Disclosures. Preoperative Treatment: Chemotherapy or ChemoRT? Adjuvant chemotherapy helps. so what about chemo first?

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1 Disclosures Preoperative Treatment: Chemotherapy or ChemoRT? Advisory boards Genentech (travel only), Pfizer Salary support for clinical trials Celgene, Merck, Merrimack Matthew Gubens, MD, MS Assistant Clinical Professor UCSF Thoracic Oncology Adjuvant chemotherapy helps LACE meta-analysis of patient-level data from ALPI, ANITA, BLT, IALT, JBR10 N=4584 patients, median f/u 5.1 years Overall HR of death: 0.89 ( , p<.005) By stage IA 1.41 ( ) IB 0.93 ( ) II 0.83 ( ) III 0.83 ( ) so what about chemo first? Improve surgical outcomes Downstage tumor Downgrade surgery Assess responsiveness to treatment Correct chemo? And more chemo Prognostic value of node clearance Tincture of time Pignon, JCO

2 Pitfalls of neoadjuvant treatment Surgical risk, especially if not downstaged Suboptimal radiation dose if patient doesn t get to surgery Neoadjuvant chemo alone SWOG 9900 Phase III, n=354, closed early when OS benefit shown with postop chemo Stage IB-IIIA, excluding superior sulcus and N2 Randomized to carbo/paclitaxel x 3, then surgery vs surgery alone OS 62 mos vs 41 mos, p=.11 So what about neoadjuvant chemorads? Neoadjuvant chemorads SWOG 8805 Phase II, n=126 IIIA (N2) or IIIB (N3 or T4) Cisplatin/etoposide x Gy Resection if stable or responding disease ChemoRT boost if unresectable, or for positive margins or nodes Resectability 85% in stage IIIA, 80% stage IIIB 3 year OS 27% in stage IIIA, 24% in stage IIIB Strongest predictor of long-tem survival was absence of tumor in mediastinal nodes (OS 30 vs 10 mo, p=.0005) Albain, JCO

3 Neoadjuvant chemorads RTOG 02-29?whether higher doses of radiation might be tolerable Phase II, n=57 III (N2 or N3) Carboplatin/paclitaxel weekly with radiation, 50.4Gy to mediastinum and primary tumor, and boost 10.8Gy to all gross disease, then resection and consolidation carbo/pac x 2 cycles Mediastinal clearance rage of 63%, only 37/57 were resected 2 year OS 54% Phase III, n=429 Stage IIIA, pn2 Intergroup 0139 Randomized to Cis/etop x 2 concurrent with 45Gy, then surgery Cis/etop x 2 concurrent with 61Gy Then 2 more cis/etop cycles for both arms Stratified by T status, KPS, contralateral mediastinal sampling Suntharalingam, Int J Radiation Oncol Biol Phys 2012 Albain KS, Lancet 2009 Intergroup 0139 PFS 12.8 vs 10.5 mos, HR 0.77, p=.017 OS 23.6 vs 22.2 mos, HR 0.87, p=.24 Sterilization of N2 nodes: 50% OS at 3 yrs Why no OS benefit? Surgery subgroups? 14/54 pneumonectomy deaths Albain KS, Lancet 2009 Intergroup 0139 Exploratory analysis Matched group 1 and 2 by age, sex, KPS and T stage Lobectomy OS 33.6 vs 21.7mo (p=.002) Pneumonectomy OS 18.9 vs 29.4mo (p=ns) Albain KS, Lancet

4 European trials EORTC08941 Phase III, induction chemo surgery vs RT n-=579, stage IIIA, N2 OS 16.4 vs 17.5 mos, HR 1.06 ( ) Though only 50% had complete resection Operative mortality of pneumonectomy 7% German Lung Cancer Cooperative Group Phase III, chemo RT surgery vs chemo surgery RT N=558, stage IIIA-B PFS 19.6 vs 21.3 mos, HR 1.07, p=.64 Operative mortality of pneumonectomy 14% Next steps: randomized data? INT0139: Chemorads/surgery vs chemorads EORTC08941: Chemo rads vs surgery GLCCC: Chemo rads surgery vs chemo surgery rads Really want to know chemo vs chemorads, then surgery Intergroup study of chemo vs chemorads, then surgery (RTOG 0412/SWOG 0332) failed to accrue, only 19/547! Van Meerbeeck, PASCO Thomas, Lancet Next steps: randomized data? SAKK trial 16/00, ASCO 2013 Phase III, n=232 Stage IIIA, N2, pathologically verified Randomized to Cisplatin/docetaxel q 3 weeks x Gy in 22 fx Cisplatin/docetaxel q 3 weeks x 3 alone Resection Next steps: randomized data? SAKK trial 16/00, ASCO 2013 Event free survival 12.8 vs 11.8 mos, NS OS 27.1 vs 26.2 mos, NS Local failure 22 vs 24% Not yet published Chemorads > sequential in definitive and adjuvant settings Pless, PASCO 2013, #7503 Pless, PASCO 2013, #7503 4

5 Next steps: observational data? Next steps: observational data? National Cancer Database (ACS COC institutions) , n=11,242, f/u 11.8 mos Compared treatments: Neoadj chemorads + lobectomy Neoadj chemorads + pneumonectomy Lobectomy + adjuvant therapy Pneumonectomy + adjuvant therapy Concurrent chemoradiation 5 year OS, with Cox PH model adjusting for SES, clinical, facility characteristics NeoCRT+L 5 year OS 33.5% Caveats are many Bulky/nonbulky # stations Extent of dz Proof N2 However, OS similar to INT0139 (as is 5 year OS 40% with nodal clearance) Koshy JTO 2013 Koshy JTO 2013 Real world? Survey of NCCN organizations on preference for neoadjuvant chemo vs chemorads Real world? Web-based survey of thoracic surgeons N=2539, 513 respondents (43% academic) In a patient with normal PFTs requiring pnuemonectomy in presence of N2 single station? 22% said chemort 12% said induction PX, any N status 30% said induction PX if N0 32% said induction lobectomy if N0 NCCN Guidelines, NSCLC, version Veeramachaneni, Ann Thor Surg

6 Targeted agents? No established use in early stage disease yet RTOG 1306: Randomized phase II study of individualized combined modality therapy for stage III NSCLC EGFR positive Erlotinib x 12 weeks chemorads with 60Gy vs chemorads alone ALK positive Crizotinib x 12 weeks chemorads with G0Gy vs chemorads alone What if N2 nodes cleared? Targeted agents? RTOG 0839: Randomized phase II study of chemorads +/- panitumumab followed by consolidation chemotherapy in potentially operable locally advanced (stage IIIA, N2+) NSCLC EGFR antibody Induction chemorads with carbo/pac + 60Gy, randomized to panitumumab or not, then surgery if operable, then consolidation carbo/pac Take home points Thank you! Randomized data lacking, no consensus INT0139 suggests patient selection is key Nodal clearance Avoidance of pneumonectomy Nonbulky disease Await Swiss trial final results, but concurrent treatment may be superior Integration of targeted therapies needs to be studied As always, multimodality collaboration key to success 6