Nuove opzioni terapeutiche nel carcinoma ovarico recidivante
dott.ssa Federica Tomao
Dip di Sc Ginecologico-Ostetriche e Sc Urologiche, Univ “Sapienza”, Roma
Evolution of adjuvant treatment
Cisplatin 1971 Different
combination regimens (until 1970)
Carboplatin 1985
Cisplatinin + Paclitaxel 1996
Carboplatin + Paclitaxel 1998
Bevacizumab 2013 Intraperitoenal CT
2006 In the future?
Tailered tretments
Dose-dense?
2009-2014
Overall Survival HR 0.79, p=0.039
Increased toxicity and reduced deliverability in dose dense arm
Ethnic pharmacogenomicdifferences
10% women received primary chemotherapy
Katsumata et al., Lancet 2009; Katsumata et al., Lancet Oncol 2013
BACKGROUND
DOSE-DENSE PACLITAXEL: JGOG 3016
Response to carboplatin/paclitaxel according to race
(from GOG218)
BACKGROUND – DOSE DENSE PACLITAXEL
Platinum-Paclitaxel cornerstone of first-line management of epithelial ovarian cancer
6-8 cycles administered 3-weekly
Increasing use of primary chemotherapy with delayed cytoreductivesurgery in IIIc-IV disease
Strong rationale for the evaluation of weekly dose-dense paclitaxel scheduling
Pre-clinical evidence of improved drug delivery, increased apoptosis and reduced angiogenesis
Efficacious and well-tolerated approach in platinum-resistant disease
Survival benefit compared to 3-weekly scheduling in breast cancer
Does incorporation of dose-dense weekly paclitaxel in first- line treatment improve survival in a predominantly European patient population?
Can weekly fractionation of both carboplatin and paclitaxel reduce toxicity, improve deliverability and maintain efficacy?
Is dose-dense weekly chemotherapy feasible in a neoadjuvant treatment pathway?
INCLUSION CRITERIA
Histologically confirmed (minimum core biopsy) epithelial ovarian, fallopian tube, Mullerian primary peritoneal carcinomas or ovarian carcinosarcoma
FIGO (1988) staging
Stage Ic/IIa-high grade histology
Stage IIb-IV-all histological types
ECOG PS 0-2
Adequate haematological, renal and hepatic function for carboplatin-paclitaxel chemotherapy
No prior systemic therapy for ovarian cancer
No planned maintenance therapy for ovarian cancer
Six cycles chemotherapy mandated Delayed Primary Surgery cohort
•Cytoreductive surgery strongly advised after 3 cycles of chemotherapy
•Cycle 3 day 15 treatment omitted in arms 2 and 3
ICON8 TRIAL SCHEMA
ICON8 STATISTICAL DESIGN
Co-primary outcomes –Progression-Free Survival and Overall Survival
Estimated median PFS = 16 months
Target HR = 0.75 with 2-sided significance level of 0.025 (due to multiple comparisons –weekly paclitaxel vs standard & weekly carbo-paclitaxel vs standard)
Require 602 events in each comparison for PFS and OS.
Sample size = 1485 women
ACCRUAL
Jun 2011 –Nov 2014
1566 women recruited
ICON8 BASELINE CHARACTERISTICS
ICON8 BASELINE CHARACTERISTICS
ICON8 CHEMOTHERAPY DELIVERY
No significant difference between IPS and DPS pathways
Difference in total G3/4+ toxicity predominantly due to uncomplicated neutropenia
Predefined Notable Adverse Events
ICON8
DELAYED PRIMARY SURGERY (DPS)
ICON8
PROGRESSION FREE SURVIVAL (PFS)
ICON8 PFS (BY IPS & DPS)
Median PFS
IPS
Standard 49.3 months Weeklypaclitaxel 43.2 months Weekly carbo-paclitaxel 43.7 months
DPS
Standard 13.8 months Weekly paclitaxel 14.6 months Weekly carbo-paclitaxel 15.4 months
ICON8 OVERALL SURVIVAL
ICON8 CONCLUSIONS
Incorporation of weekly dose-dense chemotherapy regimens into first-line treatment for women with epithelial ovarian cancer does not improve PFS
However, weekly dose-dense chemotherapy:
-Allows delivery of higher paclitaxel dose intensity
-Is safe and well-tolerated as post-operative treatment or as primary therapy in European patient group.
Primary dose-dense chemotherapy;
-Does not affect ability to perform timely interval cytoreductive surgery
-Does not improve surgical outcomes
3-weekly carboplatin-paclitaxel remains the standard
Evolution of treatment in recurrent disease
Classification of recurrence according to
PFI 1991 Different
combination regimens (until 1970)
Bevacizumab in PS 2012
Bevacizumab in PR 2014
Parp-Inhibitors in BRCAm in PS
2012
In the future?
Tailered tretments New
Classification of recurrence
Rucaparib is a potent inhibitor of PARP1, PARP2, and PARP3
Rucaparib has shown antitumour activity in patients with recurrent OC whose tumour harbours one of the following:
•A BRCAmutation
•High percentage of genomic LOH,
•A phenotypic marker of HRD
Rucaparib is approved in the United States for the treatment of patients with
deleterious BRCAmutation (germline or somatic) associated advanced OC who have been treated with ≥2 chemotherapy regimens
The ARIEL3 phase 3 trial evaluated rucaparib vs placebo following a response to second- line or later platinum-based chemotherapy in patients with high-grade, recurrent
platinum-sensitive OC, including fallopian tube and primary peritoneal carcinomas
Robillard et al. Cancer Res. 2017; Thomas HD et al. Mol Cancer Ther. 2007; Kristeleit R et al. Clin Cancer Res. 2017; Swisher EM et al. Lancet Oncol. 2017; Rucaparib
tablets [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2017.
BACKGROUND
ARIEL3: STUDY DESIGN
*CR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 (≤8 weeks of last dose of chemotherapy). †ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D,
RAD52, RAD54L, RPA1. HRR, homologous recombination repair; NGS, next-generation sequencing.
BRCAmutation and LOH in tumoursamples were measured using Foundation Medicine’s T5 NGS assay
*Investigator-assessed PFS at a two-sided 0.05 significance level
ARIEL3: PRIMARY ENDPOINT
AND STEP-DOWN ANALYSIS
ARIEL3: DIAGRAM
OF ANALYSIS COHORTS
Stand-alone secondary endpoint
•BICR-assessed PFS (per RECIST)
Select exploratory endpoints
•PFS by LOH status in patients with BRCA wild-type OC
•ORR in patients with measurable disease at baseline
Other secondary endpoints (to be reported separately)
•Patient-reported health outcomes
•Overall survival
ARIEL3:
ADDITIONAL ENDPOINTS
ARIEL3:
BASELINE DEMOGRAPHICS
ARIEL3:
BASELINE DEMOGRAPHICS
ARIEL3:
INVESTIGATOR ASSESSED PFS
ARIEL3:
BICR ASSESSED PFS
ARIEL3:
DIAGRAM OF ANALYSIS COHORTS
ARIEL3 EXPLORATORY ANALYSIS:
INVESTIGATOR-ASSESSED PFS IN
PATIENTS WITH BRCA WILD-TYPE OC
ARIEL3 EXPLORATORY ANALYSIS:
INVESTIGATOR-ASSESSED PFS IN
PATIENTS WITH BRCA WILD-TYPE OC
ARIEL3: BICR-ASSESSED PFS IN
ITT POPULATION SUBGROUPS
ARIEL3: EXPLORATORY ANALYSIS:
INVESTIGATOR-ASSESSED ORR FOR PATIENTS WITH MEASURABLE
DISEASE AT BASELINE
ARIEL3: SUMMARY OF SAFETY
Median (range) treatment duration was 8.3 (0.1–34.9) months in the rucaparib arm and 5.5 (0.0–
35.4) months in the placebo arm
•MDS/AML were reported in 3 (0.8%) patients in the rucaparib arm and no patients in the placebo arm
ARIEL3: TREATMENT-EMERGENT ADVERSE EVENTS OF ANY GRADE
REPORTED IN≥15% OF PATIENTS
IN EITHER ARM
ARIEL3 CONCLUSIONS
Rucaparib maintenance treatment significantly improved PFS vs placebo in the tested BRCA-mutant and HRD cohorts and in the overall ITT population
PFS was improved with rucaparib maintenance treatment vs
placebo in patients with BRCAwild-type OC (LOH high and LOH low)
Several patients with measurable residual disease at baseline had further reduction in tumour burden with rucaparib maintenance treatment
The most common side effects were gastrointestinal (nausea and vomiting), asthenia, and anaemia, consistent with prior studies of rucaparib
The results of ARIEL3 demonstrate the benefit of rucaparib
maintenance treatment for women with platinum-sensitive OC
following a complete or partial response to PBC.
Niraparib is a selective poly(ADP-ribose) polymerase (PARP)1/2 inhibitor.
The ENGOT-OV16/NOVA trial
demonstrated that PFS was significantly longer in patients receiving niraparib than in those receiving placebo.
Niraparib was approved in the US for the maintenance treatment of adult patients with recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based
chemotherapy.
Niraparib is currently under review with the EMA
BACKGROUND
ENGOT-OV16/NOVA Trial:
PFS RESULTS
EQ-5D-5L: A validated tool that encompasses five domains:
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores range from 1 to 5.
EQ-5D-5L can be used to calculate a health utility index (HUI), which measures overall QoLon a scale from 0-1
FOSI: A validated, 8-item measure of symptom response to treatment for ovarian cancer. Patients respond to their symptom experience over the past 7 days using a 5-point Likert scale
scored from “not at all” (0) to “very much” (4).
• Measures lack of energy, pain, nausea, vomiting, swelling in stomach area, cramps in stomach area, worry that condition will get worse, content with quality of life
• Score 0 = No symptom
• Scores 1-4 = Any symptom
• Scores 3-4 = Severe symptoms
PRO from ENGOT-OV16/NOVA Trial
PATIENTS TREATED WITH NIRAPARIB MAINTAINED THEIR QoLAS ASSESSED
BY THE EQ-5D-5L
•Baseline QoL (adjusted HUI score) was similar between niraparib and placebo-treated patients
•QoL scores during treatment were similar between niraparib and placebo-treated patients
•gBRCAmut cohort: 0.812 niraparib vs. 0.803 placebo
•Non-gBRCAmut cohort: 0.845 niraparib vs. 0.828 placebo
Baseline symptoms were similar between patients with a PR and those with a CR
20% of pts experienced nausea at baseline
PATIENTS IN RESPONSE TO PLATINUM-BASED
CHEMOTHERAPY WERE
SYMPTOMATIC AT STUDY ENTRY
RESULTS OF INDIVIDUAL FOSI MEASURES
There was a trend towards less pain in niraparib-treated patients
Placebo Niraparib
Solid lines represent “Any Symptoms”, Dashed lines represent “Severe Symptoms”
Size of circles corresponds to # of patients
RESULTS OF INDIVIDUAL FOSI MEASURES
Placebo Niraparib
Solid lines represent “Any Symptoms”, Dashed lines represent “Severe Symptoms”
Size of circles corresponds to # of patients
HEMATOLOGIC ADVERSE
EVENTS DECREASED OVER TIME AND DID NOT IMPACT QoL
Placebo Niraparib
Conclusions on QOL from ENGOT-OV16/NOVA Trial
Most common PRO symptoms at baseline were fatigue and pain.
Patients with a CR or PR to their last platinum regimen had similar symptoms at baseline.
Patients who received niraparib as maintenance treatment retained QoLcomparable to placebo during their treatment.
FOSI data suggest that treatment with niraparib improves patient QoL in certain aspects.
There was a trend toward lower pain levels in niraparib-treated patients compared to those receiving placebo
While nausea increased initially, it returned to baseline levels over time
For other FOSI symptoms, scores were similar between niraparib-
and placebo-treated patients
High unmet need to improve outcome of recurrent ovarian cancer.
Patients receive chemotherapy followed by watchful waiting. All patients recur and die after several lines of chemotherapy
PankoMab-GEX™ is a novel glyco-designed and glyco-optimized humanized monoclonal antibody, which recognizes the tumor-
specific epitope of mucin-1 (TA MUC1).
PankoMab GEX™ targets and binds to the TA-MUC1 epitopes on the surface of tumour cells, which may potentially activate the
immune system to induce antibody-dependent cellular cytotoxicity (ADCC) against the TA MUC1-expressing tumour cells.
BACKGROUND
Mucin 1 (Muc1) is a heavily glycosylated transmembrane protein normally expressed in glandular or luminal epithelial cells (ovary, breast, lung, stomach, colon....). Absent in skin epithelium and mesenchymal cells
During oncogenesis MUC1 is aberrantly glycosylated and overexpressed in most epithelial tumors (TA-MUC1); the loss of polarity allows targeting with PankoMab-GEX
MUC1 –DIFFERENCE BETWEEN NORMAL AND MALIGNANT
HUMAN TISSUES
PANKOMAB-PHASE II
25201: STUDY DESIGN
DEMOGRAPHIC AND
BASELINE CHARACTERISTICS
PROGRESSION FREE SURVIVAL:
IRRECIST
OVERALL SURVIVAL:
IRRECIST
TA-MUC1 SERUM LEVELS
TREATMENT-RELATED
GRADE ADVERSE EVENTS IN
≥5% OF PATIENTS
PANKOMAB: CONCLUSIONS
PankoMab-GEX™ did not significantly improve PFS in recurrent ovarian cancer patients
The target trough level of 50mg/ml was readily reached following an initial loading dose, then maintained with a 3-weekly schedule
Serum MUC1 levels decreased after PankoMab-GEX™ treatment, indirectly confirmed drugtarget engagement
Safety of PankoMab-GEX™ was associated with AEs mainly
grade 1 and 2 as result of infusion reactions with the majority of
patients discontinuing the treatment because disease progression
POSTERS
POSTERS
POSTERS
POSTERS
POSTERS
POSTERS
General recommendations on the platinum- combination followed by iPARP option
Courtesy of Gonzalez Martin A –ESMO 2017-
courtesy of Vergote I–ESMO 2017-
The role of secondary surgery
-The Desktop III trial-
courtesy of Vergote I–ESMO 2017-
The role of secondary surgery
-The Desktop III trial-
courtesy of Vergote I–ESMO 2017-
