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Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

Carboplatin plus paclitaxel administered every 3 weeks is standard first-line chemotherapy for patients with advanced ovarian cancer. A weekly paclitaxel schedule combined with carboplatin every 3 weeks prolonged progression-free survival and overall survival in a Japanese phase 3 trial. The aim of our study was to assess whether a weekly schedule of carboplatin plus paclitaxel is more effective than the same drugs given every 3 weeks. We did a multicentre, randomised, phase 3 study at 67 institutions in Italy and France. Women with FIGO stage IC–IV ovarian cancer, an ECOG performance status of 2 or lower, and who had never received chemotherapy were randomly allocated in a 1:1 ratio to receive either carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m2) every 3 weeks for six cycles or carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m2) every week for 18 weeks. Randomisation was done by computer-based minimisation, stratified by centre, residual disease after surgery, and ECOG performance status. The study was not blinded. Coprimary endpoints were progression-free survival and quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index [FACT-O/TOI] score), and analysis was by modified intention to treat. This report presents the final analysis. The study is registered with ClinicalTrials.gov, number NCT00660842. 822 patients were enrolled into the study between Nov 20, 2008, and March 1, 2012; 12 withdrew their consent immediately after randomisation and were excluded, and 810 were eligible for analysis. 404 women were allocated treatment every 3 weeks and 406 were assigned to the weekly schedule. After median follow-up of 22·3 months (IQR 16·2–30·9), 449 progression-free survival events were recorded. Median progression-free survival was 17·3 months (95% CI 15·2–20·2) in patients assigned to treatment every 3 weeks, versus 18·3 months (16·8–20·9) in women allocated to the weekly schedule (hazard ratio 0·96, 95% CI 0·80–1·16; p=0·66). FACT-O/TOI scores differed significantly between the two schedules (treatment-by-time interaction p<0·0001); with treatment every 3 weeks, FACT-O/TOI scores worsened at every cycle (weeks 1, 4, and 7), whereas for the weekly schedule, after transient worsening at week 1, FACT-O/TOI scores remained stable. Fewer patients assigned to the weekly group than those allocated treatment every 3 weeks had grade 3–4 neutropenia (167 [42%] of 399 patients vs 200 [50%] of 400 patients), febrile neutropenia (two [0·5%] vs 11 [3%]), grade 3–4 thrombocytopenia (four [1%] vs 27 [7%]), and grade 2 or worse neuropathy (24 [6%] vs 68 [17%]). Three deaths during the study were attributed to chemotherapy; two women died who were allocated treatment every 3 weeks and one death was recorded in the group assigned the weekly regimen. A weekly regimen of carboplatin and paclitaxel might be a reasonable option for first-line treatment of women with advanced ovarian cancer. None.

Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0–1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m2 with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5–20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36–11·02] vs 3·49 months [2·01–5·66]; hazard ratio 0·42 [95% CI 0·25–0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3–4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. National Cancer Institute of Napoli and GlaxoSmithKline.

Ovarian cancer remains a major issue for gynecological oncologists, and most patients are diagnosed when the disease is already advanced with a poor chance of survival. Debulking surgery followed by platinum‐taxane chemotherapy is the current standard of care, but based on several different strategies currently under evaluation, some encouraging data have been published in the last 4 to 5 years. This review provides a state‐of‐the‐art overview of the available alternatives to conventional treatment and the most promising new combinations. For example, neoadjuvant chemotherapy does not seem to be inferior to primary debulking. Despite its outcome improvements, intraperitoneal chemotherapy struggles for acceptance due to the heavy toxicity. Dose‐dense chemotherapy, after showing an impressive efficacy in Asian populations, has not produced equal results in a European cohort, and the results of alternative platinum doublets are not superior to those of carboplatin and paclitaxel. In this setting, adherence to a maintenance therapy after first‐line treatment and multiple (primarily antiangiogenic) agents appears to be effective. Although many questions, including the duration of maintenance treatment and the use of bevacizumab beyond progression, remain unanswered, new biologic agents, such as poly(ADP‐ribose) polymerase (PARP) inhibitors, nintedanib, and mitogen‐activated protein/extracellular signal‐regulated kinase (MEK) inhibitors, have emerged as potential therapeutic options in the very near future. Based on the multiplicity of available strategies, the histological and molecular features of the tumor, in addition to patient's clinical condition and disease state, continue to gain importance in guiding treatment choices.

Cervical cancer (CC) is the second most commonly diagnosed cancer and the third leading cause of cancer death among females. The options of treatment for recurrent/advanced CC are limited and patients experiencing recurrence after first line platinum-based chemotherapy have a poor prognosis. In this context, immune checkpoint inhibitors (ICI)s antagonizing PD-1 and programmed death-ligand 1 (PD-L1) have profoundly changed the treatment scenario and outcomes in CC in the first or subsequent lines both as monotherapies or in combination with chemotherapy or other ICIs. Herein, we report the clinical case of a 74-year-old woman with metastatic CC with negative tumor PD-L1 expression who having disease progression after first-line of systemic treatment with platinum, thus undergoing to anti-PD-1 namely cemiplimab. The patient achieved a surprising, fast and complete metabolic response to cemiplimab immediately discontinued after only two cycles due to the onset of rare and severe immune-related adverse events (irAE)s such cardiovascular toxicity and hypertransaminasemia. Despite this, thirteen months later, the patient remains disease-free despite cemiplimab was withdrawn.

Purpose of ReviewTherapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC.Recent FindingsThe first-line treatment with tyrosine kinase inhibitor monotherapy can still be considered an effective tool for addressing selected mRCCs, as highlighted by the successful outcome in a range of subjects such as favorable-risk patients, the ones suffering from autoimmune diseases, those with pancreatic or lung metastases, or previously undergoing organ transplantation and elderly subjects.SummarySome selected categories of patients may still benefit from monotherapy with TKI, and smart sequential therapies can also be considered instead of a combination strategy. Tyrosine kinase inhibitors can also act as immune modulator agents, boosting the immune response to facilitate and potentiate the therapeutic effectiveness of subsequent immunotherapy.

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l -tryptophan into the immunosuppressive metabolite l -kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Ovarian clear cell carcinoma (OCCC) is a rare, aggressive epithelial ovarian cancer subtype, accounting for approximately 10% of cases and associated with a poor prognosis due to chemoresistance and unique tumor biology. OCCC is frequently linked to endometriosis and characterized by mutations in and , hyperactivation of the PI3K/Akt/mTOR pathway, and overexpression of VEGF, HIF-1α, and IL-6. These features drive tumor proliferation, angiogenesis, immune evasion, and resistance to platinum-based chemotherapy. The tumor microenvironment of OCCC is highly immunosuppressive, with infiltration of regulatory T cells, tumor-associated macrophages, and upregulation of immune checkpoint molecules, such as PD-1, PD-L1, and LAG-3. These characteristics suggest that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and could be an attractive target for therapeutic intervention. Despite the typical composition of the immunosuppressive tumor microenvironment in ovarian cancer, until now overall the results of trials testing immune checkpoint inhibitors so far have been disappointing. It is interesting to note instead that several subgroup analyses reported exceptional OCCC sensitivity to ICIs. Indeed, current and preliminary trials exploring ICIs, anti-angiogenic agents, and combinatorial therapies in OCCC show promising outcomes. Strategies targeting multiple pathways, including VEGF, IL-6, HIF-1α, and HDAC6, alongside ICIs, are under investigation to overcome resistance mechanisms. Additionally, IL-10 inhibition or ferroptosis pathway activation offers novel therapeutic potential. Personalized, biomarker-driven approaches, targeting and mutations or combining immune and anti-angiogenic agents, are gaining traction in OCCC management. This review highlights OCCC molecular underpinnings and therapeutic challenges, emphasizing the need for innovative, multi-targeted strategies. Advances in understanding genetic-immunological interplay in OCCC may enable more effective and durable treatments and improved patient outcomes.

•A niraparib population PK model was developed using pooled data from clinical trials.•PopPK/exposure-response analyses support niraparib individualized starting dose (ISD).•Use of a niraparib ISD improved the safety profile without compromising efficacy. Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www.clinicaltrials.gov.

ABSTRACT Background A low fT3/fT4 ratio has been associated with poorer prognosis in several diseases. Inflammatory indexes (IIs) and the skeletal muscle index (SMI) are established prognostic factors in various cancer types. However, their interplay and individual contributions to the prognosis of cervical cancer remain unclear. This study aimed to evaluate the impact of these biomarkers on survival outcomes in cervical cancer patients treated with innovative immunotherapy. Methods This retrospective study included 101 patients with cervical cancer treated with cemiplimab at 12 Italian oncology centres. Patients with thyroid comorbidities or missing fT3/fT4 ratio data were excluded. The primary endpoint was overall survival (OS) in relation to the fT3/fT4 ratio. Secondary endpoints included progression‐free survival (PFS) and correlations between the fT3/fT4 ratio, ECOG Performance Status, IIs and SMI. Results An optimal fT3/fT4 cutoff for OS prediction was identified at 0.29. Median OS was 10.9 months for patients with a low fT3/fT4 ratio, while it was not reached for those with high fT3/fT4 levels (HR = 2.70; 95% CI: 1.17–6.22; p = 0.02). Multivariate analysis confirmed that both the fT3/fT4 ratio and ECOG PS independently influenced OS. Among the IIs analysed, the systemic inflammatory index (SII) demonstrated the strongest correlation with fT3/fT4 levels (OR = 3.82; 95% CI: 1.39–10.50; p = 0.0092). Exploratory analysis also revealed significantly lower SMI values in patients with lower fT3/fT4 ratios (p = 0.034). Conclusions This study highlights the prognostic significance of the fT3/fT4 ratio, IIs, and SMI in cervical cancer patients treated with cemiplimab. Given the exploratory nature of these findings, further validation in larger, prospective cohorts is warranted to support their integration into clinical practice and the development of innovative prognostic tools.