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Introduction: The advent of immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the management of mismatch repair deficient (MMR-d)/microsatellite instability-high (MSI-H) endometrial cancer (EC). Initially investigated as monotherapy in phase I-II clinical trials for recurrent disease, immunotherapy demonstrated remarkable activity, yielding overall response rates (ORR) ranging from 27% to 58%. Based on these promising findings, phase III trials have explored the integration of immunotherapy into first-line treatment regimens for advanced/recurrent EC in combination with chemotherapy or other agents such as tyrosine kinase inhibitors (TKIs), resulting in improved ORR, progression-free survival, and overall survival compared to the standard chemotherapy regimen of paclitaxel and carboplatin. As a result, the incorporation of ICIs with standard platinum-based chemotherapy is becoming a new standard of care in MMR-d/MSI-H EC., Areas Covered: This review synthesizes literature from PubMed, Embase databases, and recent congress abstracts on gynecological cancers. It covers MMR-d/MSI-H EC incidence, molecular diagnostics, clinical trial outcomes, predictive biomarkers for ICIs, patient profiles likely to benefit, resistance mechanisms, and the future of immunotherapy in this setting., Expert Opinion: By offering a comprehensive overview, this review delineates the pivotal role of ICIs in the management of MMR-d/MSI-H EC.

The 'Best of ESGO 2023' manuscript comprises a compilation of the best original research presented during the European Society of Gynaecologic Oncology annual congress held in Istanbul between September 28 and October 1, 2023. Out of 1030 submitted abstracts, 33 studies presented during the Best Oral Sessions, Mini Oral Sessions, and Young Investigator Session were selected by the ESGO Abstract Committee and the European Network of Young Gynae Oncologists (ENYGO) authors. There was a strong focus on surgical de-escalation, immunotherapy, maintenance therapy, and molecular profiling in gynecologic oncology. With this manuscript, ENYGO and ESGO aim to disseminate the valuable research results to readers interested in our field., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In recent years, ovarian cancer (OC) treatment has been enriched with many new target therapies, most of all antiangiogenic drugs and PARP inhibitors (PARPis), which have literally changed the natural history of the disease. The impressive results of immunotherapy in other malignancies, mainly melanoma and lung cancer, and the good signals of activity in gynecological neoplasms like cervical and microsatellite instable (MSI-H) endometrial cancer, opened the space to the introduction of immune-stimulatory drugs in ovarian cancer., Area Covered: The goal of this article is to summarize the newest evidence on the use of immune check point inhibitors in OC trying to explain why, at present, this strategy has failed to improve clinical outcome and focusing on the possible strategies to overcome treatment failure., Expert Opinion: Although numerous trials have been undertaken, only scanty results have been obtained so far with immune check-point inhibitors (ICIs) in OC either when used as single agents or in combination with antiangiogenic therapy and ongoing trials are exploring the association of ICIs with PARPis and other ICIs. A better knowledge of predictive biomarkers of response and mechanisms of immunotherapy resistance, will help in identifying the most appropriate population to treat with ICIs.

Objective: immunotherapy with immune checkpoint inhibitors has become one of the standard therapeutic modalities for patients with advanced melanoma. Melanoma of the female lower genital tract is a rare and aggressive disease, with poor long-term clinical outcomes. To date, no study evaluated the role of immunotherapy in metastatic melanoma of the lower genital tract., Methods: Data of women with metastatic melanoma of the lower genital tract were prospectively collected. Survival outcomes over time was assessed using Kaplan-Meier model., Results: Seven cases of metastatic melanoma of the lower genital tract (vulva [n=2], vagina [n=4], and uterine cervix [n=1]) treated with immune checkpoint inhibitors are reviewed. Two patients had metastatic disease at diagnosis, while 5 patients developed metastatic disease at a mean (standard deviation) time of 9.9 (±3.0) months from primary diagnosis. Four patients received an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) (ipilimumab) and 3 received an anti-programmed cell death 1 (PD-1) (pembrolizumab [n=2], nivolumab [n=1]) therapy. The response rate to immunotherapy was 28.5%. Patients receiving an anti-PD-1 experienced a better progression-free survival than patients treated with anti-CTLA4 (p=0.01, log-rank test). Although not reaching statistical significance, overall survival was better in patients having an anti-PD-1 therapy in comparison to anti-CTLA4 (p=0.15, log-rank test)., Conclusion: Results from our series confirm the poor prognosis of women with metastatic melanoma of the lower genital tract, thus supporting the need of exploring new treatment modalities. Further studies are warranted to improve knowledge on the role of immunotherapy in metastatic melanoma of the lower genital tract., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Simple Summary: Lynch syndrome (LS) is a genetic condition predisposing to a variety of tumors, including endometrial (EC) and ovarian cancers (OC), with cancer lifetime risk depending on the specific LS-mutation involved. Universal Screening is the standard for LS detection. Prophylactic surgery is a risk-reducing option that may be considered, and the age at hysterectomy and recommendation for bilateral oophorectomy depend on the mutated variant and offspring desire. Besides surgery, chemoprevention via contraceptives combination or progestin-alone is a viable option, and vaccination with tumor-specific antigens has shown promising results in mouse models. LS patients requiring adjuvant radiotherapy or systemic treatment for EC or OC are managed according to international standard of care. However, when conservative treatment for EC is considered, worse oncologic and obstetric outcomes are reported for patients with mismatch repair deficiency or LS. Moreover, LS-related tumors are characterized by a highly immunogenic tumor-environment that can be targeted by specific immune checkpoint inhibitors. This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: The standard treatment for advanced endometrial cancer (EC) includes platinum-based combination chemotherapy (CT), regardless of the histology, molecular status and the patient's profile. However, EC patients are a particularly frail group of patients, often with co-morbidities. Tolerance of CT can be difficult and induce long-term toxicities. In advanced EC disease, anti-PD1 immunotherapy has shown impressive results amongst mismatch repair deficient (MMRd)/high microsatellite instability (MSI-H) tumors. However, the benefit of adding CT to anti-PD1 is still an opened question. The aim of DOMENICA is to address the question if PD-1 alone has superior efficacy to CT, so that therapy in 1L advanced/recurrent MMRd/MSI-H EC could be de-escalated to avoid CT related toxicities. Methods: DOMENICA is an academic international randomized open-label, phase III trial evaluating the efficacy and safety of dostarlimab versus carboplatin-paclitaxel in patients with MMR deficient (MMRd/MSI-H) relapse or advanced / metastatic EC. Inclusion criteria for the study comprised patients with histologically confirmed EC exhibiting recurrent or advanced disease, including primary stage IIIA to C2 or Stage IV disease, or experiencing their first recurrence of EC without curative treatment, provided they had evaluable disease according to RECIST 1.1 criteria. Additionally, patients with MMRd/MSI-H tumors, determined by institutional MMR immunohistochemistry testing, and those with a performance status (ECOG) of 0-1 were eligible. The primary endpoint is progression-free survival according to RECIST 1.1, assessed by the BICR (Blinded Independent Central Review). Secondary endpoints include overall survival as key secondary endpoint, progression-free survival 2, patients reported outcome, best objective response rate, disease control rate, duration of response rate, safety and tolerability, time to first or second subsequent treatment (TFST, TSST), pharmacokinetics and immunogenicity of dostarlimab. Exploratory objectives include predictive biomarkers, efficacy according to geriatric status. The Study is ongoing in France (GINECO), Spain (GEICO), Italy (MaNGO, MITO), Canada (PMC), Singapore (GCIG), South Korea (KGOG), Japan (GOTIC), Turkey (TRSGO), and UK (NRCI). [ABSTRACT FROM AUTHOR]

Simple Summary: Approaches beyond first-line chemotherapy to treat advanced cervical cancer (CC) are currently limited. Immune checkpoint inhibitors (ICIs) are showing high efficacy, thus remodeling the therapeutic scenario of many solid tumors. With our systematic review, we aimed to summarize the latest clinical trials using ICIs in CC. Our systematic review managed to demonstrate that ICIs might represent an appealing strategy for advanced CC, with 2 out of 3 patients responding to ICIs without further concerns about safety. PD-L1 status might be an indicator of response; however, the search for new predictive biomarkers is mandatory. Further studies are needed for appropriate patient selection and a tailored approach. Background: Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario of many solid tumors. The role of ICIs in CC should be addressed. Therefore, we systematically reviewed the latest clinical trials employing ICIs in advanced CC to assess which ICIs have been employed and how ICIs might meet the need for new therapeutic options in terms of efficacy and safety. Methods: The review was conducted following the PRISMA guidelines. The following efficacy outcomes were specifically collected: overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS); for safety: type, number, and grade of adverse events (AEs). Results: A total of 17 studies were analyzed. Anti-PD1 (pembrolizumab, nivolumab, cemiplimab, balstilimab, and tislelizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab, zalifrelimab) agents were employed both as single agents or combinations. Overall ORR ranged from 0% to 65.9%. ORR ranged from 5.9% to 69.6% in PD-L1-positive patients and from 0% to 50% in PD-L1-negative patients. DCR was 30.6–94.1%. mPFS ranged from 2 to 10.4 months. mOS ranged from 8 months to not reached. PD-L1 status did not impact survival. A total of 33.9% to 100% of patients experienced AEs. Conclusion: Immunotherapy represents an appealing strategy for patients with advanced CC, as 2 out of 3 patients seem to respond to ICIs. PD-L1 status might be an indicator of response without impacting survival. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EC) represents the sixth most common female tumor. In the advanced setting, the prognosis is dismal with limited treatment options. Platinum-based chemotherapy represents the actual standard of care in first-line chemotherapy, but no standard second-line chemotherapy is approved, with less than 1/4 of patients responding to second-line chemotherapy. In the last 10 years, immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many solid tumors. Methods: The review was conducted according to the PRISMA guidelines. We searched EMBASE, MEDLINE, Cochrane Database, and conference abstracts from international societies, up to November 2021. Clinical trials employing ICIs in advanced EC, written in English, were included. Reviews, letters, and commentaries were excluded. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety (number and grade of treatment-related adverse events [TRAEs]) were evaluated. Results: 15 studies, for a total of 1,627 patients, were included: 14 non-randomized phase I/II trials and 1 randomized phase III trial. Anti-PD1 (pembrolizumab, nivolumab, dostarlimab) and anti-PD-L1 agents (avelumab, atezolizumab, durvalumab) were administered as single agents; pembrolizumab and nivolumab were combined with the tyrosine-kinase inhibitors (TKI) lenvatinib and cabozantinib, respectively; and durvalumab was associated with anti-CTLA4 tremelimumab. 4 studies selected only MSI patients. Single agents determined an ORR from 26.7% to 58% among MSI patients, from 3% to 26.7% among MSS patients. DCR ranged from 53.5% to 88.9% in MSI, 31.4% to 35.2% in MSS patients. The combination of TKI and ICIs determined 32% to 63.6% of ORR in all-comers, 32%–36.2% in MSS patients. 54.2% to 76% of patients developed TRAEs. The combination of ICIs and TKI achieved a higher toxicity rate than single agents (≥G3 TRAEs 88.9%). Conclusion: ICIs represent an effective option for pretreated advanced EC patients with a tolerable profile. Given the encouraging results in MSI patients, every woman diagnosed with EC should be investigated for MS status. In MSS women, the combination of ICIs and TKI is more effective than monotherapy, notwithstanding safety concerns. PD-L1 cannot predict ICI response, whereas other biomarkers such as MSI and tumor mutational burden seem more accurate. Ongoing randomized trials will further clarify the role of these therapeutic options. Systematic Review Registration: PROSPERO, CRD42021293538. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies. [ABSTRACT FROM AUTHOR]

• Immune checkpoints inhibitors enhance the efficacy of platinum-based chemotherapy in advanced endometrial cancer. • The benefit in progression-free survival is more pronounced among patients with microsatellite unstable disease. • For DNA mismatch repair proficient tumors, the benefit is limited to the use of anti-PD1 agents. Various randomized trials have explored the efficacy of combining immune checkpoint inhibitors (ICIs) with first-line chemotherapy in advanced endometrial cancer. We aimed to summarize available data and clarify the benefit of adding immunotherapy according to the DNA mismatch repair status (deficient, dMMR or proficient, pMMR) and the specific type of agent used (anti-PD1 or anti-PD-L1). To assess whether the addition of ICIs to standard platinum-based chemotherapy enhances progression-free survival (PFS) for patients with advanced endometrial cancer both overall and based on DNA mismatch repair status. Electronic databases (PubMed, Embase and Cochrane Library) and conference proceedings were searched for first line, randomized and controlled trials integrating ICIs with chemotherapy for the treatment of advanced endometrial cancer published or presented by November 1, 2023. Five studies, comprising 2456 patients (1308 received ICIs with chemotherapy and 1148 treated with chemotherapy alone) met the selection criteria and were included in the analysis. Experimental arms included pembrolizumab, dostarlimab (anti-PD1) and durvalumab, atezolizumab and avelumab (anti-PD-L1) combined with standard three-weekly carboplatin-paclitaxel chemotherapy backbone. Endometrial carcinosarcoma were included in 3 out of 5 trials. For comparison of PFS outcomes, extrapolation of hazard ratios (HRs), 95% confidence intervals (CI) and PFS events was performed for each included study in the overall population and according to subgroups. Data analysis was conducted using a random-effects model. The addition of ICIs to chemotherapy improved PFS compared to chemotherapy alone in the overall population (pooled HR, 0.63; 95 % CI, 0.52––0.76; P <.001). In the dMMR subgroup the benefit was more pronounced (pooled HR, 0.34; 95 % CI, 0.27––0.44; P <.001) and not affected by drugs used with pooled HRs of 0.39 (95 % CI, 0.28––0.55; P <.001) and 0.34 (95 % CI, 0.27––0.44; P <.001) for PD-L1 and PD1 inhibitors, respectively. For pMMR patients, a statistically significant benefit in terms of PFS was confirmed only when anti-PD1 were used (anti-PD-1: HR 0.64, 95 % CI: 0.46–0.90, P =.010 vs anti-PD-L1: HR 0.87, 95 % CI: 0.73–1.03, P =.104) This meta -analysis confirmed the advantage in terms of PFS of adding ICIs to standard platinum-based chemotherapy. While dMMR patients benefit from the incorporation of both anti PD-1 or anti PD-L1, this benefit is confined to the association of anti-PD1 agents in pMMR patients. Updated analysis of trials is awaited to clarify the impact of immunotherapy on overall survival. [ABSTRACT FROM AUTHOR]

Background Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment. Primary objective To test if the activity of nonplatinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab. study hypothesis The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months. Trial design Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PDL1) status. Major inclusion/exclusion criteria Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatmentfree interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria. Primary endpoint Overall survival and progression-free survival are co-primary endpoints. sample size It is planned to randomize 664 patients. Trial registration NCT03353831. [ABSTRACT FROM AUTHOR]

Objective: immunotherapy with immune checkpoint inhibitors has become one of the standard therapeutic modalities for patients with advanced melanoma. Melanoma of the female lower genital tract is a rare and aggressive disease, with poor long-term clinical outcomes. To date, no study evaluated the role of immunotherapy in metastatic melanoma of the lower genital tract. Methods: Data of women with metastatic melanoma of the lower genital tract were prospectively collected. Survival outcomes over time was assessed using Kaplan-Meier model. Results: Seven cases of metastatic melanoma of the lower genital tract (vulva [n=2], vagina [n=4], and uterine cervix [n=1]) treated with immune checkpoint inhibitors are reviewed. Two patients had metastatic disease at diagnosis, while 5 patients developed metastatic disease at a mean (standard deviation) time of 9.9 (±3.0) months from primary diagnosis. Four patients received an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) (ipilimumab) and 3 received an anti-programmed cell death 1 (PD-1) (pembrolizumab [n=2], nivolumab [n=1]) therapy. The response rate to immunotherapy was 28.5%. Patients receiving an anti-PD-1 experienced a better progression-free survival than patients treated with anti-CTLA4 (p=0.01, log-rank test). Although not reaching statistical significance, overall survival was better in patients having an anti-PD-1 therapy in comparison to anti- CTLA4 (p=0.15, log-rank test). Conclusion: Results from our series confirm the poor prognosis of women with metastatic melanoma of the lower genital tract, thus supporting the need of exploring new treatment modalities. Further studies are warranted to improve knowledge on the role of immunotherapy in metastatic melanoma of the lower genital tract. [ABSTRACT FROM AUTHOR]

Retifanlimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1 being investigated in several solid tumor types. We report final results from patients with recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer treated with retifanlimab in a POD1UM-101 expansion cohort. Eligible patients (≥18 years; histologically proven/unresectable/recurrent, MSI-H/dMMR endometrial cancer; checkpoint inhibitor naive) received retifanlimab 500 mg intravenously every 4 weeks for ≤2 years. Primary endpoint was safety/tolerability. At data cutoff (May 17, 2023), 76 patients had received at least one retifanlimab dose. Median (range) age was 67 (49–88) years; 88.2% of patients had recurrent metastatic disease and 80.3% had visceral metastases. Seventy-five patients (98.7%) had received at least one prior systemic therapy. Median retifanlimab exposure was 10.0 (0.03–25.9) months; 23 patients completed treatment. 38 patients (50.0%) had grade ≥3 treatment-emergent adverse events (TEAEs), most commonly anemia (n = 10 [13.2%]). 63 patients (82.9%) had treatment-related AEs (TRAEs; grade ≥3, n = 14 [18.4%]); most common was fatigue (n = 14 [18.4%]). Two patients had TEAEs that led to death; no TRAEs were fatal. 39 patients had objective responses (51.3%; 95% CI, 39.6−63.0%); 19 patients (25.0%) had complete response and 20 (26.3%) had partial response. Median progression-free survival was 12.2 months; 30 patients (76.9%) had duration of response (DOR) ≥12 months. Median DOR was not reached after median follow-up time of 26.0 months. Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer. • We evaluated safety and anti-tumor activity of retifanlimab in patients with recurrent MSI-H/dMMR endometrial cancer. • Retifanlimab was generally well tolerated and demonstrated a safety profile typical of the PD-(L)1 inhibitor class. • Objective response rate of 51% (95% CI, 39.6–63.0%) was observed with retifanlimab; median DOR was not reached. • Retifanlimab represents a potential new treatment option for patients with recurrent MSI-H/dMMR endometrial cancer. [ABSTRACT FROM AUTHOR]

Tisotumab vedotin (TV) is an antibody-drug conjugate used for the treatment of adult patients with recurrent or metastatic cervical cancer. TV comprised of a monoclonal antibody against tissue factor and monomethyl auristatin E (MMAE), a potent inhibitor of cell division. The innovaTV-201 and innovaTV-204/GO30xx/ENGOT-cx6 trials showed that TV has clinically meaningful and durable antitumor activity in pretreated patients with recurrent or metastatic cervical cancer. The innovaTV-204 trial showed that TV monotherapy resulted in an objective response rate of 24% (including 7% and 17% complete and partial responses, respectively). In September 2021, the US Food and Drugs Administration (FDA) granted accelerated approval to TV for the treatment of recurrent or metastatic cervical cancer patients with disease progression on or after chemotherapy. The ongoing randomized, open-label Phase 3 innovaTV-301/ENGOTcx12/GOG-30xx trial will assess the effect of TV in pre-treated recurrent or metastatic cervical cancer. Meanwhile, the phase 1b/2 trial ENGOT Cx8/GOG 3024/innovaTV-205 is testing other possible combination between TV and other treatments. TV is characterized by a promising antitumor activity and an acceptable safety profile. Moreover, the preliminary data highlighted the feasibility of using TV in first line. In the first line, TV in combination with carboplatin or pembrolizumab provides an ORR of 55% and 41%, respectively Although the effect of adding TV to the current standard of care in first-line (carboplatin plus pembrolizumab) is still under evaluation, we expected to observe impressive results in the cervical cancer population. [ABSTRACT FROM AUTHOR]

Simple Summary: We present a systematic overview of EMA-approved oncologic drugs, both as new or extensions of indications, over 6 years, from 2015 to 2020. Our analysis confirms a long-standing trend in drug development for which most of the efforts led to broadening indications of pre-existing molecules, with immunotherapy and signal transduction inhibitors contending the leadership. Many drugs with the same or a very similar mechanism of action are approved for the same indication without a direct head-to-head comparison. Moreover, we show that the majority of drugs entered the market without evidence of overall survival or quality of life benefit but based on surrogate outcomes. Our data support some considerations about the modern drug development in oncology, where the goal is to provide the patients with the fastest possible access to new drugs. The debate on the optimal methodology to develop new drugs remains an unmet need. (1) Background: Drug development in oncology is changing rapidly. The aim of the present study was to provide an insight into the features of anti-tumor drugs approved in Europe; (2) Methods: We included all the indications for solid tumors issued by the European Medicines Agency (EMA) between 2015 and 2020. We extracted data from European Public Assessments Reports (EPAR), including drug name, mechanism of action, setting, features of pivotal clinical trials, primary end-points, quality of life (QoL); (3) Results: In the explored period, EMA issued 132 new indications (81 indications' extensions) for 62 oncology drugs. In about half of indications (47%), the approval was biomarker-based. Immune check point inhibitors (ICIs) and signal transduction inhibitors were the two most representative drug categories (62%). Most of the indications were for the advanced setting (91%) and front-line therapy (66%). The most common tumor types were non-small cell lung cancer (24%), breast (16%), and melanoma (10%). Two thirds of the indications (73%) were approved based on phase III trials. Overall survival (OS) represented the primary end-point only in 39% of indications, mainly limited to advanced setting (98%) and ICI trials (80%). Almost all (94%) cell cycle and DNA repair mechanism inhibitors were approved based on progression free survival (PFS) data. In pivotal trials with signal transduction inhibitors, objective response rate (ORR) was the prevalent (45%) primary end-point. QoL was never considered as primary end-point; (4) Conclusions: In this analysis, we intended to offer an updated picture of the recent drug development in oncology. Most of the efforts led to broadening indications of pre-existing molecules, with signal transduction inhibitor and ICIs contending the leadership. Twenty-seven percent of the indication were approved without a phase III trial. The majority of drugs entered the market without evidence of OS or QoL benefit but based on surrogate outcomes. [ABSTRACT FROM AUTHOR]

Background aims. We have recently shown that thymoglobulin (TG) efficiently expands cytokine-induced killer (CIK) cells in combination with interferon (IFN)-γ and interleukin (IL)-2 (ITG2 protocol). It is presently unknown whether the infusion of autologous immune effector cells generated by TG, IFN-γ and IL-2 is feasible and safe. Methods. Five patients with advanced and/or refractory solid tumors were enrolled in the present phase I/II study. Peripheral blood mononuclear cells (PBMC) collected by leukapheresis were stimulated under good manufacturing practice (GMP)-conditions with IFN-γ, followed by TG and IL-2. After 2-3 weeks in culture, a median of 4.65 × 106 immune effector cells per kilogram of recipient's body weight was obtained and infused intravenously. The median time from enrollment into the study to infusion of the expanded CIK cells was 30 days. Results. ITG2 efficiently expanded immune effector cells that comprised both conventional natural killer (NK) cells and CD3+ CD16+ CD56+ CIK cells. One patient with advanced melanoma died because of disease progression before the infusion of CIK cells. The target dose of at least 2.5 × 106 CIK cells/kg of recipient's body weight was reached in four out of five evaluable patients. CIK cells were administered intravenously without any measurable toxicity. In vitro, CIK cells exerted lytic activity against cervical cancer cells. The median survival was 4.5 months (range 1-13) from the first infusion of CIK cells. Conclusions. This study has highlighted the feasibility and safety of the administration of CIK cells generated with the ITG2 protocol. Whether CIK cells can help control disease burden in patients with advanced malignancies will be determined in future clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer (OC) represents the fifth leading cause of cancer-related deaths among women. In the advanced disease setting, OC recurrence after chemotherapy is over 70% in the first 2 years, with few therapeutic options. Immunotherapy with the immune checkpoint inhibitors (ICIs) showed high efficacy and changed the therapeutic scenario of many tumors in the last 10 years. With our review, we aimed to summarize the clinical trials of ICIs in OC. In OC, ICIs clinical trials have reported poor outcomes in terms of patient response and survival, with some studies failing to reach their objectives. Combining immunotherapy with drugs targeting different pathways might enhance efficacy and overcome cancer resistance. The search for biomarkers predicting ICIs response is essential for the identification of patients most likely to benefit from ICI therapy. Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In an advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in OC. Methods: We searched PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were identified, of which 16 were phase I or II and 4 phase III trials. These trials used ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, aterolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab). There was no reported improvement in survival, and some trials were terminated early due to toxicity or lack of response. Combining ICIs with chemotherapy, anti-VEGF therapy, or PARP inhibitors improved response rates and survival in spite of a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs' efficacy is mandatory. Moreover, genomic and immune profiling of OC might lead to better treatment options and facilitate the design of tailored trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical cancer represents one of the main leading causes of cancer-related mortality in women worldwide. In contrast to patients with early-stage disease, those with advanced, recurrent, or metastatic cervical cancer have a poor prognosis and new treatment strategies are needed. Immunotherapy has recently modified the natural course of different tumors, such as melanoma and lung cancer. The aim of this review is to evaluate the possible role of immune checkpoint inhibitors in cervical cancer treatment. Human papillomavirus (HPV) infection is the recognized cause of almost all cervical cancers. Despite the reduction in incidence due to a wide use of screening programs and a specific vaccine, the prognosis of cervical cancer remains poor, especially for late-stage and relapsed disease. Considering the elevated rates of PD-L1 expression in up to 80% of cervical cancers, a strong rationale supports the use of immunotherapy to restore the immune response against tumor. The aim of this review is to analyze the possible role of immune checkpoint inhibitors in cervical cancer treatment, with a particular focus on the rationale and on the results of phase I and II clinical trials. An overview of ongoing phase III studies with possible future areas of development is also provided. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer treatment is the deadliest of gynecological cancers but the introduction of target therapies in its therapeutic algorithm has significantly improved outcomes. The aim of this article was to provide a review of completed and ongoing clinical trials involving the use of PARP inhibitors and/or immune checkpoint inhibitors for the treatment of ovarian cancer in front line and relapse settings. We confirmed the role of bevacizumab and PARP inhibitors which have transformed OC into a chronic disease while almost all trials involving immunotherapy were disappointing. Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment. [ABSTRACT FROM AUTHOR]

The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT03556839 , and is ongoing. Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3–16·6) with atezolizumab and 10·4 months (9·7–11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49–0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3–36·8) versus 22·8 months (20·3–28·0), respectively (HR 0·68 [95% CI 0·52–0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1–2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most common gynecological disease in developed countries. Although it is considered an indolent disease, advanced and recurrent endometrial carcinomas are characterized by poor prognosis. In the metastatic setting, after the failure of first-line platinum-based chemotherapy, patients have limited therapeutic options. However, endometrial cancer should not be considered as a single entity but as a group of heterogeneous diseases with specific genomic, molecular, and biological features by suggested the analysis of The Cancer Genome Atlas (TCGA). Accumulating data highlighted the effectiveness and safety of the adoption of immune checkpoint inhibitors (ICIs) for several types of solid tumors. In particular, immunotherapy showed promising results in MSI-H/dMMR solid tumors. Endometrial cancer is not an exception. Endometrial cancer has the highest prevalence of MSI across human cancer types, and approximately 30% of primary endometrial cancers are MSI-H/dMMR and 13% to 30% of recurrent endometrial cancers are MSI-H/dMMR. The preliminary results of the KEYNOTE-158, the Australian NCT03015129 and the GARNET trial strongly supported the adoption of ICIs as monotherapy in patients with advanced or recurrent endometrial cancer, after the failure of first-line treatments. Unfortunately, those impressive results are not achieved in patients with MMR proficient disease. Hence, other combinations were tested. In particular, the adoption of ICIs plus tyrosine kinase inhibitors (TKI) showed very compelling results. Recently, the updated results of the KEYNOTE-775 showed that pembrolizumab plus lenvatinib led to significantly longer progression-free and overall survival than chemotherapy among patients with advanced endometrial cancer, irrespective of MMR status. After EMA approval, pembrolizumab plus lenvatinib represents the new standard second-line treatment in endometrial cancer patients, regardless MMR status. Further studies are investigating the role of ICIs and TKIs in the first line and are testing new combinations (e.g. ICIs plus PARP inhibitors). • Patients with advanced / recurrent endometrial cancer have limited therapeutic options. • Chemotherapy still represent the current 1L treatment in advanced/recurrent endometrial cancer. • MSI-H/dMMR is an agnostic biomarker suggesting the efficacy of immunotherapy. • Endometrial cancer is the solid tumor with the highest prevalence of MSI-H/dMMR. • Immunotherapy is the emerging standard 2L in MSI-H/dMMR endometrial cancer • Immunotherapy plus TKI provides is the emerging standard 2L in pMMR endometrial cancer [ABSTRACT FROM AUTHOR]

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma. • Clear cell endometrial cancer represents uncommon uterine tumor. • Multi-modal treatment should be considered in patient with clear cell endometrial cancer. • Immunotherapy might play a role in patients with MMRd clear cell endometrial cancer. • ATr , PIK3CA , DDR , and HER2 might be potential targets in clear cell endometrial cancer [ABSTRACT FROM AUTHOR]

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1 , MYC, PPP2R1A , PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease. • Uterine serous carcinoma (USC) is a rare and aggressive variant of endometrial cancer. • USCs are generally mismatch repair proficient and have extensive copy number alterations. • Multi-modal treatment including surgery, chemotherapy and/or radiotherapy should be considered in the majority patient with USC. • Novel combinations of immune checkpoint inhibitors with targeted therapies are under evaluation. [ABSTRACT FROM AUTHOR]

Patients with primary metastatic/recurrent endometrial cancer have poor prognosis and available therapeutic options are limited. Current treatment is mainly based on platinum-based chemotherapy. Recently, the Food and Drug Administration (FDA) granted approval for the combination of pembrolizumab and lenvatinib for endometrial cancer patients without microsatellite instability (MSS) progressing on a previous line of therapy while European Medicines Agency (EMA) approved the combination for all comers patients failing previous platinum treatment. Anti programmed cell death protein-1 (PD-1) dostarlimab (TSR-042) was approved as monotherapy in patients with advanced, microsatellite instable (MSI) endometrial cancer progressing to platinum treatment. Phase II-III clinical trials in metastatic endometrial cancer are mainly focused on target therapies and immunotherapy as single agents or in combination. Unfortunately, most of these trials are lacking of predictive biomarkers of response to select patients most or at least likely to benefit from those treatments. [Display omitted] • Patients with metastatic endometrial cancer (MEC) have poor prognosis. • Available therapeutic options are limited in the MEC setting. • Ongoing clinical trials are investigating target therapies and immunotherapy in MEC. [ABSTRACT FROM AUTHOR]