Abstract
This commentary summarized the most important findings in the first half 2023 year based on Society of Gynecologic Oncology (SGO) annual meeting and publications in crucial journals.
This commentary provided a comprehensive overview of notable developments in the field of gynecologic oncology throughout the first half of 2023, drawing insights from the Society of Gynecologic Oncology (SGO) Annual Meeting and pivotal publications in esteemed journals. The discourse delved into the forefront of molecular mechanisms, emphasizing critical themes such as homologous recombination repair deficiency, mismatch repair, immune checkpoint blockades, and anti-angiogenesis in various cancers. Specific attention was given to advancements in targeted and immunotherapeutic modalities, notably examining the efficacy and safety profiles of poly (ADP-Ribose) polymerase inhibitors (PARPi) in ovarian cancer. Conclusively, the commentary underscored the transformative impact of molecularly guided therapies, marking them as pivotal in addressing refractory conditions and set the stage for heightened expectations in future advancements.
PARP inhibitors have become the standard maintenance treatment for ovarian cancer. Among the first six articles, two (SOLO1 and PAOLA-1) summarized evidence supporting the improvement of overall survival with PARP inhibitors in maintenance therapy, while the NOVA study reported no benefit in overall survival. The first, fourth, and sixth articles discussed the feasibility of PARP inhibitors, immune checkpoint inhibitors used alone or in combination in neoadjuvant therapy (post-chemotherapy surgery). The latter two articles focused on the application of PD-1 (immune checkpoint inhibitors) in locally advanced cervical cancer, demonstrating enhanced efficacy. Currently, immune checkpoint inhibitors are commonly used in advanced cervical and endometrial cancers due to their status as hot tumors. Their use, either alone or in combination with anti-angiogenic drugs, has shown better outcomes in recurrent and advanced refractory endometrial and cervical cancers compared to traditional chemotherapy. A study from Huashan Hospital discussed the effectiveness of immune checkpoint inhibitors combined with anti-angiogenic therapy in recurrent cervical cancer, although there might be a typo as the initial mention was about endometrial cancer. The following article discussed late-stage endometrial cancer, finding no difference in survival between chemotherapy and chemotherapy combined with radiation. Subsequent articles highlighted the superiority of immune checkpoint inhibitors combined with chemotherapy in treating recurrent endometrial cancer, as well as the efficacy of immune checkpoint inhibitors combined with anti-angiogenic therapy in endometrial cancer. The final article focused on the therapeutic effect of HER2-positive ADC class drugs in uterine cancer sarcoma.
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Advancements in the treatment on gynecological oncology have witnessed remarkable progress in the past decades. These advancements are principally attributable to insights into molecular mechanisms, particularly with regard to homologous recombination repair deficiency, mismatch repair, immune checkpoint blockages, and anti-angiogenesis in cancers. This commentary summarized the most important findings in the first half of the year 2023, derived from discussions at the Society of Gynecologic Oncology (SGO) annual meeting and key publications in prominent journals.
The SGO Annual meeting on women’s cancer was held in Tampa, USA, during March 25–28, 2023. Notably, the preeminent subjects of discourse during this event were targeted therapy and immunotherapy for gynecologic cancer, as detailed in the meeting’s scientific debrief (https://www.sgo.org/news/2023-sgo-annual-meeting-scientific-debrief/).
In the SGO Annual meeting, for the treatment of ovarian cancer, the focus of recent research for ovarian cancer treatment centered on the feasible and safety of poly (ADP-Ribose) polymerase inhibitors (PARPi) in various contexts. Dr. Westin et al. from M. D. Anderson Cancer Center reported that in a cohort of epithelial ovarian cancer (EOC) patients with BRCA1/2 mutations, Olaparib was feasible as neoadjuvant therapy with favorable surgical and safety profiles (LBA138). Meanwhile, Dr. Matulonis et al. from Harvard Medical School reported final overall survival and long-term safety in the ENGOT-OV16/NOVA phase 3 trial of niraparib in patients with recurrent ovarian cancer. However, analyses were confounded by imbalances in post-progression therapy (including subsequent PARP inhibitors) by treatment arm in both the gBRCAm and non-gBRCAm cohorts, including the HRD subgroups. The OS hazard ratio for the gBRCAm cohort was 0.85, while for the non-gBRCAm cohort, it was 1.06, with expected wide CIs given that ENGOT-OV16/NOVA was not powered for formal OS analyses. Secondary endpoints, including CFI, TFST, PFS2, and TSST, consistently demonstrated a persistent treatment effect in favor of niraparib in both cohorts (LBA 214).
Dr. DiSilvestro et al. from Women & Infants Hospital reported the 7-year follow-up of overall survival in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation who received maintenance olaparib in the SOLO1/GOG 3004 trial. They declared that SOLO1 was the first study to demonstrate a clinically meaningful, albeit not statistically significant due to alpha assignment, improvement in OS with PARP inhibitor maintenance monotherapy in the first-line setting. The HR for OS was 0.55 (95% CI 0.40–0.76), with 67.0% of olaparib patients versus 46.5% of placebo patients alive at 7 years. The survival benefit persisted despite over 40% of patients in the placebo group receiving subsequent PARP inhibitor therapy. TFST (time to first subsequent therapy or death) and TSST (time to second subsequent therapy or death) favored maintenance olaparib over placebo. These 7-year results provide further confirmation that the benefit of maintenance olaparib extends well beyond its initial 2-year treatment duration. No new safety signals were identified, and the incidence of MDS/AML remained low, with new primary malignancies balanced between treatment groups (LBA215).
As described in current literatures, multidisciplinary considerations in the maintenance treatment of poly (ADP-ribose) polymerase inhibitors for homologous recombination-proficient, advanced-stage epithelial ovarian cancer has been a clinical imperative [1]. Moreover, final overall survival results from the PAOLA-1/ENGOT-ov25 trial suggested that, in the homologous recombination deficiency (HRD)-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45–0.85; 5-year OS rate, 65.5% versus 48.4%). Additionally, at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32–0.54; 5-year PFS rate, 46.1% versus 19.2%) [2].
Despite of case reports [3], immunotherapy, currently mainly consisting of immune checkpoint blockade, had failed to show efficient in the treatment for ovarian cancer, especially for chemotherapy-resistant cases. However, Dr. Lee et al. from Yonsei University College of Medicine reported the final primary analysis of the original cohort of KGOG3046/TRU-D, a phase II study of durvalumab (PD-L1 blockage) and tremelimumab (CTLA4 blockage) with front-line neoadjuvant chemotherapy (NAC) in patients with advanced-stage ovarian cancer. The primary endpoint was met, revealing a 63.6% of 12 m-PFS rate and durable responses with a 30 m follow-up compared to historical controls (P = 0.021). The final primary analysis highlighted the clinical activity and manageable toxicity profile for the addition of durvalumab and tremelimumab to NAC in newly-diagnosed advanced ovarian cancer (LBA217). In addition, a phase III, multicenter, randomized study is in implementation, which is about olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer [4].
This year, immune checkpoint blockade, especially the PD-1 antibody, has been for a focal point in cervical cancer research. Dr. Duska et al. from the UVA Clinical Research office reported findings from a randomized phase II study investigating chemoradiation and Pembrolizumab for locally advanced cervical cancer (LACC). Patients received Pembrolizumab during or after chemoradiation, with comparable safety outcomes (LBA148). Concurrently, Dr. Zamarin et al. reported on another study examining the evolution of peripheral and tumor immune parameters as biomarkers for the differential sequencing of immune checkpoint blockade and chemoradiotherapy in LACC. They discovered that neoadjuvant administration of atezolizumab in LACC led to the early systemic expansion of tumor-associated TCR clones, indicating an early systemic tumor-specific immune response. Conversely, chemoradiotherapy resulted in the contraction of these clones, potentially implying adverse consequences for the systemic immune response. These findings provide a rationale for further investigations into neoadjuvant sequencing strategies to evaluate PD-1/PD-L1-targeted therapies in LACC (LBA143).
In light of these findings and in conjunction with previous publications on PD-1 antibody for recurrent, metastatic and advanced cervical cancer [5, 6], immunotherapy has emerged as a cornerstone in addressing these conditions. However, their sensitization role in synergetic therapy, particularly in combination with radiotherapy, warrants further exploration.
Similarly to cervical cancer, immunotherapy has become the frontline treatment for advanced, relapsed, and metastatic uterine cancer. In a single-arm, open-label, phase II trial, Dr. Peng from Peking Union Medical College Hospital reported the efficacy of toripalimab plus Bevacizumab and platinum-based chemotherapy for patients with refractory, recurrent or metastatic cervical cancer. The ORR and DCR in their cohort were 77.3% (95% CI 54.6–92.2) and 95.5% (77.2–99.9), respectively, With no new safety events observed (LBA211), Dr. Matei et al. from Northwestern University compared the impact on overall survivals of combined systemic chemotherapy and tumor volume-directed radiotherapy (C-RT) with systemic chemotherapy alone (CT) in patients with surgically staged III/IVA uterine cancer. However, Chemo-RT did not improve OS compared to chemotherapy (HR = 1.05; 95% CI 0.82–1.34), or PFS (HR = 0.9, CI 0.74–1.1). Although Chemo-RT reduced the incidence of vaginal, pelvic, and para-aortic recurrences compared to CT, distant recurrences were more common with C-RT (LBA 213).
Dr. Eskander et al. reported the results of pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable Stage3 or 4a, Stage 4b, or recurrent endometrial cancer (NRGGY018Study). They discovered that the addition of pembrolizumab to standard-of-care chemotherapy (PC), followed by pembrolizumab maintenance, resulted in a 70% and 43% reduction in the risk of disease progression or death in patients with dMMR and pMMR endometrial cancer, respectively. The efficacy curves separated early in the course of treatment, with a preserved separation throughout the evaluation period in both populations. This benefit was identified in all evaluable subgroups, including patients who received prior adjuvant chemotherapy, prior radiation, and in less common histologic subtypes. The addition of pembrolizumab did not appear to increase the frequency of adverse events commonly associated with PC combination chemotherapy. The incidence of immune-mediated adverse events was not greater than that observed in prior endometrial cancer studies examining pembrolizumab monotherapy (LBA264) [7]
Dr. Mirza et al. from Copenhagen University Hospital reported on dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer. Their study suggested that dostarlimab + CP demonstrated statistically significant and clinically meaningful PFS benefit with an early OS trend in the overall population, substantial, unprecedented benefit in dMMR/MSI-H patients, and clinically meaningful long-term benefit observed in MMRp/MSS patients. The safety profile for dostarlimab + CP was manageable and generally consistent with that of the individual drugs (LBA265). Current publications indicated that in uterine cancer, updated efficacy and safety from the randomized phase III study 309/KEYNOTE-775 showed that lenvatinib plus pembrolizumab had benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest [8]. In the STATICE trial, trastuzumab deruxtecan, an antibody–drug conjugate targeting human epidermal growth factor receptor 2 (HER2) with a topoisomerase I inhibitor payload, demonstrated efficacy in patients with uterine carcinosarcoma, regardless of HER2 status [9]. In a phase 3, global, double-blind, randomized, placebo-controlled trial, dostarlimab plus carboplatin–paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR–MSI-H population [10].
In light of the significant findings in gynecologic cancer in 2023, it is evident that targeted and immunological therapies based on molecular mechanisms have emerged as the mainstream approaches for the majority of common gynecological cancers. This trend is particularly pronounced in diseases resistant to traditional therapeutic modalities. Anticipating further developments in recent advances, we hold the expectation that additional surprises and heightened optimism will characterize the future landscape of gynecologic oncology.
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This work is supported by the State Key Laboratory for Complex, Severe and Rare Diseases in Peking Union Medical College Hospital.
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JL conceived of the original idea for the study, interpreted results, edited the paper and was overall guarantor. LL contributed to the preparation of the data set, interpreted results and contributed to drafts of the paper.
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Li, L., Lang, J. Recent advances in the treatment for gynecologic oncology. Holist Integ Oncol 3, 1 (2024). https://doi.org/10.1007/s44178-023-00068-3
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DOI: https://doi.org/10.1007/s44178-023-00068-3