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Background: An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.Methods: We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.Results: A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).Conclusions: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.). [ABSTRACT FROM AUTHOR]

Introduction: Fibroblast growth factor receptor (FGFR) mutations and fusions are relevant biomarkers in metastatic urothelial carcinoma (mUC). However, the prevalence of genomic alterations and their impact on clinical outcomes in a Latin American population remains unknown. This study aimed to explore the prevalence of FGFR mutations and/or fusions in patients with mUC in Latin America (LATAM) and its association with clinicopathological characteristics, Bellmunt's prognostic model, and survival outcomes., Patients and Methods: A multicenter retrospective cohort study from 2016 to 2019 of patients with mUC from several LACOG LATAM institutions. FGFR alterations were analyzed by real-time PCR and/or next-generation sequencing in tumor samples and clinicopathologic characteristics and survival outcomes data were collected. The prevalence of FGFR, patient characteristics, and treatment in real-world settings were summarized. Kaplan-Meier survival estimates and Cox regression analyses were used to evaluate the associations of FGFR mutation and/or fusion status with median overall survival (mOS), median time to treatment failure (mTTF), and clinicopathological characteristics., Results: In total, 222 patients were screened. Of these, 196 patients were considered eligible and were included in the analysis. FGFR mutations and/or fusions were found in 35 (17.9%) patients. There was no statistical difference in mOS and mTTF in FGFR-altered and non-altered patients (13.1 vs. 16.8 months, P = .20 and 3.9 vs. 4.1 months, P = .96, respectively). Bellmunt's prognostic model correctly predicted overall survival (P = .049)., Conclusions: This is the largest study evaluating the prevalence of FGFR alterations in patients with mUC in the LATAM population. FGFR alterations in mUC were found in 17.9% of the patients, and the presence of this biomarker was not associated with OS. We validated Bellmunt's prognostic model in this cohort., Competing Interests: Disclosure Dr. Gustavo Werutsky reports personal fees from AstraZeneca, Bayer, Beigene, Daiichi Sankyo, Genentech/Roche, GSK, Lilly, MSD, Novartis, Pfizer, Sanofi, and Seattle Genetics outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months)., Patients and Methods: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods., Results: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI., Conclusions: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120)., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial., Methods: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib., Results: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA . Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1 , but greater benefit was observed with altered, suggesting predictive potential of CCND1 . Alterations in TP53 , MYC , Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status., Conclusion: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration., Competing Interests: Aditya Bardia Consulting or Advisory Role: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Pharma, Immunomedics, Sanofi, Puma Biotechnology, Daiichi Sankyo/Astra Zeneca, Foundation Medicine, Philips, Genentech/Roche, Radius Health, Innocrin Pharma Research Funding: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius, Immunomedics, AstraZeneca/Daiichi Sankyo Open Payments Link: https://openpaymentsdata.cms.gov/physician/523675 Fei Su Employment: Novartis Stock and Other Ownership Interests: Novartis Nadia Solovieff Employment: Novartis Stock and Other Ownership Interests: Novartis Seock-Ah Im Consulting or Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, MSD, Daiichi Sankyo Research Funding: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Other Relationship: Roche Joohyuk Sohn Research Funding: MSD, Roche, Novartis, Lilly, Pfizer, Bayer, Daiichi Sankyo, AstraZeneca, GlaxoSmithKline Other Relationship: Roche Keun Seok Lee Consulting or Advisory Role: Lilly, MSD Oncology, Novartis, Roche, Pfizer Research Funding: Dong-A ST Saul Campos Gomez Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD Oncology Kyung Hae Jung Consulting or Advisory Role: Roche, AstraZeneca, Celgene, Eisai, Takeda, Novartis Marco Colleoni Research Funding: Roche Rafael Villanueva Vázquez Consulting or Advisory Role: Novartis Speakers' Bureau: Novartis, Lilly Expert Testimony: Novartis Travel, Accommodations, Expenses: Novartis, Lilly, Eisai, Daiichi Sankyo/AstraZeneca, Roche Sara Hurvitz Stock and Other Ownership Interests: Ideal Implant, ROM Tech Research Funding: Genentech/Roche, Novartis, GlaxoSmithKline, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, Biomarin, Lilly, Merrimack, Cascadian Therapeutics, Seattle Genetics, Daiichi Sankyo, Macrogenics, Ambryx, Immunomedics, Pieris Pharmaceuticals, Radius Health, Arvinas, Zymeworks, Gilead Sciences, Phoenix Molecular Designs Travel, Accommodations, Expenses: Lilly Other Relationship: Roche, Pfizer Nadia Harbeck Stock and Other Ownership Interests: West German Study Group Honoraria: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Pierre Fabre, Daiichi Sankyo, Exact Sciences, MSD, Seagen Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, Sandoz, Daiichi Sankyo, AstraZeneca, West German Study Group, Pierre Fabre, Seagen, MSD Research Funding: Roche/Genentech, Lilly, MSD, AstraZeneca Louis Chow Research Funding: Novartis Tetiana Taran Employment: Novartis Stock and Other Ownership Interests: Novartis Karen Rodriguez Lorenc Employment: Novartis, Regeneron Stock and Other Ownership Interests: Novartis, Regeneron Naveen Babbar Employment: Novartis Stock and Other Ownership Interests: Novartis Debu Tripathy Consulting or Advisory Role: Novartis, Pfizer, GlaxoSmithKline, Genomic Health, AstraZeneca, OncoPep Research Funding: Novartis, Polyphor Travel, Accommodations, Expenses: Novartis, AstraZeneca Yen-Shen Lu Honoraria: Pfizer, Roche, Merck Sharp & Dohme, Novartis, Lilly, Eisai, Eurofarma, Daiichi Sankyo/UCB Japan, AstraZeneca Consulting or Advisory Role: Pfizer, Roche, Novartis, Lilly Research Funding: Novartis, Roche, Merck Sharp & Dohme Travel, Accommodations, Expenses: Roche, Pfizer, Eisai, Novartis No other potential conflicts of interest were reported. Aditya Bardia Consulting or Advisory Role: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Pharma, Immunomedics, Sanofi, Puma Biotechnology, Daiichi Sankyo/Astra Zeneca, Foundation Medicine, Philips, Genentech/Roche, Radius Health, Innocrin Pharma Research Funding: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius, Immunomedics, AstraZeneca/Daiichi Sankyo Open Payments Link: https://openpaymentsdata.cms.gov/physician/523675 Fei Su Employment: Novartis Stock and Other Ownership Interests: Novartis Nadia Solovieff Employment: Novartis Stock and Other Ownership Interests: Novartis Seock-Ah Im Consulting or Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, MSD, Daiichi Sankyo Research Funding: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Other Relationship: Roche Joohyuk Sohn Research Funding: MSD, Roche, Novartis, Lilly, Pfizer, Bayer, Daiichi Sankyo, AstraZeneca, GlaxoSmithKline Other Relationship: Roche Keun Seok Lee Consulting or Advisory Role: Lilly, MSD Oncology, Novartis, Roche, Pfizer Research Funding: Dong-A ST Saul Campos Gomez Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD Oncology Kyung Hae Jung Consulting or Advisory Role: Roche, AstraZeneca, Celgene, Eisai, Takeda, Novartis Marco Colleoni Research Funding: Roche Rafael Villanueva Vázquez Consulting or Advisory Role: Novartis Speakers' Bureau: Novartis, Lilly Expert Testimony: Novartis Travel, Accommodations, Expenses: Novartis, Lilly, Eisai, Daiichi Sankyo/AstraZeneca, Roche Sara Hurvitz Stock and Other Ownership Interests: Ideal Implant, ROM Tech Research Funding: Genentech/Roche, Novartis, GlaxoSmithKline, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, Biomarin, Lilly, Merrimack, Cascadian Therapeutics, Seattle Genetics, Daiichi Sankyo, Macrogenics, Ambryx, Immunomedics, Pieris Pharmaceuticals, Radius Health, Arvinas, Zymeworks, Gilead Sciences, Phoenix Molecular Designs Travel, Accommodations, Expenses: Lilly Other Relationship: Roche, Pfizer Nadia Harbeck Stock and Other Ownership Interests: West German Study Group Honoraria: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Pierre Fabre, Daiichi Sankyo, Exact Sciences, MSD, Seagen Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, Sandoz, Daiichi Sankyo, AstraZeneca, West German Study Group, Pierre Fabre, Seagen, MSD Research Funding: Roche/Genentech, Lilly, MSD, AstraZeneca Louis Chow Research Funding: Novartis Tetiana Taran Employment: Novartis Stock and Other Ownership Interests: Novartis Karen Rodriguez Lorenc Employment: Novartis, Regeneron Stock and Other Ownership Interests: Novartis, Regeneron Naveen Babbar Employment: Novartis Stock and Other Ownership Interests: Novartis Debu Tripathy Consulting or Advisory Role: Novartis, Pfizer, GlaxoSmithKline, Genomic Health, AstraZeneca, OncoPep Research Funding: Novartis, Polyphor Travel, Accommodations, Expenses: Novartis, AstraZeneca Yen-Shen Lu Honoraria: Pfizer, Roche, Merck Sharp & Dohme, Novartis, Lilly, Eisai, Eurofarma, Daiichi Sankyo/UCB Japan, AstraZeneca Consulting or Advisory Role: Pfizer, Roche, Novartis, Lilly Research Funding: Novartis, Roche, Merck Sharp & Dohme Travel, Accommodations, Expenses: Roche, Pfizer, Eisai, Novartis No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: The LUME-Lung 1 study has brought consistent evidence of the effective use of nintedanib in lung adenocarcinoma as a second line of treatment; however, differences among ethnicities have been found in some studies., Methods: This was a retrospective review among 21 medical centers of 150 patients with a confirmed diagnosis of lung adenocarcinoma, included in a compassionate use program of nintedanib from March 2014 to September 2015. The current study aimed to analyze the effectiveness of nintedanib in combination with docetaxel in the Mexican population, using progression-free survival rate and the best objective response to treatment by RECIST 1.1 as a surrogate of effectiveness. In addition, we examined the toxicity profile of our study population as a secondary end point., Results: After exclusion criteria, only 99 patients met the criteria for enrollment in the current study. From the total study population, 53 patients (53.5%) were male and 46 (46.5%) were female, with an average age of 60 years and stage IV as the most prevalent clinical stage at the beginning of the compassionate use program. A total of 48 patients (48.5%) had partial response; 26 (26.3%), stable disease; 4 (4%), complete response; and 16 (16.2%), progression; and 5 (5%) were nonevaluable. We found a median progression-free survival of 5 months (95% CI, 4.3 to 5.7 months). The most common grade 3 or 4 adverse reactions were fatigue (14%) and diarrhea (13%)., Conclusion: Nintedanib, as part of a chemotherapy regimen, is an effective option with an acceptable toxicity profile for advanced lung adenocarcinoma after first-line treatment progression.

Introduction: Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC)., Methods: A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized., Results: A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6 years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800 mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2 months. The median time on treatment was 10.0 months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9 months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%)., Conclusions: Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib., Funding: Novartis Pharmaceuticals Corporation, Inc.

Background: In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer., Methods: This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients., Findings: Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient., Interpretation: Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients., Funding: Novartis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)