Activity and safety of the combination of lurbinectedin (PM1183) and 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 , 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 (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, -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 patients* Evaluable

Evaluable patients* Evaluable 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)