Le strategie di sequenza. polmonare nell era biologico. Division of Medical Oncology, S.G. MOSCATI HOSPITAL, AVELLINO - ITALY

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1 Le strategie di sequenza terapeutica nella neoplasia polmonare nell era biologico molecolare Antonio ROSSI, MD Division of Medical Oncology, S.G. MOSCATI HOSPITAL, AVELLINO - ITALY

2 Dr. Antonio Rossi In ottemperanza alla normativa ECM ed al principio di trasparenza delle fonti di finanziamento a e dei rapporti con soggetti portatori di interessi ess commerciali c in campo sanitario, si informano i discenti che negli ultimi due anni si sono avuti i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: Eli Lilly AstraZeneca Boehringer Ingelheim Roche

3 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab Squamous PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Gemcitabine Paclitaxel Vinorelbine Docetaxel 1st line

4 1 st Line Platinum Based CT in A NSCLC Efficacy Plateau Overall surv vival % Pacli + carbo (PCb) Cis + vin (CV) Months 30 Overall su rvival Pacli + cis (PC) Gem + cis (GC) Doc + cis (DC) Pacli + carbo (PCb) Months Overall su urvival Pacli + carbo (PCb) Gem + cis (GC) Cis + vin (CV) Months 30 Stud y arm OS (mo) 1 year (%) Study arm OS (mo) 1 year (%) Study arm OS (mo) 1 year (%) PCb PC PCb CV GC GC DC PCb CV K Kelly et al, JCO 2001 J Schiller et al, NEJM2002 GV Scagliotti et al, JCO 2002 OS, overall survival

5 Retrospective Analyses by Histology ECOG 1594 ILCP Hoang et al, Lung Cancer 2013 Scagliotti et al, J Thorac Oncol 2009

6 JMDB Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC No difference in OS or PFS between study arms Cis/Pem improves OS over cis/gem in non SCCA (HR: 0.81; P =.005) Cis/Gem improves OS over cis/pem in SCCA (HR: 1.23; P =.05) Survival Prob bability Probability Survival Probability Survival CP CG 0.6 CP vs CG Median (95% CI) 10.3 ( ) 10.3 ( ) Adjusted HR (95% CI) 0.94 ( ) Survival Time (Mos) in All Patients 1.0 Median (95% CI) 0.8 CP 11.8 ( ) CG 10.4 ( ) 0.6 CP vs CG Adjusted HR (95% CI) ( ) Survival Time (Mos) in Patients With Nonsquamous Histology CP CG 0.6 CP vs CG Survival Time (Mos) in Patients With Squamous Histology Median (95% CI) 9.4 ( ) 10.8 ( ) Adjusted HR (95% CI) 1.23 ( ) Scagliotti et al. J Clin Oncol 2008

7 Phase III nab P/C vs P/C: ORR & OS by Histology Percent Respon nses 50% 40% 30% 20% 10% Squamous Nonsquamous nab-p/c n = 228 n = 221 n = 292 n = 310 Nab P/C P < P = P = P = % 37% 37% 30% 29% 26% 24% 25% P/C 0% Independent Investigator Independent Investigator Radiologic Radiologic Assessment Assessment Radiologic Radiologic Assessment Assessment Review Review Review Review Carboplatin/ Carboplatin/ paclitaxel nab paclitaxel Hazard Overall Survival (n = 221) (n = 229) ratio p value Squamous 9.5 months 10.7 months * Socinski et al. Ann Oncol 2013

8 Nab-Paclitaxel and squamous histology? Desai et al, Translational Oncology 2009

9 Squamous NSCLC histology No prior treatment Stage III-IV not amenable of regional therapy ECOG PS 0-1 R N = 60 A Gemcitabine 1,250 mg/m2, day 1 & 8 N Carboplatin AUC 5, day 1 Q3W D O M I Z E No prior treatment Up to 6 cycles NCT N = 60 Nab Paclitaxel 135 mg/m2, day 1 & 8 Carboplatin AUC 5, day 1 Q3W Primary endpoint: ORR Secondary endpoints: PFS, OS, Safety, biomarker parameters (SPARC, caveolin 1)

10 NCT

11 Survival outcomes in unselected patients with advanced squamousnsclc Survival BSC (1) Old drugs (2) Third generation drugs (3) Median (months) year Survival (%) year Survival (%) 0 < NSCLC Meta Analyses Collaborative Group J Clin Oncol Delbaldo C, et al. JAMA Schiller JH, et al. N Engl J Med 2002

12 SQUIRE trial Necitumumab phase III trial in 1st line SCC NSCLC Screening Entry criteria: Stage IV squamous NSCLC 4,5 R Gem-Cis + Neci q3w (N = 545) Necitumumab (800 mg D1, D8) Gemcitabine (1250 mg/m², D1, D8) Cisplatin (75 mg/m², D1) 1 Maximum of 6 cycles 1 Gem-Cis q3w (N = 548) ECOG PS 0-2 Gemcitabine (1250 mg/m², D1, D8) Cisplatin (75 mg/m², D1) PR CR SD PD Neci q3w (800 mg D1, D8) PD PD Randomization (R) stratified by: ECOG PS (0-1 vs. 2) and geographic region (North America, Europe and Australia; vs. South America, South Africa and India; vs. Eastern Asia) Patient selection not based on EGFR protein expression Radiographic tumor asessment (investigator read) was carried out at baseline and every 6 weeks until PD Tissue collection was mandatory Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety Exploratory endpoint: EGFR expression (IHC, H-score) Thatcher et al, Lancet Oncol 2015

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14 SQUIRE vs. FLEX Toxicity

15 2015 Advanced NSCLC treatment algorithm PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities PS-comorbidities Squamous Non-squamous Histology EGFR status Eligible for bevacizumab Not eligible bevacizumab Mut. EGFR /undetermined Gemcitabine Paclitaxel Vinorelbine Docetaxel Pemetrexed Followed by Maintenance Pemetrexed 1st line

16 Stage IIIB/IV NSCLC PS 0-1 No prior chemo R Randomization: gender, PS, stage, histo vs cyto dx, brain mets JMDB: Study Design Pemetrexed 500 mg/m 2 + Cisplatin 75 mg/m 2 day 1 Primary objective: Overall Survival 15% Non-inferiority margin (HR 1.17) N = 1700 Patients, Power 80% Gemcitabine 1250 mg/m 2 + Cisplatin 75 mg/m 2 day 1; Gemcitabine 1250 mg/m 2 day 8 Scagliotti GV et al JCO 2008 Induction Therapy (4 cycles) PARAMOUNT: Study Design Maintenance Therapy (Until PD) Patients t enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d1, q21d CR, PR, SD 500 mg/m 2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Placebo + BSC, d1, q21d Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) PD Paz Ares L et al, Lancet Oncol 2012

17 PARAMOUNT Trial: ITT population Chemonaïve advanced NON SQUAMOUS NSCLC n=939 4 cycles of 1st line CDDP+PEM Non PD randomized pts n=539 Pemetrexed 500 mg/m 2 2:1 randomization PD Placebo PD Progression Free Survival Overall Survival Paz Ares L, et al J Clin Oncol 2013

18 PARAMOUNT Trial: OS outcomes CR/PR HR: 0.81 SD HR: 0.76 Paz Ares L, et al J Clin Oncol 2013

19 Survival outcomes in patients with advanced non squamous NSCLC and not selected for biological biomarkers Survival BSC (1) Old drugs (2) Third PEM- and generation BEVA-based* drugs (3) (4, 5) PEM continuation maintenance (6, 7) Median (months) year Survival (%) year Survival (%) 0 < NSCLC Meta Analyses Collaborative Group J Clin Oncol Delbaldo C, et al. JAMA Schiller JH, et al. N EnglJ Med Sandler A, et al. N Engl J Med Scagliotti GV, et al J Clin Oncol Paz Ares L, et al. Lancet Oncol Paz Ares L, et al. J clin Oncol 2013

20 2015 Advanced NSCLC treatment algorithm PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities PS-comorbidities Squamous Non-squamous Histology EGFR status Eligible for bevacizumab Not eligible bevacizumab Mut. EGFR /undetermined Eligible bevacizumab Gemcitabine Paclitaxel Vinorelbine Docetaxel Pemetrexed Followed by Maintenance Pemetrexed Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab 1st line

21 Bevacizumab in NSCLC E4599 trial design 1 Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) CP x 6 (n=444) PD* Avastin (15mg/kg) Avastin every 3 weeks + CP x 6 (n=434) PD AVAiL trial design 2 Placebo + CG x 6 (n=347) PD* Previously untreated, stage IIIB, IV or recurrent nonsquamous NSCLC (n=1,043) Avastin (15mg/kg) every 3 weeks + CG x 6 (n=351) Avastin PD *No cross over permitted CP=carboplatin + paclitaxel CG=cisplatin + gemcitabine PD=progression of disease Avastin (7.5mg/kg) every 3 weeks + CG x 6 (n=345) Avastin PD 1. Sandler, et al. N Engl J Med 2006;355: Reck, et al. J Clin Oncol 2009;27:

22 Bevacizumab in Non-squamous NSCLC Key Results ECOG 4599 AVAIL PCB PC CGB (7.5) CGB (15) CG RR 35% 15% 34.1% 30.4% 20.1% p-value <0.001 < (7.5) (15) PFS (m) HR / p-value 0.66 (<0.001) 0.75 (0.003) / (0.03) / 15 OS (m) HR / p-value 0.79 (0.003) 0.93 (ns) / (ns) / 15 Sandler, et al. N Engl J Med 2006;355: Reck, et al. J Clin Oncol 2009;27: Reck, et al Ann Oncol 2010

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24 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab Squamous PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Gemcitabine Paclitaxel Vinorelbine Docetaxel Pemetrexed Followed by Maintenance Pemetrexed Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib 1st line

25 I nuovi TKI a confronto: caratteristiche, opzioni di scelta, critiche

26 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab Squamous Gemcitabine Paclitaxel Vinorelbine Docetaxel PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Pemetrexed Followed by Maintenance Pemetrexed Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib Mut. EGFR /undetermined 3rd generation single agent according to histology or adapted doublet 1st line

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28 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab PS-comorbidities Squamous Gemcitabine Paclitaxel Vinorelbine Docetaxel PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Pemetrexed Followed by Maintenance Pemetrexed Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib Mut. EGFR /undetermined 3rd generation single agent according to histology or adapted doublet Progression Progression Progression Progression 1st line Histology Trasl. ALK + Trasl. ALK - EGFR status Ci Crizotinib ib ALK status 2nd line

29 I nuovi TKI a confronto: caratteristiche, opzioni di scelta, critiche

30 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab PS-comorbidities Squamous Gemcitabine Paclitaxel Vinorelbine Docetaxel PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Pemetrexed Followed by Maintenance Pemetrexed Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib Mut. EGFR /undetermined 3rd generation single agent according to histology or adapted doublet Progression Progression Progression Progression 1st line Histology Trasl. ALK + Trasl. ALK - EGFR status Ci Crizotinib ib ALK status Pemetrexed d( (non-squam.) Docetaxel Erlotinib 2nd line

31 Second Line Therapy: Grade 3/4 Toxicities Erlotinib [a] Pemetrexed [a,b] << Docetaxel [b] 40.2% Percent Reporting Adverse Event a. Vamvakas L, et al. Cancer. 2013;119: b. Hanna N, et al. J Clin Oncol. 2004;22:

32 Selecting Second Line Therapy in Unselected dnsclc Pti Patients t Patient Factors First Line Treatment History Tumor Characteristics Performance Status First line regimen Smoke Duration of Age response to firstline treatment Patient co morbidity Pti Patient tpreference Tolerability Tumor burden Histology Targetable alterations Erlotinib?

33 Nintedanib 200 mg BID p.o.,., D R + A Docetaxel 75 mg/m 2 IV, D1, q3wks Stage IIIB/IV or N N=655 recurrent NSCLC D t progression patients after 1 st line O 1:1 chemotherapy (All M I Placebo BID p.o.,., D histologies) Z + E Docetaxel l75 mg/m 2 IV, D1, q3wks N=659 N = 1314 Treatment until disease progression or unacceptable toxicity Stratification factors: ECOG PS 0 vs 1 Prior bevacizumab Histology (squamous vs non squamous) Brain metastases (yes or no) Primary endpoint: Progression Free Survival Secondary endpoints: OS, ORR, safety, patient reported outcomes

34 All histologies Adenocarcinoma Squamous Progression Free Survival Nintedanib/ Docetaxel (months) Placebo/ Docetaxel (months) HR p value ( ) ( ) p All histologies Adenocarcinoma Squamous

35 Adenocarcinoma 9 months within start of 1 st line All adenocarcinoma All histologies Overall Survival ADK 9 mos within 1 st line Nintedanib/ Docetaxel (months) Placebo/ Docetaxel (months) HR p value ( ) ( ) p Adenocarcinoma All histologies

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37 Nintedanib EMA Approval _Initial_authorisation/human/002569/WC pdf

38 1:1 Stage IV NSCLC after one platinum based chemo +/ maintenance Prior Bev allowed All histologies i PS 0 or 1 R A N D O M I Z E Ramucirumab b10 mg/kg + Docetaxel 75 mg/m 2 q3wks N=628 Placebo + Docetaxel 75 mg/m 2 q3wks N=625 Treatment until disease progression or unacceptable toxicity Stratification factors: ECOG PS 0 vs 1 Gender Prior maintenance East Asia vs. ROW Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient reported outcomes

39 (%) ment ee Survival igator Assessm ession-fre ulation, Investi Progre ITT pop RAM+DOC PL+DOC Censored Median (95% CI) Censoring Rate RAM+DOC 4.5 ( ) 11.1% PL+DOC 3.0 ( ) 6.7% RAM+DOC vs PL+DOC: Stratified HR (95% CI) = 0.76 ( ) Stratified log-rank P = Survival Time (months) Number at risk RAM+DOC PL+DOC

40 Overall Su urvival (%) ITT pop pulation RAM+DOC PL+DOC Censored Median (95% CI) Censoring Rate RAM+DOC 10.5 ( ) 31.8% PL+DOC 9.1 ( ) 27.0% RAM+DOC vs PL+DOC: Stratified HR (95% CI) = ( ) Stratified log rank P =.023 Number at risk RAM+DOC PL+DOC Survival Time (months)

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43 First anti-angiogenetic approved for squamous NSCLC

44 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab PS-comorbidities Squamous Gemcitabine Paclitaxel Vinorelbine Docetaxel PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Pemetrexed Followed by Maintenance Pemetrexed Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib Mut. EGFR /undetermined 3rd generation single agent according to histology or adapted doublet Progression Progression Progression Progression 1st line Histology Trasl. ALK + Trasl. ALK - EGFR status Ci Crizotinib ib ALK status Pemetrexed d( (non-squam.) Docetaxel Erlotinib Platinum-based CT 2nd line

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46 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab PS-comorbidities Squamous Gemcitabine Paclitaxel Vinorelbine Docetaxel PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Pemetrexed Followed by Maintenance Pemetrexed Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib Mut. EGFR /undetermined 3rd generation single agent according to histology or adapted doublet Progression Progression Progression Progression 1st line Histology Trasl. ALK + Trasl. ALK - EGFR status Ci Crizotinib ib ALK status Pemetrexed d( (non-squam.) Docetaxel Erlotinib Platinum-based CT 2nd line Progression Erlotinib 3rd line

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48 T-cell activation and therapeutic opportunities in lung cancers Anti-CTLA-4: Ipilimumab Tremelimumab Anti-PD-1 Nivolumab Pembrolizumab Anti-PD-L1 MPDL3280A MEDI4736 BMS Il futuro dell inibizione di PD 1 e PD L1 nella neoplasia polmonare non a piccole cellule LYMPH NODE Intlekofer & Thompson, JLB 2013

49 2015 Advanced NSCLC treatment algorithm PS-comorbidities Histology EGFR status Eligible for bevacizumab PS-comorbidities Squamous Gemcitabine Paclitaxel Vinorelbine Docetaxel PS 0-1 NSCLC PS 2; > 75 years comorbidities Stage IV co-morbidities Not eligible bevacizumab Pemetrexed Followed by Maintenance Pemetrexed Non-squamous Mut. EGFR Mut. EGFR + /undetermined Eligible bevacizumab Pemetrexed or Carboplatin + Paclitaxel + bevacizumab Followed by Maintenance Pemetrexed or Bevacizumab Gefitinib Erlotinib Afatinib Mut. EGFR /undetermined 3rd generation single agent according to histology or adapted doublet Progression Progression Progression Progression 1st line Histology Trasl. ALK + Trasl. ALK - EGFR status Ci Crizotinib ib ALK status Pemetrexed d( (non-squam.) Docetaxel Erlotinib Platinum-based CT 2nd line Progression Erlotinib 3rd line