRG2 NRG3 Heregulins Betacellulin Heregulins Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433.

48 Potential Consequences of EGFR Dysregulation Signaling cascades EGFR PI3K MAPK Nucleus Gene activation Cell cycle progression M G1G1 S G2G2 Myc Fos Jun P P MAPK = mitogen-activated protein kinase. Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433. Survival Proliferation Angiogenesis Invasion Apoptosis Metastasis

49 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

50 EGFR-Targeted Approaches Anti-EGFR blocking antibodies Antiligand blocking antibodies Tyrosine kinase inhibitors Ligand- toxin conjugates HER dimerization inhibitors TOXIN Adapted from Noonberg and Benz. Drugs. 2000;59:753.

51 Cisplatin/Vinorelbine/Cetuximab Randomized Phase III trial Cis/Vinorelbine With or without Cetuximab Cetuximab till disease progression Pirker et al, PASCO 2008

52 Cetuximab Toxicity with Chemo Rash Febrile neutropenia No difference in treatment-related mortality Pirker et al, PASCO 2008

53

54 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?

55 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

56 Chemotherapy Second-Line

57 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

58 Docetaxel Survival Curve Shepherd et al, JCO 2000 Improvement in overall QOL, pain, appetite, and fatigue with Docetaxel compared with BSC

59 Pemetrexed RANDOMIZERANDOMIZE 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%

60 Pemetrexed RANDOMIZERANDOMIZE 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%

61 Targeted Agents— Erlotinib

62 Proposed Mechanism of Action of EGFR-Targeted TKIs P P P P MG1G1 S G2G2 Arteaga. Semin Oncol. 2003;30(suppl 7):3. Tumor cell survival Tumor cell proliferation ApoptosisG 1 arrest No signaling MAPK BAX  BCL2  PI3K Inhibit EGFR kinase activity TKIs Phosphorylation

63 Erlotinib single agent trial RANDOMIZERANDOMIZE Advanced NSCLC, 731 Patients 1-2 Prior Chemo Regimens Arm B: Placebo Arm A: Erlotinib Shepherd et al, PASCO 2004

64 Erlotinib single agent trial RANDOMIZERANDOMIZE Advanced NSCLC, 731 Patients 1-2 Prior Chemo Regimens Arm B: Placebo Arm A: Erlotinib Shepherd et al, PASCO 2004 Overall Survival Erlotinib6.7 mo Placebo 4.7 mo P<0.001

65 Erlotinib Single Agent Survival Shepherd et al, PASCO 2004

66 Erlotinib in Combination StudyPatientsMedian Survival Median TTP TALENT 1 (Gem/Cis with Erlotinib or placebo) days v 309 days 167 days v 179 days TRIBUTE 2 (Carbo/Tax with Erlotinib or placebo) m v 10.6m 5.1m v 4.9m 1. Gatzmeier et al, PASCO Herbst et al, PASCO 2004

67 Chemotherapy for Metastatic Disease First, second, third-line therapy: Improves survival Improves quality of life

68 What next? Histology-derived treatment selection Treatment/Prognosis driven by molecular profiles Ongoing efforts to understand interactions between targeted agents and chemo

69 Small Cell Lung Cancer

70 10-15% new lung cancers are SCLC Decreasing proportion over time ~32,000 cases yearly

71 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

72 Survival Limited Stage –Median survival 3 months without treatment –Median survival months with treatment –~25% 5-year survival* *Turrisi et al, NEJM, 1999

73 Survival Limited Stage –Median survival 3 months without treatment –Median survival 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

74 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

75 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

76 Clinical Trials Help to Provide Answers

77


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

Similar presentations


Ads by Google