Search

Background: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy., Methods: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m 2 ; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31)., Findings: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment])., Interpretation: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted., Funding: Pfizer., Competing Interests: Declaration of interests SP received grants or contracts from Pfizer and personal honoraria from AstraZeneca, MSD, Roche, GSK, and Clovis. GS received grants or contracts from MSD; consulting fees from TESARO Bio and Johnson and Johnson; and personal honoraria from Clovis Oncology. UDG received personal honoraria from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Eisai, Janssen, MSD, Pfizer, Ipsen, and Roche; and support for attending meetings or travel support (or both) from Janssen, Bristol Myers Squibb, and Ipse. CDA received consulting fees from Novartis, GSK, and Eli-Lilly; personal honoraria from Novartis, Pfizer, GSK, Eli-Lilly, and Seagen; and support for attending meetings or travel support (or both) from Seagen, Gilead, Pfizer, and Ipsen. DP received personal honoraria from Clovis and GSK; and support for attending meetings or travel support (or both) from Pierre Fabre Pharma. VS received consulting fees from Novocure, MSD, AstraZeneca, and GSK; personal honoraria from Novocure, MSD, AstraZeneca, and GSK; support for attending meetings or travel support (or both) from GSK and PharmaMar; and personal payment for an advisory board from MSD, Novocure, AstraZeneca, and GSK. AF received personal honoraria from AstraZeneca, GSK (Tesaro), and Clovis; travel grants from Astellas, MSD, and Bayer; and personal payment for an advisory board from Janssen, GSK (Tesaro), and AstraZeneca. DL received consulting fees from AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Amgen, Seagen, and PharmaMar; personal honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, and PharmaMar; payment for expert testimony from Clovis; travel grants from Roche, PharmaMar, AstraZeneca, Clovis Oncology, and GSK; personal payment for an advisory board from Merck Serono, Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro, AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, and Gynecologic Cancer InterGroup for being a member of the board of directors; and institutional grants for research activities from AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, PharmaMar, Seagen, Immunogen, Novartis, Roche, and Incyte. FP received institutional financial support for clinical trials promoted by the National Cancer Institute of Naples from Roche, Bayer, AstraZeneca, Pfizer, Incyte, GSK (Tesaro), and Merck; and personal honoraria from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab., Methods: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m 2 ) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints., Results: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported., Conclusions: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors., Trial Registration Number: EudraCT 2012-003043-29; NCT01706120., Competing Interests: Competing interests: Dr Daniele reports travel and accommodations from Roche, outside the submitted work. Dr Raspagliesi reports grants from Roche, grants from GSK, grants from MSD, grants from Pharmamar, outside the submitted work. Dr Colombo reports personal fees from Roche, personal fees from Pharmamar, personal fees from AstraZeneca, personal fees from MSD, personal fees from Tesaro, personal fees from GSK, personal fees from Clovis, personal fees from Amgen, personal fees from Pfizer, personal fees from Biogen, personal fees from BIOCAD, outside the submitted work. Dr De Giorgi reports personal fees from Astellas - Pharma, personal fees from Bayer, personal fees and non-financial support from Bristol Myers-Squibb, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Janssen, personal fees and non-financial support from Pfizer, grants and personal fees from Sanofi, personal fees from Novartis, personal fees from MSD, grants and non-financial support from Roche, grants from AstraZeneca, personal fees from Pharmamar, outside the submitted work. Dr Lorusso reports grants, personal fees and non-financial support from Pharmamar, grants and personal fees from MSD, grants and personal fees from Clovis, grants, personal fees and non-financial support from GSK, personal fees and non-financial support from AstraZeneca, personal fees from Merck Serono, personal fees from Amgen, non-financial support from Roche, outside the submitted work. Dr Salutari reports personal fees from MSD, personal fees from GSK, personal fees from Tesaro, personal fees from AstraZeneca, personal fees from Roche, personal fees from Eisai, personal fees from Clovis, outside the submitted work. Dr Piccirillo reports personal fees from Daichii Sankyo, personal fees from GSK, personal fees from MSD, grants from Roche, grants and personal fees from AstraZeneca, non-financial support from Bayer, outside the submitted work. Dr Perrone reports grants from Roche, during the conduct of the study; grants, personal fees and non-financial support from Bayer, personal fees from Sandoz, grants and personal fees from Incyte, personal fees from Celgene, grants and personal fees from AstraZeneca, personal fees from Pierre Fabre, personal fees from Janssen Cilag, grants from Roche, grants from Pfizer, outside the submitted work. Dr Pignata reports grants from Roche, during the conduct of the study; personal fees from AZ, personal fees from MSD, personal fees from Clovis, personal fees and non-financial support from Tesaro GSK, personal fees from Roche, outside the submitted work. The other authors do not declare conflicts of interests., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: 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., Methods: 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/m(2) 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., Findings: 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., Interpretation: 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., Funding: National Cancer Institute of Napoli and GlaxoSmithKline., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Carboplatin/paclitaxel every 3 weeks is the standard for patients with ovarian cancer, but elderly patients frequently receive modified schedules or single agent chemotherapy to avoid toxicity. A phase II study was conducted to describe tolerability of a weekly schedule of both drugs in elderly patients., Methods: Patients aged>or=70 years with stage IC-IV ovarian cancer, performance status

The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting. [ABSTRACT FROM AUTHOR]

Background: Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer. Methods: 120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute — Common Toxicity Criteria. Results: 55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7-58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy. Conclusion: A significant proportion of patients with advanced ovarian cancer treated with firstline carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease. [ABSTRACT FROM AUTHOR]