Activity and safety of the combination of lurbinectedin (PM1183) and doxorubicin in relapsed SCLC. Final results of a phase Ib trial. Emiliano Calvo1, Martin Forster2, Víctor Moreno3, María Eugenia Olmedo4, María Pilar López Criado5, José Antonio López-Vilariño6, Carmen Kahatt6, Arturo Soto6. 1 START Madrid - HM CIOCC, Hospital Madrid Norte Sanchinarro, Madrid, Spain. 2 University College of London Hospital and UCL Cancer Institute, London, UK. 3 START Madrid – FJD (Hospital Fundación Jiménez Díaz), Madrid, Spain. 4 Hospital Ramon y Cajal, Madrid, Spain.5 M.D. Anderson Cancer Center, Madrid, Spain. 6 Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain. SLIDE 2 DISCLOSURE SLIDE PRESENTING AUTHOR MANDATORY • Lurbinectedin (Zepsyre®, PM1183) is a novel anticancer drug that inhibits activated transcription, induces DNA double-strand breaks generating apoptosis, and modulates tumor microenvironment. Inhibition of active transcription Generation of DNA breaks I- Binding of Lurbinectedin to the VII- Induction of apoptosis DNA Tumor Microenvironment Effect (Cytosine Guanine-rich motifs) Inhibition of Tumor Associated Macrophages (TAM) II- Phosphorylation of Pol II III- Stalling of elongating Pol II IV- Recruitment of the ubiquitin- proteasome machinery V- RNA Pol II degradation VI- Recruitment of XPF and Study design • Phase Ib 3+3 dose escalation and expansion a • Due to high G3/4 hematologic toxicity and FN • Selected diseases: observed in in cohort A o Metastatic Breast Cancer, EOC, Endometrial, HNSCC, HCC, GEP NET, SCLC, UKPS o The study was amended to reduce the DOX dose RD 2 • Less than 3 prior CHT lines for advanced by 20% (i.e., to 40 mg/m ) and transformed PM1183 4.0 mg FD to 2.0 mg/m2 q3wk disease. • Cohort B Doxorubicin 40mg/m2 + PM1183 2mg/m2 Treatment Schedule Day1 q3w and cont. with PM1183 4mg/m2 after • Cohort A Doxorubicin 50mg/m2 + PM1183 3- DOX cumulative dose of 450mg/m2 5 mg FD Day 1 q3w and cont. with PM1183 7mg FD after DOX cumulative dose of • This cohort included patients with SCLC and 450mg/m2 Endometrial cancer based in activity observed in Cohort A. – RD Doxorubicin 50mg/m2 + PM1183 4 mg FD Baseline Characteristics: SCLC 2nd line (n=48) Cohort A (n=21) Cohort B (n=27) Median age in years (range) 62 (48-73) 64 (49-77) Gender (M / F) 76% / 24% 75% / 25% ECOG PS (0 / 1) 43% / 57% 32% / 68% Median prior therapy lines (range) 1 (1-2*) 1 (1-2*) Previous PCI 43% 54% Known CNS involvement 33% 4% Visceral metastases 71% 68% Median number of metastatic sites (range) 3 (1-5) 3 (1-5) Bulky disease (>50 mm) 62% 75% Median CTFI in months (range) 3.1 (0.5-10.6) 3.4 (0-15.9) CTFI ≤ 3 months (Resistant) 48% 36% CTFI >3 months (Sensitive) 52% 64% Median TTP to 1st line platinum-based combination in months (range) 6.6 (1.2-13.6) 6.8 (1.4-18.9) CNS, central nervous system; CTFI, chemotherapy-free interval; ECOG PS, Eastern Cooperative Oncology Group performance status; F, female; M, male; PCI, prophylactic cranial irradiation; TTP, time-to-progression. * Prior nivolumab/atezolizumab 2 pts Activity observed in patients with SCLC 2nd line: Cohort A and B Objective responses in SCLC according to Chemotherapy-free interval (CTFI) RECIST (n=48) ≥90 days or < 90 days (sensitive vs resistant) Cohort A Cohort B Cohort A Cohort B (n=21) (n=27) (n=21) (N=27) ORR 1 (4%) ORR 10 (10%) 1 (6%) 67% 37% 2 (18%) 3 (30%) 9 (33%) 2 (20%) 2 (10%) ORR 8 (47%) 53% 3 (30%) ORR 12 (57%) 100% 10 (37%) 9 (82%) 7 (70%) Evaluable Evaluable patients* Evaluable Evaluable patients* 6 (35%) 4 (40%) 3 (14%) 7 (26%) 2 (12%) 4 (195) CTFI<90days CTFI>90days CTFI<90days CTFI>90days SCLC (2nd line) SCLC (27) (n=10) (n=11) (n=10) (n=17) PD SD PR CR Cohort A: Waterfall 3D plot PM1183-A-003-10, showing maximal Cohort B: Waterfall 3D plot PM1183-A-003-10 Cohort B, showing L+DOX tumor variation in size according EFFICACYto CTFI and PFS (n=21) maximal tumor variation in size according to CTFI and PFS (n=27) Response Cohort A Cohort B Evaluable patients (n=21) (n=27) CR 2 (10%) 1 (4%) PR RR:67% 12(57%)RR:37% 9 (33%) Median DOR:4.5mo Median DOR:5.2mo ORR 14 (67%) 10 (37%) SD 3 (14%) 9 (33%) PD 4 (19%) 8 (30%) DCR 17 (81%) 19 (70%) DOR (mo) 4.5 5.2 PFS (mo) CTFI >30d 4.7 5.3 PFS (mo) platinum sensitive 5.8 6.2 D, day; DCR, disease control rate; DOR, duration of response; FD, flat dose; mo, months; q3wk, every 3 weeks; +, ongoing. Safety: Cohort A Combination (n=21) Safety: Cohort B Combination (n=27) MyelosupressionToxicity byMost cycles Common AE MyelosupressionToxicity byMost cycles Common AE 2% 13% 5% 10% 17% 2% 19% 31% 6% 19%14% 35% 43% 7% 4% 14% 64% 17% 86% 47% 12% 6% 19% 24% 2%6% 19% 14% 43% 6% 29% 10% 24% 6% 5% 14% 7% 36% 5% 10% 43%0 5% 6% 2% 16% 8% 52% 14% 2% 1% 47% 13% 10% 10% 38%31% 6% 2% 7% 53% 2% 6% 21% 40% 2% 1% 13% 47% 4% 21% 1% 11% 38% 36%40% 6% 11% 33% 33% 34% 1%32% 32% 3% 13% 12% 29% 22% 29% 26% 26% 10% 24% 18% 24%1% 24% 19% 24% 12% 21% 23% 3% 1% 2% 1% 15% 6% 1% 14% 9% 9% 15% 15% 15% 14% 15% 13% 6% 6% 6% 6% 10% 6% 6% 8% 9% 10% 5% 2% 1% 2%1% GCSF 71%, Dose reduction 33% Dose delays 38% pts GCSF 43%, Dose reduction 21% Dose delays 39% pts Grade 1 Grade 2 Grade 3 Grade 4 Remarkable antitumor activity in terms or RR DOR and PFS was found for the doxorubicin/PM01183 combination in relapsed SCLC The q3wk doxorubicin/PM01183 combination showed a predictable and manageable safety profile. Reversible myelosuppression was the most common toxicity. Episodes of neutropenia, thrombocytopenia and febrile neutropenia were transient and successfully managed dose modification and CSF and does not hamper patients with clinical benefit to stay on treatment. Two studies ongoing: ATLANTIS: Phase III Randomized Clinical Trial of Lurbinectedin (PM1183)/Doxorubicin (DOX) versus Cyclophosphamide (Cy), Doxorubicin (DOX) and Vincristine (VCR) (CAV) or Topotecan as Treatment in Patients with Small-Cell Lung Cancer (SCLC) Who Failed One Prior Platinum-containing Line BASKET: Phase II Trial of PM1183 in Selected Solid Tumors: ORR 37% in 2nd line SCLC patients (Olmedo et al. ESMO 2017. Madrid).