The sun was out, and the weather was beautiful for the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer held in Tampa, Florida, in March 2023. Participants came from across the world for this second hybrid gathering since the COVID-19 pandemic to share ongoing advances in the field of gynecologic malignancies. Here are brief summaries of some of the important and practice-informing data presented this year.
GUEST EDITOR
Joyce F. Liu, MD, MPH
Immunotherapy for Endometrial Cancer
Following press releases reporting positive outcomes in December 2022 and February 2023, the highly anticipated results from two landmark phase III trials combining PD-1 checkpoint blockade with carboplatin and paclitaxel chemotherapy in patients with advanced or recurrent endometrial cancer were presented in a late-breaking abstract session. In the GOG-3031/RUBY trial, 494 patients were randomly assigned to receive standard carboplatin and paclitaxel chemotherapy with either the PD-1 inhibitor dostarlimab followed by 3 years of dostarlimab maintenance therapy or chemotherapy with placebo followed by placebo maintenance.1 Similarly, the NRG GY018/KEYNOTE-868 trial randomly assigned 816 participants to receive carboplatin and paclitaxel chemotherapy with either the PD-1 inhibitor pembrolizumab followed by roughly 20 months of pembrolizumab maintenance therapy or chemotherapy with placebo followed by placebo maintenance.2 Notably, both trials enrolled patients with both mismatch repair–deficient (dMMR) and -proficient (pMMR) tumors; RUBY was powered hierarchically for the cohort of patients with dMMR tumors and then the intention-to-treat cohort, whereas GY018 was separately powered for patients with either dMMR or pMMR tumors.
For patients with dMMR tumors, the results were striking for both trials, with a hazard ratio of 0.28 for progression-free survival in RUBY and a hazard ratio of 0.30 in NRG GY018. In both trials, the median progression-free survival for the control group was approximately 7.5 months in patients with dMMR tumors and was not reached in the intervention groups. Both trials also reported progression-free survival benefit, albeit less pronounced, in patients with pMMR tumors. In RUBY, which was not powered for this subgroup analysis, the hazard ratio for these patients was 0.76 (95% confidence interval [CI] = 0.59–0.98), translating to a 2-month progression-free survival benefit from 7.9 to 9.9 months. In
NRG GY018, the hazard ratio was 0.54 (95% CI = 0.41–0.71), with a 4.4-month progression-free survival benefit from 8.7 to 13.1 months. RUBY also reported preliminary overall survival data with 33% maturity, with trends toward improved overall survival in all populations.
These results are practice-changing for endometrial cancer and bring immunotherapy into the first-line treatment setting. Even so, there is much still to learn and build upon as we await longer-term follow-up and overall survival results. In dMMR tumors, future questions include examining the role of chemotherapy in this setting as well as whether activity varies between Lynch syndrome–like and MLH1-hypermethylated tumors. In pMMR tumors, the degree of activity is more modest; as these data mature, it will be important to understand whether activity is observed across molecular and histologic subtypes, and further strategies to enhance activity within these tumors may be warranted.
CDK4/6 Inhibition in Low-Grade Serous Ovarian Cancer
The treatment of recurrent low-grade serous ovarian cancer remains a challenge and an area of unmet need, given the resistance to chemotherapy of these tumors. One outstanding question has been whether the addition of CDK4/6 inhibition to hormonal therapy might be active in these tumors, given the promising activity seen in breast cancer.
Earlier this year, a neoadjuvant trial of abemaciclib and fulvestrant in newly diagnosed low-grade serous ovarian cancer reported encouraging preliminary activity, with 7 of 15 patients experiencing a partial response.3 At this year’s SGO meeting, the results of GOG-3026, a phase II study of combined ribociclib and letrozole in patients with recurrent low-grade serous ovarian cancer were reported.4 A total of 51 patients were enrolled on the trial, with 48 patients included in the efficacy analysis; 27% of patients had received prior hormonal therapy. The overall response rate was 23%, with a duration of response of 19.1 months. The median progression-free survival for the study was 19.1 months. The adverse event profile was as expected for this combination, with the most common events including hematologic toxicities and nausea. The results from GOG-3026 provide promising initial data, and future trials will be needed to confirm the activity of CDK4/6 inhibitor/hormonal combinations in low-grade serous ovarian cancers.
Novel Approaches for PARP Inhibitors in Ovarian Cancer
Over the past decade, PARP inhibitors have altered the landscape of therapy in ovarian cancer. The NOW study represented the first attempt to move PARP inhibitors into the primary therapy space as neoadjuvant therapy for patients with BRCA-mutated ovarian cancer.5 This novel proof-of-concept study treated 15 patients with BRCA-mutated ovarian cancer with two cycles of neoadjuvant olaparib, with a primary endpoint of feasibility. Of the 15 patients, 7 had partial responses after two cycles of therapy, and 14 were able to proceed to interval cytoreductive surgery. NOW provides evidence that neoadjuvant therapy with PARP inhibitors is feasible, although much remains to be understood about how clinical outcomes compare with the current standard of care and potential long-term effects, including development of therapeutic resistance and myelodysplasia risk.
Final overall survival data from the phase III NOVA trial of niraparib maintenance following response to platinum therapy in recurrent platinum-sensitive ovarian cancer were also presented.6 Following data-retrieval efforts, the missing survival status was reduced to 2%, with a median follow-up of more than 75 months across both the germline BRCA–mutated and non–germline BRCA–mutated cohorts. With overall survival maturity of 77.9%, the hazard ratio was 0.85 (95% CI = 0.61–1.20) for niraparib vs placebo maintenance in the germline BRCA–mutated cohort and 1.06 (95% CI = 0.81–1.37) in the non–germline BRCA–mutated cohort. Within exploratory homologous recombination deficiency subgroups in the non–germline BRCA–mutated cohort, the hazard ratio for overall survival was 1.29 (95% CI = 0.85–1.95) for patients with homologous repair–deficient and 0.93 (95% CI = 0.61–1.41) for patients with homologous repair–proficient disease.
Evolving Therapies for Platinum-Resistant Ovarian Cancer
At this past year’s SGO Annual Meeting, the first presentation of outcomes from the SORAYA study, demonstrating the activity of the folate receptor alpha (FRα)-targeting antibody drug conjugate mirvetuximab soravtansine-gynx in FRα-positive platinum-resistant ovarian cancer, generated significant excitement, and these data led to the accelerated approval of mirvetuximab soravtansine in November 2022. Updated data from the SORAYA trial were presented at this year’s meeting, confirming the previously reported results with an objective response rate of 32.4% and a median duration of response of 6.9 months.7 Median overall survival was 15 months, with 37% of patients alive at 24 months. Patients who received mirvetuximab soravtansine as their first treatment for platinum-resistant ovarian cancer had a response rate of 34.8%, whereas patients who had received prior treatment for platinum-resistant ovarian cancer had a response rate of 28.2%. These updated findings confirm that mirvetuximab soravtansine is a novel and important therapeutic option for patients with FRα-high platinum-resistant ovarian cancer.
Immunotherapy has been an elusive target in platinum-resistant ovarian cancer, and novel approaches to potentiate the immune response in ovarian cancer remain of high interest. In a report from a phase I trial of an Fc-enhanced CTLA-4 inhibitor botensilimab together with a PD-1 inhibitor balstilimab, investigators reported a response rate of 33% in an expansion cohort of 24 evaluable patients with platinum-resistant ovarian cancer.8 Further work to confirm whether this may become a successful strategy to leverage immune checkpoint inhibition in ovarian cancer will be needed.
Overall, the 2023 SGO Annual Meeting brought exciting advances in gynecologic oncology, with both practice-changing studies of immunotherapy in endometrial cancer and promising data for novel targeted therapies and strategies, fulfilling the meeting’s focus on patients, purpose, and progress.
DISCLOSURE: Dr. Liu has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, and Regeneron; and has received research funding from 2X Oncology, Acetylon Pharmaceuticals, Agenus, Aravive, Arch Oncology, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, CytomX Therapeutics, Genentech/Roche, Impact Therapeutics, Regeneron, Surface Oncology, Vigeo Therapeutics, and Zentalis.
REFERENCES
1. Mirza MR, Chase D, Slomovitz B, et al: Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: A placebo-controlled randomized phase 3 trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 27, 2023.
2. Eskander RM, Sill MW, Beffa L, et al: Pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: The phase 3 NRG GY018 study. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 27, 2023.
3. Cobb LP, Davis J, Hull S, et al: A pilot phase II study of neoadjuvant fulvestrant plus abemaciclib in women with advanced low-grade serous carcinoma. 2022 ASCO Annual Meeting. Abstract 5522. Presented June 2, 2022.
4. Slomovitz BM, Deng W, Killion J, et al: GOG-3026: A phase II trial of letrozole + ribociclib in women with recurrent low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum: A GOG Foundation study. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 24, 2023.
5. Westin SN, Michael V, Fellman BM, et al: Neoadjuvant window trial in newly diagnosed BRCA mutant ovarian cancer. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 26, 2023.
6. Matulonis UA, Herrstedt J, Oza A, et al: Final overall survival and long-term safety in the ENGOT-OV16/NOVA phase III trial of niraparib in patients with recurrent ovarian cancer. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 25, 2023.
7. Coleman RL, Oaknin A, Pignata S, et al: Mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Evaluation of sequence of therapy on anti-tumor activity in the SORAYA study. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 25, 2023.
8. Bockorny B, Matulonis UA, O’Day SJ: Botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti–PD-1) in patients with recurrent platinum refractory/resistant ovarian cancer (NCT03860272). Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 27, 2023.
