Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study

Seguretat; Càncer d'ovariSeguridad; Cáncer de ovarioSafety; Ovarian cancerPURPOSE Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population

Incorporation of anti-PD1 or anti PD-L1 agents to platinum-based chemotherapy for the primary treatment of advanced or recurrent endometrial cancer. A meta-analysis

Endometrial cancer; ImmunotherapyCàncer d'endometri; ImmunoteràpiaCáncer de endometrio; InmunoterapiaImportance 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). Objective 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. Data sources 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. Study selection 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. Data extraction and synthesis 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. Results 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) Conclusions and relevance 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

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer

Endometrial cancer; Guidelines; TreatmentCàncer d'endometri; Pautes; TractamentCáncer de endometrio; Pautas; TratamientoThe most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.All costs relating to this consensus conference were covered by the ESMO and the ISMPO from central dedicated funds. There was no external funding of the event or the manuscript production

Investigational drugs for recurrent or primary advanced metastatic cervical cancer: what is in the clinical development pipeline?

Recurrent cervical cancer; Combination therapy; ImmunotherapyCáncer cervical recurrente; Terapia de combinación; InmunoterapiaCàncer cervical recurrent; Teràpia combinada; ImmunoteràpiaIntroduction: Recurrent or primary advanced metastatic cervical cancer (R/M CC) has a poor prognosis with a 5-year-survival rate of 16.5%, demanding novel and improved therapies for the treatment of these patients. The first-line standard of care for R/M CC now benefits from the addition of the immune checkpoint inhibitor, pembrolizumab, to platinum-based chemotherapy with paclitaxel and bevacizumab. Additionally, new options for second-line treatment have become available in recent years. Areas covered: Here, we review current investigational drugs and discuss their relative targets, efficacies, and potential within the R/M CC treatment landscape. This review will focus on recently published data and key ongoing clinical trials in patients with R/M CC, covering multiple modes of action, including immunotherapies, antibody-drug conjugates, and tyrosine kinase inhibitors. We searched clinicaltrials.gov for ongoing trials and pubmed.ncbi.nih.gov for recently published trial data, as well as recent years' proceedings from the annual conferences of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO), and the International Gynecologic Cancer Society (IGCS). Expert opinion: Therapeutics currently attracting attention include novel immune checkpoint inhibitors, therapeutic vaccinations, antibody-drug conjugates, such as tisotumab vedotin, tyrosine kinase inhibitors targeting HER2, and multitarget synergistic combinations

Pegylated liposomal doxorubicin in the management of ovarian cancer

Among the pharmaceutical options available for treatment of ovarian cancer, much attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation, which entraps conventional doxorubicin in a bilayer lipidic sphere surrounded by a polyethylene glycol layer, prolongs the persistence of the drug in the circulation and potentiates intratumor drug accumulation. These properties enable this drug to sustain its very favorable toxicity profile and to be used safely in combination with other drugs. PLD has been already approved for treatment of advanced ovarian cancer patients failing first-line platinum-based treatment. Moreover, phase III trials have been already completed, and results are eagerly awaited, which hopefully will expand the range of PLD clinical application in this neoplasia both in front-line treatment, and in the salvage setting in combination with other drugs. Moreover, attempts are continuing to enable this drug to be combined with novel cytotoxic drugs and target-based agents. This review aims at summarizing the available evidence and the new perspectives for the clinical role of PLD in the management of patients with epithelial ovarian cancer

Maintenance treatment with rucaparib for recurrent ovarian carcinoma in ARIEL3, a randomized phase 3 trial: The effects of best response to last platinum-based regimen and disease at baseline on efficacy and safety

Assaigs clínics; Oncologia ginecològica; Càncer de les donesEnsayos clínicos; Oncología ginecológica; Cáncer de las mujeresClinical trials; Gynecological oncology; Women's cancerBackground The efficacy and safety of rucaparib maintenance treatment in ARIEL3 were evaluated in subgroups based on best response to most recent platinum-based chemotherapy and baseline disease. Methods Patients were randomized 2:1 to receive either oral rucaparib at a dosage of 600 mg twice daily or placebo. Investigator-assessed PFS was assessed in prespecified, nested cohorts: BRCA-mutated, homologous recombination deficient (HRD; BRCA mutated or wild-type BRCA/high loss of heterozygosity), and the intent-to-treat (ITT) population. Results Median PFS for patients in the ITT population with a complete response to most recent platinum-based chemotherapy was 11.1 months in the rucaparib arm (126 patients) versus 5.6 months in the placebo arm (64 patients) (HR, 0.33 [95% CI, 0.23–0.48]), and in patients with a partial response (249 vs. 125), it was 9.0 versus 5.3 months (HR, 0.38 [0.30–0.49]). In subgroups of the ITT population based on baseline disease, median PFS was 8.2 versus 5.3 months (HR, 0.40 [0.28–0.57]) in patients with measurable disease (141 rucaparib vs. 66 placebo), 10.4 versus 4.5 months (HR, 0.31 [0.20–0.48]) in those with nonmeasurable but evaluable disease (104 vs. 56), and 14.1 versus 7.3 months (HR, 0.35 [0.24–0.51]) in those with no residual disease (130 vs. 67). Across subgroups, significantly longer median PFS was observed with rucaparib versus placebo in the BRCA-mutated and HRD cohorts. Objective responses were reported in patients with measurable disease and in patients with nonmeasurable but evaluable baseline disease. Safety was consistent across subgroups. Conclusion Rucaparib maintenance treatment provided clinically meaningful efficacy benefits across subgroups based on response to last platinum-based chemotherapy or baseline disease.A.O. has served on advisory boards for Clovis Oncology, AstraZeneca, Deciphera, Genmab/Seattle Genetics, GlaxoSmithKline/Tesaro, ImmunoGen, Merck/Merck Sharp & Dohme, Mersana Therapeutics, PharmaMar, and Roche; has received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche; and reports institutional research grant support from Clovis Oncology, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Eisai, ImmunoGen, Merck/Merck Sharp & Dohme, Millennium Pharmaceuticals, PharmaMar, Roche, and Tesaro

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I

Chemotherapy; Mirvetuximab soravtansine; Ovarian cancerQuimioterapia; Mirvetuximab soravtansina; Cáncer de ovariosQuimioteràpia; Mirvetuximab soravtansina; Càncer d'ovarisBackground Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). Patients and methods Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. Results A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. Conclusions In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.This work was supported by ImmunoGen, Inc (no grant number)

A cost-minimization analysis of a preventive testing strategy for relatives of patients with BRCA mutated ovarian cancer

Purpose: This study aims to estimate the cost-minimization strategy of a preventive testing strategy destined to relatives of patients with BRCA mutated cancer versus a no test strategy in Italia. Methods: A BRCA testing pathway was designed by a panel of experts based on the MSTM Excel (2010) tool; the analysis was carried out considering the perspective of the Italian National Health Service. Two alternatives were considered: 1) preventive BRCA testing for relatives of patients affected by ovarian cancer carrying a BRCA1/BRCA2 mutation; 2) no test. Cost and effectiveness data, derived from literature and published sources validated by a Board of experts, were discounted using a discount factor equal to 3%. Probabilistic sensitivity analysis was performed. Results: Considering an average cost of therapy for breast and ovarian cancer major of €90,000.00 per case, the economic impact related to the preventive testing strategy are equal to –€17,814,767.25. The sensitivity analysis confirms these results in the totality of the simulations performed. Conclusions: Preventive genetic testing in relatives of patients affected by ovarian cancer is cost-effective and represents a sustainable cost for the National Healthcare System in Italia, also in the light of its reference values

Oncologic effectiveness of nerve-sparing radical hysterectomy in cervical cancer

Objective: Nerve-sparing radical hysterectomy (NSRH) was introduced with the aim to reduce pelvic dysfunctions related to conventional radical hysterectomy (RH). Here, we sought to assess the effectiveness and safety of NSRH in a relatively large number of the patients of cervical cancer (CC) patients undergoing either primary surgery or neoadjuvant chemotherapy (NACT) followed by surgery. Methods: Outcomes of consecutive patients undergoing NSRH and of a historical cohort of patients undergoing conventional RH were retrospectively reviewed. Results: This study included 325 (49.8%) and 327 (50.2%) undergoing NSRH and RH, respectively. Via a multivariable model, nodal status was the only factor predicting for DFS (hazard ratio [HR]=2.09; 95% confidence interval [CI]=1.17\u20133.73; p=0.01). A trend towards high risk of recurrence was observed for patients affected by locally advanced cervical cancer (LACC) undergoing NACT followed by surgery (HR=2.57; 95% CI=0.95\u20136.96; p=0.06). Type of surgical procedures (NSRH vs. RH) did not influence risk of recurrence (p=0.47). Similarly, we observed that the execution of NSRH rather than RH had not a detrimental effect on OS (HR=1.19; 95% CI=0.16\u20139.01; p=0.87). Via multivariable model, no factor directly correlated with OS. No difference in early complication rates was observed between the study groups. Conversely, a significant higher number of late complications was reported in RH versus NSRH groups (p=0.02). Conclusion: Our data suggested that NSRH upholds effectiveness of conventional RH, without increasing recurrence and complication rates but improving pelvic dysfunction rate

Sourdough fermented breads are more digestible than those started with baker’s yeast alone. An in vivo challenge dissecting distinct gastrointestinal responses

As a staple food, bread digestibility deserves a marked nutritional interest. Combining wide-spectrum characterization of breads, in vitro nutritional indices, and in vivo postprandial markers of gastrointestinal function, we aimed at comparing the digestibility of sourdough and baker’s yeast breads. Microbiological and biochemical data showed the representativeness of the baker´s yeast bread (BYB) and the two sourdough breads (SB and t-SB, mainly differing for the time of fermentation) manufactured at semi-industrial level. All in vitro nutritional indices had the highest scores for sourdough breads. Thirty-six healthy volunteers underwent an in vivo challenge in response to bread ingestion, while monitoring gallbladder, stomach, and oro-cecal motility. SB, made with moderate sourdough acidification, stimulated more appetite and induced lower satiety. t-SB, having the most intense acidic taste, induced the highest fullness perception in the shortest time. Gallbladder response did not differ among breads, while gastric emptying was faster with sourdough breads. Oro-cecal transit was prolonged for BYB and faster for sourdough breads, especially when made with traditional and long-time fermentation (t-SB), whose transit lasted ca. 20 min less than BYB. Differences in carbohydrate digestibility and absorption determined different post-prandial glycaemia responses. Sourdough breads had the lowest values. After ingesting sourdough breads, which had a concentration of total free amino acids markedly higher than that of BYB, the levels in blood plasma were maintained at constantly high levels for extended time