CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: December 13, 2023
Expiration: December 12, 2024
Studies of Interest Presented at ESGO for Endometrial Cancers
Domenica Lorusso, MD, PhD:
Thank you, Dr Colombo. At ESGO 2023, key studies were presented for cervical cancers. I would like to start by covering key data presented for endometrial cancer.
Long-term Follow-up From SIENDO: Selinexor vs Placebo Maintenance in TP53wt Advanced/Recurrent EC
Domenica Lorusso, MD, PhD:
At ESGO 2023, we saw new data presented for the long-term follow-up from the phase III ENGOT-EN5/GOG-3055/SIENDO study evaluating the XPO1 inhibitor selinexor vs placebo maintenance in patients with metastatic or first relapse advanced endometrial cancer, including endometrioid, serous, undifferentiated, or carcinosarcoma, who are currently in partial response/complete response after 12 weeks or longer of first-line carboplatin/taxane (N = 263).19 The primary endpoint of improving PFS per investigator was previously reported at ESGO 2022 and showed an improvement in median PFS for selinexor vs placebo maintenance in patients with TP53wt (HR: 0.375; P = .0003) and the ITT population (HR: 0.705; P = .024).20
During ESGO 2023, Pérez-Fidalgo and colleagues reported PFS in prespecified exploratory TP53wt and TP53-mutated/abnormal (mut/abn) subgroups after 25.3 months and 22.9 months of follow-up, respectively.
Long-term Follow-up From SIENDO: Selinexor vs Placebo Maintenance in TP53wt Advanced/Recurrent EC
Domenica Lorusso, MD, PhD:
In the updated analysis from SIENDO, the long-term median PFS results for the TP53wt population were much improved with selinexor vs placebo maintenance at 27.4 months vs 5.2 months (HR: 0.42; 1-sided P = .0003). By contrast, in the TP53mut/abn population, there was no benefit with selinexor but potentially a detrimental effect, with median PFS of 4.2 months vs 5.4 months with placebo (HR: 1.34; 1-sided P = .9202).
Long-term Follow-up From SIENDO: PFS in TP53wt Based on Microsatellite Status
Domenica Lorusso, MD, PhD:
In the subgroup of patients with TP53wt and microsatellite stable/mismatch repair proficiency, the median PFS after 27.2 months of follow-up was not reached with selinexor (95% CI: 20.8 months-NR) and was 4.9 months (95% CI: 2.0 months-NR) with placebo (HR: 0.32; 1-sided P = .0006). By contrast, although improved overall, the magnitude of median PFS benefit after 22.6 months of follow-up was lower in the TP53wt and microsatellite unstable/mismatch repair deficient population at 13.1 months vs 3.7 months (HR: 0.45; 1-sided P = .0643) in favor of selinexor.
Long-term Follow-up From SIENDO: TEAEs
Domenica Lorusso, MD, PhD:
Overall, the safety profile of selinexor was manageable and in line with previous reports. In this long-term follow-up, the most common grade 3/4 treatment-emergent AEs reported with selinexor were neutropenia (18.4% vs 0%), nausea (11.8% vs 0%), thrombocytopenia (9.2% vs 0%), and fatigue (7.9% vs 0%), which can easily be managed in the clinic.
Global, Open-Label Phase I/IIa of HER2-Targeting ADC (DB-1303) in Recurrent/Metastatic EC: Study Design
Alexandra Leary, MD, PhD:
Another key study in endometrial cancer presented at ESGO was the phase I/IIa study of the HER2‑targeting antibody–drug conjugate known as DB‑1303 in patients with immunohistochemistry or next-generation sequencing (NGS)–documented HER2-positive or HER2-expressing recurrent or metastatic endometrial cancer (N = 463).21
At ESGO 2023, Moore and colleagues presented data from cohort 2b of this phase I/IIa study of DB‑1303 in patients with endometrial cancer (including uterine carcinosarcoma and uterine serous carcinoma) who were HER2 positive by preexisting assessment or fresh biopsy testing (defined as positive if immunohistochemistry 3+, 2+, or 1+ and in situ hybridization positive, or HER2-amplification by NGS). The objectives in the phase II portion included safety, tolerability, and efficacy, pharmacokinetics, and antidrug antibodies. Women with HER2-positive endometrial cancer (n = 32) had previously treated disease and were assigned to receive the recommended phase II dose of DB-1303 of 8 mg/kg. Approximately 60% of the patients had received immunotherapy and 35% already had a previous anti-HER2 antibody–based therapy.
Phase I/IIa of DB-1303: Efficacy Summary
Alexandra Leary, MD, PhD:
DB-1303 had very promising activity in this heavily pretreated population with an ORR of approximately 60% overall—also remarkable because this cohort included carcinosarcomas. In the 8-mg/kg group, the unconfirmed ORR was 62%; in the 7-mg/kg group, the unconfirmed response was 50%; and the unconfirmed disease control rate was 94%. Again, these are very encouraging data for this novel antibody–drug conjugate targeting HER2.
Phase I/IIa of DB-1303: Safety Summary
Alexandra Leary, MD, PhD:
Treatment-emergent AEs were reported in approximately 94% of patients overall, with grade ≥3 AEs reported in 32% of patients. Serious treatment-related AEs leading to dose reduction and dose interruptions occurred in 3% and 6% of patients, respectively. There were no patient deaths reported.
Bevacizumab Subgroup Analysis Based on Protocol Specified Final OS From KEYNOTE-826: Study Design
Domenica Lorusso, MD, PhD:
At ESGO 2023, I presented data from subgroup analyses by bevacizumab use from a protocol-specified final OS results of the phase III KEYNOTE-826 trial comparing the addition of pembrolizumab or placebo to standard-of-care chemotherapy with or without bevacizumab in patients with advanced recurrent or metastatic cervical cancer (N = 617).22
As you may recall, in KEYNOTE-826, bevacizumab was given according to the physician preference and was not mandatory for all the patients. Overall, 63% of patients received bevacizumab. The most frequent reasons for not receiving bevacizumab were clinical including potential gastrointestinal fistula (~35%), hemorrhage (~5%), and new or worsening hypertension (31% to 36%).
Bevacizumab Subgroups From KEYNOTE-826: PFS by Bev Use in PD-L1 CPS ≥1 Population
Domenica Lorusso, MD, PhD:
Looking at PFS in the PD-L1 combined positive score (CPS) ≥1 population and with bevacizumab use, we saw a remarkable increase in median PFS in the pembrolizumab-containing arm vs placebo-containing arm (15.3 vs 10.3 months; HR: 0.56).
By contrast, those without bevacizumab use experienced much lower median PFS benefit at 7.0 months vs 6.0 months (HR: 0.61). Looking at the 12-month and 24-month PFS rates, we saw remarkable improvement with the addition of pembrolizumab regardless of bevacizumab use and at both time points.
Bevacizumab Subgroups From KEYNOTE-826: OS by Bev Use in PD-L1 CPS ≥1 Population
Domenica Lorusso, MD, PhD:
Median OS in the PD-L1 CPS ≥1 population and with bevacizumab use was also improved (43.9 vs 23.0 months; HR: 0.60). Similarly, those without bevacizumab use experienced improved median OS benefit at 17.5 months vs 11.9 months (HR: 0.61). The 12-month and 24-month OS rates were higher with the addition of pembrolizumab regardless of bevacizumab use.
Bevacizumab Subgroups From KEYNOTE-826: PFS by Bev Use in All-Comer Population
Domenica Lorusso, MD, PhD:
In the all-comer population with bevacizumab use, here as well we see a remarkable increase in median PFS in the pembrolizumab containing arm vs placebo containing arm (15.2 vs 10.2 months; HR: 0.57). By contrast, those in the all-comer population without bevacizumab use experienced much lower median PFS benefit at 6.3 with pembrolizumab vs 6.2 months with placebo (HR: 0.69). When we look at the 12-month and 24-month PFS rates, we saw remarkable improvement with the addition of pembrolizumab regardless of bevacizumab use and at both time points.
Bevacizumab Subgroups From KEYNOTE-826: OS by Bev Use in All-Comer Population
Domenica Lorusso, MD, PhD:
Median OS in the all-comer population and with bevacizumab use was 37.6 in the pembrolizumab-containing arm vs 22.5 months in the placebo arm (HR: 0.61). Similarly, those without bevacizumab use experienced improved median OS of 17.1 months vs 12.6 months (HR: 0.67). Here as well, the 12-month and 24-month OS rates were improved with pembrolizumab regardless of bevacizumab use.
Bevacizumab Subgroups From KEYNOTE-826: Responses
Domenica Lorusso, MD, PhD:
In the PD-L1 CPS ≥1 population with bevacizumab or without bevacizumab, the ORR with the addition of pembrolizumab were approximately 77% and 53%, respectively, compared with 61% and 33% for those receiving placebo.
In the all-comer population with bevacizumab or without bevacizumab, the ORR with the addition of pembrolizumab were approximately 76% and 50%, respectively, compared with 62% and 35% for those receiving placebo.
Bevacizumab Subgroups From KEYNOTE-826: TRAE (≥20%)
Domenica Lorusso, MD, PhD:
The most commonly reported AEs with pembrolizumab vs placebo arms for patients who also received bevacizumab were alopecia (56% vs 61%), anemia (41% vs 38%), nausea (34% vs 37%), and hypertension (29.6% vs 28.5%). The most common AEs in the pembrolizumab cohort without bevacizumab vs placebo were alopecia (54% vs 46%), anemia (61% vs 50%), and nausea (34% vs 41%).
Of importance, the addition of pembrolizumab did not significantly increase the toxicities associated with bevacizumab when compared with placebo (eg, hypertension, 11% vs 13%; gastric perforation, 2.5% vs 1.5%; pelvic fistula, 2.5% vs 4.7%; other fistula, 0.5% vs 1.5%; or embolism, 0.5% vs 1.0%).
Weekly DD-CT + Bev vs Q3W CT + Bev as First Line in High-Risk Epithelial OC (ICON8B): Study Design
Domenica Lorusso, MD, PhD:
Another study I would like to comment on was presented for ovarian cancer at ESGO 2023 by Clamp and colleagues and later highlighted at IGCS 2023 by Lederman and colleagues.23 The phase III ICON8B study compared carboplatin, paclitaxel, and bevacizumab every 3 weeks (Q3W; arm B1) against dose-dense weekly paclitaxel plus bevacizumab Q3W (arm B3) in patients with newly diagnosed high-risk epithelial ovarian cancer, either stage III (with residual disease or requiring new adjuvant chemotherapy) or stage IV (N = 590).24 In ICON8B, arm B2, evaluating dose-dense weekly paclitaxel without bevacizumab, was discontinued because of futility. The primary endpoint of the ICON8B study was PFS per study redesign, defined as a target HR of 0.75 for PFS at 87% power.
ICON8B: PFS
Domenica Lorusso, MD, PhD:
We previously saw several trials report negative results in the White patient population exploring dose-dense weekly paclitaxel.25,26 But to our surprise, ICON8B reported a significant increase in median PFS in patients with high-risk disease receiving the dose-dense weekly paclitaxel vs Q3W paclitaxel (22.2 vs 16.7 months; HR: 0.75; P = .002).
ICON8B: PFS in Subgroups
Domenica Lorusso, MD, PhD:
Looking at the forest plot analyses, most patients experienced benefit. The populations with the most benefit, although not statistically significant, included those with no previous surgery/deferred primary surgery/inoperable and those with stage III disease.
ICON8B: OS (Interim Analysis)
Domenica Lorusso, MD, PhD:
When we look at median OS, in the interim analysis, there was a 10.2-month improvement in favor of dose-dense weekly paclitaxel vs Q3W paclitaxel (51.1 vs 40.9 months; HR: 0.77; P = .020).
ICON8B: Key AEs
Domenica Lorusso, MD, PhD:
The most common grade ≥3 AEs included anemia, febrile neutropenia, and peripheral sensory neuropathy, which were relatively comparable between treatment arms. I would conclude that Q3W paclitaxel and dose-dense weekly paclitaxel do not appear to differ substantially, although hypertension appears to be slightly higher in arm B1 compared with arm B3. These results are quite puzzling because both of these groups received bevacizumab at the same dose and schedule. However, we know that most patients delayed surgery, and for these high-risk patients, it appears that both treatment modalities were comparable.
ICON8B Discussion and Implications for Current Practice
Alexandra Leary, MD, PhD:
Dr Lorusso, as you alluded to, the data become confusing with the phase III JGOG 3016 study (NCT00226915) in patients of Japanese descent,27 showing that weekly paclitaxel and carboplatin is better than conventional Q3W, and European study that notes there is no difference (ICON8).26 What are your thoughts? Should new results from ICON8B change our practice or not?
Domenica Lorusso, MD, PhD:
It is difficult to change the standard of care, which I should note has been in place for more than 20 years, based on the results of one new trial reporting positive data―which appear to be inconsistent with respect to what we have seen until now. I believe that the reason ICON8B is positive whereas others were not because of a different patient population. Here we are talking about a very high–risk population with many receiving neoadjuvant chemotherapy and interval debulking surgery, and more than 40% of them were stage IV. Another hypothesis of mine is that dose-dense weekly paclitaxel may also perform as an antiangiogenic agent, particularly in patients with a high volume of disease and vascularization.
At this time, I could not say dose-dense paclitaxel is a new standard of care. I say this because the standard of care now also includes a PARP inhibitor with or without bevacizumab, which was not part of the design of this study.
Alexandra Leary, MD, PhD:
Thank you for your answer, Dr Lorusso.
HRD Testing on Cell-Free Tumor DNA From Peritoneal Fluid of Patients With Newly-Diagnosed EOC
Alexandra Leary, MD, PhD:
It is not always feasible to perform BRCA mutation and genomic instability testing on formalin-fixed paraffin-embedded (FFPE) tumor samples. These samples are often small or of poor quality, and often we obtain noncontributive test results leading to approximately 15% of our patients lacking information on HRD status. We also know that blood-based cell-free DNA is not ideal, but another potential source of liquid biopsy in advanced epithelial ovarian cancer is peritoneal fluid. At ESGO 2023, I presented a study of HRD testing using cell‑free tumor DNA extracted from peritoneal fluid of patients with newly diagnosed epithelial ovarian cancer.
In a preliminary feasibility study, we demonstrated that with just 20 mL of peritoneal fluid, we could obtain high-quality cell‑free DNA to perform NGS. The aim of the study was to prospectively validate our findings in a larger group of patients with newly diagnosed epithelial ovarian cancer who underwent diagnostic laparoscopy or who had been diagnosed elsewhere and came to us after 3 cycles of chemotherapy and had a diagnostic laparoscopy again (N = 53).
HRD Testing on Cell-Free Tumor DNA: Sample Characteristics, Quantity, and Quality
Alexandra Leary, MD, PhD:
In most patients, we successfully collected ≥20 mL of peritoneal fluid and we confirmed it originated from the tumor with TP53 pathogenic variant in the sample. We obtained high-quality cell‑free DNA samples (peaks around 160 pb, 360 pb, and 520 pb), including on peritoneal lavage.
HRD Testing on Cell-Free Tumor DNA: Detection of Pathogenic Variants in Tumor Sample
Alexandra Leary, MD, PhD:
Pathogenic variant testing for TP53 mutation confirmed cell-free DNA originated from the tumor. We found BRCA1/2 mutations in 24% of the samples and, including in 1 patient whose matched FFPE sample did not identify a BRCA1/2 mutation. Of importance, 100% of genome identification signature and shallow whole genome sequencing from peritoneal fluid cell-free tumor DNA yielded contributive results vs only 73% of matched FFPE samples and reduced testing turnaround time from 43 to 21 days. All genome identification signature and shallow whole genome sequencing tumor cell-free tumor DNA samples yielded contributive information. FFPE sample analysis by MYRIAD/Genomic Identification Signature yielded 73% contributive results and 27% noncontributive or pending at the time of this analysis.
HRD Testing on Cell-Free Tumor DNA: Implications
Alexandra Leary, MD, PhD:
To my knowledge, this is the first study showing that we can obtain high-yield and high-quality cell-free tumor DNA from 20 mLs of peritoneal fluid from epithelial ovarian cancer to perform clinically meaningful HRD testing. These results also allow us to set FFPE samples aside for later biomarker testing if we need to and potentially evolve our diagnostic pathways for newly diagnosed advanced epithelial ovarian cancer.
Back
