المؤلفون: Sweeney, Christopher J, Hainsworth, John D, Bose, Ron, Burris, Howard A, Kurzrock, Razelle, Swanton, Charles, Friedman, Claire F, Spigel, David R, Szado, Tania, Schulze, Katja, Price, Richard, Malato, Julia, Lo, Amy A, Levy, Jonathan, Wang, Yong, Yu, Wei, Meric-Bernstam, Funda

المصدر: Journal of Clinical Oncology , 42 (3) pp. 258-265. (2024)

الوصف: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor 2 (HER2)–amplified and/or –overexpressed and/or –mutated solid tumors. The primary end point was objective response rate (ORR); secondary end points included survival and safety. At data cutoff (March 2022), 346 patients with HER2 amplification and/or overexpression with/without HER2 mutations (n = 263), or HER2 mutations alone (n = 83) had been treated. Patients with HER2 amplification and/or overexpression had an ORR of 25.9% (68/263, 95% CI, 20.7 to 31.6), including five complete responses (urothelial [n = 2], salivary gland [n = 2], and colon [n = 1] cancers). Activity was higher in those with wild-type (ORR, 28.1%) versus mutated KRAS (ORR, 7.1%). Among patients with HER2 amplification, ORR was numerically higher in patients with immunohistochemistry (IHC) 3+ (41.0%; 32/78) or 2+ (21.9%; 7/32), versus 1+ (8.3%; 1/12) or no expression (0%; 0/20). In patients with HER2 mutations alone, ORR was 6.0% (5/83, 95% CI, 2.0 to 13.5). Pertuzumab + trastuzumab showed activity in various HER2-amplified and/or -overexpressed tumors with wild-type KRAS, with the range of activity dependent on tumor type, but had limited activity in the context of KRAS mutations, HER2 mutations alone, or 0-1+ HER2 expression.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10186706/1/sweeney-et-al-2023-mypathway-human-epidermal-growth-factor-receptor-2-basket-study-pertuzumab-trastuzumab-treatment-of.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10186706Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10186706/1/sweeney-et-al-2023-mypathway-human-epidermal-growth-factor-receptor-2-basket-study-pertuzumab-trastuzumab-treatment-of.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10186706Test/

المؤلفون: Friedman, Claire F., D'Souza, Anishka, Bello Roufai, Diana, Tinker, Anna V., de Miguel, Maria, Gambardella, Valentina, Goldman, Jonathan, Loi, Sherene, Melisko, Michelle E., Oaknin, Ana, Spanggaard, Iben, Shapiro, Geoffrey I., ElNaggar, Adam C., Panni, Stefano, Ravichandran, Vignesh, Frazier, Aimee L., DiPrimeo, Daniel, Eli, Lisa D., Solit, David B.

المساهمون: Cycle for Survival, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Puma Biotechnology Inc

المصدر: Gynecologic Oncology ; volume 181, page 162-169 ; ISSN 0090-8258

مصطلحات موضوعية: Obstetrics and Gynecology, Oncology

الإتاحة: https://doi.org/10.1016/j.ygyno.2023.12.004Test
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المؤلفون: Friedman, Claire F, Spencer, Christine, Cabanski, Christopher R, Panageas, Katherine S, Wells, Daniel K, Ribas, Antoni, Tawbi, Hussein, Tsai, Katy, Postow, Michael, Shoushtari, Alexander, Chapman, Paul, Karakunnel, Joyson, Bucktrout, Samantha, Gherardini, Pier, Hollmann, Travis J, Chen, Richard O, Callahan, Margaret, LaVallee, Theresa, Ibrahim, Ramy, Wolchok, Jedd

المصدر: Journal for ImmunoTherapy of Cancer. 10(1)

مصطلحات موضوعية: Cancer, Patient Safety, Clinical Trials and Supportive Activities, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Antigen Presentation, Biomarkers, Tumor, Female, Humans, Immune Checkpoint Inhibitors, Interferon-gamma, Ipilimumab, Male, Melanoma, Middle Aged, Neoplasm Recurrence, Local, Nivolumab, Prospective Studies, Sequence Analysis, RNA, Tumor Microenvironment, immunotherapy, melanoma, tumor microenvironment

الوصف: There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade. We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples. Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3-4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB. In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts. NCT02731729.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/50n903xcTest

المؤلفون: Oaknin, Ana, Friedman, Claire F, Roman, Lynda D, D’Souza, Anishka, Brana, Irene, Bidard, François-Clement, Goldman, Jonathan, Alvarez, Edwin A, Boni, Valentina, ElNaggar, Adam C, Passalacqua, Rodolfo, T.M., Khanh, Santin, Alessandro D, Keyvanjah, Kiana, Xu, Feng, Eli, Lisa D, Lalani, Alshad S, Bryce, Richard P, Hyman, David M, Meric-Bernstam, Funda, Solit, David B, Monk, Bradley J

المصدر: Gynecologic Oncology. 159(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, Administration, Oral, Adult, Diarrhea, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Mutation, Nausea, Neoplasm Recurrence, Local, Progression-Free Survival, Protein Kinase Inhibitors, Quinolines, Receptor, ErbB-2, Response Evaluation Criteria in Solid Tumors, Severity of Illness Index, Uterine Cervical Neoplasms, Cervical cancer, HER2 mutant, Neratinib, Clinical trial, Tyrosine kinase inhibitor, Receptor, erbB-2, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine

الوصف: ObjectiveSomatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.MethodsPatients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.ResultsSixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.ConclusionsNeratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.Trial registration numberNCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/83m8v37nTest

المؤلفون: Disis, Mary L, Adams, Sarah F, Bajpai, Jyoti, Butler, Marcus O, Curiel, Tyler, Dodt, Shelley A, Doherty, Laura, Emens, Leisha A, Friedman, Claire F, Gatti-Mays, Margaret, Geller, Melissa A, Jazaeri, Amir, John, Veena S, Kurnit, Katherine C, Liao, John B, Mahdi, Haider, Mills, Anne, Zsiros, Emese, Odunsi, Kunle

المصدر: Journal for ImmunoTherapy of Cancer ; volume 11, issue 6, page e006624 ; ISSN 2051-1426

الوصف: Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.

الإتاحة: https://doi.org/10.1136/jitc-2022-006624Test

المؤلفون: Rios-Doria, Eric, Momeni-Boroujeni, Amir, Friedman, Claire F., Selenica, Pier, Zhou, Qin, Wu, Michelle, Marra, Antonio, Leitao, Mario M., Iasonos, Alexia, Alektiar, Kaled M., Sonoda, Yukio, Makker, Vicky, Jewell, Elizabeth, Liu, Ying, Chi, Dennis, Zamarin, Dimitry, Abu-Rustum, Nadeem R., Aghajanian, Carol, Mueller, Jennifer J., Ellenson, Lora H., Weigelt, Britta

المصدر: Gynecologic Oncology ; volume 174, page 262-272 ; ISSN 0090-8258

مصطلحات موضوعية: Obstetrics and Gynecology, Oncology

الإتاحة: https://doi.org/10.1016/j.ygyno.2023.05.059Test
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المؤلفون: Friedman, Claire F., Manning-Geist, Beryl L., Zhou, Qin, Soumerai, Tara, Holland, Aliya, Da Cruz Paula, Arnaud, Green, Hunter, Ozsoy, Melih Arda, Iasonos, Alexia, Hollmann, Travis, Leitao, Mario M., Mueller, Jennifer J., Makker, Vicky, Tew, William P., O’Cearbhaill, Roisin E., Liu, Ying L., Rubinstein, Maria M., Troso-Sandoval, Tiffany, Lichtman, Stuart M., Schram, Alison, Kyi, Chrisann, Grisham, Rachel N., Causa Andrieu, Pamela, Wherry, E. John, Aghajanian, Carol, Weigelt, Britta, Hensley, Martee L., Zamarin, Dmitriy

المصدر: Nature Medicine; May 2024, Vol. 30 Issue: 5 p1330-1338, 9p

مستخلص: Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7–100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5–100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6–87.1%). At the median follow-up of 42.1 months (range, 8.9–59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9–89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n= 10, 29%), fatigue (n= 10, 29%), pain (n= 10, 29%) and pruritis (n= 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8or SETD1Bsomatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.

المؤلفون: Rios-Doria, Eric, Abu-Rustum, Nadeem R, Alektiar, Kaled M, Makker, Vicky, Liu, Ying L, Zamarin, Dmitriy, Friedman, Claire F, Aghajanian, Carol, Ellenson, Lora H, Chiang, Sarah, Weigelt, Britta, Mueller, Jennifer J, Leitao, Mario M

المساهمون: National Institutes of Health, Cycle for Survival, Breast Cancer Research Foundation

المصدر: International Journal of Gynecologic Cancer ; page ijgc-2024-005522 ; ISSN 1048-891X 1525-1438

الوصف: Objective We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease. Methods Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January 1, 2007 to December 31, 2019. All SLNs underwent ultrastaging according to the institutional protocol. Patients with cytokeratin positive cells, micrometastases, and macrometastases were excluded. Clinical, pathology, and molecular subtype data were reviewed. Results Overall, 1214 patients with early stage endometrioid endometrial cancer met the inclusion criteria, of whom 1089 (90%) had node negative disease and 125 (10%) had isolated tumor cells. Compared with node negative disease, the presence of isolated tumor cells had a greater association with deep myometrial invasion, lymphovascular space invasion, receipt of adjuvant therapy, and adjuvant chemotherapy with or without radiation (p<0.01). There was no significant difference in survival rates between patients with isolated tumor cells and node negative disease (3 year progression free survival rate 94% vs 91%, respectively, p=0.21; 3 year overall survival rate 98% vs 96%, respectively, p=0.45). Progression free survival did not significantly differ among patients with isolated tumor cells who received no adjuvant therapy or chemotherapy with or without radiation (p=0.31). There was no difference in the distribution of molecular subtypes between patients with isolated tumor cells (n=28) and node negative disease (n=194; p=0.26). Three year overall survival rates differed significantly when stratifying the entire cohort by molecular subtype (p=0.04). Conclusions Patients with isolated tumor cells demonstrated less favorable uterine pathologic features and received more adjuvant treatment with similar survival compared with patients with nodenegative disease. Among the available data, molecular classification did ...

الإتاحة: https://doi.org/10.1136/ijgc-2024-005522Test

المؤلفون: Sia, Tiffany Y, Wan, Vivian, Finlan, Michael, Zhou, Qin C, Iasonos, Alexia, Zivanovic, Oliver, Sonoda, Yukio, Chi, Dennis S, Long Roche, Kara, Jewell, Elizabeth, Tew, William P, O'Cearbhaill, Roisin E, Cohen, Seth, Makker, Vicky, Liu, Ying L, Friedman, Claire F, Kyi, Chrisann, Zamarin, Dmitriy, Gardner, Ginger

المساهمون: National Institutes of Health

المصدر: International Journal of Gynecologic Cancer ; volume 34, issue 4, page 594-601 ; ISSN 1048-891X 1525-1438

الوصف: Objective To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade. Methods Patients with gynecologic cancers treated with immune checkpoint blockade between January 2013 and October 2021 who underwent procedural interventions including surgical resection, interventional radiology ablation, or radiation therapy for oligoprogressive disease were identified. Procedures performed before immune checkpoint therapy initiation or ≥6 months after therapy completion were excluded. Long immunotherapy duration prior to intervention was defined as ≥6 months. Progression-free survival and overall survival were calculated from procedure date until disease progression or death, respectively. Results During the study period, 886 patients met inclusion criteria and received immune checkpoint blockade therapy. Of these, 34 patients underwent procedural interventions for oligoprogressive disease; 7 underwent surgical resection, 3 underwent interventional radiology ablation, and 24 underwent radiation therapy interventions. Primary disease sites included uterus (71%), ovary (24%), and cervix (6%). Sites of oligoprogression included abdomen/pelvis (26%), bone (21%), lung (18%), distant lymph node (18%), brain (9%), liver (6%), and vagina (3%). Most tumors (76%) did not exhibit microsatellite instability or mismatch repair deficiency. Approximately half (53%) of the patients had long immune checkpoint therapy duration prior to intervention. Median progression-free survival following the procedure was 5.3 months (95% CI, 3.1–9.9), and median overall survival was 21.7 months (95% CI, 14.9–not estimable). Long versus short immune checkpoint therapy duration prior to procedure and length of immune checkpoint therapy had no effect on progression-free or overall survival. Conclusions Procedural interventions for ...

الإتاحة: https://doi.org/10.1136/ijgc-2023-004842Test

المؤلفون: Freites-Martinez, Azael, Navitski, Anastasia, Friedman, Claire F., Chan, Donald, Goldfarb, Shari, Lacouture, Mario E., O'Cearbhaill, Roisin E.

المساهمون: National Cancer Institute, National Institutes of Health

المصدر: Gynecologic Oncology Reports ; volume 44, page 101095 ; ISSN 2352-5789

الإتاحة: https://doi.org/10.1016/j.gore.2022.101095Test
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