CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: December 13, 2023
Expiration: December 12, 2024
Highlights of Seminal Practice-Changing Studies of Interest Presented at IGCS 2023 for Endometrial, Cervical, And Ovarian Cancers
Brian Slomovitz, MD, MS, FACOG:
As my colleagues discussed before me, in 2023, exciting key data for highly anticipated and practice-changing clinical trials was presented at international conferences around the world, and some of the seminal studies were also highlighted during the 2023 IGCS meeting. Together with my friend and esteemed colleague, Dr Keiichi Fujiwara, I share our takeaways from the most important studies for gynecologic cancer in 2023.
Practice Changing Studies for Endometrial Cancer
Brian Slomovitz, MD, MS, FACOG:
At IGCS we saw seminal data highlighted in endometrial cancer for NRG GY018, RUBY, AtTEnd, and DUO-E.40-43 Three of these studies evaluated the addition of an immune checkpoint inhibitor (ICI) to chemotherapy, and one looked at ICI therapy plus PARP inhibition.
Eskander and colleagues highlighted data previously presented at SGO 2023 for the phase III NRG GY018 study.
In NRG GY018, the 2 prespecified endpoints (ie, in dMMR and pMMR populations) are a key difference in this study compared with other studies, where pMMR status was not a prespecified or powered endpoint.
In the dMMR population, we saw that adding pembrolizumab to chemotherapy in the first-line management is practice changing with unprecedented HRs for median PFS (HR: 0.30). Moreover, in the pMMR population, the HR for median PFS was 0.54. Unfortunately, once the PFS was reported, the trial ended, and OS data will not be part of the final analysis. Investigators also looked at whether methylation status had an effect on response to ICI compared with those who were nonmethylated. And the simple answer is no. It did not matter whether those classified as dMMR were methylated or nonmethylated, and the methylation status did not affect prognosis.
Also highlighted were data for the randomized phase III RUBY trial evaluating carboplatin and paclitaxel with or without dostarlimab followed by dostarlimab or placebo maintenance for 3 years in patients with primary advanced or recurrent endometrial cancer. Again, this was another study that was presented at SGO 2023.
RUBY has a different statistical design than that of NRG GY018. As you may recall, the primary endpoint for RUBY was PFS by the investigator in the dMMR and in the overall population, and OS analysis in the dMMR patients was reported. Similar to NRG GY018, in the dMMR population the HR for median PFS was 0.28 and it was 0.64 in the overall population when adding dostarlimab. These data are unprecedented and is comparable with what we have come to expect with PARP inhibition in the BRCA-mutant ovarian cancer. Although still preliminary, there was a clinically meaningful difference in OS in the dMMR population with an HR of 0.30 if dMMR and 0.64 for the overall population.
What I find most interesting about the RUBY trial were the subgroup analyses by molecular subtypes to see if we could predict responses based on those 4 molecular subtypes (eg, POLE, dMMR, P53, NSMP).44 POLE mutations are the least common subclassification seen with endometrial cancer and it portends the best prognosis, and in this population, it appeared as if adding dostarlimab had no effect. All those patients did well. And as discussed earlier by my colleagues, we saw unprecedented benefit for adding dostarlimab in the dMMR subgroup (HR: 0.31). In the P53-mutated population subgroup, the HR was 0.55. Finally, in the NSMP subgroup, HR was 0.77, but the confidence interval did in fact cross 1. It is important to highlight that this study included carcinosarcomas, and we know based on prior work by Powell that carcinosarcomas should be included in the subgroup of endometrial adenocarcinomas. These were results from small, not prespecified, subgroup analyses but important nonetheless in helping inform which patients would do best with ICI.
Together, I think these results for NRG GY018 and RUBY clearly show that patients with dMMR tumors need immunotherapy to attain the best overall outcome and has now changed the standard of care. We look forward to 2024 for additional data for the RUBY trial.
Another study we saw highlighted at IGCS was the phase III AtTEnd trial evaluating atezolizumab, a PD‑L1 inhibitor, together with the standard of care of carboplatin with paclitaxel followed by atezolizumab maintenance until disease progression vs carboplatin with paclitaxel followed by placebo maintenance in patients with newly diagnosed or recurrent endometrial cancer. As you may recall, the coprimary endpoints were improving PFS per RECIST v1.1 in the dMMR/MSI-H and ITT population, as well as OS.
A key distinction of AtTEnd vs the previous 2 studies was the use of the anti‒PD-L1 atezolizumab. With a median follow-up of 26.2 months, the HR for median PFS was 0.36, and the 12-month and 24-month PFS rates were approximately 63% and 50% in patients receiving atezolizumab vs 23% and 16% in patients receiving placebo.
Although we believe that the AtTEnd OS data for all-comers in the dMMR population are clinically meaningful, we still need to see more mature data (43% maturity to date) to assess how the benefit carries out.
Similar to RUBY, the AtTEnd trial also included carcinosarcomas, but there were more nonendometrioid histologies in RUBY and AtTEnd than NRG GY018. Moreover, the platinum-free interval was ≥6 months in RUBY and AtTEnd and ≥12 months in NRG GY018.
In all, the HRs for PFS were similar among the 3 studies for the dMMR population (0.28, 0.30, and 0.36), with a signal in RUBY subgroups that patients with NSMP/P53wt disease may experience less benefit and opportunity for improvement in pMMR disease, representing an unmet need as we move forward. But how are we doing this? The next study highlighted at IGCS 2023 was DUO-E, which had shown provocative results in the pMMR population.
The phase III DUO‑E trial is exploring the addition of durvalumab, also an anti‒PD-L1, to carboplatin with paclitaxel followed by durvalumab with or without olaparib as maintenance in patients with newly diagnosed, previously untreated stage III/IV or recurrent endometrial cancer (N = 718). The primary endpoint was PFS by RECIST v1.1 with durvalumab with or without olaparib vs the control arm.
Unlike the 3 other studies, DUO-E added PARP inhibitor maintenance to ICI therapy, looking at whether adding olaparib could improve patient outcomes—and the study showed just that. In the ITT population, when comparing the median PFS in the control arm vs the durvalumab arm or the durvalumab plus olaparib arm, we saw a HR of 0.71 (P = .003) and 0.55 (P <.0001). There was a trend in OS favoring durvalumab plus olaparib maintenance compared with durvalumab maintenance or the control arm (HR: 0.59 or 0.77, respectively).
Of importance, in the pMMR population (80%), there appears to be increased benefit for those receiving dual maintenance with durvalumab plus olaparib vs durvalumab alone, also compared with the control arm (HR: 0.57 vs 0.77). The data suggest that this is a group of patients who may in fact benefit from the addition of PARP inhibition.
At IGCS 2023, we also discussed long-term data from the SIENDO trial. As you may recall, SIENDO is a phase III 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). In the long-term follow-up from SIENDO, in median PFS results for the TP53wt population we saw unprecedented improvement with selinexor vs placebo maintenance of 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). Looking deeper into the data, in the subgroup of patients with TP53wt and microsatellite stable/pMMR disease, 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).
Expert Discussion on Seminal Studies Highlighted for Endometrial Cancer at IGCS 2023
Keiichi Fujiwara, MD, PhD:
Thank you, Dr Slomovitz. How will you apply these results for endometrial cancer in your practice? How will you select between immunotherapy agents (eg, pembrolizumab, dostarlimab, atezolizumab, and durvalumab with or without olaparib)?
Brian Slomovitz, MD, MS, FACOG:
Data for durvalumab with or without the PARP inhibitor olaparib (DUO-E) and the atezolizumab data (AtTEnd) were reported recently. Thus, I have not had a chance to incorporate this into my practice. As for the addition of dostarlimab or pembrolizumab to the standard of carboplatin and paclitaxel, I agree with what my colleagues have previously said and I am already using both approaches. I believe the data to be consistent for both agents. With pembrolizumab, efficacy in dMMR and pMMR populations was a prespecified endpoint of the trial, so that may help determine which one to go with. But overall, I think both dostarlimab and pembrolizumab are active agents, and I use them interchangeably in my practice.
Keiichi Fujiwara, MD, PhD:
I think I can agree with that.
Practice Changing Studies for Cervical Cancer
Keiichi Fujiwara, MD, PhD:
I would like to comment on seminal data highlighted at GCS 2023 for localized cervical cancer. As our readers may recall, the current standard of care LACC is chemoradiation using weekly cisplatin.
At IGCS 2023, we saw data highlights from the phase III INTERLACE trial evaluating induction chemotherapy with weekly paclitaxel 80 mg/m2 and carboplatin AUC 2 for 6 weeks given on Days 1, 8, 15, 22, 29, and 36, followed by CRT vs CRT using external-beam radiation in patients with newly diagnosed FIGO 2008 stage IB1N+, IB2, II, IIIB, and IVA squamous, adeno, and adenosquamous cervical cancer (N = 500). The serologic types included squamous, adeno, and adenosquamous cervical cancer; nodes above the aortic bifurcation on the imaging were not allowed; and there was no previous pelvic radiation therapy. The coprimary endpoints were PFS and OS.
Adherence to therapy was good in both groups, and patients tolerated treatments very well, although incidence of hematologic toxicities was more frequent in the induction chemotherapy group. As reported previously for the efficacy data, coprimary endpoints of OS and PFS were met.
The HR for PFS was 0.65 (P = .013), and the 3-year and 5-year PFS rates were 75% and 73% with induction chemotherapy plus CRT vs 72% and 64% with CRT alone. For OS, we saw similar benefit with an HR of 0.61 (P = .04), and the 3-year and 5-year OS rates were 88% and 80% with induction chemotherapy plus CRT vs 80% and 72% with CRT alone.
My perspective is that this type of induction chemotherapy can be easily applied anywhere in the world, so I think it will likely become part of the standard of care.
Another seminal study highlighted at IGCS was the phase III KEYNOTE-A18 trial. As you may recall, KEYNOTE‑A18 evaluated the efficacy and safety for the addition of pembrolizumab to cCRT vs cCRT alone in patients with newly diagnosed high-risk, previously untreated LACC.
In KEYNOTE-A18, approximately 50% of patients were White, 30% were of Asian descent, and 20% comprised other races. More than 55% were stage III and IVA, which is a key difference from the INTERLACE trial, and 85% were node positive; 89% of the patients received high-tech radiation therapy such as intensity-modulated radiation therapy or volumetric-modulated arc therapy.
This was the first interim analysis to evaluate the treatment effects on PFS and OS. The 24-month PFS rate was 67.8% in the arm containing pembrolizumab and 57.3% in the arm with placebo. HR was 0.70 (P = .0020). In subgroup analyses, we saw benefit of adding pembrolizumab across all protocol-specified subgroups.
After median follow-up of approximately 18 months, and although data are not yet mature, the 24-month OS rate was 87.2% with pembrolizumab vs 80.8% with placebo (HR: 0.73). As for the safety analyses, addition of pembrolizumab to cCRT did not result in new safety signals.
Based on this data for KEYNOTE-A18, I believe we have another tool in our armamentarium using pembrolizumab to improve survival outcomes for LACC.
Expert Discussion on Seminal Studies Highlighted for Cervical Cancer at IGCS 2023
Brian Slomovitz, MD, MS, FACOG:
Thank you, Dr Fujiwara. My question for you is what do you plan to do in your practice based on the positive results of INTERLACE and KEYNOTE-A18? Would you use INTERLACE or the KEYNOTE-A18 regimen?
Keiichi Fujiwara, MD, PhD:
For high-risk LACC, I will definitely use the induction chemotherapy based on the INTERLACE regimen, probably in combination with pembrolizumab once this treatment is approved.
Highlighted Studies for Ovarian Cancer: Implications
Keiichi Fujiwara, MD, PhD:
Last, but not least, I would like to move on to a highlighted study presented for high-risk ovarian cancer. Lederman and colleagues23 presented data from the phase III ICON8B study comparing carboplatin, paclitaxel, and bevacizumab Q3W (arm B1) vs 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.
Dose-dense chemotherapy was shown to yield superior PFS and OS in Japanese patients compared with chemotherapy Q3W. However, follow-up studies were not able to show a similar result in White patients. For example, in the GOG-0262 study, using dose-dense chemotherapy with bevacizumab failed to show a survival benefit, and the ICON8 study, using dose-dense chemotherapy without bevacizumab also failed in high-risk ovarian cancer. Nevertheless, primary debulking surgery was performed in 85% of the patient population. When we look at the result from ICON8B, both PFS and OS were better in the dose-dense chemotherapy group. The median PFS was 5.5 months longer (HR: 0.75; P = .002) in the dose-dense chemotherapy vs Q3W group. Median OS was also 10.2 months longer (HR: 0.77; P = .02) in the dose-dense chemotherapy group vs Q3W group. There also were no new safety signals.
My takeaway from ICON8B is that dose-dense chemotherapy remains the standard of care worldwide, not just for Japanese patients, although the Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup had concluded that it was only for Japanese patients. However, whether we should use bevacizumab remains controversial. My personal opinion is that we could go either way at this moment.
Final Thoughts
We are in a very fortuitous moment in the care of gynecologic cancers because of recent advances and novel treatment options entering the treatment paradigm. However, the advent of novel treatment options has inadvertently increased the gap in care for the most vulnerable groups, including underrepresented racial and ethnic minority patients worldwide.
All healthcare professionals must endeavor not only to remain aware of the existing and growing gaps in the delivery of equitable care for patients with gynecologic cancers, but also to do their best to take steps to help patients overcome these barriers.
Working together, all members of the healthcare team—nurses, pharmacists, physicians, and social workers—can help deliver equitable care for all patients regardless of race or socioeconomic status.
To deliver equitable gynecologic cancer care to a diverse and multicultural patient population, we must be able to translate or find interpreters to support and educate patients about their disease, optimal available treatments, and goals and prepare them to recognize and report AEs during their visits or via the health portal. Moreover, we must share with them any available resources from nonprofit organizations or drug manufacturers that could help with molecular or genetic testing and medication assistance as appropriate.
Learn more about novel advances in gynecologic cancer by accessing a downloadable slideset, short expert authored commentaries, and podcasts associated with this discussion, visit the online program page entitled “Key Findings and Expert Recommendations in Gynecologic Malignancies: Independent 2023 Conference/Congress Coverage.”
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