Mammakarzinom/ Gynäkologische Malignome (Ovar, Uterus)

V69 Machbarkeitsstudie eines indirekten Behandlungsvergleichs und bevölkerungsbereinigten indirekten Behandlungsvergleichs von Niraparib, Olaparib und Bevacizumab als Erhaltungstherapien bei Frauen mit neu
diagnostiziertem fortgeschrittenem Eierstockkrebs

Klaus Baumann, Ludwigshafen am Rhein, D

Although randomized controlled trials (RCTs) have demonstrated the benefit of PARP inhibitors and bevacizumab as monotherapies and combination therapies, there is limited direct head-to-head evidence of their relative clinical efficacy. The objectives of the study were to assess feasibility of an indirect treatment comparison (ITC) and a population-adjusted indirect treatment comparison (PAIC) for estimating the relative efficacy of niraparib compared with olaparib, olaparib plus bevacizumab, and bevacizumab as maintenance therapy following first-line chemotherapy in ovarian cancer. The study focused on fully powered statistical cohorts.

Trials included in the ITC analysis were based on a systematic literature review conducted in February 2020. Guidelines from the Cochrane Handbook for Systematic Reviews of Interventions were used to assess the level of heterogeneity. The feasibility of PAIC for the PRIMA and PAOLA-1 trials was assessed based on assumptions outlined in the guidance by the Decision Support Unit in NICE DSU Technical Support Document 18; progression-free survival (PFS) was the outcome for the analysis.

All 12 RCTs assessed for ITC feasibility were excluded based on various factors including: lack of a common comparator with PRIMA within the network (ICON-7, GOG-0218, PAOLA-1, VELIA/GOG-3005); differing measurement of PFS and overall survival starting time point (ICON-7, GOG-0218, VELIA/GOG-3005); inclusion of stage III patients with no visible residual disease following debulking surgery (PAOLA-1, SOLO-1, VELIA/GOG-3005); and disparity between disease biomarkers (SOLO-1).

For PAIC, 3 fundamental differences between the PRIMA and PAOLA trials were identified: inclusion criterion related to residual disease violated the “conditional constancy of absolute effects”; receipt of neoadjuvant chemotherapy was identified as a confounding factor; discrepancies in assessment of type and frequency of measurement of PFS outcome.

Based on the currently available evidence, neither an ITC nor a PAIC would meet current guidelines, such as those outlined by the International Society for Pharmacoeconomics and Outcomes Research. Their results would not be considered appropriate evidence for use in clinical decision making or reimbursement decisions. The extent of imbalance caused by differences in patient inclusion/exclusion criteria for intended comparisons is unknown and a recognized limitation of PAICs.

Encore statement: Data presented on behalf of the original authors with their permission. Presented at the European Society for Gynecological Oncology (ESGO) State of the Art Conference, December 14-16, 2020, virtual.


V408 Erhöhte Frequenz PD1+TIGIT+CD73-Vδ1+ T-Zellen im neu diagnostizierten Ovarialkarzinom

Pauline Weimer, Hamburg, D

Introduction: Ovarian cancer (OC) is a highly aggressive disease with an overall 5 year survival rate of 48%. There is upcoming clinical evidence that the presence of T-cells in ovarian tumors strongly correlates with improved survival, suggesting that ovarian cancer patients may benefit from immunotherapeutic strategies. Little is known about the γδ T-cell population - especially of their coinhibitory receptor ligand interactions with tumor cells. In this study, we analyzed γδ T-cells to design future targeted therapeutic concepts that will be able to overcome immune escape.

Methods: We performed 16-color, multiparameter flow cytometry (MFC) on mononuclear cells of the peripheral blood (PB) and malignant ascites (MA) of 10 patients with newly diagnosed OC and PBMCs of 10 aged-matched healthy donors (HDs), looking at different γδ T-cell subpopulations, the activation (OX40), differentiation (CD45RA, CD27), and exhaustion (PD-1, TIGIT, TIM3) status, as well as the expression of purinergic signaling molecules (CD39, CD73).

Results: The frequency of Vδ1 T-cells was increased in MA whereas the Vδ2 T-cell population was increased in PB of patients with OC (MA vs. PB 64.6% vs. 42.8%; p=0.002 and MA vs. PB 29.2% vs. 46.2%; p=0.004). The subpopulations varied in ascites and peripheral blood: the frequencies of EMRA Vδ1 (CD27-CD45RA+(hi)) were increased in MA and PB, respectively (EMRA MA Vδ1 vs. Vδ2: 49.0% vs. 8.4%; p=0.002 and EMRA PB Vδ1 vs. Vδ2 60.4% vs. 13.5%; p=0.004). Moreover, TIGIT and PD1 emerged as checkpoints of interest on Vδ1 T-cells. The frequency of TIGIT+ and PD1+ Vδ1+ T-cells was increased in contrast to Vδ2 T-cells in MA (77.6% vs. 14.1%; p=0.002 and 21.2% vs. 6.3%; p=0.006) as well as in PB from patients with newly diagnosed OC (82.7% vs. 10.9%; p=0.002 and 8.0% vs. 4.6%; p=0.04). To further evaluate the exhaustion status, coexpression analysis revealed an increased subpopulation of TIGIT+PD1+CD73-Vδ1+ T-cells in MA in contrast to PB (MA vs. PB 32.1% vs 17.5%; p=0.006), whereas the Vδ2 T-cells displayed lower coexpression of the checkpoint receptors.

Conclusion: In summary, we could show that in MA from patients with newly diagnosed OC, an aberrant γδ T-cell population of PD1+TIGIT+CD73- Vδ1+ T-cells is prevalent in contrast to PB. Based on these data, we are currently carrying out functional assays to evaluate the role of TIGIT and PD1 on Vδ1+ T-cell function with regard to the boosting of anti-ovarian cancer immune responses.


V131 Auswertung von Sacituzumab Govitecan (SG) bei Patienten (pts) mit metastasiertem triple-negativem Mammakarzinom (mTNBC) in der Phase 3 ASCENT Studie, nach vorheriger neoadjuvanter/adjuvanter Chemotherapie
Susanna Hegewisch-Becker, Hamburg, D

Introduction: mTNBC is a heterogenous disease with few treatment options and poor outcomes. Pts who recur ≤12 mo after completing (neo)adjuvant chemotherapy may have more aggressive disease. SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. Clinical benefit for SG over treatment of physician's choice (TPC) was confirmed in the phase 3 ASCENT study (NCT02574455; median progression-free survival [PFS; 5.6 vs 1.7 mo], median overall survival [OS; 12.1 vs 6.7 mo], objective response rate [ORR; 35% vs 5%]), clinical benefit rate [CBR; 45% vs 9%], and median duration of response [6.3 vs 3.6 mo]). This ASCENT subanalysis assessed the benefit of SG in pts with mTNBC who recurred ≤12 mo after (neo)adjuvant chemotherapy and received 1 line of therapy in the metastatic setting.

Methods: Pts with mTNBC refractory/relapsing after ≥2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine). Per protocol, a pt was eligible after 1 prior regimen in the metastatic setting if their disease recurred within 12 mo of completing (neo)adjuvant therapy. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts.

Results: In total, 33 and 32 BMNeg pts (median age, 49 and 51 y) received SG and TPC, in this subgroup of pts with mTNBC who recurred ≤12 mo after (neo)adjuvant chemotherapy and received 1 line of therapy in the metastatic setting, respectively. In this subgroup, SG (vs TPC) treatment improved median PFS (5.7 vs 1.5 mo; HR, 0.41), median OS (10.9 vs 4.9 mo; HR, 0.51), ORR (30% vs 3%), and CBR (42% vs 6%), with a median response duration (SG vs TPC) of 6.7 mo vs not calculable. Efficacy outcomes from this subgroup are similar to those for SG vs TPC in the overall BMNeg population. The safety profile of SG in pts in this subgroup was consistent with prior reports. There were no treatment- related deaths with SG.

Conclusions: Pts with mTNBC who recurred ≤12 mo after (neo)adjuvant therapy and had 1 line of prior therapy in the metastatic setting may have more aggressive disease. In this subgroup, pts had superior outcomes with SG vs TPC in the second-line metastatic setting, consistent with the benefit seen in the overall BMNeg population. Studies are ongoing (NeoSTAR, NCT04230109; SASCIA, NCT04595565) to evaluate SG as an earlier-line treatment option for TNBC.


V540 Aktualisierte Ergebnisse von Tucatinib versus Plazebo in Kombination mit Trastuzumab und Capecitabin (HER2CLIMB-Studie) bei PatientInnen mit vorbehandeltem HER2-positiven metastasierten Brustkrebs mit und ohne Hirnmetastasen

Volkmar Müller, Hamburg, D

Background: Tucatinib (TUC) is an oral tyrosine kinase inhibitor (TKI) highly specific for HER2. TUC is approved for use in combination with trastuzumab (T) and capecitabine (C) in patients (pts) with HER2+ metastatic breast cancer, with and without brain metastases (BM), who have received 2 prior anti- HER2-based regimens. In the primary analysis from the pivotal HER2CLIMB trial, the addition of TUC to T and C in pts with HER2+ metastatic breast cancer showed a statistically significant and clinically meaningful prolongation of progression-free survival (PFS) (HR=0.54 [95% CI: 0.42, 0.71]; P< 0.001) and overall survival (OS) (HR=0.66 [95% CI: 0.50, 0.88]; P=0.005) (Murthy, et al. NEJM 2020). TUC in combination with T and C was well tolerated with few discontinuations other than for disease progression. Based on these data, the protocol was amended for unblinding of sites to treatment assignment to allow for crossover from the placebo arm to receive TUC in combination with T and C.

Methods: HER2CLIMB (NCT02614794) is a global, randomized, double-blind, placebo-controlled trial in pts with unresectable locally advanced or metastatic HER2+ breast cancer previously treated with T, pertuzumab, and T-emtansine (T-DM1), including pts with untreated, treated stable, or treated and progressing BM. Overall 612 pts were randomized 2:1 to receive TUC 300 mg BID or placebo, each in combination with T and C. Randomization was stratified by BM, ECOG performance status, and geographic region. Protocol prespecified analysis of OS, PFS (by investigator assessment) and safety in the total study population will be performed at approximately 2 years from the last patient randomized.

Results: Updated Kaplan-Meier time-to-event analysis of OS and PFS with hazard ratios and 95% confidence intervals for TUC arm vs placebo arm will be presented overall, as well as for OS in the prespecified subgroups reported previously. Safety and tolerability assessments will include frequency of adverse events by severity, dose modifications and discontinuation of study medications.

Conclusions: Conclusions will be presented in the presentation.


V519 Der kollaborative Review von ePROs für die gemeinsame Berichterstattung bei Brustkrebspatientinnen wirkt sich positiv auf die Anzahl der Symptomeinträge in der Consilium Care App aus
Andreas Trojan, Zürich, CH

Aims: Digital monitoring of treatment related symptoms and patient self-reported outcome gain importance for quality of care in cancer. Here we compare the utility of two versions of a subsequently employed mobile application (app) for monitoring of electronically captured patient-reported outcome (ePRO), and test our hypothesis that an intended shared review of symptoms in patient-physician collaboration creates an impact on the number of data entries.

Materials and methods: The "Consilium Care" app engages cancer patients for standardized reporting of wellbeing and treatment related symptoms in outpatient settings. For descriptive comparison of utility of two slightly different app versions information was made available from an early breast cancer trial (app version 1) and an ongoing study also including patients with advanced disease (version 2). In both app versions, patients and doctors were allowed to share the information from data entries during consultations. App version 2, however, randomly selected symptoms with request for a detailed and shared regular patient-doctor review in order to focus on collection and appropriate interpretation regarding awareness and guidance for severity grading. Number and type of symptom entries, satisfaction with both app versions and patients` perceived effects during consultations were included for the analysis.

Results: Symptom severity grading according to CTCAE was performed using a horizontal slider and indicated in descriptive terminology in both apps, while a graphical display facilitated the illustration of symptom history charts. In total, 192 patients electronically reported 11`437 data entries on wellbeing and 33`380 data entries on individual symptoms. 628 (of 872 intended) requested patient-doctor symptom reviews were performed in App version 2. Both, the amount of data entries per patient and day for wellbeing (0.3 vs 1.0; p< 0.001) and for symptoms appeared significantly higher in App version 2 (1.3 vs 1.9 data entries; p=0.04).Overall satisfaction with both app versions was high, although version 2 was perceived in general to be more helpful.

Conclusions: Request of collaborative patient-doctor symptom review is likely to affect the number of digital symptom data entries.