Innovation in 2 nd line treatment of NSCLC

Innovation in 2 nd line treatment of NSCLC Multi-target agents and angiogenesis Roberto Bianco Laboratori di Terapia Molecolare dei Tumori Università di Napoli “Federico II”

New drugs for the 2° line. The outline……. • Blocking the RAS/MEK signaling • Antibodies against the VEGF pathway • Multitarget agents • Combination therapies

• Blocking the RAS/MEK signaling • Antibodies against the VEGF pathway • Multitarget agents • Combination therapies

Selumetinib SELUMETINIB • Potent, highly selective MEK 1 inhibitor with IC 50 of 14 n. M in cellfree assays • Also inhibits ERK 1/2 phosphorylation with IC 50 of 10 n. M • No inhibition to p 38α, MKK 6, EGFR, Erb. B 2, ERK 2, B-Raf

Selumetinib plus docetaxel for KRAS-mutant advanced NSCLC: a randomized, multicentre, placebo-controlled phase II trial Selumetinib 75 mg tw/die Patients: NSCLC (IIIB–IV) 2 nd line patients KRAS mutant 87 pz + Docetaxel 75 mg/m 2 q 21 1: 1 randomisation Placebo + Docetaxel 75 mg/m 2 q 21 Primary • Overall Survival Secondary • Progression Free Survival • Objective Response Rate • Duration of Response • Use of plasma & serum as source of CFDNA for analysis of KRAS mutation status • Investigate PK of selumetinib Janne P, Lancet Oncol. 2013

Selumetinib plus docetaxel for KRAS-mutant advanced NSCLC: a randomized, multicentre, placebo-controlled phase II trial Median OS: 9· 4 months vs 5· 2 months Median PFS: 5· 3 months vs 2· 1 months Janne P, Lancet Oncol. 2013

SELumetinib Evaluation as Combination Therapy-1 (SELECT-1): Selumetinib plus docetaxel for KRAS-mutant advanced NSCLC: a randomized, multicentre, placebo-controlled phase III trial Selumetinib 75 mg tw/die Patients: NSCLC (IIIB–IV) 2 nd line patients KRAS mutant WHO PS 0– 1 634 pz + Docetaxel 75 mg/m 2 q 21 1: 1 randomisation Placebo + Docetaxel 75 mg/m 2 q 21 Recruitment ended: 12/2015 Primary • PFS Secondary • OS • Objective Response Rate • Duration of Response • Symptom improvement rate • Safety and tolerability • Pharmacokinetics

• Blocking the RAS/MEK signaling • Antibodies against the VEGF pathway • Multitarget agents • Combination therapies

Tumor angiogenesis play a relevant role in lung cancer growth and progression Gene Methylation HYPERPLASIA Mutations DYSPLASIA Translocations CARCINOMA INVASIVE CARCINOMA Limitless potential for replication Cellular proliferation through independent growth signaling Promotion of survival signals and evasion of apoptosis Vascular recruitment and endothelial cell growth Bronchial Epithelium Tissue invasion and metastasis Adapted from Weinberg RA. Sci Am. 1996; 275: 62 -70.

Single-arm phase II NCCTG/SWOG study N 0426: pemetrexed and bevacizumab Primary end-point not meet: NEGATIVE TRIAL! Adjei et al JCO 2010

Phase II study of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone Large phase III trial (ULTIMATE) in now ongoing: docetaxel + bevacizumab vs docetaxel in 2° line therapy Herst et al JCO 2017

Aflibercept + Docetaxel vs Docetaxel in 2 nd line therapy: randomized, controlled phase III Trial (VITAL) Aflibercept 6 mg/kg d 1 + Docetaxel 75 mg/m 2 q 21 Patients: NSCLC (IIIB–IV) 2 nd line patients 913 pz 1: 1 randomisation Placebo + Docetaxel 75 mg/m 2 q 21 Primary • OS Secondary • PFS • Objective Response Rate • Qo. L

Aflibercept + Docetaxel vs Docetaxel in 2 nd line therapy: randomized, controlled phase III Trial (VITAL) Median OS: 10. 1 m vs 10. 4 m (HR 1. 01, p=0. 9) Median PFS: 5. 2 m vs 4. 3 m (HR 0. 82, p=0. 0035) ORR: 23. 3% vs 8. 9% (p=0. 001) Ramlau et al, JCO 2012

Ramucirumab (IMC-1121 B), a fully human Ig. G 1 monoclonal antibody, targets VEGFR 2 VEGF- B 167 VEGF- B 186 Pl. GF- 1, 2 VEGF- A 121 VEGF- A 145 VEGF- A 165 VEGF- A 189 VEGF- A 206 VEGF- C VEGF- D s-s VEGFR 1 (Flt-1) NRP-1 VEGFR 2 (Flk-1/KDR) s-s VEGFR 3 (Flt-4) NRP-2 Ramucirumab Vasculogenesis Angiogenesis Lymphangiogenesis www. researchvegf. com Youssoufian H, Hicklin DJ, Rowinsky EK. Review: monoclonal antibodies to the vascular endothelial growth factor receptor-2 in cancer therapy. Clin Cancer Res. 2007 Sep 15; 13(18 Pt 2): 5544 s-5548 s.

Studies of ramucirumab in NSCLC Study ID NCT 00735696 Ph Eligibility/Line II Stage IIIB or IV (AJCC 6 th ed. ), first line NCT 01160744 II Stage IV , first line NCT 01168973 III Stage IV, second line Arm(s) N (projected) Ramucirumab + paclitaxel + carboplatin 40 Ramucirumab + Premetrexed + Carboplatin or Cisplatin Ramucirumab + Gemcitabine + Carboplatin or Cisplatin 280 Docetaxel + Ramucirumab Docetaxel + Placebo 1156

NCT 00735696 - Phase 2 study in NSCLC (1 st-line: Ramucirumab + paclitaxel/carboplatin) PFS: 7. 85 mo OS: 16. 85 mo Camidge et al, JTO 2014

NCT 01160744 - Phase 2, randomized, study in NSCLC (1 st-line: Pemetrexed/platinum +/- Ramucirumab) Doebele et al, Cancer 2015

NCT 01160744 - Phase 2, randomized, study in NSCLC (1 st-line: Pemetrexed/platinum +/- Ramucirumab) Doebele et al, Cancer 2015

REVEL: Randomized Phase 3 Study in NSCLC 2 nd line: Docetaxel +/- Ramucirumab 1: 1 - Stage IV NSCLC after one platinumbased chemo +/maintenance - Prior Bev allowed - All histologies - PS 0 or 1 R A N D O M I Z E Stratification factors: • • ECOG PS 0 vs 1 Gender Prior maintenance East-Asia vs. ROW Ramucirumab 10 mg/kg + Docetaxel 75 mg/m 2 q 3 wks N=628 Placebo + Docetaxel 75 mg/m 2 q 3 wks N=625 Treatment until disease progression or unacceptable toxicity Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes Abbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; PFS=progression-free survival; ROW=rest of the world; q 3 wks=every 3 weeks. Garon et al, The Lancet 2014

REVEL: Patient Disposition Screened (N=1825) Excluded (n=572) Randomized (ITT) Population N=1253 RAM+DOC (N=628) Patients not receiving treatment (n=4) wt 33% mutant 2. 4% unknown 64% RAM+DOC (N=627)* 31% PL+DOC (N=625) Patients not receiving treatment (n=4) PL+DOC (N=618)* Safety Population N=1245 Reasons for discontinuation (N=613) PD 341 Adverse event 94 Subject decision 90 Investigator decision 37 Death due to adverse events 30 Death from study disease 12 Other 9 Reasons for discontinuation (N=611) PD 429 Adverse event 55 Subject decision 53 Investigator decision 19 Death due to adverse events 31 Death from study disease 14 Other 10 On treatment at data cutoff N=11 On treatment at data cutoff N=10 *Three PL+DOC arm patients were inadvertently treated with RAM and are therefore considered part of the RAM+DOC arm for the safety analyses, but the PL+DOC arm for the ITT efficacy analysis. Garon et al, The Lancet 2014

REVEL: Tumor Response by RECIST v 1. 1 ITT Population, Investigator Assessment RAM+DOC N=628 PL+DOC N=625 3 (0. 5) 141 (22. 5) 258 (41. 1) 128 (20. 4) 98 (15. 6) 2 (0. 3) 83 (13. 3) 244 (39. 0) 206 (33. 0) 90 (14. 4) P-value Response, n (%) CR PR SD PD Unknown/not assessed ORR (CR+PR), % (95% CI) 22. 9 (19. 7 -26. 4) 13. 6 (11. 0 -16. 5) <. 001 DCR (CR+PR+SD), % (95% CI) 64. 0 (60. 1 -67. 8) 52. 6 (48. 6 -56. 6 ) <. 001 Abbreviations: CI=confidence interval; CR=complete response; DCR=disease control rate; ITT=intention-to-treat; ORR=objective response rate; PD=progressive disease; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease. Garon et al, The Lancet 2014

REVEL: Progression-Free Survival ITT Population, Investigator Assessment Progression-Free Survival (%) 100 Median (95% CI) Censoring Rate RAM+DOC 4. 5 (4. 2 -5. 4) 11. 1% PL+DOC 3. 0 (2. 8 -3. 9) 6. 7% RAM+DOC vs PL+DOC: Stratified HR (95% CI) = 0. 762 (0. 677 -0. 859) Stratified log-rank P <. 0001 80 60 40 20 RAM+DOC PL+DOC 0 0 3 6 9 12 15 18 21 24 27 30 33 36 7 4 3 3 3 2 0 0 0 Survival Time (months) Number at risk RAM+DOC PL+DOC 628 625 383 301 204 172 120 95 59 37 38 17 11 9 Garon et al, The Lancet 2014

REVEL: Overall Survival ITT Population 100 RAM+DOC PL+DOC Overall Survival (%) 80 Median (95% CI) Censoring Rate 10. 5 (9. 5 -11. 2) 31. 8% 9. 1 (8. 4 -10. 0) 27. 0% RAM+DOC vs PL+DOC: Stratified HR (95% CI) = 0. 857 (0. 751 -0. 979) Stratified log-rank P =. 0235 60 40 20 RAM+DOC PL+DOC 0 0 3 6 9 12 15 18 21 24 27 30 33 36 45 36 23 23 11 9 2 0 0 0 Survival Time (months) Number at risk RAM+DOC 628 PL+DOC 625 527 501 415 386 329 306 231 197 156 129 103 86 70 56

REVEL: Adverse events

• Blocking the RAS/MEK signaling • Antibodies against the VEGF pathway • Multitarget agents • Combination therapies

Combination chemotherapy with targeted therapy versus chemotherapy alone in second-line

Vandetanib + docetaxel vs docetaxel as 2° line (ZODIAC): a double-blind, randomised, phase 3 trial Vandetanib 100 mg/die + Patients: NSCLC (IIIB–IV) 2 nd line patients 1391 pz Docetaxel 75 mg/m 2 q 21 1: 1 randomisation Primary • PFS Secondary • OS • Objective Response Rate • Duration of Response Placebo + Docetaxel 75 mg/m 2 q 21 Herbst et al, Lancet 2010

Vandetanib + docetaxel vs docetaxel as 2° line (ZODIAC): a double-blind, randomised, phase 3 trial Herbst et al, Lancet 2010

Nintedanib: multitarget antiangiogenic TKI § Oral angiokinase inhibitor targeting VEGFR 1 -3, FGFR 1 -3, and PDGFR α/β as well as RET[1, 2] § Manageable safety profile in combination with – Docetaxel[3] – Pemetrexed[4] – Paclitaxel/carboplatin[5] – Gemcitabine/cisplatin[6] – Afatinib[7] § Single-agent nintedanib active in a phase II trial in recurrent NSCLC[8] 1. Hilberg F, et al. Cancer Res. 2008; 68: 4774 -4778. 2. Data on file. 3. Stopfer P, et al. Xenobiotica. 2011; 41: 297 -311. 4. Bousquet G, et al. Br J Cancer. 2011; 105: 1640 -1645. 5. Ellis PM, et al. Clin Cancer Res. 2010; 16: 2881 -2889. 6. Doebele RC, et al. Ann Oncol. 2012; 23: 2094 -2102. 7. Soria JC, et al. Ann Oncol. 2012; 23(suppl 9): Abstract 979. 8. Reck M, et al. Ann Oncol. 2011; 22: 1374 -1381. Used with permission.

LUME-Lung 1 Study Design Stage IIIB/IV or recurrent NSCLC patients after 1 st line chemotherapy (all histologies) R A N D O M I Z E N=1314 Stratification: Nintedanib 200 mg BID p. o. , D 2– 21, + Docetaxel 75 mg/m 2 IV, D 1, 21 -day cycles (n=655) PD Placebo BID p. o. , D 2– 21, + Docetaxel 75 mg/m 2 IV, D 1, 21 -day cycles (n=659) PD 1: 1 Number of docetaxel cycles not restricted Monotherapy allowed after ≥ 4 cycles of combination therapy ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (squamous vs nonsquamous) Brain metastases (yes vs no) Primary end point: PFS Next analysis step only allowed if PFS confirmed with all PFS events at time point of OS analysis Reck M et al, Lancet Oncol 2014

LUME 1: PFS 3. 4 mo vs 2. 7 mo TOTAL population HR 0· 79 [95% CI 0· 68– 0· 92], p=0· 0019 ADENOCARCINOMA 3. 7 mo vs 2. 7 mo HR 0· 77 [95% CI 0· 62– 0· 96], p=0· 0193 SQUAMOUS CARCINOMA 3. 0 mo vs 2. 5 mo HR 0· 77 [95% CI 0· 62– 0· 96], p=0· 020 Reck M et al, Lancet Oncol 2014

LUME 1: OS Adenocarcinoma <9 mo 10. 9 mo vs 7. 9 mo HR 0· 75 [95% CI 0· 60– 0· 92], p=0· 0073 12. 6 mo vs 10. 3 mo ADENOCARCINOMA HR 0· 83 [95% CI 0· 70– 0· 99], p=0· 0359 Total population 10. 1 mo vs 9. 1 mo HR 0· 94 [95% CI 0· 83– 1· 05], p=0· 272 Reck M et al, Lancet Oncol 2014

Effect of treatment on survival in subgroups by baseline characteristics in patients with adenocarcinoma histology PFS OS Reck M et al, Lancet Oncol 2014

Confirmed best tumor response and disease control Reck M et al, Lancet Oncol 2014

LUME 1: Safety Reck M et al, Lancet Oncol 2014

LUME-1: conclusions • Second-line combination therapy with nintedanib and docetaxel significantly improved PFS vs docetaxel alone in patients with NSCLC independent of disease histology • Addition of nintedanib to docetaxel also significantly improved OS vs docetaxel in patients with adenocarcinoma • Safety profile of nintedanib in combination with docetaxel was manageable, with no unexpected safety signals

• Blocking the RAS/MEK signaling • Antibodies against the VEGF pathway • Multitarget agents • Combination therapies

Combination therapy with targeted anti-angiogenic agents in second-line NSCLC

Overview of Current Second-line Treatment § Numerous factors involved in choice of treatment – Previous therapy – Histology – Performance status – Organ function § Ramucirumab + Docetaxel better than Docetaxel alone in all histologies § Nintedanib + Docetaxel better than Docetaxel alone in adenocarcinoma