1. 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.

2. SLIDE 2
DISCLOSURE SLIDE
PRESENTING AUTHOR
MANDATORY

3. 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
I- Binding of Lurbinectedin to the DNA
(Cytosine Guanine-rich motifs)
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
Generation of DNA breaks
VII- Induction of apoptosis
Tumor Microenvironment Effect
Inhibition of Tumor Associated Macrophages (TAM)

4. Phase Ib 3+3 dose escalation and expansion a Selected diseases:
Study design
Phase Ib 3+3 dose escalation and expansion a
Selected diseases:
Metastatic Breast Cancer, EOC, Endometrial, HNSCC, HCC, GEP NET, SCLC, UKPS
Less than 3 prior CHT lines for advanced disease.
Treatment Schedule
Cohort A Doxorubicin 50mg/m2 + PM mg FD Day 1 q3w and cont. with PM1183 7mg FD after DOX cumulative dose of 450mg/m2
RD Doxorubicin 50mg/m2 + PM mg FD
Due to high G3/4 hematologic toxicity and FN observed in in cohort A
The study was amended to reduce the DOX dose RD by 20% (i.e., to 40 mg/m2) and transformed PM mg FD to 2.0 mg/m2 q3wk
Cohort B Doxorubicin 40mg/m2 + PM1183 2mg/m2 Day1 q3w and cont. with PM1183 4mg/m2 after DOX cumulative dose of 450mg/m2
This cohort included patients with SCLC and Endometrial cancer based in activity observed in Cohort A.

5. 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*)
Previous PCI
43%
54%
Known CNS involvement
33% 4%
Visceral metastases
71%
68%
Median number of metastatic sites (range)
3 (1-5)
Bulky disease (>50 mm)
62%
75%
Median CTFI in months (range)
3.1 ( )
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 ( )
6.8 ( )
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

6. Activity observed in patients with SCLC 2nd line: Cohort A and B
RECIST (n=48)
Objective responses in SCLC according to Chemotherapy-free interval (CTFI) ≥90 days or < 90 days (sensitive vs resistant)
Cohort A (n=21)
Cohort B
(n=27)
Cohort A
(n=21)
Cohort B
(N=27)
ORR
67%
ORR
37%
ORR 53%
PD SD PR CR

7. PFS (mo) platinum sensitive
Cohort A: Waterfall 3D plot PM1183-A , showing maximal tumor variation in size according to CTFI and PFS (n=21)
Cohort B: Waterfall 3D plot PM1183-A Cohort B, showing maximal tumor variation in size according to CTFI and PFS (n=27)
EFFICACY
Response
Evaluable patients
L+DOX
Cohort A
(n=21)
Cohort B
(n=27) CR
2 (10%)
1 (4%) PR
12(57%)
9 (33%)
ORR
14 (67%)
10 (37%) SD
3 (14%) 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.
RR:67%
Median DOR:4.5mo
RR:37%
Median DOR:5.2mo

8. Grade 1 Grade 2 Grade 3 Grade 4
GCSF 71%, Dose reduction 33% Dose delays 38% pts
GCSF 43%, Dose reduction 21% Dose delays 39% pts
Grade Grade Grade Grade 4

9. 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 Madrid)