Presentation on theme: "Ana Oaknin, MD Medical Oncology Department. Gyneacological Cancer Unit"— Presentation transcript:
1Avances Terapéuticos en el Tratamiento de los Tumores Ginecológicos: Papel de la Angiogénesis Ana Oaknin, MDMedical Oncology Department. Gyneacological Cancer UnitVall d´Hebron University Hospital. Vall d’Hebron Institute of OncologyBarcelona, Spain
2Gynecologic Tumors(GYNT): Epidemiology GYNT comprises 19% of new cancer cases each year.Endometrial cancer is the GYNT most common.Cervical Cancer is the second most common cancer in women after breast cancer .Ovarian cancer is the fifth cause of cancer death and the most lethal GYNTSource: American Cancer Society. Cancer Facts&Figures 2013.
3Tumour Vasculature effect The angiogenic switch in tumour developmentTumour Vasculature effectAngiogenic switchResults in over-expression of pro-angiogenic signals, such as VEGFSmall tumour (1–2mm)AvascularDormantLarger tumourVascularMetastatic potentialIt is generally accepted that no solid tumour can grow beyond a critical size of 1–2mm or about 106 cells without an adequate vascular supply. The angiogenic ‘switch’ is reviewed in Bergers et al.1Tumour-associated angiogenesis can be thought to go through two phases, which are separated by the ‘angiogenic switch’. The first is an ‘avascular’ phase, in which tumours are not more than 1–2mm in diameter. These tumours remain dormant, as they are in a steady state between cell proliferation and apoptosis.Some of these small tumours will switch to the second – vascular – phase, in which the tumour grows exponentially.A classic model of the angiogenic switch is that of a pair of scales laden with pro-angiogenic molecules on one side and anti-angiogenic molecules on the other side. An imbalance of these pro- and anti-angiogenic factors triggers the ‘switch’.The onset of angiogenesis or the ‘angiogenic switch’ is a discrete step that can occur at any stage of tumour progression, dependent upon the type of tumour and its micro-environment. Induction of the switch is dependent upon the balance tipping in favour of the pro-angiogenic molecules.Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nature Reviews Cancer 2003;3:401–10.Bergers G. et al . Nature Reviews Cancer 2003;3:401–10.Bergers, et al. Nature 2002
4Therapeutic Targeting of Angiogenesis One of the most prolific arenas of drug developmentMore than 360 agents in various phases of developmentCompounds: modeled for direct and/or indirect AA propertiesApproaches: ligand, receptor, signal, and regulatorsTargets: endothelial cells, tumor cells, pericytesApproved: 9 (2 others with indirect effects)Most recent Everolimus (3/30/09) in RCC
6Key Signaling Pathways Involved in Ovarian Cancer Angiogenesis The clinical efficacy of angiogenesis inhibitors targeting VEGF marked a milestone in the field of angiogenesis research however overlapping and compensatory alternative angiogenic pathways provide escape mechanisms that likely limit the Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are functional ligands of the Tie2 receptor tyrosine kinase that is expressedon endothelial cells . Ang-1 is expressed by pericytes, smooth muscle cells and fibroblasts and acts in a paracrine manner asa physiological agonist of Tie2. It acts as a maturation factor that stabilizes the mature vasculature by promoting recruitment ofpericytes and smooth muscle cells . In contrast, Ang-2 is expressed by endothelial cells and stored in Weibel-Palade-bodies.It acts as an antagonist of Tie2 by blocking Ang-1 dependent Tie2 activationAng-2 is further described to act as a functional destabilization factor, rendering vasculature in a more plastic state amenable to sprouting (under the influence of other angiogenic cytokines suchas VEGF) and is found to be particularly increased in highly vascularized tumors and in pro-angiogenic diseases (e.g. macula degeneration, rheumatoid arthritis, osteoarthritis, psoriasis) .Ang-2 is primarily expressed in endothelial vasculature and only rarely in tumor cells.A shift in the Ang-1-to-Ang-2 expression ratio in favor of Ang-2 was found to be associated with tumor angiogenesis and poor prognosis [11–13]. Ang-2 therefore is considered as a major playerof the angiogenic switch in the course of tumor progression. Ang-2 is therefore considered pivotal for the angiogenic switch in the course of tumor progression and, together withVEGF-A, promotes the initiation of angiogenesis and maturation of new vessels. High levels of Ang-2 correlate with increased metastatic and invasive potential in breastcancer, malignant melanoma and lung cancerIn contrast to its broad expression in the vasculature of human tumors, Ang-2 shows limited postnatal expression in normal tissue making it a tumor specific target for anti-angiogenic therapies.Recently, different approaches have been described to target the Angiopoietin axis including Tie2-kinase inhibitors,Ang1 binding to Tie2 activates downstream signaling pathways (Fig 1B), which promote blood vessel stability by enhancing interactionsbetween perivascular cells and endothelium, enhancing endothelial cell survival and leading to a more stable vasculature with decreased permeability.Ang2 expression is tightly regulated, and it is synthesized and secreted primarily by endothelial cells at sites of vascular remodeling, in response to proinflammatory stimuli,14 other proangiogenic cytokines (eg, VEGF, insulin-like growth factor 1, and platelet-derived growth factor B), or hypoxia.Ang2 interrupts Ang1 mediated vessel normalization, resulting in impaired pericyte coverage,vessel destabilization, and increased vascular permeability, conditionsconducive for sprouting angiogenesis. Studies suggest that for angiogenesis to progress, additional factors, such as VEGF, must be present.Interestingly, Ang2may also play an agonistic role, bfull potential of VEGF monotherapiesYap TA, et al. Nat Cancer Rev 2009; 9:2583; J Clin Oncol, Vol 30, Nº 4, 2012;
7VEGF and Angiopoetin-2 Levels Markers of Poor Prognosis in Ovarian Cancer El porque en cancer de ovario la angigogenesis tumoral es tan importante, es debido a que en estudios experimentales se ha demostrado que una relación directa entre la expresión de VEGF y el grado de angiogenesis tumoral marcado (por la densidad de microvasos) con la mayor formación de ascitis, un menor tiempo a la progresión y menor supervivencia tras recibir la primera línea de tratamiento. Por el contrario,El tratamiento en modelos xenografts de OvCa con un anticuerpo frente al VEGF , ha mostrado una resolución de la ascitis, enlentecimiento de la progresión tumoral, y algo muy importante como vemos en esta diapositiva que es la normalización de la vasculatura aberrante, con lo cual mejoraría la penetración de los citotóxicos en el tumor.Duncan: Using a tissue microarray of 339 primary ovarian cancers, the expressionof VEGF was assessed immunohistochemically. Coupled to a comprehensive database ofclinicopathologic variables, its effect on these factors and survival was studied.Results: Tumors expressing high levels of VEGF had significantly poorer survival (P = 0.04).Factors shown to predict prognosis independently of each other were age, International Federationof Gynecologists and Obstetricians stage, and the absence of macroscopic disease aftersurgery. VEGF was independently predictive of prognosis on multivariate analysis (P = 0.02).There was no correlation between VEGF and any clinicopathologic variable. High expression ofVEGF was seen in only 7% of the tumors, suggesting that the role of antiangiogenic drugs maybe limited to a small subset of patients.Duncan et al; Clin Cancer Res 2008; 14: ; Sallinen et al; Int Journal Gyn Oncol; 20; 2010.7
8Targeting the VEGF Pathway Strategies Soluble VEGF receptors- afliberceptAntibodies to VEGFBevacizumabVEGFVEGFR2VEGFR tyrosine kinase inhibitors:PazopanibBIBF1120CediranibTherefore, we have developed many strategies to inhibit the Angiogenesis.Monoclonal antibodies against VEGF, namely Bevacizumab or small molecules that inhibit the TK domain of the Receptors.To date , the larger amount of clinical evidence in ovarian cancer comes from Bevacizumab.RibozymesMigration, permeability, DNA synthesis, survival8
9Angiogenesis as a Target in Ovarian Cancer: Anti-VEGF-VEGFR Pathway Anti-vascular endothelial growth factor (VEGF) therapy improves progression-free survival (PFS)GOG 218* Front-line: Bevacizumab HR = 0.72; 95% CI, 0.63–0.821ICON 7* Front-line: Bevacizumab HR = 0.81; 95% CI, 0.70–0.942AGO-OVAR Front-line: Nintedanib HR = 0.84; 95% CI, 0.72, 0.983AGO-OVAR Maintenance: Pazopanib HR = 0.77; 95% CI, 0.64–0.914AURELIA** Platinum-resistant, recurrent / 1 or 2 prior regimens: Bevacizumab HR = 0.48; 95% CI, 0.38–0.605OCEANS* Platinum-sensitive, recurrent / 1 prior regimen: Bevacizumab HR = 0.48; 95% CI, 0.41–0.706ICON Platinum-sensitive, recurrent / 1 prior regimen: Cediranib HR = 0.57; 95% CI, 0.44–0.747*EMA ApprovedBurger RA et al. N Engl J Med. 2011;365:2473‒2483.Perren TJ et al . N Engl J Med. 2011;365:2484‒2496.du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503.du Bois A et al. LBA ESGO 2013 Liverpool, UKPujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002.Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045.Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA*FDA ApprovedHR = hazard ratio; 95% CI = confidence interval
10Single- Agent BEVACIZUMAB in Ovarian Cancer: Phase II Efficacy Results Parameter, %Cannistra et al.(N = 44)Garcia et al.2](N = 70)Burger et al.(N = 62)GOG#170Prior regimens123524810024661o platinum DFI < 6 mos, %844060Dose/schedule15 mg/kg every 21 days10mg/kg plus Ciclophosphamide 50mg/dayRR, n (%)7 (16%)17(24%)13(21%)≥ G3 Proteinuria (%)<16≥ G3 HTA(%)1410Gastrointestinal perforations (%)116There is no doubt that the most developed antiangiogenesis agent in Ovarian cancer is Bevacizumab so far.Bevacizumab is very well known for all of you. It is a monoclonal antibody against all VEGF isoforms.By contrast with other solid tumors, Bevacizumab has shown activity as a single agent in ovarian cancer. The first clinical data come from 2 phase II clinical trials. Bevacizumab showed objective response rates that range from 16% to 21% in a very poor prognosis population since the majority of them had a platinum resistant relapse. These results compared well with historic data from GOG trials in resistant relapse in ovarian cancer.Based on these results, Bevacizumab was listed in NCCC guidelines as an active therapy in recurrent ovarian cancer.Following these promising results, the development of BEV in ovarian cancer moved forward both in first line and in the relapsed setting. Today, we will focus only in first line treatment..1. Cannistra SA, et al. J Clin Oncol. 2007;25: Burger RA, et al. J Clin Oncol. 2007;25:2.Garcia AA, et al. J Clin Oncol. 2008;26:76-82.1010
11GOG#218ICON-7Two landmark studies have studied the role of Bevacizumab in first line treatment in advanced ovarian cancer. The GOG 218 and ICON- 7 . The GOG was run in the USA and Corea and the ICON-7 in Europe and Canada. Both studies were published in the NEJM in 2011.Let´s start to review the GOG 218 since it is the most solid trial and had served as pivotal study to be submitted to Regulatory Agencies.
12GOG#218: Schema I II III Arm 1ºEnd-Point: PFS PFS HR0.77 2008GOG#218: Schema15 monthsPaclitaxel (P) 175 mg/m2Carboplatin (C) AUC 6PlaceboIArmCytotoxic (6 cycles)Maintenance(16 cycles)(CP)Front-line: Epithelial OV, PP or FT cancerStage III optimal (macroscopic)Stage IIIsuboptimalStage IVN=1873RANDOMIZ E1:1:1Carboplatin (C) AUC 6Paclitaxel (P) 175 mg/m2PlaceboBEV 15 mg/kgII(CP + BEV)The GOG 218 is a Phase III , double blinded randomized trial with three arms that analyze if adding bevacizumab to the standard arm improves the results.The eligible patients were patients with Stage IV, stage III with suboptimal surgery and stage II with optimal surgery but with macroscopic residual disease.. As you know the poorest prognostic group in ovarian cancer.The patients were randomized to receive standard treatment with PC + placebo, standard treatment plus concurrent BEVACIZUMAB followed by placebo or paclitaxel/carboplatin concurrent with BVZ and followed by Bevacizumab as maintenance treatment for a total of 15 months. I would like to point out several issues. Bevacizumab was administered at 15 mg/kg. This is the dose used in the GOG Phase II studies. The treatment with Bevacizumab began with the second course of chemotherapy in order to prevent would healing complications. The treatment was stopped in course six cycle in arm 2 and upon 22 courses in Arm III. These data are important to keep in mind since they are important differences with the European study.Well, the primary end-point of the study was Progression Free Survival. The objective of the trial was to show that the incorporation of BEV to standard treatment would be able to reduce the risk of recurrence compare with standard treatment.Remarkably, according to the statistical design the standard arm was compared with both experimental arms, however only if both experimental arms were positive we could establish a comparison between them.The PFS were determined by RECIST Criteria, CA125 and clinical deterioration.BEV 15 mg/kgCarboplatin (C) AUC 6Paclitaxel (P) 175 mg/m2III(CP + BEV BEV)1ºEnd-Point: PFSPFS HR0.77M. PFS shift: 14.0 m 18.2MN Engl J Med 2011;365: ,1212
13GOG-0218: PFS RECIST, global clinical deterioration, or CA-1251 Arm ICP (n=625)Patients with event, n (%)423 (67.7)Median PFS, months10.3Stratified analysis HR (95% CI)One-sided p-value (log rank)Arm IICP + BEV (n=625)418(66.9)11.20.908(0.759–1.040)0.080aArm IIICP + BEV BEV (n=623)360(57.8)14.10.717(0.625–0.824)<0.0001a1.00.90.80.126.96.36.199.30.20.1Proportion surviving progression freeLet´s see the resultsRegarding the primary end-point , PFS. When we compare the Arm II to Standard Arm, the incorporation of Bevacizumab only during the chemotherapy, does not improve the results. However, when Bevacizumab is administered concurrent and later as maintenance therapy, the study met its primary end-point. Adding Bevacizumab reduces the risk of recurrence in a 28% with a HR of The median PFS was 10 months in standard arm and 14 months in the experimental arm.In addition, I would like to remark that we should not draw erroneous conclusions. I mean, since the concurrent arm was negative, we cannot conclude that the ARM III is positive only because of maintenance phase. We only would have stated that if the trial had had a four arm based on Maintenance Bevacizumab only.I would like to bring your attention to the time when Bevacizumab was stopped. As you can see this is the point were the curves achieved a maximum separation. We will go back over this issue later.CP (Arm I)+ BEV (Arm II)ap-value boundary =+ BEV → BEV maintenance (Arm III)Months since randomizationN Engl J Med 2011;365:13
14GOG-0218 CA-125 To Determine Progression Protocol-defined PFS analysisCA-125-censored PFS analysisMedian PFSCP (Arm I)10.3 months12.0 monthsCP + BEV BEV (Arm III)14.1 months18.0 monthsAbsolute diff. median PFS3.8 months6.0 monthsHazard ratio0.7170.645Censored for CA125, %2029Since the GOG 218 was a pivotal study, the Regulatory Agency requested an analysis censoring the progression events exclusively determined by CA125. The results of this analysis even showed better results with a HR OF Once again, adding Bevacizumab reduced the risk of recurrence in 36% an improved the PFS by 6 months.
15Overall survival at time of final PFS analysis 1.00.90.80.188.8.131.52.30.20.1Proportion aliveArm ICP + PLA → PLA(n=625)Arm IICP + BEV → PLAArm IIICP + BEV BEV(n=623)Patients with events, n (%)156(25)150(24)138(22)Median (months)39.338.739.7HR (stratified)(95% CI)1.036(0.827–1.297)0.915(0.727–1.152)One-sided p-value0.3610.2521-year OS rate, %90.690.491.3According to the Protocol, the Median Overall Survival was determined at the time of PFS. As you can see in the slide, there were no differences among the three arms.We will analyze the potential reasons for these results later during this talk.Months since randomization625623442432437173162171463940No. at riskN Engl J Med 2011;365: ,
16Epithelial ovarian, primary peritoneal or fallopian tube cancer ICON7: Study designEpithelial ovarian, primary peritoneal or fallopian tube cancerHigh-risk stage I–IIA (grade 3 or clear cell)Stage IIB–IVn=1528Carboplatin AUC 6* (C)Paclitaxel 175 mg/m2 (P)R1:1Carboplatin AUC 6*Paclitaxel 175 mg/m2 (P)Bevacizumab 7.5 mg/kg q3wIt is time to move to the European/Canadian Study, The ICON-7 Study.Which are the main differences with the GOG218?First all, the ICON-7 Study is an open label Phase III with 2 arms. The standard arm compared with experimental arm. As you can see in the slide, Bevacizumab was administered at 7.5 mg, half of GOG doses. In addition, the duration of the treatment was only 12 months compared to 15 months in the GOG.The primary end-point was also the Progression-free survival (PFS) but in this trial exclusively defined by RECIST guidelines .CA-125 elevation alone not defined as disease progression.I think to understand both studies it is important to remark the population enrolled in the ICON-7. This study included a 10% of high-risk early stages , 70% had an optimal surgery according the criteria previous 4th ovarian cancer consensus and a 25% had suboptimal surgery . The study pre-defined a high-risk subgroup that included the Stages III with residual disease greater than 1 cm and Stages IV. This group was a 31% of the global population. In addition, as you know, this is exactly the same population enrolled in the GOG 218.Stratification variables:Stage I–III debulked ≤1 cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage IIIIntent to start treatment ≤/> 4 weeks after surgery1º End- Point: PFS only determined by RECIST Criteria12 monthsHIGH RISK GROUP( 31% ) : FIGO III>1cm/FIGO IV DebulkingPerren TJ et al . N Engl J Med. 2011;365:2484‒2496.16
17Summary of Updated Results High risk: FIGO IV or III with >1cm RDHR 0.68 (95% CI )Median 10.5 vs 15.9moHR = 0.81 (95% CI 0.70–0.94)The study met its primary end-point. The addition of Bevacizumab to standard arm reduces the risk of recurrence with a HR of The median PFS was 19.8 months in bev arm vs 17.4 months in the standard therapy( 2.4 months). These results are considered modest. However, when we focused on the high-risk group the benefit is much greater and comparable to the GOG 218. Adding BEV reduces the risk of recurrence in a 32%, with a HR of Interestingly, adding bev also brings a benefit in terms of OSHR 0.64 (95% CI )Median 36.6 vs 28.8moHR = 0.81 (95% CI 0.63–1.04)Perren T et al N Engl J Med Dec 29;365(26):
18GOG-0218 and ICON7: Efficacy Across the Trials (Arm I vs III)ICON7Results of primary analysisnPFS (HR)Median PFS, monthsPFS ∆ , monthsp value1,2480.7210.3 vs 14.13.8<0.00011,5280.8717.4 vs 19.82.40.04Results based on RECIST only (regulatory analysis*)0.6512.0 vs 18.06Subgroup of advanced disease only(operated FIGO IV/IIIC 1cm+ residuals)N4650.6810.5 vs 15.95.4<0.001*Censoring CA 125I would like to summarize the efficacy results from both trials in this slide.As you can see , in both trials the HR for PFS are in the same range ( 0.65 for GOG218 and .68 for ICON7), when we studied the same population, namely the global population in the GOG218 and the High-Risk group in the ICON7 and when the PFS had been determined only by RECIST Criteria.
19Is the PFS a valid primary end-point? 4th Ovarian Cancer Consensus Conference. June 25 – 27, 2010UBC Life Sciences Institute, Vancouver, BCA1-2: What are the appropriate endpoints for different trials: (maintenance, upfront chemotherapy trials including molecular drugs)The recommended primary endpoints for future front line/maintenance clinical trials in ovarian cancer are:Phase II Screening for activityPFS, PFS at defined time point, or ResponsePhase IIIEarly ovarian cancer - Recurrence free survival (note: recurrence = recurrent disease + deaths from any cause)Advanced ovarian cancer - Both PFS and OS are important endpoints to understand the full impact of any new treatment. Although overall survival is an important endpoint, progression free survival is most often the preferred primary endpoint for trials because of the confounding effect of the post-recurrence/progression therapy on overall survival. Each protocol should specify if PFS or OS is the preferred endpoint. Regardless of which is selected, the study should be designed and powered for both PFS and OS when feasible.Maintenance trials: These criteria should be applied to trials that include maintenance therapy.Int J Gynecol Cancer 2011: 21;Then, is the PFS a valid primary end-point in advanced ovarian cancer?The 4th Ovarian Cancer Consensus states that
20Magnitude of Clinical Benefit: Is PFS a valid End-Point? Advanced ovarian cancer has a long survival post-progression and subsequent interventions can impact on the OS result, especially the crossover.In GOG 218, 39% of patients received any anti-angiogenic therapy at relapse1.In ICON-7 less than 5% of cross-over could explain the OSWhen SPP is long enough( >12 months), the chance of expecting a statistically significant prolongation of PFS translating into an OS benefit is extremely low and the number of patients required for demonstrating a survival benefit is extremely large( >2000)2.For clinical trials with a PFS benefit, a lack of statistical significance in OS does not mean a lack of improvement in OS.1. Chan, et al. SGO 2013: Abstract 292; 2. Broglio et al: J Natl Cancer Inst Dec 2;101(23):1642-9Why no global overall survival benefit has been reported in BEV first line OC trials?This lack of overall survival benefit may be explained by two main facts: the confusion factors: use of subsequent therapies and cross over to experimental therapies and the Long post progression survival.So this take us to the following question: is PFS a valid end-point in first line treatment?Well, let´s go over these different facts
21Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of advanced (FIGO stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancerBevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Bevacizumab as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlierThe recommended dose of Bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusionBased on the GOG data supported by ICON.7 the European Agency in approved Bevacizumab in combination with Carboplatin and Paclitaxel for the front –line treatment of patients with Stage III and IV ovarian cancer. The EMA recommended the dose of 15mg for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier.
23AGO-OVAR 16: Study Design Du Bois A. et al ; Journal Clin Oncol ;
24Median PFS was 17.9 months (95% CI, 15.9 to 21.8) HR= 0.77; (95% CI, 0.64 to 0.91)17.9m12.3mHR=1.08; 95% CI, 0.87 to 1.33; P.499Median PFS was 17.9 months (95% CI, 15.9 to 21.8)for pazopanib and 12.3 months (Du Bois A. et al ; Journal Clin Oncol ;
25Du Bois A. et al ; Journal Clin Oncol ; 2014.57.4574
26Recommended Guidelines of Systemic therapy in Relapsed Ovarian Cancer /Cediranib/AMG386
28OCEANS: Study schema Platinum-sensitive recurrent OCa No prior BV Measurable diseaseECOG 0/1No prior chemo for recurrent OCNo prior BV(n=484)CG + PLC AUC 4G 1000 mg/m2, d1 & 8PL q3w until progressionCG for 6 (up to 10) cyclesC AUC 4G 1000 mg/m2, d1 & 8CG + BVBV 15 mg/kg q3w until progressionCG + PL(n=242)CG + BVEvents, n (%)187 (77)151 (62)Median PFS, months (95% CI)8.4(8.3–9.7)12.4(11.4–12.7)Stratified analysis HR (95% CI)Log-rank p-value0.484(0.388–0.605)<0.0001Carbo/gem from AGO trial (identical dose and schedule), allowed up to 10 cycles in responding pts.Bev continued until progression in contrast to GOG-0218 and ICON7.All pts had measurable disease as defined by RECIST (older criteria).Stratification by cytoreductive surgery was probably not necessary as all pts had measurable disease – driven by thoughts that treatment paradigm was changing in US.Median OS: 18.0 months → 22.8 months60% power; HR 0.79; 353 eventsInterim OS at time of PFS analysis; α =0.001Final OS will be tested at α =0.049Aghajanian et al. J Clin Oncol; Vol 30;17;201228
29AURELIA trial design & PFS Results Platinum-resistant OCa≤2 prior anticancer regimensNo history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvementChemotherapyTreat to PD/toxicityOptional BEV monotherapycRBEV 15 mg/kg q3wb + chemotherapyTreat to PD/toxicityInvestigator’s choice (without BEV)1:129
31ICON 6Cediranib with Platinum-based Chemotherapy in platinum-sensitive relapsed ovarian cancerTreatment continued to 18 months or until progression (>18 for patients continuing to benefitContinueplaceboSwitch toMaintenance cediranibChemotherapy + cediranibChemotherapy + placeboArm A(Chemo only)Arm B (Concurrent)Arm C (Maintenance)Relapse > 6 months after completion of first line platinum-based chemotherapyRandomise2 : 3 : 3Cediranib: Tirosin Kinase Inhbitor of VEGFR1,2,3N=456 pts6 Cycles platinum-basedChemotherapyCarboplatin/paclitaxelCarboplatin/GemcitabineSingle agent platinumCediranib x selectivity for VEGFR2. Phase II trials SA activityDose reduced 30mg to 20mg due to toxicity in safety phaseReduction in trial size. Due to AZ discontinuing devpt of cediranib. Required a change in primary endpoint from PFS to OS. Main comparison Arm A vs Arm CBaseline characteristics of interest66% >12month treatment-free interval90% prior paclitaxel5% prior bevacizuamb>80% serous carcinomaChemo- 75% platinum + paclitaxel, 15% platinum-gemcitabine, 11% carboSA456 patients from 63 centres were enrolled; median age 62 years, ECOG performance status 0/1. Baseline characteristics, e.g. previous treatment interval >12 months (67%) were balanced between arms. PFS comparing reference and concurrent+maintenance using a log-rank test gave a p-value of with an associated Hazard Ratio (HR) of 0.57 (95% CI ). Adverse events significantly more common in the cediranib-maintenance arm were hypertension, diarrhoea, hypothyroidism, hoarseness, haemorrhage, proteinuria and fatigue.Maintenance phaseLedermann et al ECCO2013
32Overall survival Chemo. Maint. MaintenanceRestricted mean survival time increases by 2.7 months with maintenance treatment (over two years)ChemotherapyChemo.Maint.OS events, n (%)63 (53.3)75 (45.7)Median, months20.326.3Log-rank testp=0.042HR (95% CI)0.70 (0.51 – 0.99)Test for non-proportionality p=0.0042Restricted means, months17.6Chemo.Maint.Ledermann et al ECCO2013
33AMG-386 is a first-in-class recombinant peptide- Fc fusion protein(peptibody). A peptibody fuses a specific peptide with the Fc region of IgG.AMG 386 suppresses tumor angiogenesis by binding to both angiopoietin-1 and -2 (Ang1 and Ang2), thereby preventing their interaction with the Tie2 receptor1.Phase I study demonstrated that AMG 386 was well tolerated and had a safety profile that was distinct from inhibitors of the VEGF pathway2.AMG386
34Weekly Paclitaxel + Trebananib Recurrent EOC≤ 3 prior anticancer regimensEvaluable or measurable diseaseGOG Performance Status of 0 or 1PFI < 12 monthsTreat to PD/toxicityWeekly Paclitaxel + TrebananibWeekly Paclitaxel +PlaceboR1:1Las pacientes podian haber recibido hasta tres lineas de tratamiento de quimioterapia:38% 1 linea; 38% 2 lineas y un 25% habian recibido 3 lineas previas.El 53% de las pacientes eran PlatinoResistentes.Prior anti-angiogenic therapy — 8 % en ambos brazos46% of patients w ILP>6Months25% 3 previous lines of therapy.Stratification factorsPlatinum-free interval (PFI) (≤ 6 vs. > 6 months)Measurable disease (Yes/No)Region (North America, Western Europe/Australia, Rest of World)Lancet Oncol, 2014 Jul;15(8),
37Crossmab technology allows dual binding capabilities Vanucizumab: RO : A2V CrossMab (Anti-human VEGF-A &Anti-human/murine Ang-2) Molecular characteristicsAnti-VEGF-ABevacizumabAnti-Ang-2LC06Ang-2VEGF-ADATA AT ASCO 2015VHVHVLVLCH1CLRO is a bi-specific monoclonal antibody based on a human IgG1 framework. It is comprised of two different heavy chains and two different light chains. One arm of theantibody binds Angiopoietin-2 (Ang2) and one arm binds Vascular Endothelial Growth Factor A (VEGF-A). Point mutations in the CH3 domain (“Knobs-into-holes”) promotethe assembly of two different heavy chainExchange of the constant part of the heavy chain 1 and constant part of the light chain domains in the Ang2 binding Fab promotethe correct assembly of the two different light chains called the “CrossMab approach”Roche have developed a new method to construct bispecific antibodies. Standard IgG mAbs, such as Avastin bevacizumab and the anti–angiopoietin 2 (ANG2; ANGPT2) antibody LC06 [a], consist of two identical light chain–heavy chain pairs, which each bind to the same antigen.To construct a bispecific IgG-like CrossMab antibody that could bind to two antigens by using two distinct light chain–heavy chain pairs, a two-step modification process was applied.First, a dimerization interface was engineered into the C-terminus of each heavy chain using previously developed Knob-into-hole (KiH) technology [b]. This ensured that only a heterodimer of two distinct heavy chains, one from Avastin and one from LC06, would be efficiently formed.Next, the constant heavy 1 (CH1) and constant light (CL) domains of LC06 were exchanged [c], keeping the variable heavy (VH) and variable light (VL) domains consistent. The exchange of the CH1 and CL domains ensured that the modified LC06 light chain would only efficiently dimerize with the modified LC06 heavy chain, while the unmodified Avastin light chain would only efficiently dimerize with the Avastin heavy chain. Thus only the desired bispecific CrossMab would be efficiently formed.CH2CH3Knobs- into- HolesCrossmab technology allows dual binding capabilitiesClinicalTrials.gov Identifier:NCT
39Angiogenesis In Cervical Cancer Accumulating evidence supports the concept that angiogenesis plays a central role in cervical carcinogenesis and disease progressionTumor neovascularization is associated with an aggressive course in cervical cancer. Vascular markings seen at colposcopy in women with abnormalPapanicolaou tests are hallmarks for invasive disease, and increased microvessel density and strong immunostaining for the endothelialcell marker, CD31, in cervical cancers suggest apoor prognosisCD31 es una proteina expresada en la superficie celular de células endotelialesAtypical vessels on colposcopyCD31 – Intratumoral microvessel densityTewari KS, Monk BJ. Invasive Cervical Cancer. In: Clinical Gynecologic Oncology, 8th ed. DiSaia PJ, Creasman WT (eds). Mosby, 2012.
40Warrant phase III: GOG#240 GOG #227-C: Bevacizumab in the treatment of Recurrent/Metastatic Cervical CancerWarrant phase III: GOG#240Monk BJ et al Gynecol Oncol 2008;108:21S abstr 45
41Carcinoma of the cervix GOG #240: Incorporation of Bevacizumab in the treatment of Recurrent and Metastatic Cervical Cancer SchemaIPaclitaxel 135 or 175 mg/m2 IVCisplatin 50 mg/m2 IVIIIPaclitaxel 175 mg/m2 IVTopotecan 0.75 mg/m2 d1-3Chemo aloneActivated: 4/6/09Closed to accrual: 1/3/121:1:1:1RANDOMIZECarcinoma of the cervixPrimary stage IVBRecurrent/persistentMeasureable diseaseGOG PS 0–1No prior chemotherapy for recurrence(N=452)IIPaclitaxel 135 or 175 mg/m2 IVCisplatin 50 mg/m2 IVBevacizumab 15 mg/kg IVIVPaclitaxel 175 mg/m2 IVTopotecan 0.75 mg/m2 d1-3Q21d Rx to PD, toxicity, CRChemo + Bev135 is over 24 hrsStratification factors:Stage IVB vs recurrent/persistent diseasePerformance statusPrior cisplatin Rx as radiation-sensitizer1º End-Points:If adding BEV to Chemo improves OSIf a non-platinum doublet improves OSIdentifier: NCT41
42Chemotherapy + Bev (n=227) GOG #240:OS for Chemo vs Chemo + BevChemotherapy + Bev (n=227)131 (58)17.0HR=0.71 (97% CI, )P=0.0035Chemotherapy(n=225)Events, n (%)140 (62)Median OS, mos13.30.00.10.184.108.40.206.220.127.116.11.0123624Median follow-up mosProportion SurvivingMonths on StudyTewari KS, et al. N Engl J Med 2014;370:734-43
43Chemotherapy + Bev (n=227) GOG #240:PFS for Chemo vs Chemo + BevChemotherapy + Bev (n=227)183 (81)8.2HR=0.67 (95% CI, )2-sided P=0.0002Chemotherapy(n=225)Events, n (%)184 (82)Median PFS, mos5.90.00.10.18.104.22.168.22.214.171.124.0361224RR, %36 (CR, n=14)48 (CR, n=28)2-sided P=Proportion Progression-FreeThe improvement in the primary efficacy endpoint of OS was supported by a statistically significant and clinically meaningful improvement in PFS for patients with persistent, recurrent, or stage IVB carcinoma of the cervix.The Kaplan-Meier plot of PFS showed separation of the curves approximately 2 months after randomization in favor of the Chemo Bv group which was maintained over time until approximately 24 months when there were few patients at riskMonths on StudyTewari KS, et al. N Engl J Med 2014;370:734-43
44GOG 240: Chemotherapy in Advanced Cervical Cancer Phase III Studies Median Overall Survival in MonthsCTX vs. CTX BEV*p< 0.0513.3 vs. 17.0*CIS/TOP vs.CIS/PAC10.3 vs. 12.9CIS vs.CIS/TOPMonths126.5 vs. 9.4CIS50 vs.CIS100CIS vs.CIS/IFO7.0 vs. 7.18.0 vs. 8.3*19851997200520092013Courtesy of: Gottfried Konecny MD
45FDA News : For Immediate Release August 14, 2014FDA approves Bevacizumab to treat patients with aggressive and late-stage cervical cancerFirst targeted agent licensed for gynecologic malignancy in the USA
46Endometrial Cancer GOG#0086P Phase II Randomized 1º End-Point: PFS Arm 1:Paclitaxel 175 mg/m2 IV over 3 hours day 1Carboplatin AUC = 6 IV day 1Bevacizumab 15mg/kg IV day 1Maintenance regimen - Bevacizumab 15mg/kg IV every 21 days until disease progression or prohibition of further therapy.Phase II Randomized1º End-Point: PFSN= 349GOG#0086PArm 2:Paclitaxel 175 mg/m2 IV over 3 hours day 1Carboplatin AUC = 5 IV day 1Temsirolimus 25 mg IV days 1 and 8Maintenance regimen – Temsirolimus 25 mg IV weekly. Days 1,8and 15 until disease progression or prohibition of further therapy.Eligibility:Stage III or IVA EC measurable diseaseStage IVB or Recurrent EC (whether there is measurable disease or not)No prior ChemotherapyArm 3:Ixabepilone 30 mg/m2 IV over 1 hour day 1Carboplatin AUC = 6 IV day 1Bevacizumab 15mg/kg IV dayMaintenance regimen - Bevacizumab 15mg/kg IV every 21 daysuntil disease progression or prohibition of further therapy.PI: Carol Aghajanian, M.D.From: 9/14/2009 to 9/9/2014ClinicalTrials.gov Identifier:NCT
47Anti-Angiogenic Therapy in GYNT: Conclusions There is a strong rationale.Four clinical trials incorporating BEV in first line and recurrence :Level 1 evidence( EMA Approved)Meaningful differences in PFSOS benefit in ICON-7 High-Risk groupPazopanib Trial has a poor therapeutic index( benefit/toxicity)Trinova- 1 trial met its 1º End-Point: PFSResults from GOG240 have led to a new standard of care in Metastatic/ Recurrent Cervical CancerAntiangiogenic Therapy is here to stay.