Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

PURPOSE: Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. METHODS: A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. RESULTS: Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. CONCLUSION: Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

BYL719 (alpelisib) for the treatment of PIK3CA-mutated, recurrent/advanced cervical cancer.

PURPOSE: Advanced/recurrent cervical cancer has limited therapeutic options, with a median progression-free survival after the failure of systemic treatments ranging between 3.5 and 4.5 months. Here, we reported our preliminary experience in the use of BYL719 (alpelisib) in advanced/recurrent cervical cancer after failure of at least 2 lines of treatment. The Istituto Nazionale dei Tumori di Milano approved this investigation. METHODS: From April 2020 to September 2020, 17 consecutive patients with recurrent cervical cancer had Next Generation Sequencing (NGS). Of these, six patients harboring the PIK3CA mutation were included in the study. All patients had been treated with at least 2 previous lines of systemic treatment: 3 patients received >2 prior lines of treatment in the recurrent or metastatic setting; 60% had received prior bevacizumab in combination with chemotherapy. All patients started alpelisib at the daily dosage of 300 mg. RESULTS: Investigator-assessed confirmed objective response rate (ORR) was 33%. The disease control rate (DCR) was 100%. According to RECIST 1.1, two patients had a partial response (PR), and four patients had stable disease (SD). No complete response was observed. The mean duration of response (DOR) was 11.5 (SD 3.75) months; five patients had PR lasting for >9 months. One patient stopped the treatment at 0.82 months due to the onset of a grade 2 adverse event (AE) (skin rash). Grade 3 treatment-related AEs included: lymphoedema (n = 1, 17%) and rash (n = 1, 17%). No treatment-related grade 4-5 AEs occurred. CONCLUSIONS: Our preliminary data highlighted a high level of efficacy in this setting of patients. Further trials are needed to assess the safety and effectiveness of alpelisib in PIK3CA-mutated recurrent/advanced cervical cancer.

Efficacy and safety of trabectedin for the treatment of advanced uterine or ovarian carcinosarcoma: Results of a phase II multicenter clinical trial (MITO-26).

OBJECTIVE: This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC). METHODS: Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/m2 was administered as a 3-h infusion every three weeks. The primary endpoint was objective response rate (ORR) as per RECIST v.1.1. If at least 8 of 43 patients (18.6%) achieve an objective response, trabectedin would be declared worthy for further investigations. RESULTS: Forty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6-23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20-44). Median progression-free survival was 2.01 months (95% CI: 1.78-2.30) and median overall survival was 4.64 months (95% CI: 3.19-8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3-5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity. CONCLUSION: Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug.

A decision support system based on radiomics and machine learning to predict the risk of malignancy of ovarian masses from transvaginal ultrasonography and serum CA-125.

BACKGROUND: To evaluate the performance of a decision support system (DSS) based on radiomics and machine learning in predicting the risk of malignancy of ovarian masses (OMs) from transvaginal ultrasonography (TUS) and serum CA-125. METHODS: A total of 274 consecutive patients who underwent TUS (by different examiners and with different ultrasound machines) and surgery, with suspicious OMs and known CA-125 serum level were used to train and test a DSS. The DSS was used to predict the risk of malignancy of these masses (very low versus medium-high risk), based on the US appearance (solid, liquid, or mixed) and radiomic features (morphometry and regional texture features) within the masses, on the shadow presence (yes/no), and on the level of serum CA-125. Reproducibility of results among the examiners, and performance accuracy, sensitivity, specificity, and area under the curve were tested in a real-world clinical setting. RESULTS: The DSS showed a mean 88% accuracy, 99% sensitivity, and 77% specificity for the 239 patients used for training, cross-validation, and testing, and a mean 91% accuracy, 100% sensitivity, and 80% specificity for the 35 patients used for independent testing. CONCLUSIONS: This DSS is a promising tool in women diagnosed with OMs at TUS, allowing to predict the individual risk of malignancy, supporting clinical decision making.

Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile.

BACKGROUND: Targeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity. OBJECTIVE: The phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS: This was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days. RESULTS: We enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls. CONCLUSIONS: The maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03462212; registered March 2018.