The past year has been a remarkable and noteworthy time with much exciting progress made in gynecologic cancers, despite the underlying presence of the COVID-19 pandemic. Several key studies were presented in 2020–2021 that detailed the results of novel therapies for our patients with cervical, ovarian, and endometrial cancers.
We learned about updates from the SOLO-1, SOLO-2, and ENGOT-OV16/NOVA trials, as well as results from studies that focused on more traditional therapies such as bevacizumab and chemotherapy. In the realm of immunotherapy, the addition of checkpoint inhibitors to ovarian cancer therapy failed to improve survival outcomes, unlike in cervical and endometrial cancers. On an international scale, good news has been reported that, globally, the incidence and mortality rates of cervical cancer have been stable or decreasing.1 Unfortunately, the incidence of uterine cancer and the racial disparities associated with this cancer continue to mount.2
GUEST EDITOR
Ursula A. Matulonis, MD
Novel Therapies for Advanced Cervical Cancer Show Promise
Progress has been made in cervical cancer therapy for advanced disease. The EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial, which was reported in June 2021 as a European Society for Medical Oncology (ESMO) Virtual Plenary presentation, examined the anti–PD-1 inhibitor cemiplimab-rwlc vs chemotherapy.3 The study enrolled 608 women with recurrent or metastatic cervical cancer regardless of PD-L1 status who had experienced disease progression after platinum-based chemotherapy; prior therapy had to include paclitaxel and bevacizumab. Women were randomly assigned to either cemiplimab or chemotherapy including pemetrexed, gemcitabine, topotecan, irinotecan, or vinorelbine. Median overall survival, the primary endpoint, was 12.0 months in the cemiplimab group vs 8.5 months in the chemotherapy group (hazard ratio [HR] = 0.69; P = .00011), and cemiplimab demonstrated improvement in both the squamous cell and adenocarcinoma populations compared with chemotherapy. Median progression-free survival did not differ significantly between treatment groups: 2.8 months with cemiplimab vs 2.9 months with chemotherapy (HR = 0.75; P = .00048). Overall response rates were 16.4% with cemiplimab and 6.3% with chemotherapy, and the estimated duration of response was longer with cemiplimab, 16.4 months vs 6.9 months.
Other checkpoint inhibitors have also been evaluated in cervical cancer; two phase II studies presented at the ESMO Virtual Congress 2020 tested balstilimab, an anti–PD-1 agent, either as monotherapy or combined with zalifrelimab, a novel Fc-optimized anti–CTLA-4 antibody.4 Single-agent balstilimab had a response rate of 14%, and the combination of balstilimab and zalifrelimab yielded an overall response rate of 22%. Responses were seen in the PD-L1–negative population as well as in those with unknown PD-L1 status. The median duration of response was 15.4 months with balstilimab and not reached with the combination. Clinical trials are ongoing, including a phase III trial testing balstilimab vs physician’s choice of chemotherapy for recurrent cervical cancer (ClinicalTrials.gov identifier NCT04943627) and a phase II study of balstilimab vs balstilimab plus zalifrelimab in the second-line treatment of advanced cervical cancer (NCT03894215).
Also showing promise in advanced cervical cancer is tisotumab vedotin, an antibody-drug conjugate (ADC) directed at tissue factor and linked to monomethyl auristatin E. In the innovaTV 204 study, which was presented at the ESMO Virtual Congress 2020 and subsequently published in The Lancet Oncology, tisotumab vedotin was tested in women with metastatic cervical cancer.5,6 Overall response rate—the study’s primary endpoint—was 24%, median duration of response was 8.3 months (95% confidence interval [CI] = 4.2 months to not reached), and median progression-free survival was 4.2 months (95% CI = 3.0–4.4 months); responses were noted in squamous and nonsquamous histologies. In April 2021, the U.S. Food and Drug Administration (FDA) granted Priority Review designation to this novel agent, and the biologics license application is requesting accelerated approval in recurrent cervical cancer that has progressed on prior chemotherapy.
Limits of Adjuvant Chemotherapy Revealed in OUTBACK
In newly diagnosed cervical cancer, we have also learned about the limitations of the use of additional chemotherapy beyond primary treatment with combined radiation therapy and radiation-sensitizing cisplatin. The OUTBACK study, presented at the 2021 ASCO Annual Meeting, tested whether four cycles of adjuvant chemotherapy following primary radiation therapy/weekly cisplatin improved overall survival compared with no additional treatment.7 A total of 919 women were enrolled, and eligible patients included those with stages IB1, IB2, II, IIIB, or IVA cervical cancer. For those women randomly assigned to additional chemotherapy, treatment consisted of carboplatin at AUC 5 and paclitaxel at 155 mg/m2 every 3 weeks for four cycles. Results revealed that both overall survival and progression-free survival were the same for both groups and that the pattern of recurrence was similar for both groups.
PARP Inhibitors in Advanced Ovarian Cancer
Several important trials have also been reported in ovarian cancer over the past year. The impact of poly (ADP-ribose) polymerase (PARP) inhibitors on outcomes in women with newly diagnosed advanced ovarian cancer continues to remain significant, especially in BRCA-mutated advanced ovarian cancer, per the updated results of the SOLO-1 trial presented at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer.8 Median progression-free survival in SOLO-1 was 56 months for olaparib maintenance vs 13.8 months with placebo (HR = 0.33; 95% CI = 0.25–0.43), and the 5-year progression-free survival was 48% vs 21% for olaparib compared with placebo. Other data at SGO 2021 that pertained to women with newly diagnosed ovarian cancer came from the OVARIO study, presented by Hardesty et al; this was a single-arm phase II study that tested niraparib plus bevacizumab maintenance in patients with newly diagnosed advanced ovarian cancer following response to first-line platinum-based chemotherapy plus bevacizumab.9 Progression-free survival rates for the overall population were 90% at 6 months and 75% at 12 months; at 18 months, progression-free survival was 62% in the overall population and 76% in the homologous recombination–deficient population.
Several PARP inhibitor trials in the recurrent ovarian cancer setting have also been presented. Final results of SOLO-2 were presented at the 2020 ASCO Annual Meeting and published in The Lancet Oncology in 2021; there was a 12.9-month median overall survival benefit for patients receiving olaparib maintenance vs placebo, which was not statistically significant but clinically meaningful.10,11 The final analysis also demonstrated that the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in this recurrent population with BRCA-mutated cancer was 8% for the olaparib group vs 4% in the placebo group11; this is important information that patients should be aware of. The SOLO-2 results continued to show a significant improvement in progression-free survival with olaparib vs placebo, 19.1 months vs 5.5 months, respectively (HR = 0.3, 95% CI = 0.22–0.41).
Final results of the ENGOT-OV16/NOVA trial, presented at SGO 2021, showed that maintenance niraparib compared with placebo maintenance resulted in prolonged second progression-free survival for niraparib, a non–statistically significant overall survival improvement of 9.7 months in the germline BRCA-mutated population for niraparib, and no overall survival improvement for the non–germline BRCA-mutated group.12 There were more cases of AML/MDS in the germline BRCA-mutated group treated with niraparib, which paralleled the final SOLO-2 results.
Also presented at SGO 2021 was the ARIEL4 trial comparing rucaparib with standard-of-care chemotherapy in women with relapsed BRCA-mutated ovarian cancer.13 Patients with a platinum-free interval of more than 12 months received platinum-based chemotherapy, and if the platinum-free interval was less than 6 months, the standard-of-care chemotherapy was weekly paclitaxel. Progression-free survival was improved with rucaparib, the overall response rate was the same in both groups, and the duration of response was better with rucaparib. Additionally, an exploratory analysis of patients who had BRCA reversion mutations by cell-free DNA testing showed improved progression-free survival with chemotherapy compared with rucaparib, suggesting a potential future biomarker for PARP inhibitor responsiveness.
For patients with recurrent cancer, a new PARP inhibitor called fuzuloparib showed an improvement in progression-free survival for patients with platinum-sensitive, high-grade serous ovarian cancer with and without known BRCA mutations.14
Maintenance Bevacizumab in Newly Diagnosed Ovarian Cancer
Use of longer-duration bevacizumab maintenance in newly diagnosed ovarian cancer did not yield improved outcomes in the phase III ENGOT/GCIG trial15; 927 women with stage IIB to IV newly diagnosed ovarian cancer underwent upfront cytoreductive surgery followed by six cycles of carboplatin and paclitaxel chemotherapy and were randomly assigned to the standard 15 months of bevacizumab vs 30 months of bevacizumab. No differences were noted between the groups for either progression-free survival nor overall survival.
Adding checkpoint inhibitors to chemotherapy for newly diagnosed ovarian cancer patients was tested in the IMagyn050/GOG 3015/ENGOT-OV39 trial study, which was recently published in the Journal of Clinical Oncology.16 This study enrolled 1,301 patients with advanced ovarian cancer who either had macroscopic residual cancer following primary cytoreductive surgery or received neoadjuvant chemotherapy and interval cytoreductive surgery followed by additional chemotherapy. Patients were randomly assigned to receive carboplatin/paclitaxel, bevacizumab, and bevacizumab maintenance with either atezolizumab or placebo. The addition of atezolizumab to chemotherapy and then used as maintenance did not improve progression-free survival; immature overall survival results also did not show a benefit with the addition of atezolizumab.
Advances in Recurrent Endometrial Cancer
Progress has also been made in recurrent endometrial cancer. The KEYNOTE-775 trial, presented at SGO 2021, enrolled 827 women with recurrent endometrial cancer to either the combination of the tyrosine kinase inhibitor lenvatinib and pembrolizumab vs physician’s choice of chemotherapy (either paclitaxel at 175 mg/m2 or doxorubicin at 60 mg/m2).17 Overall survival, progression-free survival, overall response rate, and duration of response were all significantly better with pembrolizumab/lenvatinib compared with chemotherapy. However, toxicities were quite significant in the combination arm, with 70% of patients requiring dose reductions of lenvatinib and 33% of those patients needing to discontinue lenvatinib because of toxicities. This regimen is effective but quite toxic and received full FDA approval on July 21, 2021. Another recent FDA approval is for dostarlimab-gxly, which was approved on April 22, 2021, for recurrent or advanced microsatellite instability–high endometrial cancer that has progressed after a platinum-based chemotherapy. The approval was based on the results of the GARNET study, showing a 42.3% overall response rate in this population.18
These practice-changing studies and more are detailed in this 2020–2021 Gynecologic Oncology Almanac. I look forward to the progress that will be made in the coming year and the results of many more trials. Therapeutic headway is being made for our patients with ovarian, cervical, and endometrial cancers. Oncologists must be ready to face the challenge of making clinically meaningful improvements in the outcomes of our patients by continuing to identify, study, and target novel and exploitable genetic and biologic changes in gynecologic cancers.
DISCLOSURE: Dr. Matulonis has received honoraria from Advaxis; has served as a consultant or advisor to Merck, NextCure, and Novartis; has received research funding from Fujifilm, ImmunoGen, Leap Therapeutics, Merck, Mersana, Novartis, SQZ Biotechnologies, Syndax, and Tesaro; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca.
REFERENCES
1. Lin S, Gao K, Gu S, et al: Worldwide trends in cervical cancer incidence and mortality, with predictions for the next 15 years. Cancer. August 9, 2021 (early release online).
2. Siegel RL, Miller KD, Fuchs HE, et al: Cancer statistics, 2021. CA Cancer J Clin 71:7-33, 2021.
3. Tewari KS, Monk BJ, Vergote I, et al: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs. investigator’s choice chemotherapy in recurrent/metastatic cervical
carcinoma. ESMO Virtual Plenary. Abstract VP4-2021. Presented May 12, 2021.
4. O’Malley DM, Oaknin A, Monk BJ, et al: Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic cervical cancer: Preliminary results of two independent phase II trials. ESMO Virtual Congress 2020. Abstract LBA34. Presented September 18, 2020.
5. Coleman RL, Lorusso D, Gennigens C, et al: Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: Results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. ESMO Virtual Congress 2020. Abstract LBA32. Presented September 21, 2020.
6. Coleman RL, Lorusso D, Gennigens C, et al: Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 22:609-619, 2021.
7. Mileshkin L, Moore KN, Barnes EH, et al: Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase 3 OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274). 2021 ASCO Annual Meeting. Abstract LBA3. Presented June 8, 2021.
8. Bradley W, Moore K, Colombo N, et al: Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO-1. Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer. Abstract 39. Presented March 20, 2021.
9. Hardesty MM, Krivak T, Wright GS, et al: Phase 2 OVARIO study of niraparib plus bevacizumab therapy in advanced ovarian cancer following frontline platinum-base chemotherapy with bevacizumab. Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. Poster 22. Presented March 19, 2021.
10. Poveda A, Floquet A, Ledermann JA, et al: Final overall survival results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation. ASCO20 Virtual Scientific Program. Abstract 6002. Presented at press briefing on May 12, 2020.
11. Poveda A, Floquet A, Ledermann JA, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 22:620-631, 2021.
12. Matulonis U, Herrstedt J, Oza A, et al: Long-term safety and secondary efficacy endpoints in the ENGOT-OV16/NOVA phase III trial of niraparib in recurrent ovarian cancer. Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. Abstract 37. Presented March 20, 2021.
13. Kristeleit R, Lisyanskaya A, Fedenko A, et al: Rucaparib vs chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation. Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. Abstract 1. Presented March 19, 2021.
14. Li N, Zhang Y, Wang J, et al: Fuzuloparib maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer: A multicenter, randomized, double-blind, placebo-controlled, phase III trial. Society of Gynecologic Oncology 2021 Annual Meeting on Women’s Cancer. Abstract 99. Presented March 25, 2021.
15. Pfisterer J, Joly F, Kristensen G, et al: Optimal treatment duration of bevacizumab combined with carboplatin and paclitaxel in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. 2021 ASCO Annual Meeting. Abstract 5501. Presented June 7, 2021.
16. Moore KN, Bookman M, Sehouli J, et al: Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: Placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol 39:1842-1855, 2021.
17. Makker V, Colombo N, Casado Herráez A, et al: A multicenter, open-label, randomized phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. Abstract 37. Presented March 19, 2021.
18. Oaknin A, Tinker AV, Gilbert L, et al: Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: A nonrandomized phase 1 clinical trial. JAMA Oncol 6:1766-1772, 2020.
