1 st line chemotherapy and contribution of targeted agents in non-driver addicted NSCLC

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1 1 st line chemotherapy and contribution of targeted agents in non-driver addicted NSCLC Dr Ross Soo, FRACP National University Cancer Institute, Singapore National University Health System Cancer Science Institute, Singapore ESMO Preceptorship Programme, Non-small cell lung cancer, Singapore, November 2017

2 Disclosures Honorarium/ advisory board: Astra-Zeneca, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho Research funding: Astra-Zeneca

3 1 st line chemotherapy and contribution of targeted agents in non-driver addicted NSCLC Historical management Role of histology in treatment selection 1 st line management of nonsquamous NSCLC Anti-angiogenic agents ECOG 4599 EGFR inhibitors MoAb: FLEX, INSPIRE EGFR TKI: 1 st line & maintenance 1st line management of squamous NSCLC EGFR inhibitors SQUIRE

4 In the beginning role of 1 st line chemotherapy 2,714 patients,16 RCTs ESMO guidelines: Chemotherapy should be considered in all stage IV NSCLC patients with EGFR- and ALK-negative disease, without major co-morbidities and PS 0-2 Platinum-based doublets are the recommended option in all stage IV NSCLC patients with no contraindications to platinum compounds Chemotherapy improves OS vs BSC: HR 0.77 One-year OS: 29% from 20% NSCLC Meta-Analyses Collaborative Group. JCO 2008

5 Platinum doublet with 3 rd generation drugs ECOG1594 TAX 326 FACS: IP, TC, GP, NP Schiller NEJM 2002, Fossella JCO 2003, Ohe Ann Oncol 2008

6 Classification and subsequent treatment of NSCLC has evolved Molecular biomarkers in NSCLC- unknown drivers in large % cases Li T et al. J Clin Oncol 2013;31(8):

7 Differences between ADC vs SCC Squamous Adenocarcinoma Markers: CK7-ve/CK20-ve, TTF-1 ve, P63 or p40+ or CK5/6+ve More central location Higher incidence of locoregional recurrence Relatively more common in men, smokers Declining incidence overall, 20% No approved molecular targeted therapy Markers: CK7+/CK20-, TTF-1+ More peripheral Higher incidence of metastasis Increasing incidence; relatively more common in women Approved agents targeting EGFR, ALK, ROS1, BRAF,

8 Regional differences in prevalence of ADC NSCLC without Driver Mutations HER2 1% BRAF 2% PI3KCA 2% KRAS 33% France ALK 1% unknown 33% EGFR 12% full WT 16% HER2 3% ALK 5% MET 4% Japan MET 5% China KRAS 15% BRAF 1% unknown 22% EGFR 50% BRAF 2% KRAS 7% ALK 16% unknown 26% EGFR 44% Barlesi Lancet 2016, Mitsudomi Jpn J Clin Oncol 2010, Wu, Ann Oncol 2011

9 Histology as a biomarker No longer adequate to call NSCLC only Need to determine histologic subtypes: ADC or SCC Why? Different histologic subtype has impact on: Molecular subtypes and testing. In non-driver addicted NSCLC, histology can be used to guide selection chemotherapy choice and biologic therapy

10 Impact of histology as a biomarker on treatment selection: efficacy JMDB: Phase III cisplatin/gemcitabine vs cisplatin/ pemetrexed Cisplatin 75mg/m2 D1 + gemcitabine 1250mg/m2 D1, 8 Q3w x6 cycles (n=863) Stage 4, NSCLC Treatment naïve ECOG PS=0-1 N=1725 OS Safety Cisplatin 75mg/m2 D1 + pemetrexed 500mg/m2 D1 q3w x6 cycles (n=862) Scagliotti G, et al. J Clin Oncol 2008

11 Survival Probability Pemetrexed platinum and gemcitabine platinum have differential efficacy based on histology: JMDB CP CG 0.6 CP vs CG Survival Time (Mos) in All Patients Pemetrexed restricted to Non-Squamous Histology OS Nonsquamous in NSCLC Median (95% CI) 10.3 ( ) 10.3 ( ) Adjusted HR (95% CI) 0.94 ( ) Intention to treat (all histologies): no difference between CP and GC Squamous NSCLC OS in Squamous NSCLC Median (95% CI) 11.8 ( ) 10.4 ( ) Adjusted HR (95% CI) 0.81 ( ) P =.005 Median (95% CI) 9.4 ( ) 10.8 ( ) Adjusted HR (95% CI) 1.23 ( ) P = 0.05 Cisplatin/ Pem superior in non-scc Cisplatin/gemcitabine superior in SCC Scagliotti J Clin Oncol 2008

12 Impact of histology as a biomarker on treatment selection: toxicity Study Phase Treatment Outcome in SCC subgroup (HR, 95% CI) AVF0757g II CP+ bevacizumab Increased risk of pulmonary hemorrhage: 31% ESCAPE III CP+ Sorafenib vs CP PFS: 1.31 ( ) OS: 1.85 ( ) MONET-1 III CP+ AMG706 vs CP Enrolment of SCC discontinued: risk of hemoptysis and mortality Reference Johnson JCO 2004 Scagliotti JCO 2010 Scagliotti JCO 2012 Anti-angiogenic agents in lung squamous cell carcinoma: increased risk of pulmonary hemorrhage No overall survival benefit in SCC subset Increased risk of pulmonary hemorrhage Increased risk of mortality

13 Age, Performance status 1L treatment of advanced non-squamous NSCLC without driver oncogenes (NSCC) Treatment determined by age, performance status Age <70 PS 0-1 Age < 70, PS 2 Age >70, PS 0-2 PS 3-4 Platinum-doublet +/- bevacizumab Single-agent or Cb baseddoublet Best supportive care Maintenance: Pemetrexed (switch or continuation) Erlotinib (if EGFR+) Bevacizumab (if given previously First-line regimen options Cisplatin + pemetrexed Docetaxel + Cisplatin Paclitaxel + Carboplatin nab-paclitaxel + Carboplatin Gemcitabine + Cisplatin Vinorelbine + Cisplatin Single-agent: Gemcitabine Docetaxel Vinorelbine Maintenance options: Pemetrexed (switch or continuation) Erlotinib Bevacizumab (if given previously) Novello. Ann Oncol

14 Novello. Ann Oncol

15 nab-paclitaxel and Carboplatin in Advanced NSCLC ESMO Guidelines: Nab-PC regimen could be considered a chemotherapeutic option in advanced NSCLC patients, particularly in patients with: 1. greater risk of neurotoxicity, 2. pre-existing hypersensitivity to paclitaxel 3. or contraindications for standard paclitaxel premedication Socinski JCO 2012

16 Inhibition of angiogenesis via inhibition of the VEGF pathway Agents targeting the VEGF pathway Anti-VEGF antibodies Bevacizumab A recombinant, humanised, monoclonal VEGF antibody, P P P P VEGFR-1 VEGF P P Endothelial cell P P VEGFR-2 Soluble VEGF receptors (VEGF-Trap) Anti-VEGFR antibodies Small-molecule VEGFR inhibitors (Sorafenib, vandetanib Sunitinib, Cediranib Axitinib, ABT-869)

17 Addition of bevacizumab to chemotherapy: ECOG 4599 Paclitaxel + carboplatin + bevacizumab x6 cycles q3w Bevacizumab until PD, intolerable toxicity Stage 4, NSCLC Treatment naïve ECOG PS=0-1 N=878 OS Safety Paclitaxel + carboplatin q3w x6 cycles Sandler NEJM 2006

18 Overall survival (%) ECOG4599: addition bevacizumab to carboplatin/ paclitaxel improves OS Carboplatin / paclitaxel + bevacizumab Carboplatin / paclitaxel HR (95% CI) = 0.79 (0.67, 0.92), p=0.003 OS= 12.3 vs 10.3 months PFS: 6.2m vs 4.5m ORR: 35% vs 15% Time (months) Sandler NEJM 2006

19 1 st Bevacizumab+ chemotherapy in nonsq NSCLC E4599 AVAiL JO19907 BEYOND Outcome PCB PC GCB (7.5mg/kg) GCB (15mg/kg) GC PCB Placebo PCB PC ORR PFS HR 0.66* 0.75* 0.85* 0.61* 0.40* OS OS HR 0.79* * Significant p value

20 Meta-analysis of 1 st Bevacizumab+ chemotherapy OS PFS ESMO Guidelines: The combination of bevacizumab and other platinum-based chemotherapies may be considered in eligible patients with NSCC and PS 0-1 significant improvement in OS and PFS for the combination of bevacizumab and platinum-based chemotherapy Soria Ann Oncol 2013

21 Other issues Can I give it in the elderly? Is CNS mets a contraindication? Are there predictors for pulm hemorrhage?

22 Elderly Study Age cutoff Outcome Laskin SAiL (MO19390) 65 years OS benefit Leighl AVAiL 65 years OS benefit Zhu SEER 65 years No OS benefit Ramalingam E years No OS benefit, more AEs Langer E4599 and PointBreak 75 years No OS benefit, more AEs The survival benefit for bevacizumab added to chemotherapy seems limited to patients aged less than 75 years. Laskin JTO 2012, Leighl JTO 2010, Zhu JAMA 2012, Ramalingam JCO 2008, Langer Am J Clin Oncol. 2016, Gridelli Clin Lung Ca

23 CNS mets Besse Study Design Outcome retrospective exploratory analysis Socinski PASSPORT Phase II, prior treated CNS mets CNS metastases: risk of CNS bleed independent of bevacizumab No grade 2 cerebral hemorrhage was observed EMA removed label restriction on March 25, 2009, to allow patients with untreated CNS metastases to receive bevacizumab Lynch ARIES prospective observational safety profile similar to other studies Zhu SEER 65 years No OS benefit Besse CCR 2010, Socinski JCO 2009, Lynch JTO 2014

24 Predictors for pulm hemorrhage Reck Ann Oncol 2012

25 1 st line chemotherapy + VEGF receptor TKIs too high a mountain? Sorafenib (ESCAPE, NExUS) Motesanib (MONET 1) Cediranib (BR29) AMG-706 Axitinib ABT-869

26 Inhibition of the EGFR pathway is an attractive approach EGFR activation, downstream effects Proliferation Increased survival Angiogenesis Metastasis EGFR-directed monoclonal antibodies Cetuximab Chimeric IgG1 monoclonal Ab Necitumumab Recombinant human IgG1 monoclonal Ab Matuzumab, nimotuzumab, panitumumab EGFR TKI Inhibits kinase domain EGFR TKI MoAb

27 Phase III 1 st line chemotherapy + cetuximab in NSCLC (FLEX) Vinorelbine + CDDP+ cetuximab q3w x6 (n=557) SD, PR, CR Cetuximab D1, 8 q3w PD Stage IIIB/IV NSCLC EGFR chemonaive ECOG PS=0-2 N=1125 Vinorelbine + CDDP x6 q3w (n=568) PD OS PFS, ORR QOL, safety Pirker Lancet 2009

28 Overall survival: marginal benefit MS: 11 3 m vs 10 1m Pirker Lancet 2009

29 1 st line chemo+ cetuximab: a meta-analysis Phase N FLEX III 1125 BMS099 III 676 BMS100 II 131 LUCAS II 86 HR 0.88 ( ; p = 0.009) Pujol Lung Cancer 2014

30 Phase III 1 st line chemotherapy + necitumumab in ADC NSCLC (INSPIRE) Stage IV Non Sq NSCLC chemonaive ECOG PS=0-2 N=633 CDDP+ pemetrexed + Necitumumab q3w x6 (n=315) CDDP+ pemetrexed x6 q3w (n=318) SD, PR, CR Necitumumab D1, 8 q3w Primary endpoint OS Secondary endpoints PFS, ORR, TTF, QOL, safety, biomarkers PD PD Study closed early IDMC recommendation Paz-Ares Lancet Oncol 2015

31 Efficacy OS: HR 1 01 ( ) 11.3m vs 11.5m NEGATIVE STUDY PFS: HR 0 96 ( ), 5.6m vs 5.6m TTF: HR 1 18 ( ), 3.5m vs 4.3m ORR: 31% vs 32% EGFR H score >200 not predictive for outcomes Paz-Ares Lancet Oncol 2015

32 How about using 1 st line EGFR TKIs in unselected patients? Hypothesis: 1 st line erlotinib followed by CDDP/ Gem at progression is not inferior in terms of survival to the standard inverse sequence. In unselected patients, 1 st line erlotinib followed by chemotherapy is inferior to 1 st line chemotherapy followed by erlotinib Gridelli JCO Lung Cancer 2012

33 Maintenance EGFR TKIs in unselected patients Dr Egbert Smit Cappuzzo Lancet Oncol 2010, Takeda JCO 2010, Zhang Lancet Oncol 2012

34 Treatment options in advanced SCC NSCLC are limited: efficacy/ toxicity Squamous Non Squamous

35 1 st line treatment options in SCC NSCLC are limited: efficacy/ toxicity Squamous Non Squamous 1 st line Platinum doublet Nil pemetrexed Nil bevacizumab Platinum doublet incl pemetrexed Bevacizumab Erlotinib, gefitinib, afatinib Crizotinib, alectinib Maintenance Nil Pemetrexed

36 Age, Performance status 1L treatment of advanced Squamous NSCLC Treatment determined by age, performance status Platinum-doublet First-line regimen options Cisplatin + gemcitabine + necitumumab Docetaxel + Cisplatin Paclitaxel + Carboplatin nab-paclitaxel + Carboplatin Age <70 PS 0-1 CDDP/ Gem/ ESMO Guidelines: necitumumab (EGFR+ IHC) Gemcitabine + Cisplatin Platinum-based doublets with a third-generation cytotoxic Age >70, PS 0-2 PS 3-4 Vinorelbine + Cisplatin agent (gemcitabine, Age < 70, PS 2 Single-agent vinorelbine, Cb based- taxanes) Single-agent: are recommended doublet in advanced SCC patients. Best supportive care Gemcitabine Docetaxel Vinorelbine Novello. Ann Oncol 2016.

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38 Role EGFR inhibitors in SCC A potential signal...

39 FLEX subset: benefit in SCC histology Pirker Lancet 2009

40 Cetuximab meta-analysis: benefit in SCC histology Pujol Lung Cancer 2014

41 Phase III 1 st line Necitumumab in SCC (SQUIRE) Gemcitabine+ CDDP+ necitumumab q3w x6 (n=545) SD, PR, CR Necitumumab D1, 8 q3w PD Stage 4 Lung SCC chemonaive ECOG PS=0-2 Gemcitabine+ CDDP x6 q3w (n=548) PD OS PFS, ORR, safety EGFR protein expression Thatcher ASCO 2014

42 OS (%) Overall survival Pts censored, n (%) Median OS, mos (95% CI) Stratified P value (log rank) Stratified HR (95% CI) OS Cisplatin/ Gemcitabine + Necitumumab 127 (23) 11.5 ( ) ( ) Cisplatin/ Gemcitabine 106 (19) 9.9 ( ) ORR: 31.2% vs 28.8% (NS) DCR: 81.8% vs 77.0% (P =.04) PFS HR: 0.85 (P =.02) Exploratory EGFR H-score analysis: NS 20 Cisplatin/gemcitabine + necitumumab Cisplatin/gemcitabine Months Thatcher Lancet Oncol 2015

43 EGFR+ tumors benefit from necitumumab EGFR-ve (IHC): no benefit with necitumumab Paz-Ares Ann Oncol 2016

44 Thatcher Lancet Oncol 2015 Toxicities: more skin reactions

45 Toxicity Analysis Gem-Cis + Neci (N=538) % Chemotherapy phase Gem-Cis (N=541) % Monotherapy phase Neci (N=275) % ESMO guidelines: Necitumumab plus gemcitabine and cisplatin represents a treatment option for advanced SCC expressing EGFR by IHC Any AE Grade 3 AEs Serious AEs AEs leading to discontinuation of any study drug AEs with outcome of death* Treatment-related death** No significant increase in AEs, serious AEs, or fatal AEs with addition of Neci to Gem-Cis Thatcher Lancet Oncol 2015

46 Conclusions Non-squamous NSCLC: Doublet chemotherapy ± bevacizumab Carboplatin based doublet, monotherapy Maintenance erlotinib not recommended for WT EGFR Squamous NSCLC Platinum-based doublets with a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) Necitumumab plus gemcitabine and cisplatin (EGFR+ve by IHC) Carboplatin based doublet, monotherapy Developing novel therapeutic agents (immune checkpoint inhibitors) Identifying biomarkers in oncogene WT NSCLC