4th International Congress - Clinical de Oncología Astorga, Panamá, 27-29 de Junio, 2019

1. Options in Platinum
-Resistant Ovarian Cancer (PROC)-
Mauricio Lema-Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín
@onconerd

2. Conflict of Interest
Mauricio Lema Medina MD
Speaker for:
AZ, BMS, MSD

3. @onconerd

4. Oronsky B, Med Oncol, 2017
25% are deemed PROC Over time, most OC
become PROC

5. Cytotoxic chemotherapy

6. Topotecan versus paclitaxel for the treatment of PROC
Huinnink WtB, JCO, 1997
Paclitaxel
175 mg/m2 q3wPROC
n=226 Topotecan
1.5 mg/m2 d1-5 q3w
Topotecan
ORR: 20.5%
OS: 14 mo
Paclitaxel
ORR: 13.2%
OS: 9.7 mo

7. Topotecan vs Pegylated Liposomal Doxorubicin (PLD) in PROC
Gordon AN, Gynecol Oncol, 2004
PLD
50 mg/m2 q3wPROC
n=255* Topotecan
1.5 mg/m2 d1-5 q3w
median OS:
9.3 mo
*A subgroup

8. PLD 50 vs 40 mg/m2 (JGOG3018)
Yabuno A, Proc ASCO, 2019

9. PLD 50 vs 40 mg/m2 (JGOG3018)
Yabuno A, Proc ASCO, 2019
Closed prematurely, less mucositis with 40
PFS
OS

10. Gemcitabine in PROC
Lorusso D, Ann Oncol, 2006

11. Salvage chemotherapy in recurrent platinum refractory
ovarian cancer patients
Lorusso D, Ann Oncol, 2006

12. ORR: about 15%
PFS: about 3 months
Chemo in PROC

13. Bevacizumab

14. Bevacizumab Combined With Chemotherapy for
Platinum-Resistant Recurrent Ovarian Cancer: The
AURELIA Open-Label Randomized Phase III Trial
Pujade-Lauraine E , JCO, 2014
Non-platinum
chemotherapy (NPC)PROC
n=361* NPC +
Bevacizumab
NPC
ORR: 11.8%
mPFS: 3.4 mo
mOS: 13.3 mo
*A subgroup
NPC:
Topotecan
PLD
Paclitaxel
NPC+ Bev
ORR: 27.3%
mPFS: 6.4 mo
mOS: 16.6 mo (NS)
NPC+Bev

15. ORR: 27%
PFS: about 6 months
Chemo + Bev in PROC
No OS benefit

16. PARP1 inhibitors

17. Olaparib in R/R OC with a gBRCA1/2 mutation
Kaufman B , JCO, 2015
Single-agent Olaparib
400 mg PO q12h
gBRCA1/2
n=193*
*A subgroup with PROC
Endpoint
ORR
ORR
31%
PFS
7.0 mo

18. Slide 3
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

19. CLIO (NCT02822157):<br />Randomized phase II study evaluating efficacy of olaparib monotherapy versus physician’s choice chemotherapy in platinum-resistant ovarian cancer
(PROC)
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

20. Slide 4
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

21. Slide 5
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

22. Slide 7
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

23. Slide 9
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

24. Slide 10
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

25. Slide 11
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

26. Slide 12
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

27. Slide 13
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

28. Slide 14
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

29. Slide 19
Presented By Adriaan Vanderstichele at 2019 ASCO Annual Meeting

30. Hormonal therapy

31. Ovarian Tumor Tissue Analysis
Consortium study
Sieh W, Lancet Oncol, 2013

32. Hormone-receptor expression and OC survival
Sieh W, Lancet Oncol, 2013
2933 patients
Invasive Serous,
Endometrioid,
Mucinous or
Clear-Cell OC
Tissue Micro-Arrays
Relevant clinical info

33. Images courtesy Ursula Matulonis, MD.
Serous
Endometrioid
Mucinous
Clear cell
Histological Categories of Ovarian Cancer
Serous Mucinous
Endometrioid Clear-Cell
High HR
expression
Low HR
expressio
n

34. Hormone-receptor expression and OC survival
Sieh W, Lancet Oncol, 2013
PR expression in (A) HGS and © endometrioid
PR and ER are prognostic biomarkers HGS and endometriosis OC

35. Hormone-receptor expression and OC survival
Sieh W, Lancet Oncol, 2013
ER expression in (A) HGS and (C) endometrioid

36. Hormone-receptor expression and OC survival:
an OTTA consortium study
Sieh W, Lancet Oncol, 2013
HGS
ER+/PR-
(53%)
LGS
ER+/PR-
(34%)
HGS
ER+/PR+
(28%)
LGS
ER+/PR+
(55%)
HGS: High-grade serous, LGS: Low-grade serous

37. Clinical benefit and risk of death
with endocrine therapy in ovarian
cancer: A comprehensive review
and meta-analysis
Peleary L, Gynecol Oncol, 2017

38. Endocrine therapy in OC: A Meta-analysis
Peleary L, Gynecol Oncol, 2017
2490 patients53 trials
Endpoint
SCB
(Summary of Clinical Benefit)

39. Endocrine therapy in
OC: A Meta-analysis
Peleary L, Gynecol Oncol, 2017
Aromatase inhibitors
SCB: 0.39
Tamoxifen
SCB: 0.43
Fulvestrant
SCB: 0.41
Overall
SCB: 0.40

40. Endocrine therapy in OC: A Meta-analysis
Peleary L, Gynecol Oncol, 2017
Endocrine therapy an death risk stratified by first line regimen

41. Endocrine therapy in OC: A Meta-analysis
Peleary L, Gynecol Oncol, 2017
Endocrine therapy and death risk stratified by tumor grade.

42. A phase II study of fulvestrant in R/R OC
Argenta P , Gyn Oncol, 2009
Fulvestrant 250 mgER-positive,
multiply recurrent
ovarian or primary
peritoneal
carcinoma and
either measurable
disease according
to RECIST criteria
or an abnormal
and rising CA-125
Endpoint
Clinical Benefit
(CR+PR+SD at 90 days
modified RECIST
Clinical Benefit at 90 days: 50%

43. Immuno-Oncology

44. Immunotherapy in PROC
Oronsky B, Med Oncol, 2017
ORR Comments Ref.
Nivolumab 3/20 (15%) mPFS: 3.5 mo
Hamanishi J, JCO,
2015
Nivolumab 2/8 (25%)
Hamanishi J, Proc
ASCO, 2014
Pembrolizumab 3/20 (15%)
Varga A, Proc ASCO,
2015
Avelumab 11% DCR: 57%
Brahmer JR, NEJM,
2012

45. TOPACIO/KN-162: Single-Arm Phases 1 and 2 Trial of
Niraparib in Combination With Pembrolizumab in Patients
With Recurrent Platinum-Resistant Ovarian Carcinoma
Konstantinopoulos PA , JAMA Oncol, 2019
Pembrolizumab +
Niraparib (iPARP)
PROC
n=62*
*A subgroup
Endpoint
ORR
ORR: 18%
CR: 5% (3 pts)
DCR: 65%
Niraparib in combination with
pembrolizumab is tolerable, with
promising antitumor activity for patients
with ovarian carcinoma who have limited
treatment options regardless of platinum
status, biomarker status, or prior
treatment with bevacizumab

46. Immunotherapy in PROC
Oronsky B, Med Oncol, 2017
ORR Comments Ref.
Nivolumab 3/20 (15%) mPFS: 3.5 mo
Hamanishi J, JCO,
2015
Nivolumab 2/8 (25%)
Hamanishi J, Proc
ASCO, 2014
Pembrolizumab 3/20 (15%)
Varga A, Proc ASCO,
2015
Avelumab 11% DCR: 57%
Brahmer JR, NEJM,
2012
Pembrolizumab
+ Niraparib
19% DCR: 65%
Konastinopoulos PA,
JAMA Oncol, 2019

47. The future…

48. Adavosertib
WEE1 kinase
https://www.rcsb.org/3d-view/3BIZ/1
WEE1 G2 checkpoint tyrosine kinase
Phosphorilates CDK1
It is upregulated in DNA damage
Prolongs S phase
Phosphorilates Histone H2B
Delays G2/M (allowing DNA repair)
WEE1 inhibitor

49. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin
in Patients With TP53-Mutated Ovarian Cancer Refractory
or Resistant to First-Line Therapy Within 3 Months
Leijen S, JCO, 2016
24 patients enrolled
tp53 mutated, PROC
ORR: 43%

50. P2T comparing gemcitabine to gemcitabine + adavosertib in PROC
Lheureux S, Proc ASCO, 2019

51. P2T comparing gemcitabine to gemcitabine + adavosertib in PROC
Lheureux S, Proc ASCO, 2019
mcitabine in women with platinum resistant/refractory OC improved response rate, PFS and

52. P2T adavosertib + Chemo in PROC
Moore K, Proc ASCO, 2019

53. P2T adavosertib + Chemo in PROC
Moore K, Proc ASCO, 2019

54. P2T adavosertib + Chemo in PROC
Moore K, Proc ASCO, 2019
C showed greatest benefit. The increased but not unexpected hematologic toxicity is a challenge and co

55. FORWARD II: Mirvetuximab soravtansine - Bevacizumab in PROC
O’Malley DM, Proc ASCO, 2019
CR: 5 patients
PR: 21 patients
uPR: 6 patients
ORR: 39%
PFS: 6.5 mo
55 pts
a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC)

56. FORWARD II: Mirvetuximab soravtansine - Bevacizumab in PROC
O’Malley DM, Proc ASCO, 2019
The combination of
mirvetuximab soravtansine with
BEV exhibits favorable
tolerability in pts with platinum-
resistant ovarian cancer,
characterized by a manageable
side-effect profile. The
encouraging efficacy compares
favorably to reported outcomes
for BEV and chemotherapy seen
in similar patient populations.
These data support continued
exploration of the combination in
ovarian cancer.

57. Tivozanib in PROC
Swetzig WM Proc ASCO, 2019
Tivozanib is active in patients
with recurrent OC, FTC or
PPC, without substantial
toxicity, supporting its further
development.

58. Conclusions
BRCA wt or
unknown
No prior
bevacizumab
Bevacizumab + Chemotherapy
Consider “other” cytotoxic
Current options for PROC are rather limited
Consider iPARP +/- IO
Consider hormonal Rx
Off-label
Off-label
Cytotoxics
Paclitaxel
Topotecan
PLD
Gemcitabine

59. Conclusions
BRCA wt or
unknown
Prior bevacizumab
Chemotherapy
Consider “other” cytotoxic
Current options for PROC are rather limited
Consider iPARP +/- IO
Consider hormonal Rx
Off-label
Off-label
Cytotoxics
Paclitaxel
Topotecan
PLD
Gemcitabine

60. Conclusions
BRCA mutated
Chemotherapy
Consider “other”
cytotoxic
Current options for PROC are rather limited
Consider iPARP
Consider hormonal Rx
Consider iPARPChemotherapy

61. @onconerd