BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib.
METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events.
RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%).
CONCLUSIONS: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.

BACKGROUND: Treating older adults with chemotherapy remains a challenge, given their under-representation in clinical trials and the lack of robust treatment guidelines for this population. Moreover, older patients, especially those with frailty, have an increased risk of developing chemotherapy-related toxicity, resulting in a decreased quality of life (QoL), increased hospitalisations and high healthcare costs. Phase II trials have suggested that upfront dose reduction of chemotherapy can reduce toxicity rates while maintaining efficacy, leading to fewer treatment discontinuations and an improved QoL. The DOSAGE aims to show that upfront dose-reduced chemotherapy in older patients with metastatic colorectal cancer is non-inferior to full-dose treatment in terms of progression-free survival (PFS), with adaption of the treatment plan (monotherapy or doublet chemotherapy) based on expected risk of treatment toxicity.
METHODS: The DOSAGE study is an investigator-initiated phase III, open-label, non-inferiority, randomised controlled trial in patients aged≥70 years with metastatic colorectal cancer eligible for palliative chemotherapy. Based on toxicity risk, assessed using the Geriatric 8 (G8) tool, patients will be stratified to either doublet chemotherapy (fluoropyrimidine with oxaliplatin) or fluoropyrimidine monotherapy. Patients classified as low risk will be randomised between a fluoropyrimidine plus oxaliplatin in either full-dose or with an upfront dose reduction of 25%. Patients classified as high risk will be randomised between fluoropyrimidine monotherapy in either full-dose or with an upfront dose reduction. In the dose-reduced arm, dose escalation after two cycles is allowed. The primary outcome is PFS. Secondary endpoints include grade≥3 toxicity, QoL, physical functioning, number of treatment cycles, dose reductions, hospital admissions, overall survival, cumulative received dosage and cost-effectiveness. Considering a median PFS of 8 months and non-inferiority margin of 8 weeks, we shall include 587 patients. The study will be enrolled in 36 Dutch Hospitals, with enrolment scheduled to start in July 2024. This study will provide new evidence regarding the effect of dose-reduced chemotherapy on survival and treatment outcomes, as well as the use of the G8 to choose between doublet chemotherapy or monotherapy. Results will contribute to a more individualised approach in older patients with metastatic colorectal cancer, potentially leading to improved QoL while maintaining survival benefits.
BACKGROUND: This trial has received ethical approval by the ethical committee Leiden Den Haag Delft (P24.018) and will be approved by the Institutional Ethical Committee of the participating institutions. The results will be disseminated in peer-reviewed scientific journals.
BACKGROUND: NCT06275958.

UNASSIGNED: The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor (TKI) as the first-line therapy for patients with metastatic renal cell carcinoma (mRCC) in terms of overall survival (OS), progression-free survival (PFS), and rates of discontinuation and adverse effects during the treatment period.
UNASSIGNED: This is a retrospective, nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017. We focused on patients at either \"favorable\" or \"intermediate\" risk according to the International mRCC Database Consortium criteria, and they were followed up (median 335 days). Finally, a total of 1409 patients were selected as the study population. We generated a Cox proportional hazard model adjusted for covariates, and the different therapy schemes were statistically tested in terms of OS as well as PFS. In addition, frequencies of discontinuation and adverse events were compared among the therapy schemes.
UNASSIGNED: Of the primary patterns of treatment sequences (24 sequences), \"sunitinib-pazopanib\" and \"sunitinib-everolimus-immunotherapy\" showed the most beneficial results in both OS and PFS with significantly lower hazards than \"sunitinib\", which is the most commonly treated agent in Korea. Considering that the \"TKI-TKI\" structure showed relatively higher discontinuation rates with higher adverse effects, the overall beneficial sequence would be \"sunitinib-everolimus-immunotherapy\".
UNASSIGNED: Among several sequential therapy starting with TKIs, \"sunitinib-everolimus- immunotherapy\" was found to be the best scheme for mRCC patients with \"favorable\" or \"intermediate\" risks.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer.
METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics.
RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%).
CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals.
BACKGROUND: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

BACKGROUND: The MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies.
METHODS: Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS.
RESULTS: As of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies.
CONCLUSIONS: These data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1-3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

UNASSIGNED: Real-world data for patients with endometrial cancer (EC) are limited, particularly in Latin America. We present treatment pattern findings from ECHOS-A - Endometrial Cancer Health Outcomes Study in Argentina.
UNASSIGNED: A retrospective study using clinical data from privately insured patients with EC diagnosed from 2010 to 2019. Index (diagnosis proxy) was first date of an EC-related health term or treatment. Demographics, clinical characteristics, and FIGO staging were described. Disease progression and survival were assessed until study end, loss to follow-up, or death.
UNASSIGNED: Of 805 patients with EC, 77.4 % (n = 623/805) received any treatment and 22.6 % (n = 182/805) received none. Among those treated, 31.8 % (n = 198/623) had first-line (1L) systemic therapy, and 45.5 % (n = 90/198) proceeded to second-line (2L) therapy. Mean follow-up was 33.6 (SD 31.8) months. Of those receiving any treatment, 87.3 % (n = 544/623) had FIGO stage data (I, 62.9 %; II, 18.6 %; III, 13.6 %; IV, 5.0 %). Treatment by class in 1L and 2L, respectively, were platinum chemotherapy, 73.7 %, 36.7 %; non-platinum chemotherapy, 73.7 %, 62.2 %; immunotherapy, 1.0 %, 11.1 %; hormone therapy, 17.7 %, 26.7 %. Carboplatin/paclitaxel was the most frequent 1L (52.5 %) and 2L (14.4 %) regimen. Mean time to progression was 14.1 (SD 16.3) and 8.8 (SD 8.3) months in 1L and 2L, respectively. Adjusted 1- to 5-year risk of progression/death was 46.5-77.5 % and 65.0-86.2 % in 1L and 2L, respectively.
UNASSIGNED: Approximately one-quarter of patients with EC received no treatment, and approximately two-thirds were not treated with 1L systemic therapy. Efforts to better understand the reasons for these treatment patterns are crucial for improving patient outcomes.

UNASSIGNED: Lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time.
UNASSIGNED: 100 patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS), investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by the best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020).
UNASSIGNED: ORR was 43.0% (95% CI 33.1-53.3%) and median DOR was 17.1 months (95% CI 6.9-19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4-9.8 months) and 20.4 months (95% CI 14.4-25.9 months), respectively. No treatment-emergent ADAs were detected.
UNASSIGNED: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting.

BACKGROUND: The effect of primary cytoreductive surgery versus interval cytoreductive surgery on FIGO IV ovarian cancer outcomes remains uncertain, and may vary depending on the stage and the extraperitoneal metastasis location. Emulating target trials through causal assessment combined with propensity score adjustment has become a leading method for evaluating interventions using observational data.
OBJECTIVE: To assess the effect of primary versus interval cytoreductive surgery on progression-free and overall survival in patients with FIGO IV ovarian cancer using target trial emulation.
METHODS: Utilizing the comprehensive French national health insurance database, we emulated a target trial to explore primary versus interval cytoreductive surgery causal impacts on FIGO IV ovarian cancer prognosis (Surgery for Ovarian cancer FIGO 4: SOFI-4). The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and balance baseline characteristics between the groups. Subgroup analyses were conducted based on FIGO stages and extraperitoneal metastasis locations. The study included patients under 75 years of age, in good health condition, diagnosed with FIGO IV ovarian cancer between January 1, 2014, and December 31, 2022. The primary and secondary outcomes were respectively five-year progression-free survival and seven-year overall survival.
RESULTS: Among the 2,772 patients included in the study, 948 (34.2%) were classified as FIGO IVA and 1,824 (65.8%) as FIGO IVB at inclusion. Primary cytoreductive surgery was performed on 1,182 patients (42.6%), while interval cytoreductive surgery was conducted on 1,590 patients (57.4%). The median progression survival for primary cytoreductive surgery was 19.7 months (interquartile range [IQR]: 19.3-20.1), compared to 15.7 months (IQR: 15.7-16.1) for those who underwent interval cytoreductive surgery. The median overall survival was 63.1 months [IQR: 61.7-65.4] for primary cytoreductive surgery, in comparison to 55.6 months [IQR: 53.8-56.3] for interval cytoreductive surgery. The findings of our study indicate that primary cytoreductive surgery is associated with a 5.0-month increase in five-year progression-free survival (95% Confidence Intervals [CI]: 3.8-6.2) and a 3.9-month increase in seven-year overall survival (95% CI: 1.9-6.2). These survival benefits of primary over interval cytoreductive surgery were observed in both the FIGO IVA and IVB subgroups. Primary cytoreductive surgery demonstrated improved progression-free survival and overall survival in patients with pleural, supra-diaphragmatic, or extra-abdominal lymph node metastasis.
CONCLUSIONS: SOFI-4 advocates for the benefits of primary cytoreductive surgery over interval cytoreductive surgery for patients with FIGO IV ovarian cancer, suggesting extraperitoneal metastases like supra-diaphragmatic or extra-abdominal lymph nodes should not automatically preclude primary cytoreductive surgery consideration in suitable patients.