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Background

Staging Standard of Care (RTOG 9410, LAMP). Background. Induction chemo Induction chemoXRT (INT 0139). Resectable IIIA. Inhibitors EGFR, VEGF RTOG 1306/Alliance 31101. Novel Therapies. Outline: Stage III NSCLC. Induction chemo (CALGB 39-801) Consolidation (SWOG 9504) (SWOG 0023).

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Background

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  1. Staging Standard of Care (RTOG 9410, LAMP) Background Induction chemo Induction chemoXRT (INT 0139) Resectable IIIA Inhibitors EGFR, VEGF RTOG 1306/Alliance 31101 Novel Therapies Outline: Stage III NSCLC Induction chemo (CALGB 39-801) Consolidation (SWOG 9504) (SWOG 0023) Unresectable IIIA/B

  2. Lung Cancer During 2013, ~228,190 new cases and ~159,480 deaths are expected in the United States Second most common cancer and leading cause of cancer death 5-Year Relative Survival Rate by Stage at Diagnosis 100 90 80 70 Localized (stage I/II) 15% Distant (stage IV) 56% 60 53% Survival (%) 50 40 24% 30 20 Regional (stage III) 22% 4% 10 0 Localized Regional Distant Stage at Diagnosis American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer Society; 2013; Siegel. CA Cancer J Clin.61(4):212.

  3. New Staging Stage III Detterbeck F C et al. Chest 2009;136:260-271

  4. Classic Stage IIIA Patient Presentations • Multi-station N2 lymph nodes • Induction chemo then chemoXRT • Induction chemo then surgery then XRT • Induction chemoXRT then surgery • ChemoXRT • Early clinical stage Surgery – find microscopic disease in N2 Lymph nodes so pathologic stage IIIA • Radiation then adjuvant chemotherapy • T3-4 chest wall invasion • (superior sulcus tumors) • Induction chemo then chemoXRT • ChemoXRT • Induction chemoXRT then surgery • Single station N2 lymph nodes • Induction chemo then chemoXRT • Induction chemo then surgery then XRT • Induction chemoXRT then surgery • ChemoXRT

  5. Stage III NSCLC Treatment 17 (n=709) Median OS 14 (n=716) Choy, ASCO 2003 P < 0.05 (Kruskal-Wallis Test) The optimal regimen has not been defined yet although stage III patients require multi-modality therapy to achieve long-term survival. Concurrent chemo-radiation is better than XRT alone and sequential chemo-radiation in unresectable stage III NSCLC

  6. Stage III NSCLC Treatment • ASCO Guidelines • Patients with a good performance status (FEV1 > 800 cm3 ) should receive 2-4 cycles of platinum-based chemotherapy and should receive no less than the biologic equivalent of 60 GyXRT in 1.8 –2.0 fractions Pfister et al. JCO 22 (2): 330-353, 2004

  7. Stage III NSCLC • Unanswered questions: • Optimal chemotherapy, dosing, timing • Induction regimen • Consolidation • Sequencing Tri-modality Therapy • Biologic therapies

  8. Staging Standard of Care Background Induction chemo Induction chemoXRT (INT 0139) Resectable IIIA Inhibitors EGFR, VEGF RTOG 1306/Alliance 31101 Novel Therapies Outline: Stage III NSCLC Induction chemo (CALGB 39-801) Consolidation (SWOG 9504) (SWOG 0023) Unresectable IIIA/B

  9. Phase III Induction Chemo-surgery Trials for IIIA Depierre et al. found that the benefit of chemo was in N0-1 disease (RR 0.68) and not in N2 disease (RR 1.04) PE = cisplatin, etoposide MIC = mitomycin, ifosfamide, cisplatin CEP = cisplatin, etoposide, cyclophosphamide Pass et al Ann Thor Surg 1992, Rosell et al NEJM 1994, Roth JNCI 1994, Depierre JCO 2002

  10. Induction Chemotherapy Trials • Bimodality Lung Oncology (BLOT) (carboplatin,taxol) • French Thoracic Cooperative Group (gemcitabine, cisplatin vs. carboplatin, taxol) • Medical research Council LU-22 (MIC vs. mitomycin, vinblastine, and cisplatin) • NATCH (carboplatin, taxol) • CLINCH (carboplatin, taxol) • CHEST(gemcitabine, cisplatin) The role of surgery in IIIA patients after neoadjuvant chemotherapy remains controversial.

  11. Prognostic Factors for Improved Survival to Surgery after Neoadjuvant Chemo • Response to chemotherapy • Down-stage N2 disease • Single-station N2 is better than multi-station N2 disease • R0 resection • Pathologic CR

  12. Resectable IIIA – Induction Chemo • Limited Data - Conflicting for pN2 patients • Reasonable to offer induction chemotherapy (ideally on protocol) • Patients with objective response should be offered surgery • Positive subcarinal nodes or multiple level involvement portends a poor prognosis  Definitive chemoradiation may be better for the patient

  13. INT 0139 Phase III Trial of CT/RT vs. CT/RT/S Stage IIIA T1-3pN2 Surgery Feasible Predicted post-surgery FEV1> 800cc Medically fit Surgery *R A N D O M I Z E Induction PE x 2 + XRT Chemotherapy (PE) Cisplatin 50 mg/m2 d1, 8, 29, 36 Etoposide 50 mg/m2 d1-5, d29-33 Radiation Thoracic Radiation 45 Gy starting on Day 1 (1.8 Gy/day) XRT to 61 Gy + PE x 2 *Stratified by KPS, T-stage Primary endpoint: overall survival in ITT Albain K, et al Lancet 374: 379-386, 2009

  14. INT 0139 PFS Favors Tri-modality Arm CT/RT/SCT/RT 5-yr Median PFS (mo) 12.8 10.5 5-yr PFS Rate 22.4% 11.1% 100 100 75 75 / / 50 50 % Alive without Progression / / / / / / / / / / 25 25 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 0 0 0 0 12 12 24 24 36 36 48 48 60 60 Months from Randomization HR 0.77, p=0.017 CT/RT/S N=202 CT/RT N=194 Albain K, et al Lancet 374: 379-386, 2009

  15. INT 0139 Overall Survival CT/RT/SCT/RT 5-yr Median OS (mo) 23.6 22.2 5-yr OS Rate 27.2% 20.3% 100 100 75 75 HR 0.87 p=0.24 50 50 % Alive % Alive CT/RT/S N=202 25 25 CT/RT N=194 0 0 0 0 12 12 24 24 36 36 48 48 60 60 Months from Randomization Months from Randomization Albain K, et al Lancet 374: 379-386, 2009

  16. INT 0139 Deaths Deaths on surgery arm mostly occurred in pneumonectomy patients (14 of the 16 pts). 26% (n=14/54) of all pneumonectomy cases died; mostly from ARDs and respiratory failure. Albain K, et al Lancet 374: 379-386, 2009

  17. 100 75 CT/RT / N= 42 p = NS CT/RT/S 50 % Alive / N=38 / / / / / / 25 / / 0 0 12 24 36 48 60 Months from Randomization INT 0139 OS by Pneumonectomy vs CT/RT Albain K, et al Lancet 374: 379-386, 2009

  18. INT 0139 OS by Lobectomy vs CT/RT 100 CT/RT/S N=57 75 CT/RT N=74 % Alive p = 0.002 / / / 50 / / / / / / / / / / / / / / / 25 / / / / / 0 0 12 24 36 48 60 Months from Randomization Albain K, et al Lancet 374: 379-386, 2009

  19. Summary: INT 0139 • Neoadjuvant chemo-radiation before surgery improves PFS but not OS over definitive chemo-radiation in stage IIIA (T1-3 pN2) NSCLC patients. • There was a trend towards increased 5-year OS rates with the tri-modality arm. • N0 status at surgery predicts for greater 5-yr survival; i.e. down-staging is associated with improved survival. Albain K, et al Lancet 374: 379-386, 2009

  20. Summary: INT 0139 • No significant differences in toxicity beyond increased esophagitis in the chemo-radiation alone arm. • In patients that require a pneumonectomy, neoadjuvant chemo-radiation is associated with a high risk of post-operative death (26%). • At this time, can safely consider neoadjuvant chemo-radiation in very good PS patients who can receive a lobectomy.

  21. Future Issues How to determine which patient should receive aggressive tri-modality? • Develop prognostic molecular models to help guide treatment decisions How to optimize down-staging? • Improve systemic therapies • Personalize medicine to molecular genotype

  22. Staging Standard of Care (RTOG 9410, LAMP) Background Induction chemo Induction chemoXRT (INT 0139) Resectable IIIA Inhibitors EGFR, VEGF RTOG 1306/Alliance 31101 Novel Therapies Outline: Stage III NSCLC Consolidation (SWOG 9504) (SWOG 0023) Unresectable IIIA/B

  23. Consolidation Chemotherapy SWOG Phase II Trials S9504, n=83 S9019, n= 50 pStage IIIB Cisplatin/VP-16 XRT Cisplatin/VP-16 pStage IIIB Cisplatin/VP-16 XRT Docetaxel

  24. SWOG 9504 NSCLC Stage IIIB (T4N0-2, TanyN3) Cytology negative pleural effusion PS 0-2 Cisplatin 50 mg/m2 d1, 8, 29, 36 Etoposide 50 mg/m2 d1-5, d29-33 + Thoracic Radiation 61 Gy 45Gy (1.8 Gy/fx), 16 Gy boost (2Gy/fx) Docetaxel Cycle 1: 75 mg/m2 Cycle 2-3: 100 mg/m2 Gandara D, et al. (SWOG 9504), Abstract # 7059, ASCO 2005

  25. SWOG 9504 Overall Survival PE: cisplatin/etoposide; RT: 61 Gy Radiotherapy; D: docetaxel Gandara D, et al. (SWOG 9504), Abstract # 7059, ASCO 2005

  26. SWOG 9504 • Long-term survival results are impressive for stage IIIB NSCLC. • Certain subsets of stage IIIB can have survival range of 20-37%. • However, confirmatory randomized trials are needed. • Cisplatin/Etoposide given concurrently with radiation followed by docetaxel for 3 cycles is an appropriate regimen to use in stage IIIB NSCLC. Gandara D, et al. (SWOG 9504), Abstract # 7059, ASCO 2005

  27. R A N D O M I Z E Placebo SWOG 0023 PE/RT -> Docetaxel Gefitinib R A N D O M I Z E Hoosier Oncology Group LUN01-24 PE/XRT Docetaxel PE/XRT Confirmatory Consolidation Trials

  28. HOG LUN 01-24(Closed to Accrual 7/06, n=244/259) Unresectable, Stage IIIA-IIIB NSCLC; ECOG PS 0-1; <5% Weight Loss in Prior 3 mo ChemoRT InductionCisplatin 50 mg/m2 d 1,8,29,36Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy CR, PR, or SD;ECOG PS 0-2 Randomize Docetaxel 75 mg/m2 q 3 wk  3 Observation There was no difference in outcome between the two arms

  29. Gefitinib 250 mg or 500 mg daily Placebo SWOG 0023 NSCLC Unresect IIIA, or IIIB Cytology negative pleural effusion PS 0-1 Predicted post-surgery FEV1> 800cc Cisplatin 50 mg/m2 d1, 8, 29, 36 Etoposide 50 mg/m2 d1-5, d29-33 + Thoracic Radiation 61 Gy Docetaxel Cycle 1-3: 75 mg/m2 Kelly K, et al. (SWOG 0023), Abstract # 7058, ASCO 2005

  30. SWOG 0023 PFS SWOG 9504 Gefitinib Kelly K, et al. (SWOG 0023), Abstract # 7058, ASCO 2005

  31. Median N Events in Months 100% Gefitinib 124 43 19 Placebo 131 32 29 80% P=0.09 2-sided stratified Log-rank 60% 40% 20% 0% 0 12 24 36 Months After Randomization SWOG 0023: Overall Survival P-value for alternative hypothesis 33% improvement with gefitinib was p= 0.0015 Kelly K, et al. (SWOG 0023), Abstract # 7058, ASCO 2005

  32. SWOG 0023 • Gefinitib maintenance after concurrent chemoradiation and docetaxel consolidation does not improve progression-free nor overall survival. • In fact, it is possible that gefitinib may have a detrimental effect. This remains under investigation. • SWOG 9504 regimen has favorable survival and can be used as a standard regimen for unresectable stage IIIB NSCLC. Kelly K, et al. (SWOG 0023), Abstract # 7058, ASCO 2005

  33. Staging Standard of Care (RTOG 9410, LAMP) Background Induction chemo Induction chemoXRT (INT 0139) Resectable IIIA Inhibitors EGFR, VEGF RTOG 1306/Alliance 31101 Novel Therapies Outline: Stage III NSCLC Consolidation (SWOG 9504) (SWOG 0023) Unresectable IIIA/B

  34. Systemic Therapy • Clear survival benefit seen in stage III with down-staging • Distant relapse remains a significant cause of death in stage III patients • Improving systemic therapies would potentially improve survival outcomes

  35. Tsao Stage IV Algorithm: Histology and Molecular Profiling NSCLC PATIENT SCC Non-SCC Neuroendocrine Adenocarcinoma Avoid pemetrexed or bevacizumab Platinum-etoposide; Switch Maintenance: pemetrexed, erlotinib EGFR mutation EGFR wild-type Consider 2nd line EGFR TKI or maintenance erlotinib (BR.21, SATURN) EML 4 ALK, ROS1 EGFR TKI 1st or 2nd line Maintenance (IPASS, BR.21, SATURN) crizotinib Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

  36. Cetuximab • IgG1 chimerized antibody to EGFR • Blocks ligand binding of EGF/TGFa to EGFR • Potentiates apoptosis • Inhibits cell cycle progression • Decreases production • of angiogenic factors • Inhibits invasion and metastasis

  37. RTOG 0324 Treatment Schema N=84 1o Endpoint: Feasibility/Safety 20 Endpoint: 1 year survival, TTP, Overall Survival Blumenschein et al. JCO 2011

  38. RTOG 0324 - Response Rate Blumenschein et al. JCO 2011

  39. Efficacy Median PFS 12 months 2-year progression-failure rate 55.2% Median OS time 22.7 months 2-year survival rate 49.3% Blumenschein et al. JCO 2011

  40. RTOG 0324 Conclusions • The addition of cetuximab to chemo-radiation is feasible. • Radiotherapy was delivered per protocol or within acceptable variation for 86% of patients. • Incidence of Grade ≥ 3 non-hematologic AE rate of 68% was similar to historical control • LAMP/ ACR 427 – 68% • Most common toxicities: skin, GI, pulmonary, and metabolic or laboratory abnormalities • There were six grade 5 events with the addition of cetuximab; 3 were in cases where > 20 Gy was administered to a significant volume of lung • A confirmatory phase III trial RTOG 0617 has completed accrual on May 12, 2011. Additional trials have also used cetuximab with other chemotherapy backbones.

  41. RTOG 0617: Conventional vs. High Dose RT +/- C225 R A N D O M I Z E XRT: 60 Gy Carbo-paclitaxel +/- cetuximab Carbo-paclitaxel X 2 cycles N=464 XRT: 74 Gy Carbo-paclitaxel +/- cetuximab The high-dose XRT 74 Gy arms were closed due to lack of OS benefit on May 2011. Primary endpoint: OS Weekly carboplatin AUC 2, paclitaxel 45 mg/m2, cetuximab 400 mg/m2 LD then weekly 250 mg/m2 Bradley et al. ASCO 2013 Abstract 7501

  42. RTOG 0617 Results • There was no difference in distant metastases rate. • Multivariate analysis for Poor prognostic factors: higher XRT dose, higher esophagitis/dysphagia rate, greater tumor volume, and heart volume > 5 Gy. • Data on effects of cetuximab were presented IASLC 2013. Bradley et al. ASCO 2013 Abstract 7501

  43. RTOG 0617 Cetuximab Effects • 237 patients received cetuximab • No significant benefit in overall or progression-free survival with cetuximab. • Higher overall grade 3-5 toxicity (85% vs 69%, p<0.0001). • Higher non-hematologic grade 3-5 toxicities (70.5% vs 50.7%, p<0.0001) • Patients with EGFR IHC H-score > 200 may have more benefit with cetuximab.

  44. Pemetrexed • Pemetrexed inhibits thymidylate synthase and other folate-dependent enzymes (GARFT, TS, DHTR) • Preclinical data indicate that high expression of TS correlates with reduced sensitivity to Pemetrexed. • SCC have higher baseline TS gene and protein expression compared to adenocarcinomas • Cells with MTAP deletions may be particularly sensitive to agents that reduce de-novo purine synthesis. Ceppi et al. Cancer 2006; Sigmond et al. Biochem. Pharmacol. 2003; Giovannetti et al. Mol. Pharmacol. 2005, Schmid et al. Oncogene, 1998

  45. Abstract #7505 Phase II CALGB 30407 Eligible Patients: Untreated stage III, PS 0-1, No pleural effusions Primary endpoint: Overall Survival Secondary endpoint: FFS, RR, toxicity, tissue EGFR expression and mutation Stats: 90% power to detect whether median survival is 20.9 months or more compared to historical control (CALGB 39801) 13.9 months Govindan et al. ASCO abstract #7505

  46. CALGB 30407 RR and FFS Govindan et al. ASCO abstract #7505

  47. FFS by Histology Govindan et al. ASCO abstract #7505

  48. CALGB 30407 by OS Govindan et al. ASCO abstract #7505

  49. CALGB 30407 OS by Histology Govindan et al. ASCO abstract #7505

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