Landscape of systemic therapy for recurrent ovarian cancer · Psychological assessments of...
Transcript of Landscape of systemic therapy for recurrent ovarian cancer · Psychological assessments of...
Landscape of systemic therapy
for recurrent ovarian cancerSandro Pignata
Istituto Nazionale Tumori di Napoli
Disclosures
• Honoraria from AZ Roche Clovis Tesaro Pharmamar MSD Incyte
Pfizer Merck Genmab
• Funding from AZ Roche MSD
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Treatment for recurrent disease:
standard treatmentSandro Pignata
National Cancer Institute, Naples, Italy
• Marisa 69 Y
• Serous High grade, stage IIIc
• First line chemo includin bevacizumab
• Recurring with carcinomatosis
How we decide next therapy?
What is changed in clinical practice since 2017?
Is Platinum free Interval still the main driver of our
decision?
What is changed in clinical practice since 2017?
The concept of PFI is not the only driver of our decisions today
Biology, histology, treatment free interval,…. more important?
The resistance to platinum-based treatment is not a categorical variable
ESMO-ESGO Consensus Conference on Ovarian Cancer
Pathology and molecular biology, early and advanced stages, borderline ovarian tumours and recurrent disease
© 2018 European Society of Gynaecological Oncology, European Society for Medical Oncology. All rights reserved.
Coming soon…..
Patients with recurrent OC
ESGO ESMO guidelines: Treatment of recurrent OC
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Surgery an option?
(AGO score, etc.)
Tumour biology/histology
Number of prior lines of treatment
Prior response
TFI for platinum
Persistent toxicity
Symptoms
Patient preference
Unfit or not willing to receive
anticancer therapyBest supportive care
Platinum might not be the best option
• Early symptomatic release
• Progression on prior platinum
• Platinum intolerability
Platinum might be the best option/
re-challenge seems to be justified
• Response to prior platinum
ESGO ESMO Consensus Guidelines – Oral Presentation at ESGO 2018
Patients candidate to receive platinum again
Patients candidate to receive platinum again: Histology/Biology
• Are histolgy driven therapies feasible in
our practice?
• Do we have good biomarkers?
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OVARIAN CANCER IS NOT A SINGLE DISEASE
Patients candidate to receive platinum: What is changed for 2017?
Biomarkers?
Olaparib, Niraparib and Rucaparib
highly effective in BRCA mut
Niraparib
gBRCA mut
21 vs 5.5 months (HR 0.27)
Olaparib
gBRCA mut
19.3 vs 5.5 months (HR 0.27)
Rucaparib
gBRCA mut
16.6vs 5.4 months (HR 0.27)
1. Matulonis UA, et al. Int J Gynecol Cancer 2008;18:1183-1193; 2. Mirabeau-Beale KL, et al. Gynecol
Oncol 2009;114:353-359; 3. Kyriacou J, et al. Can Oncol Nurs J 2017;27:236-242.
Should we still do “Watch & Wait”?
0
10
20
30
40
50
60
70
Psychologicaldistress
Fear of CA-125testing
Fear ofrecurrence
Scoressuggestive of
PTSD
Psychological assessments of early-stage ovarian cancer survivors (N=58)1
Su
rviv
ors
(%
)
Fear of disease recurrence is a psychological burden
PARP inhibitor in maintenance for All responders to platinum-based chemotherapy in late relapse
NIRAPARIB MAINTENANCE THERAPY IMPROVED PFS
BRCAwt, breast cancer susceptibility; CI, confidence interval; gBRCAmut, germline breast cancer susceptibility gene mutation; HR, hazard ratio; HRD, homologous recombination deficiency; neg, negative; PARP, poly adenosine diphosphate ribose polymerase; PFS, progression-free survival; pos, positive.
Mirza MR et al. N Engl J Med. 2016;375:2154–64.
NiraparibPlacebo
gBRCAmut100
75
50
25
0
0 4 8 12 16 20 24
Months since randomisation
PF
S (
%)
gBRCAmut (n=203)
Niraparib (n=138) Placebo (n=65)
21.0 5.5
HR=0.27
95% CI 0.17–0.41,
P<0.001
Non-gBRCAmut HRD-pos100
75
50
25
0
0 4 8 12 16 20 24
Months since randomisation
PF
S (
%)
Non-gBRCAmut HRD-pos (n=162)
Niraparib (n=106) Placebo (n=56)
12.9 3.8
HR=0.38
95% CI 0.24–0.59,
P<0.001
HRD-neg (n=134)
Niraparib (n=92) Placebo (n=42)
6.9 3.8
HR=0.58
95% CI 0.36–0.92,
P<0.023
100
75
50
25
0
0 4 8 12 16 20 24
Months since randomisation
PF
S (
%)
Non-gBRCAmut overall (n=350)
Niraparib (n=234) Placebo (n=116)
9.3 3.9
HR=0.45
95% CI 0.34–0.61,
P<0.001
Niraparib study NOVAPFS months
NiraparibPlacebo
NiraparibPlacebo
HRD-neg100
75
50
25
0
0 4 8 12 16 20 24
Months since randomisation
PF
S (
%)
NiraparibPlacebo
Non-gBRCAmut overall
Rucaparib maintenance
BID, twice daily; BRCA, breast cancer gene; CR, complete response; HRR, homologous recombination repair; ITT, intention to treat; PFS, progression free survival;
PR, partial response; R, randomisarion; gBRCA, germline breast cancer gene; sBRCA, somatic breast cancer gene; OC, ovarian cancer
1. Ledermann J, et al. Lancet Oncol 2014;15:852-861.
2. Pujade-Lauraine E, et al. Lancet Oncol 2017;18:1274-1284.
3. Coleman RL, et al. Lancet 2017;390:1949-1961.
Placebo
N=189
Rucaparib
600 mg BID
N=375
Primary endpoint
Investigator-assessed PFS in molecularly
defined HRR gene status subgroups
• BRCAmut
• HRD
• ITT
Patients
• High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers
• ≥2 prior lines of platinum-based treatments
• Sensitive to penultimate platinum
• Responding to most recent platinum (CR or PR)
• CA-125 within normal range
• No restriction on size of residual tumour
R2:1
ARIEL33 (Phase III)
N=564
LONG-TERM EXPOSURE TO OLAPARIB IN STUDY 19
• Median follow-up of 5.9 years: 15 patients (11%) still receiving olaparib(8 BRCAm, 7 BRCAwt); one patient (<1%) still receiving placebo (BRCAm)
0
5
10
15
20
25
30
35
40
45
50
≥1 ≥2 ≥3 ≥4 ≥5 ≥6
Pati
en
ts o
n o
lap
ari
b (
%)
Time on olaparib (years)
Overall study population
BRCAm subgroup
BRCAwt subgroup
Courtesy of J Ledermann ASCO 2016
33%
19%
14% 14%12%
5%
When Platinum is an option: Chemotherapy followed by PARPi
• PARPi prolong PFS in patients that respond to platinum
based therapy
• No significant difference in efficacy appears among the
different PARPi
• Effect larger in BRCA mut
• Long responders not strictly related to BRCA status
When Platinum is an option: Chemotherapy followed by PARPi
Open questions?
• What happens after PARPi?
• Mechanism of resistance?
• How to identify long responders?
Mechanism of resistance to PARPi?
Targeting angiogenesis has a role in patients candidatesfor Platinum rechallange?
AGO Ovar 2.21 (Pfisterer ESMO 2018)
0
0,5
1
0 6 12 18 24 30 36 42 48 54
HR = 0.807 (95% P = 0.0128
Carbo PLD bev better than Carbo Gem bev
• 655 patients randomized
• First recurrence
• Previous bev allowed
• Previous surgery allowed
Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line. The randomized phase 3 trial MITO16B - MaNGO OV2B -
ENGOT OV17
Sandro Pignata, Domenica Lorusso, Florence Joly, Ciro Gallo, Nicoletta Colombo, Cristiana Sessa, Aristotelis
Bamias, Carmela Pisano, Frédéric Selle, Eleonora Zaccarelli, Giovanni Scambia, Patricia Pautier,
Maria Ornella Nicoletto, Ugo De Giorgi, Coraline Dubot, Alessandra Bologna, Michele Orditura,
Isabelle Ray-Coquard, Francesco Perrone, Gennaro Daniele
on the behalf of MITO, GINECO, MaNGO, SAKK and HeCOG groups
Sandro Pignata
PFS Investigator assessed
Standard Experimental Log Rank
P
# events 161 143
Median PFS 8.8 mos 11.8 mos <0.001
HR* (95%CI) 0.51 (0.41-0.65)
*adjusted by:
age, PS, centre size, bevacizumab at relapse, chemo backbone,
residual disease at initial surgery
0.0
00
.25
0.5
00
.75
1.0
0
Pro
ba
bili
ty o
f P
FS
202 179 83 30 9 3 0 0 0Experimental203 137 35 10 5 1 0 0 0Control
Number at risk
0 6 12 18 24 30 36 42 48months
Control Experimental
Kaplan-Meier survival estimates
Sandro Pignata
When Platinum is an option: Chemotherapy combined with bevacizumab
• Bevacizumab combined to chemotherapy prolong PFS
and has higer response rates compared to chemo alone
• Carbo PLD the best chemo option
• Bev after bev prolong PFS
When??
Patients with recurrent OC
ESGO ESMO guidelines: Treatment of recurrent OC
Surgery an option?
(AGO score, etc.)
Tumour biology/histology
Number of prior lines of treatment
Prior response
TFI for platinum
Persistent toxicity
Symptoms
Patient preference
Unfit or not willing to receive
anticancer therapyBest supportive care
Platinum might not be the best option
• Early symptomatic release
• Progression on prior platinum
• Platinum intolerability
Platinum might be the best option/
re-challenge seems to be justified
• Response to prior platinum
Eligible for platinum/
potentially platinum-responsive
No priority for symptomatic
response or contraindications to
bevacizumab
Platinum-based re-challenge
Offer PARPi after response to
platinum if not contraindicated
(observed platinum response)
Priority for symptomatic response
and no contraindications to
bevacizumab
Offer platinum-based
re-challenge plus bevacizumab
ESGO ESMO Consensus Guidelines – Oral Presentation at ESGO 2018
Patients not candidate to receive platinum again
Summary of recommendations LoE GoR Consensus
There are currently no molecular biomarkers to predict platinum-response.
Resistance to platinum in recurrent ovarian cancer is a therapeutic-oriented definition :
1. Proven platinum resistance: progression during platinum therapy
2. Assumed /expected platinum resistance: early symptomatic relapse with low probability of
response to platinum.
These patients should be treated with sequential non-platinum therapy adding bevacizumab if
indicated.
Sensitivity to platinum in recurrent ovarian cancer is a therapeutic-oriented definition :
1. Proven platinum sensitivity: response to platinum; these patients can receive maintenance
PARP inhibitors
2. Assumed /expected platinum sensitivity: previous response to platinum without early symptomatic
relapse; these patients should be treated with platinum-based therapy adding bevacizumab or
followed by maintenance PARP Inhibitor therapy, if indicated. This group includes those who did
not receive prior platinum or those who received adjuvant platinum post-surgery without any
evaluable residual disease to assess chemotherapy response .
I-IV A
Yes: 75% (30 voters)
No: 10% (4 voters)
Abstain: 2.5% (1 voter)
Missing: 12.5% (5 voters)
RECURRENT DISEASE
What defines platinum resistance and how does that influence subsequent treatment?
© 2018 European Society of Gynaecological Oncology, European Society for Medical Oncology. All rights reserved.
Patients with proven platinum resistance
No news from 2017!!
• Single agent non platinum therapy is the standard
• Bevacizumab combined to chemotherapy in patients
bevacizumab naive
Patients with assumed/expected platinum resistance
Trabectedin/PLD vs. PLD monotherapy: Results of the OVA-301 trial in platinum-sensitive ROC
• Response Rate (CR+PR):1
– Trabectedin/PLD: 35.3%
– PLD: 22.6% p=0.0042
Median PFS1
Time (months)
1. Monk BJ et al. J Clin Oncol. 2010; 28(19):3107-3114; 2. Krasner CN et al. Gynecol Oncol. 2012; 127: 161-167; 3. Colombo N. Expert Rev Anticancer
Ther. 2018;18(sup1):13-17.
Global Health Status Scale Over
Time2
Trabectedin/PLD in real-life clinical practice:
• Prospective, European phase IV NIMES-ROC: trabectedin/PLD in platinum-sensitive ROC
Pignata S, et al. Ann Oncol. 2018; vol 29 (Supl 8) pages 352 Abs Nº987P
• Preliminary results of an Interim Analysis; N=158
• Trabectedin/PLD was administered:
• As 2nd line in ≈ 25% of patients
• As 3rd line in ≈ 34% of patients
• As 4th or further line in ≈ 40% of patients
• Patients received a median of 6 cycles of trabectedin/PLD (range: 1-34)
• An overall response rate of 38% and a disease control rate of 66.5% were reported.
Trabectedin/PLD in real-life clinical practice:
• Prospective, European phase IV NIMES-ROC trial evaluating the use of trabectedin/PLD in
platinum-sensitive ROC:
Pignata S, et al. Ann Oncol. 2018; vol 29 (Supl 8) pages 352 Abs Nº987P
Trabectedin/PLD in BRCAmut platinum-sensitive ROC:
• The population of BRCA mutated patients is enriched in advanced lines of ovarian cancer.2
Trabectedin/PLD in BRCAmut patients showed:
1. Nicoletto TJ, et al. Tumori. 2015 Sep-Oct;101(5):506-510; 2. Alsop K, et al. J Clin Oncol. 2012;30:2654-63; 3. Monk BJ, et al. Ann Oncol. 2015;
26(5):914-20; 4. Lorusso D, et al. Ann Oncol. 2014;25(suppl 4): iv309.
• Longer PFS and OS compared to PLD in BRCA mut3
• Higher rates of response and survival4
Trabectedin/PLD: 23.8 months
PLD: 12.5 months
p=0.0086
Trabectedin/PLD: 13.5 months
PLD: 5.5 months
p=0.0002
Median OSMedian PFS
BRCA-mutated: 52.2 %
Wild type: 39.5 %
Overall response rate
DESIGN
MITO-23Randomized phase III trial on Trabectedin (ET 743) vs clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients
Recurrent ovarian, primary peritoneal or
fallopian tube cancers of BRCA mutated or
BRCAness phenotype
R (1:1)
Arm A: III line chemotherapy (physician choice)
- PLD 40 mg/mq d1 q28;- Topotecan 4 mg/mq d1,8,15 q 28- Weekly Paclitaxel 80 mg/mq d1,8,15 q28- Gemcitabine 1000 mg/mq gg1,8,15 q28- Carboplatin AUC 5 g 1 q 21
Arm B: Trabectedin 1.3 mg/m2 -3h D1, q21
OBJECTIVES1. PRIMARY:
▪ Overall Survival (OS)
2. STRATIFICATION CRITERIA:
– Measurable Disease
– Platinum Sensitivity
– Number of Previous CHT Lines (<3 vs >3)
– BRCA status
Accrual completed
New concepts under investigation: The near horizon
Second line – PARPi/IO-based regimens
Niraparib – TSR 042
Carboplatin–paclitaxel–
Atezo–PARPi
Carboplatin–paclitaxel +/-
checkpoint inhibitor
Carboplatin–paclitaxel +/-
checkpoint inhibitor–bev
Checkpoint inhibitor-based regimens
Checkpoint inhibitor monotherapy or in combination with liposomal doxorubicin
Until progression
Atezo PARPi maintenance
Checkpoint inhibitor maintenance
Checkpoint inhibitor +
bev maintenance
MITO32 ENGOT OV51
Anita
JAVELIN OVARIAN 200
Atalante
KEYNOTE-100, JAVELIN OVARIAN 200
Immunotherapy in combination with PARPi TOPACIO/KEYNOTE-162
ADC, antibody-drug conjugate; Bev, bevacizumab; OC, ovarian cancer; PARPi, poly-ADP ribose polymerase inhibitor
Mirvetuximab soravtansine FORWARD I
Second-line – Checkpoint inhibitor/Bev-based regimens
(FRα)-targeting ADC
DNA damage and cell cycle checkpoint pathways
p21p53
CDK
Cyclin
Cell
cycle
WEE-1
CDC25A/B/C
CHK2
CHK1
Double
Strand
Breaks
ATM
DNA
replication
stressATR
DNA
damage
G1
G2
Prexasertib: inhibitor of both CHK1 and CHK2in heavily pretreated recurrent OC
months
HGSOC
BRCAwt
gBRCAm
OvCa
ORR= 7/20 (35%)
ORR= 0/6Partial response
White: platinum-sensitive disease
Grey: platinum-resistant or refractory
disease
Conclusions
• Decisions not only based on PFI
• Other factors to be considered (histology, biology…)…but
not always treatments available
• PARPi as maintenance have strong activity in the
recurrence
• Bevacizumab chemo regimens effective in recurrent
patients
• Effect of maintenance on the following therapies still
poorly investigated
Having more options is always better for our
patients
But the right sequence may be important…