Latest in treatment of lung cancer Dr Sanjay Popat Clinical Senior Lecturer Honorary Consultant Medical Oncologist [email protected] The Royal Marsden Overview: NSCLC Surgery for NSCLC Stage 3 (locally advanced) NSCLC is a mixture of disease types Personalized medicine and advanced NSCLC Small cell lung cancer (SCLC) QUESTIONS FOR THE AUDIENCE The Royal Marsden In women, the commonest cause of death from cancer is: 1. Breast cancer 2.Colorectal cancer 3.Lung cancer 4.Prostate cancer The Royal Marsden What is the 5-year survival after resection of stage 1a NSCLC 1. 95% 2.85% 3.75% 4.55% The Royal Marsden NSCLC Survival by stage Goldstraw et al. JTO 2007 The Royal Marsden The absolute benefit of adjuvant chemotherapy at 5 years after curative resection of a N2 positive tumour is: 1. 50% 2.30% 3.15% 4.5% The Royal Marsden Which of the following is the commonest cause of death from cancer? 1. Oesophageal cancer 2.Non-Hodgkin lymphoma 3.Renal cell cancer 4.Ovarian caner 5.Leukaemia 6.Pancreatic cancer 7.Lung cancer in never smokers The Royal Marsden Deaths from lung cancer in never smokers 16-24,000 deaths per year Operable (Stage 1-2) NSCLC The Royal Marsden The Royal Marsden Adjuvant chemotherapy improves survival •Combination cisplatin-vinorelbine •4 Cycles (q21 = 3 months) •Indication: All node-positive tumours (stage 2-3); Possibly in node-negative tumours ≥4cm Douillard JTO 2010 The Royal Marsden Adjuvant chemotherapy improves survival Douillard JTO 2010 The Royal Marsden What is the price for adjuvant chemotherapy? The Royal Marsden Stereotactic radiotherapy for small NSCLCs •Focussed radiation delivery to ablate tumours •Can be delivered using different systems •Cyberknife system allows tracking of tumour during RT delivery •Superior outcomes to radical lung RT •A possible approach vs surgery •Treatment of oligo-metastatic disease The Royal Marsden Surgical advances •Staging the mediastinum: is it really not N2 disease – Sampling vs Systematic nodal dissection (SLND) – UICC recommend 6 stations sampled for pN0 status •VATS lung resection – Many series, few randomized studies – Improved blood loss, post operative stay, recovery •Sub-lobar resections – Possible role in small tumours – Anatomic segmentectomy superior to non-anatomic wedge Locally Advanced (Stage 3) NSCLC The Royal Marsden Stage 3 NSCLC is a heterogeneous set of diseases The Royal Marsden Concurrent chemoradiotherapy is standard of care for most NSCLC Chemotherapy Radiotherapy: >50Gy Pre-1990: Median survival 9.7 months Radiotherapy: >50Gy Dillman et al. 1990 NEJM Median survival 13.8 months Chemotherapy Radiotherapy: >50Gy Chemotherapy Radiotherapy Surgery MacGuire et al. 2011 J Clin Oncol Median survival 27.4 months Albain et al. 2009 Lancet NO improvement with surgery •Unless no pneumonectomy Advanced (Stage 4) NSCLC The Royal Marsden Stage 4: NSCLC is an obsolete term Adenocarcinoma ~45% ↑ Squamous carcinoma ~45%↓ Other rarer sub-types ~10% Sub-type of NSCLC determines 1. Drug therapy Bevacizumab is contraindicated in squamous carcinoma Pemetrexed is contraindicated in squamous carcinoma 2. Tumour genotype EGFR mutation commoner in adenocarcinomas ALK gene-rearrangement commoner in adenocarcinomas The Royal Marsden Lung cancer: the new molecular landscape Pao, Girard Lancet Oncol 2011 The Royal Marsden Lung cancer: 1995-2000 Advanced NSCLC Platinum doublet chemotherapy1 Docetaxel2 monotherapy Best supportive care The Royal Marsden Lung cancer: 2000-2011 Advanced NSCLC Wild-type EGFR NSCLC Squamous NSCLC Mutant EGFR NSCLC Non-Squamous NSCLC Gefitinib5 or Erlotinib9 Platinum doublet Chemo: not pem or bev1 Pem Platinum doublet Chemo7 ± bev8 Maintenance Docetaxel2 monotherapy Erlotinib3 monotherapy Erlotinib3 monotherapy Best supportive care Pemetrexed4 monotherapy 1. 2. 3. 4. 5. 6. 7. 8. 9. Schiller et al NEJM 2002;346,92 Shepherd et al JCO 2000;15,2095 Shepherd et al. NEJM 2005;353,123 Hanna et al. JCO 2004;22,1589 Mok et al NEJM 2009;361,947 Morita et al. CCR 2009;15,4493 Scagliotti et al. JCO 2008;26,3543 Sandler et al. JCO 2006;355,2542 Rosell et al Lancet 2012 The Royal Marsden Lung cancer: 2012- and beyond Advanced NSCLC Wild-type EGFR NSCLC Squamous NSCLC Non-Squamous NSCLC Platinum doublet Chemo: not pem or bev1 Mutant EGFR NSCLC Gefitinib5 or Erlotinib9 Pem Platinum doublet Chemo7 ± bev8 Afatinib ALK+ Docetaxel2 monotherapy Erlotinib3 monotherapy Erlotinib3 monotherapy Best supportive care Pemetrexed4 monotherapy Crizotinib BRAF+ BRAF inhibitor KRAS+ MEK inhibitor HER2+ Afatinib What’s new in Small Cell Lung Cancer (SCLC)? The Royal Marsden SCLC and anti-angiogenic trials Study Target Agent Design Result NCI-C/EORTC MMP Marimastat +/- Maintenance Negative BAY 12-9566 +/- Maintenance Negative BAYER ECOG CALGB HOG VEGF BEV (B) Chemo + B Chemo + B Chemo + B Positive Negative Negative LLCG Vascular stabilizer Thalidomide Chemo +/- T Negative NCI-C VEGFR TKi ZD 6474 +/- Maintenance Negative SWOG VEGFR TKi Sorafenib Monotherapy Negative NCI VEGFR TKi ZD 2171 Monotherapy Negative The Royal Marsden SCLC and targeted therapy Study Target Drug Design Result Rudin Bcl-2 Oblimersen Chemo +/- Negative Langer Bcl-2 Obatoclax Chemo +/- Negative ECOG mTOR CCI-779 +/- Maintenance Negative HOG EGFR gefitinib Monotherapy Negative Johnson Krug Dy Kit Imatinib Monotherapy Monotherapy Monotherapy Negative Negative Negative EORTC GD-3 BEC2/BCG +/- Maintenance Negative SWOG Proteosome Bortezomib Monotherapy Negative SWOG RAS/VEGF Sorafenib Monotherapy Negative The Royal Marsden New chemotherapy in SCLC Study Target Drug Design Result JCOG 9511 SWOG 0124 HOG S0124 Topoismerase CPT-11 PE vs PI PE vs PI PE vs P PE vs PI Positive Negative Negative Negative Socinski TS Pemetrexed PE vs Pem Negative Von Pawel Topoisomerase Topotecan Topo vs CAV Positive O’Brien Topoisomerase Topotecan Topo vs BSC Positive SPEAR Platinum Picoplatin Amb vs BSC Negative Amrubicin Amb vs AmbC vs PE Negative EORTC 08062 Anthracycline The Royal Marsden Management of SCLC ES-SCLC LS-SCLC Platinum-etoposide Platinum-etoposide Concurrent thoracic RT Prophylactic cranial irradiation CAV or ACE or topotecan chemotherapy Best supportive care The Royal Marsden Conclusions Minimally invasive surgery instead of thoracotomy Stereotactic radiotherapy for medically inoperable….for operable…. Chemoradiotherapy for stage 3 NSCLC What is the role for surgery? Stage 4 and relapsed NSCLC The molecular revolution SCLC: sadly, no major advances