Heather Wakelee, M.D. Assistant Professor of Medicine, Oncology Stanford University Sponsored by Educational Grant Support from Adjuvant (Post-Operative) Lung Cancer Chemotherapy Heather Wakelee, M.D. Assistant Professor of Medicine, Oncology Stanford University 1
TNM Staging of NSCLC T: Tumor size and invasion N: Lymph Nodes M: Metastases Stage I T1/T2 N M Stage II T1/2 N1 M Stage IIIA T1-3 T3 N2 N1 M *T indicates primary tumor; N, nodal involvement ; M, distant metastasis. AJCC Cancer Staging Manual. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997:13-131 Stage I/II NSCLC: Overview Stage I Surgical resection: cure 6-8% Controversy about adjuvant (postoperative) chemotherapy Stage II Surgical resection: cure 5-7% Post-operative (Adjuvant) chemotherapy improves cure rates 5-15% 2
1995 Meta-Analysis Adjuvant Cisplatin Trials (1394 patients) Percentage Survival 1 8 6 4 2 Surgery plus Chemotherapy Surgery HR.87 p=.8 Brit Med J 31: 899-98, 1995 12 18 24 36 48 54 6 Time from Randomization (months) 5% absolute survival benefit at 5 years, (non-significant) Lung Adjuvant Cisplatin Evaluation (LACE) 5 trials - 4,584 patients Median follow-up: 5.1 years OS HR.89 [.82-.96], p=.5 Stage IA HR 1.4 [.95, 2.6] Stage IB HR.93 [.78, 1.1] Stage II/III HR.83 [.73,.95] 5 % improvement in cure at 5 years Pignon J Clin Oncol 26:3552, 28 3
Updated Overall Survival by Treatment Arm - JBR.1 >9yr f/up ' 1 8 Fig.1 All Patients Observation Stratified Log-Rank: p=.4 HR:.78(.613,.993) Chemo Vinorelbine Percentage 6 4 2 5 yr: 67% vs 56% MST 94m vs 72m At Risk Observation Vinorelbine 24 242 3 155 182 6 117 135 9 Time(Years) 58 67 Absolute improvement in 5 yr overall survival 11% All benefit in Stage II 12 9 12 15 Stage IB Analysis: CALGB 9633 Trial T < 4 cm T 4 cm CALGB 9633 HR OS p HR OS p 1.2.51.66.4 JBR.1 1.73.7.66.13 No Chemo Benefit Potential Chemo Benefit Strauss, J Clin Oncol 28 4
The Future of Adjuvant Therapy for Early Stage NSCLC Prognostic vs. Predictive Markers Prognostic Marker Indicates survival benefit/detriment regardless of therapy Stage, tumor size, sex Predictive Marker Predicts for differential benefit from a particular therapy Varlotto,Cancer 29 5
IALT: Prognostic and Predictive Value of ERCC1 in Adjuvant Treatment of NSCLC Patients With ERCC1-Negative Tumors Patients With ERCC1-Positive Tumors Overall survival (%) 1 8 6 Chemotherapy (15 deaths) 4 Control (113 deaths) 2 HR =.65 (.5-.86) P=.2 1 2 3 4 5 Overall survival (%) 1 8 6 Control (8 deaths) 4 Chemotherapy (92 deaths) 2 HR = 1.14 (.84-1.55) P=.4 1 2 3 4 5 Years Years 28:HR.76 [.59-.98] 28:HR 1.2 [.91-1.59] Olaussen KA. NEJM ;355:983, 26 Predictive Markers in NSCLC To date, these prognostic + predictive factors in early stage are based on RETROSPECTIVE analyses PREDICTIVE markers in advanced NSCLC In general low levels = sensitivity ERCC1 - platinum Thymidylate Synthase (TS) - pemetrexed RRM1 - Gemcitabine BRCA 1 - low platinum, but HIGH for taxanes EGFR mutation - EGFR-TKIs 6
Prospective Biomarker Adjuvant Therapy Trials Stage Therapy Marker C356 Stage I +/- Chemotherapy Metagene SWOG 72 Stage I +/- Chemotherapy (Cis/Gem) ERCC1 /RRM1 ITACA Stage I-IIIA Cisplatin/Pemetrexed ERCC1/TS TASTE Stage I-IIIA Cisplatin / Erlotinib ERCC1/ EGFR mut SCAT Stage I-IIIA Platinum / Docetaxel BRCA1/ RAP8 Targeted Agents Lung Cancer is heterogeneous No magic bullet is likely Chemotherapy targets DNA replication Multiple other cellular targets EGFR inhibitors - Epidermal Growth Factor Receptor VEGF inhibitors - Vascular Endothelial Growth Factor Vaccines 7
EGFR Signaling: Survival, Proliferation, Angiogenesis EGFR Adaptor proteins Nucleus PLC P P GRB2 Gene activation Cell cycle progression M G 1 MYC FOS G 2 S JUN Signaling cascades Proliferation Survival Angiogenesis Harari and Huang. Clin Cancer Res. 2;6:323; Herbst. Int J Radiat Oncol Biol Phys. 24;59(suppl):21. EGFR: Targeted Approaches Tarceva (erlotinib) Iressa (gefitinib) Anti-receptor blocking antibodies Adapted from Noonberg and Benz. Drugs. 2;59:753. Tyrosine kinase inhibitors Antiligand blocking antibodies 8
Erlotinib-EGFR inhibitor Phase III data BR.21: 2nd or 3rd line Adv NSCLC Endpoint Erlotinib Placebo (n=427) (n=211) Response 9% <1% Survival (mo) 6.7 4.7 1 year survival 31% 22% * p<.1 **p=.4,.1,.2 for cough, dyspnea, pain respectively Shepherd, ASCO 23:722, 24, NEJM 25 RADIANT Adjuvant NSCLC +/- Tarceva (Erlotinib) ELIGIBLE: N=945 Resected I-IIIA Chemo optional R A N D O M I Z E 2:1 Tarceva (Erlotinib) 15 mg by mouth daily x 2 yrs Placebo x 2 years Disease-Free Survival as primary endpoint 9
The Angiogenic Switch VEGF critical for the pathway Angiogenic 1-2 mm Switch Small tumor Nonvascular Dormant Larger tumor Vascular Metastatic potential VEGF: Targeted Approaches Avastin (Bevacizumab) Anti-receptor blocking antibodies Adapted from Noonberg and Benz. Drugs. 2;59:753. Tyrosine kinase inhibitors Antiligand blocking antibodies 1
E4599: Survival with Chemo +/- Avastin (Bevacizumab) for Advanced NSCLC Probability 1..8.6.4.2 878 patients PC PCB HR:.77 (.65,.93) P =.7 Medians: 1.3, 12.3 mo 12 mo. 24 mo. 44% 17% 52% 22%. 6 12 18 24 3 36 Months Sandler ASCO 23:LBA 4, 25 Avastin (Bevacizumab) in Adjuvant Therapy for Resected NSCLC: Rationale for E155 Benefit of adjuvant chemotherapy for resected NSCLC clearly established Benefit of VEGF inhibition proven in adv NSCLC 2 month survival benefit with bevacizumab added to chemotherapy for stage IV NSCLC Next logical step: study anti-angiogenesis with bevacizumab in the adjuvant setting Optimal chemotherapy not established, so 4 chemotherapy options Controversy over stage IB benefit - limited to those with tumors at least 4 cm in size 11
ECOG 155 : Chemo+/- Avastin Bevacizumab As Adjuvant Therapy for Resected NSCLC ELIGIBLE: Resected IB-IIIA R A N D O M I Z E Chemotherapy X 4 cycles Chemotherapy x 4 cycles + Avastin (Bevacizumab) x 1 year * Investigator choice of 4 chemo regimens Adjuvant Vaccine Trials: MAGE A3 MAGE-A3 - cancer specific tumor antigen 35-5% of lung cancer Give purified recombinant protein and immunologic adjuvant together (GSK1572932A) Phase II trial showed minimal toxicity (mostly local reaction) Promising randomized phase II results 12
MAGRIT Adjuvant NSCLC (+/-Chemo)+/- MAGE-A3 Vaccine ELIGIBLE: N=227 screened Resected IB-IIIA Required MAGE-A3 Expression (<4%) Chemo optional R A N D O M I Z E MAGE-A3 vaccine x 13 injections over 27 mo Placebo injections on same schedule Disease-Free Survival as primary endpoint Conclusions Adjuvant cisplatin chemotherapy is now standard of care for pts with resected stage II/IIIA NSCLC Long term follow-up important Critical issues are: Better patient selection (ERCC1, gene analysis, etc.) Better drugs are needed (targeted) EGFR, VEGF, VACCINES 13