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ESGO: Key Gyn Data
Insight on Key Data From the 2023 ESGO Annual Congress Informing Treatment for Endometrial, Cervical, and Ovarian Cancers

Released: October 27, 2023

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Key Takeaways
  • In metastatic or first relapse advanced endometrial cancer, selinexor maintenance following partial response/complete response to 12 weeks or longer of first-line carboplatin/taxane yields remarkable improvement in PFS in patients with TP53 wild type.
  • The novel anti-HER2 ADC DB-1303 yields promising efficacy and has manageable safety profile in patients with previously treated HER2-positive advanced endometrial cancer, including in those previously receiving anti-HER2 antibody.
  • Pembrolizumab with chemotherapy with or without bevacizumab is the new standard for patients with advanced/recurrent or metastatic cervical cancer with PD-L1 CPS ≥1, including those who discontinue bevacizumab because of AEs.

In this commentary, adapted from a discussion between Domenica Lorusso, MD, PhD, and Alexandra Leary, MD, PhD, the experts share their thoughts on key new clinical data and updates presented at the 2023 European Society of Gynaecological Oncology (ESGO) annual congress. Experts also share their opinion on how these some of these results could potentially change current clinical practice.

Endometrial Cancer
 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 (EC), 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). The primary endpoint of improving progression-free survival (PFS) per investigator was previously reported at ESGO 2023 and showed an improvement in median PFS for selinexor vs placebo maintenance in patients with TP53wt (HR: 0.375; P = .0003) and the intention-to-treat population (HR: 0.705; P = .024). During ESGO 2023, Pérez-Fidalgo reported PFS in prespecified exploratory TP53–wild-type (wt) and TP53-mutated/abnormal (mut/abn) subgroups after 25.3 months and 22.9 months of follow-up, respectively.

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). 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 and 4.9 months 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.

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 adverse events (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.

Alexandra Leary, MD, PhD:
Another key study in endometrial cancer was the phase I/IIa study of the HER2‑targeting antibody–drug conjugate (ADC) known as DB‑1303 in patients with immunohistochemistry (IHC) or next-generation sequencing (NGS)–documented HER2-positive or HER2-expressing recurrent or metastatic endometrial cancer (N = 463). At ESGO 2023, Kathleen Moore 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 IHC 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.

DB-1303 had very promising activity in this heavily pretreated population with an overall response rate (ORR) of 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 ADC targeting HER2.

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.

Cervical Cancer
 Domenica Lorusso, MD, PhD:
At ESGO 2023, I presented data from subgroup analyses by bevacizumab use from protocol-specified final overall survival 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).

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%).

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. 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.

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 intention-to-treat 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. 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.

In the PD-L1 CPS ≥1 population with bevacizumab or without bevacizumab, the ORR with the addition of pembrolizumab were 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 76% and 50%, respectively, compared with 62% and 35% for those receiving placebo.

The most commonly reported toxicities 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 increase or 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%).

Ovarian Cancer
 Domenica Lorusso, MD, PhD:
Now I would like to move on to talk about key new data presented for ovarian cancer at the congress. During ESGO 2023, Professor Andrew Clamp presented data from the phase III ICON8B study comparing carboplatin, paclitaxel, and bevacizumab every 3 weeks (Q3W; Arm B1) vs with 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)—a very high-risk population. Arm B2, with dose-dense weekly paclitaxel without bevacizumab, was discontinued because of futility. The primary endpoint of the study was PFS per study redesign, defined as a target HR of 0.75 for PFS at 87% power.

We previously saw several trials report negative results in the White patient population exploring dose-dense weekly paclitaxel. 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). Looking at the forest plot analyses, most patients experienced benefit, but the populations with the most benefit, although not statistically significant, included those with no previous surgery/deferred primary surgery/inoperable and stage III disease. When we look at median OS, 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).

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 a bit higher in Arm B1 compared with Arm B3. These results are quite paradoxical 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.

Alexandra Leary, MD, PhD:
Dr. Lorusso, as you alluded to, the data become confusing with the phase III JGOG 3016 study (NCT00226915) in Japanese patients showing that weekly paclitaxel and carboplatin is better than conventional Q3W, and European study that notes there is no difference. 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 is 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 would 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:
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 homologous recombination deficiency (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 (EOC) is peritoneal fluid. At ESGO, I presented a study of HRD testing using cell‑free tumor DNA extracted from peritoneal fluid of patients with newly diagnosed EOC.

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 EOC 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).

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.

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.

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 EOC 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 EOC.

Your Thoughts?
What are your thoughts on current advances and trial results presented at recent gynecologic cancer meetings for endometrial, cervical, and ovarian cancers? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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