EFFICACY AND SAFETY PROFILE OF LURBINECTEDIN IN SECOND-LINE SCLC PATIENTS: Results from a phase II single-agent trial Paz Ares L.1;Trigo JM.2; Besse B.3; Moreno V.4; Lopez R.5; Sala MA.6; Ponce S.1; Fernandez C.7; Siguero M.7; Kahatt C.7; Zeaiter A.7; Zaman K.8; Boni V.9; Arrondeau J.10; Martinez M.11; Delord JP.12; Awada A.13; Kristeleit R.14; Olmedo ME.15; Subbiah V. 16 Hospital Universitario 12 de Octubre, CNIO, Universidad Complutense & Ciberonc, Madrid, Spain1; Hospital Universitario Virgen de la Victoria, Málaga, Spain2; Gustave Roussy Cancer Campus, Villejuif, France3; Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain4; Hospital Clínico Universitario de Santiago de Compostela, Santiago De Compostela, Spain5; Hospital Universitario de Basurto, Bilbao, Spain6; PharmaMar, Colmenar Viejo, Spain7; University Hospital CHUV, Lausanne, Switzerland8; START Madrid-CIOCC, Hospital Universitario Sanchinarro, Madrid, Spain9; Hôpital Cochin, Paris, France10; Complejo Hospitalario de Navarra, Pamplona, Spain11; Institut Claudius Regaud, Toulousse, France12; Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium13; UCL Cancer Institute, London, United Kingdom14; Hospital Universitario Ramón y Cajal , Madrid, Spain15; Md. Anderson Cancer Center, Houston, USA16 Dr. Luis Paz Ares Disclosure Honoraria (self/spouse)– Scientific advice, speaker: Lilly, MSD, BMS, Roche, PharmaMar, Merck, Astra-Zeneca, Novartis, Boehringer, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint Board – Genómica Co-founder - Altum Sequencing Research grants to Institution – MSD, BMS, Astra-Zeneca, Pfizer Dr. Luis Paz Ares SCLC – A High Unmet Medical Need SCLC is an aggressive malignancy with a dismal prognosis; 5-year OS rate < 7% SCLC is a transcription-addicted tumor1. Recently four molecular SCLC subtypes have been described, defined by differential expression of four key transcription regulators2 Topotecan is the only FDA-approved treatment in 20 years in 2L SCLC, for platinum- sensitive disease Modest clinical benefit (ORR=5-24%; mOS=6-8 months) and significant hematological toxicity Lurbinectedin antitumor activity in SCLC was initially observed in a PhI/II study in combination with doxorubicin (ORR 37% and DoR 5.2 months)3 1 Christensen et al. Cancer Cell 2014; 2 Rudin et al. Nature 2019; 3 Forster et al. P1.12-20. IASLC 2018; 3 Dr. Luis Paz Ares Lurbinectedin - a Selective Inhibitor of Oncogenic Transcription CANCER IS FREQUENTLY A TRANSCRIPTIONAL BY INHIBITING ACTIVE TRANSCRIPTION IN TUMOR DISEASE CAUSED BY DEREGULATED ONCOGENIC ASSOCIATED MACROPHAGES (TAMS), LURBINECTEDIN TRANSCRIPTION FACTORS DOWNREGULATES IL-6, IL-8, CCL2 AND VEGF Transcription Factors Lurbinectedin SWI/SNF IL-6 VEGF IL-8 TAMs IL-8 SWI/SNF ARID1A ARID1A CCL2 Induction of Induction of Tumor IL-6 Cell Proliferation angiogenesis 5’-AGC-3’ DNA 5’-CGG-3’ 5’-TGG-3’ Inhibition of Immune Response 5’-AGG-3’ 5’-GGC-3’ Activation of Immune Checkpoints Harlow et al, 2016; Cancer Res 72: 6657-68 Harlow et al, 2019; Clin Cancer Res doi: 10.1158/1078-0432.CCR-18-3511 Promoter Santamaría et al, 2016. Mol Cancer Ther 15:2399-412 Belgiovine et al, 2017 Br J Cancer 117:628-38 Dr. Luis Paz Ares Lurbinectedin as Single Agent in Second Line SCLC: Phase II BASKET Trial PRIMARY OBJECTIVE : ORR by RECIST V.1.1 (confirmed responses) Statistical assumptions for SCLC cohort SCLC patients Null hypothesis : ≤15% get a response 2 Lurbinectedin 3.2 mg/m , 1h iv, q3wk (p ≤ 0.15) PS 0-2 Alternative hypothesis: One prior chemotherapy line ≥ 2 Enroll up to ≥30% get a response responses Prior immunotherapy was 100 patients (p ≥ 0.30) allowed in first 15 patients* CNS mets excluded Statistical power 95% * 5 confirmed responses observed in the first 15 treated patients ≥ 23% of confirmed responses needed to reject the null hypothesis Data cut-off: January 15th 2019 Dr. Luis Paz Ares Patient Disposition Trial Recruitment - First patient in October 2015 - Last patient in October 2018 Total Patients Treated 105 - Still on treatment 11 - Treatment discontinued and in follow-up 25 - Deaths/Lost to follow up 66/3 Cycles Administered - Median (range) 4 (1-24) Median Follow up; months 17.1 - Median follow up for alive patients; months (range) 6.1 (1-33) Dr. Luis Paz Ares Patient Characteristics n=105 Age (years) Median (range) 60 (40-83) ≥ 65 years 35.2 % ≥ 75 years 6.7 % Gender Male/Female 60 %/40 % ECOG PS 0 36.2 % 1 56.2 % 2 7.6 % CNS* metastases History 3.8 % Liver metastases 41 % Prior lines of therapy Median (range) 1 (1-2) Prior Immunotherapy Single agent or in combination 7.6 % Response to prior CR 8.6 % Platinum-based therapy PR 66.7 % SD 18.1 % PD/UNK 3.8 %/2.9 % Chemotherapy Median, months (range) 3.5 (0-16.1) Free- Interval (CTFI) < 90 days (resistant) 43 % <30 days 20 % *Central Nervous System ≥ 90 days (sensitive) 57 % Dr. Luis Paz Ares Antitumor Activity Duration of Response (DoR) Overall (n=105) ORR, % 35.2 (95% CI) (26.2-45.2) Best response n (%) mDoRmDoR== 5.3 5.3 months months (95%(95% CI:4.1 CI:4.1-6.4)-6.4) - PR (confirmed) 37 (35.2) # - SD 35 (33.3) - PD 28 (26.7) - NE* (non- evaluable) 5 (4.8) Disease Control Rate,% 68.6 (95% CI) (58.8-77.3) # 5 of 8 patients who failed prior immunotherapy had confirmed response * Treatment discontinuation without any tumor assessment performed Dr. Luis Paz Ares Antitumor Activity According to Sensitive or Resistant Population Duration of Response (DoR) Resistant Sensitive CTFI< 90 days CTFI ≥ 90 days (n=45) (n=60) ORR, % 22.2 45.0 (95% CI) (11.2-37.1) (32.1-58.4) mDoRmDoR SensitiveSensitive Best response (confirmed) n (%) n (%) 6.26.2 months months (95% (95% CI CI 3.5 3.5-7.3)-7.3) Resistant - PR 10 (22.2) # 27 (45.0) # Resistant 4.74.7 months months (95% (95% CI CI 2.6 2.6-5.6-5.6) ) - SD 13 (28.9) 22 (36.7) - PD 18 (40.0) 10 (16.7) - NE* (non- evaluable) 4 (8.9) 1 (1.7) Disease Control Rate), % 51.1 81.7 (95% CI) (35.8-66.3) (69.6-90.5) # 3 of 5 patients with resistant disease and 2 of 3 patients with sensitive disease who failed prior immunotherapy had confirmed response * Treatment discontinuation without any tumor assessment performed Dr. Luis Paz Ares Decrease in Tumor Size Decrease in tumor size in 65% patients Dr. Luis Paz Ares Progression Free Survival: PFS mo PFS at 6 mo n median % (95% CI) (95% CI) 3.9 33.6 All 105 (2.6-4.6) (24.0-43.1) Dr. Luis Paz Ares Progression Free Survival: Sensitive and resistant SCLC populations PFS mo PFS at 6 mo n median % (95% CI) (95% CI) 3.9 33.6 All 105 (2.6-4.6) (24.0-43.1) Resistant 2.6 18.8 45 CTFI< 90d (1.3-3.9) (6.8-30.9) Sensitive 4.6 44.6 60 CTFI≥ 90d (3.0-6.5) (31.2-57.9) Dr. Luis Paz Ares PFS - Prior Treatment vs Lurbinectedin Sensitive disease (n=60) Resistant disease (n=45) PFS PFS PFS PFS Prior treatment Lurbinectedin Prior treatment Lurbinectedin Dr. Luis Paz Ares Overall Survival OS mo OS at 12 mo n median % (95% CI) (95% CI) 9.3 34.2 All 105 (6.3-11.8) (23.2-45.1) Median Follow-up= 17.1 months Dr. Luis Paz Ares Overall Survival: Sensitive and Resistant SCLC Populations OS mo OS at 12 mo n median % (95% CI) (95% CI) 9.3 34.2 All 105 (6.3-11.8) (23.2-45.1) Resistant 5.0 15.9 CTFI< 90d 45 (4.1-6.3) (3.6-28.2) Sensitive 11.9 48.3 60 CTFI≥ 90d (9.7-16.2) (32.5-64.1) Dr. Luis Paz Ares Safety and Tolerability: Related or Unknown Adverse Events (AE) n=105 n (%) AEs 89 (84.8) - Gr ≥3 36 (34.3) SAEs 11 (10.5) AEs leading to death 0 (0.0) AEs leading to treatment discontinuation 2 (1.9) Dose delays treatment related 21 (22.1*) Dose reductions # 25 (26.3*) G-CSF 23 (21.9) Transfusions (red blood cells and/or platelets) 10 (9.5) # Per protocol: dose had to be reduced in case of grade 4 neutropenia * Based on 95 patients who received ≥ 2 cycles of treatment Dr. Luis Paz Ares Treatment Related (or Unknown) Adverse Events (AEs) Events in >5% of patients or Gr 3-4 n=105 Gr 1-2 Gr 3-4 n (%) n (%) Neutropenia 6 (5.7) 24 (22.9) Hematological AEs * Anemia 2 (1.9) 7 (6.7) Thrombocytopenia 2 (1.9) 5 (4.8) Febrile neutropenia . 5 (4.8) Fatigue 54 (51.4) 7 (6.7) Nausea 34 (32.4) . Decreased appetite 22 (21.0) . Vomiting 19 (18.1) . Non-Hematological AEs Diarrhea 13 (12.4) 1 (1.0) Constipation 10 (9.5) . Pneumonia . 2 (1.9) Alanine aminotransferase increased * . 2 (1.9) Skin ulcer . 1 (1.0) * Lab abnormalities associated with a specific treatment, were considered a SAE, or were reasons for dose reduction or treatment delay Dr. Luis Paz Ares Conclusions Lurbinectedin is active as single-agent in second line SCLC (ORR: 35.2%; mOS : 9.3 months) Antitumor activity is notable in Sensitive disease (ORR= 45.0%), as well as in Resistant disease (ORR: 22.2%) where no drugs are approved Lurbinectedin has a favorable and manageable safety profile, and is well-tolerated Most common related AEs are neutropenia, nausea/vomiting and fatigue Low percentage of treatment-related SAEs, discontinuation due to AEs and no toxic deaths Lurbinectedin emerges as a potential new treatment alternative for 2L SCLC Dr.