Back Back
ASCO: Key Gyn Data
Expert Commentary and Insight on Key Data From the 2023 ASCO Annual Meeting Informing Treatment for Endometrial, Cervical, and Ovarian Cancers

Released: June 29, 2023

Nicoletta Colombo
Nicoletta Colombo, MD, PhD
Kathleen N. Moore
Kathleen N. Moore, MD, MS, FASCO
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Combination immunotherapy with platinum-based doublet chemotherapy is the new standard of care in previously untreated advanced endometrial cancer with mismatch repair deficient/microsatellite instability‒high status, with benefit also seen in the overall population.
  • Pembrolizumab plus chemotherapy is now established as the new standard first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer, with sustained improvement in PFS and OS outcomes.
  • Combining a PARP inhibitor and durvalumab in advanced ovarian cancer is feasible and yields encouraging outcomes in patients with non‒BRCA-mutated HRD-positive status.

In this commentary, adapted from a discussion between Kathleen Moore, MD, and Nicoletta Colombo, MD, MPH, the experts provide their thoughts on key clinical trial results presented at the 2023 ASCO Annual Meeting. Experts also share their opinion on how these results could be incorporated into clinical practice for patients with ovarian, cervical, and endometrial cancers.

Ovarian Cancer

Kathleen Moore, MD:
At ASCO 2023, I presented the results from the global, open-label, randomized phase III MIRASOL trial comparing the antibody‒drug conjugate mirvetuximab soravtansine vs investigator’s choice of chemotherapy in patients with platinum‑resistant recurrent ovarian cancer with high expression of folate receptor α (FRα; N = 453). Patients could be enrolled on the MIRASOL study if they had 1-3 previous lines of chemotherapy; they could have previously received bevacizumab, but it was not required. The primary endpoint was progression‑free survival (PFS) measured by the investigator. Key secondary analytic endpoints were overall response rate (ORR) and overall survival (OS), as well as patient‑reported outcomes (PROs).

The primary endpoint was met. We showed statistically significant and clinically meaningful PFS improvement for the mirvetuximab soravtansine arm vs chemotherapy (5.62 vs 3.98 months; P <.0001; HR: 0.65), as well as improvement in response (ORR: 42% vs 16%; complete response: 5% vs 0%). Of importance, at the 3-month mark, approximately 50% of patients in the chemotherapy arm are already had discontinued due to progression, and we do not see that in the mirvetuximab soravtansine arm. In other words, there is an early separation of the curves that is maintained throughout.

At this preplanned interim analysis, OS also was significantly improved with mirvetuximab soravtansine compared with chemotherapy (16.46 vs 12.75 months; P = .0056; HR: 0.67), with a 33% reduction in the hazard of death with use of mirvetuximab soravtansine compared with chemotherapy.

From a safety standpoint, we did not see any new adverse events (AEs) from those previously described in previous clinical trials, including the single‑arm phase III study SORAYA. Of importance, ocular and gastrointestinal AEs of interest were common but of low severity. AE prevention and mitigation strategies are in place for mirvetuximab soravtansine and work well. Only 9% vs 16% of patients discontinued treatment in the mirvetuximab soravtansine arm due to AEs vs the chemotherapy arm, respectively.

Nicoletta Colombo, MD, PhD:
In the AURELIA study, the addition of bevacizumab to chemotherapy (paclitaxel) improved response and PFS. What are your thoughts on the addition of bevacizumab to mirvetuximab soravtansine to improve these outstanding results potentially further? Any thoughts for when best to screen for FRα?

Kathleen Moore, MD:
Thank you for those questions, Dr Colombo. Starting with the easier one first, I would say to test for FRα at the time of diagnosis—or at least at the time of first recurrence. The question regarding adding bevacizumab is a great one. Data from the FORWARD II study evaluating bevacizumab and mirvetuximab soravtansine in 100 patients with either platinum-resistant or platinum-sensitive tumors show ORR of approximately 60% for medium and high expression and approximately 70% in the platinum‑sensitive setting, with a long duration of response and no additive toxicity. I feel very comfortable offering mirvetuximab soravtansine to my first platinum‑resistant line of therapy with bevacizumab instead of one of the AURELIA chemotherapy partners. At this time, we do not yet have randomized data to support this, and I acknowledge that, but I feel very comfortable that I am doing the right thing for my patients with this combination.

Nicoletta Colombo, MD, PhD:
Thank you for your answers, Dr Moore.

Another key study presented for ovarian cancer at ASCO 2023 was the phase III DUO-O trial evaluating frontline carboplatin/paclitaxel chemotherapy plus bevacizumab with or without durvalumab followed by maintenance bevacizumab with or without olaparib and durvalumab or durvalumab placebo (N = 1130). The primary endpoint was investigator-assessed PFS (per Response Evaluation Criteria in Solid Tumors [RECIST]) for carboplatin/paclitaxel chemotherapy plus bevacizumab, durvalumab, and olaparib compared with chemotherapy plus bevacizumab in non‒BRCA-mutated tumors and who had homologous recombination deficiency (HRD), as well as those in the intention-to-treat populations.

DUO-O investigators showed that the trial met its primary endpoint, with significantly prolonged PFS with the addition of durvalumab plus olaparib to maintenance bevacizumab following first-line carboplatin/paclitaxel plus bevacizumab and durvalumab compared with carboplatin/paclitaxel plus bevacizumab and maintenance bevacizumab in patients with non‒BRCA-mutated tumors. In patients who were HRD positive, the median PFS was significantly prolonged in the experimental arm at 37.3 vs 23.0 months (HR: 0.49; P <.0001); in the intention-to-treat population, the median PFS was 24.2 vs 19.3 months (HR: 0.63; P <.0001). The positive trend was consistent in all clinical subgroups, including surgical strategy used and in patients who were HRD negative. In the latter population, the HR was 0.68—and this was the largest cohort in this trial. Of importance, the phase III PAOLA-1 trial did not show a benefit of adding PARP inhibition to bevacizumab, making DUO-O the first trial showing an effect of PARP inhibitors with immune checkpoint inhibitor combination compared with an active control.

It is very important to underline that DUO-O is the first phase III clinical trial to meet its primary endpoint in ovarian cancer using an immune oncology agent—in this case durvalumab—in combination with a PARP inhibitor. Although these results are very encouraging, we should remember that DUO-O lacked a control arm to isolate the effects of durvalumab by comparing the experimental triplet therapy with the olaparib/bevacizumab combination that proved successful in PAOLA-1. Despite this limitation, this study opens the door to explore immunotherapy options in ovarian cancer, which had failed to yield a clinical benefit until DUO-O.

Kathleen Moore, MD:
Thank you for that summary, Dr Colombo. I want to switch gears and cover some key data presented at ASCO 2023 for cervical cancer, starting with the SHAPE trial, and let you walk us through the final OS data presented for the KEYNOTE-826 trial.

Cervical Cancer

Kathleen Moore, MD:
The other study I would like to discuss is very exciting—and one of the top 10 most important studies presented at ASCO 2023. The Canadian Cancer Trials Group SHAPE trial is an international, randomized phase III trial comparing radical hysterectomy and pelvic node dissection vs simple hysterectomy and pelvic node dissection in patients with low‑risk, early‑stage cervical cancer (N = 700). Of importance, standard of care for early‑stage cervical cancer has been radical hysterectomy for decades, and the quality of this surgery is incredibly important. We get one opportunity to cure cervical cancer, because if you do not, when these tumors recur, they are incurable.

There are a few important points to make about the SHAPE trial. First, regardless of the assignment of surgical technique, both types of hysterectomy required that a pelvic lymph node dissection be performed; surgeons had the option of doing sentinel lymph node mapping if they chose, but lymph nodes were required. Second, patients who were included in this clinical trial were highly selected to be appropriate for considering this simple hysterectomy approach. Early, small studies really have shown that in these smaller tumors, when looking at the pathology evaluation, there is no spread to the parametria—it is not where they go. Tumors often are found in lymph nodes, but they are not in the parametria, and they are not in the extensive vaginal resection margins, which really justified asking the question addressed by the SHAPE trial.

At ASCO 2023, authors of the SHAPE study showed that simple hysterectomy was noninferior to radical hysterectomy as assessed by 3-year pelvic recurrence rate (2.52% vs 2.17%, with noninferiority threshold of 95% CI: 4%). Moreover, simple hysterectomy was associated with fewer urologic surgical complications, better quality of life, and better sexual health measures in patients with early/low-risk cervical cancer. Regarding AEs, we really saw more urinary complications in the radical hysterectomy group. There was statistically significantly more urinary incontinence or urinary retention for early complications of radical vs simple hysterectomy, as well as late complications from surgery—and this is important.

Investigators concluded that following an adequate and rigorous preoperative assessment, simple hysterectomy now can be considered the new standard of care for patients with low-risk, early-stage cervical cancer (with low risk defined as stage IA2-IB1 ≤2 cm, <10 mm depth of stromal, invasion by loop electrosurgical excision procedure/cone, and <50% depth of stromal invasion by preoperative magnetic resonance imaging).

Nicoletta Colombo, MD, PhD:
Dr Moore, the majority of patients in this trial underwent minimally invasive surgery, and there was actually a slight imbalance, with more patients undergoing laparoscopy in the simple hysterectomy group. How do you interpret these results in light of the LACC trial? Does this mean laparoscopic simple hysterectomy is safe for cervical cancer, but laparoscopic radical hysterectomy is not? Again, in this respect, do you believe that the higher proportion of extrapelvic recurrences in the simple hysterectomy group may be related to the laparoscopic approach?

Kathleen Moore, MD:
This is one of the most important questions following the SHAPE trial and in context with the results from LACC. As a reminder, the LACC trial put an end to minimally invasive surgeries in this setting—primarily laparoscopic radical hysterectomies—and we all converted back to doing open procedures, at least in the United States. The LACC study demonstrated a higher risk of death with the minimally invasive approach, and it was minimally invasive laparoscopic surgery—very little robotic use. In the SHAPE trial, we see more use of robotic interventions, with approximately 25% of patients in each arm who had robotic intervention (40%-50% being laparoscopic). All that we can say from the SHAPE trial is that simple hysterectomy in the setting of cervical cancer was noninferior to radical hysterectomy. I do think this trial gives us a sense that laparoscopic simple hysterectomy is safer than what we saw in LACC with radical hysterectomy, and this remains an ongoing question. The ongoing ROCC trial (NCT04831580) led by Drs Kristin Bixel and Mario Leitao is looking at minimally invasive radical hysterectomy done robotically vs open, and it will include some of these smaller tumors and—we hope—will inform on this question.

Nicoletta Colombo, MD, PhD:
Next, we would like to comment on the abstract related to final OS results from KEYNOTE-826 presented by Dr Bradley Monk. This is a phase III study of pembrolizumab plus chemotherapy with or without bevacizumab vs placebo plus chemotherapy as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer (N = 617). The dual primary endpoints were OS and PFS, per RECIST 1.1 and assessed by investigator review, with each tested sequentially in 3 different populations—PD-L1 combined positive score (CPS) ≥1, PD-L1 CPS ≥10, and all-comers. We published the primary analyses in The New England Journal of Medicine in 2021.

After a follow-up of 39.1 months, investigators showed that the addition of pembrolizumab to chemotherapy with or without bevacizumab continued to demonstrate clinically significantly prolonged median OS (26.4 vs 16.8 months; HR: 0.63; P <.0001) and median PFS (10.4 vs 8.2 months; HR: 0.61; P <.0001) in the all-comer population. Median OS was improved in PD-L1 subgroups (PD-L1 CPS ≥1: 28.6 vs 16.5 months, HR: 0.60; PD-L1 CPS ≥10: 29.6 vs 17.4 months, HR: 0.58). Median PFS also was improved in the PD-L1 subgroups (PD-L1 CPS ≥1: 10.5 vs 8.2 months, HR: 0.58; PD-L1 CPS ≥10: 10.4 vs 8.1 months, HR: 0.52). Of importance, benefit was consistent across subgroups with or without bevacizumab. Safety outcomes were as expected based on individual agent profiles, with no new safety signals.

Endometrial Cancer

Nicoletta Colombo, MD, PhD:
Moving to endometrial cancer, I would like to share a few comments on the ENGOT-EN6-NSGO/GOG-3031/RUBY trial, which was presented at ASCO 2023. RUBY is a phase III study evaluating dostarlimab or placebo plus chemotherapy followed by dostarlimab or placebo maintenance for 3 years in patients with primary advanced or recurrent endometrial cancer (N = 494). The primary endpoints of PFS and OS already were published in The New England Journal of Medicine concurrently with the SGO Congress presentation. At ASCO 2023, 2 trials were focusing on the RUBY trial outcomes of blinded independent central review and PROs.

Dr Mathew Powell and colleagues reported analyses by blinded independent central review and showed that the HRs for PFS mirror those per investigator assessment in the mismatch repair deficient/microsatellite instability‒high population (PFS HR: 0.28 vs 0.29) and overall population (PFS HR: 0.64 vs 0.66), confirming the benefit of adding dostarlimab to standard frontline platinum-based chemotherapy and/or maintenance for patients with primary advanced or recurrent endometrial cancer.

Dr Manzoor-Raza Mirza reported the quality-of-life assessment among the 494 patients enrolled on the RUBY study. The EORTC QLQ-C30 and QLQ-EN24 were prespecified secondary endpoints, and the investigators reported the assessment for cycle 7 at the end of chemotherapy and cycle 13 at the end of 1 year of study. Looking at the PROs, they were similar for dostarlimab plus standard-of-care chemotherapy and placebo plus standard-of-care chemotherapy throughout the chemotherapy treatment period. Moreover, no differences were observed across the 3-year period between the 2 treatment arms. Of importance, significant differences were seen in favor of dostarlimab compared with chemotherapy at the start of cycle 7 in the mismatch repair deficient population, with reduction in pain and back and pelvis pain reported by patients. On the other hand, there was deterioration in global quality of life, social functioning, and body image, as well as change in taste, for patients on the placebo plus chemotherapy arm compared with the dostarlimab-containing arm.

My takeaway from the RUBY results presented at ASCO 2023 is that the addition of dostarlimab to standard-of-care platinum-based chemotherapy significantly improved PFS while maintaining or improving quality of life, further supporting this regimen as the new standard of care in patients with recurrent and advanced endometrial cancer. 

Going forward, affordability and drug access are among the most critical issues to address when it comes to regions with the highest incidence of these cancers. Companies sponsoring these trials should put in place several strategies to help these patients, for example, individual-based timely access programs and clinical trials. I for one think access to these novel therapies remains a major challenge in developing countries. 

Your Thoughts?
What are your thoughts and questions on the management of patients with endometrial, cervical, and ovarian cancers? Please answer the polling question and join the conversation by posting a comment in the discussion section.

Continue

Poll

1.

Which of the following statements is most accurate regarding integrating new standard-of-care options for your patients with endometrial, cervical, and ovarian cancers?

Submit