ABSTRACT:Because frail patients and patients aged ≥80 years with chronic lymphocytic leukemia (CLL) are still underrepresented in clinical trials, the CLL-Frail trial aimed to evaluate the efficacy and safety of acalabrutinib in these patients. The primary end point was the overall response rate (ORR) after 6 cycles of treatment to test the null hypothesis of ORR ≤65%. Fifty-three patients were included in the trial, and 34 patients are still on therapy. Adverse events (AEs) were the most frequent reason for early discontinuation (10 patients), whereas 5 patients stopped treatment because of death. Median age was 81 years, and 47.2% of patients were frail. The ORR for the 46 patients receiving ≥3 cycles of treatment was 93.5% (95% confidence interval, 82.1-98.6) meeting the primary end point of this trial (P < .001). The estimated 12-month progression-free and overall survival rates were 93.3% and 95.7%, respectively, after a median follow-up of 19 months. 53.5% of patients reported an improvement in their self-perceived frailty. Although all patients experienced AEs, and severe (Common Terminology Criteria of ≥3) events were reported in 63.5% of patients, there were no events of severe bleeding and atrial fibrillation was rare (2 cases of Common Terminology Criteria Grades 2 and 3). Five patients died, of which 4 deaths happened during or <28 days after treatment. Infections/COVID-19 were the cause of death in 3 cases. To our knowledge, this is the first prospective trial in older and/or frail patients with CLL demonstrating a high efficacy and safe treatment with acalabrutinib monotherapy. This trial was registered at www.ClinicalTrials.gov as #NCT04883749.
Not all patients with advanced pancreatic cancer (PC) profit from 2nd-line chemotherapy. We evaluated predictive factors that are routinely collected during clinical care with the aim to support an informed and shared decision. In a prospective study across 35 German sites, 151 patients with PC previously treated with gemcitabine/nab-paclitaxel were enrolled and 146 patients received biweekly nanoliposomal irinotecan/5-fluorouracil/FA. We investigated whether time-to-treatment-failure of 1st-line (TTF1) predicts 2nd-line treatment outcome. Patients were stratified into three equal cohorts based on TTF1. Primary endpoint was TTF2, with secondary endpoints including overall survival (OS) and growth modulation index (GMI). Median TTF2 was 3.71 months (95
Selinexor besitzt als Exportin-1-Inhibitor einen neuartigen Wirkmechanismus. In Kombination mit Bortezomib und Dexamethason (SVd) ist es zur Behandlung des rezidivierten/refraktären Multiplen Myeloms ab der 2. Linie zugelassen. Bei nicht transplantierbaren Patienten stellt SVd unter dem Gesichtspunkt des Substanzklassenwechsels eine relevante Kombination nach einer Erstlinientherapie mit Daratumumab, Lenalidomid und Dexamethason dar. Klinische Daten belegen, dass insbesondere Proteasom-Inhibitor-naive und Lenalidomid-refraktäre Patienten von SVd profitieren. Der Einsatz von Selinexor-Kombinationen in der klinischen Routine hat gezeigt, dass sie bei patientenindividuell adaptierter Dosierung und mit einer antiemetischen Prophylaxe nach modernem Standard sicher und wirksam einsetzbar sind.
3543 Background: BRAF V600E mutation in metastatic colorectal cancer (mCRC) is associated with poor prognosis. Registrational approval of anti-EGFR antibodies does not exclude their use in BRAF V600E mutated (mut) mCRC, while current guidelines explicitly advise against the use of anti-EGFR-directed therapy and recommend the use of chemotherapy plus anti-VEGF antibodies. The present analysis of single-patient data evaluates the therapeutic benefit from anti-EGFR- vs. anti-VEGF-directed therapy in BRAF V600E mut mCRC. Methods: We conducted a pooled analysis of eight first-line AIO-studies (FIRE-1, FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including 251 evaluable pts with BRAF V600E mut and RAS wild-type mCRC. Right-sided primary tumors (RSPT) included tumors from the caecum to the colon transversum, while left-sided tumors (LSPT) included the splenic flexure to the rectum. Results: Of 251 BRAF V600E mut pts, exact primary tumor location was available in 230 pts. In this cohort, 117 were male (50.9%) and 113 female (49.1%). LSPT was observed in 106 (46.1%) pts compared to 124 (53.9%) with RSPT. In the entire cohort, median OS (mOS) of LSPT vs. RSPT did not differ significantly (15.2 months vs. 13.4 months; HR 0.96; 95% CI, 0.70–1.29; P=0.77). Pts with LSPT showed a numerical survival benefit with anti-EGFR therapy compared to anti-VEGF therapy (17.8 months vs. 11.8 months; HR 0.71; 95% CI, 0.45–1.14; P=0.16). This effect was observed independent of sex. In contrast, pts with RSPT showed a trend towards inferior outcome with anti-EGFR vs. anti-VEGF therapy (11.6 months vs. 17.1 months; HR 1.31; 95% CI, 0.84–2.05; P=0.23). This effect was primarily driven by females, who experienced a significant survival disadvantage with anti-EGFR therapy (10.2 months vs. 17.1 months; HR 1.85; 95% CI, 1.05–3.25; P=0.031). For males, however, both anti-VEGF and anti-EGFR antibodies were associated with comparable outcome. Conclusions: The present analysis performed in the first-line treatment of BRAF V600E mut mCRC suggests a survival benefit from anti-EGFR antibodies in pts with LSPT, independent of gender. Male pts with RSPT appear to derive comparable benefit from anti-EGFR and anti-VEGF antibodies, while female pts exhibit a survival disadvantage from anti-EGFR antibodies. Clinical trial information: NCT00433927 (FIRE-3), NCT02934529 (FIRE-4), NCT04034459 (FIRE-4.5), NCT01249638 (ML22011), NCT00254137 (CIOX), NCT01991873 (PANAMA), NCT01328171 (VOLFI). [clinicaltrials.gov].
3610 Background: Postoperative circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker for disease recurrence in patients (pts) with resected colorectal cancer (CRC) and may potentially guide adjuvant treatment decisions. The timing of ctDNA screening is critical, as postop. plasma cell-free DNA (cfDNA) levels may vary due to factors such as tissue disruption from the surgical resection. The CIRCULATE trial (NCT04089631) investigates ctDNA guided adjuvant therapy in stage II CRC pts in > 140 centres in Germany and Austria. Methods: To investigate the impact of blood sampling time points on cfDNA concentrations and the ctDNA positivity rates, we analyzed the postop. plasma samples of 1439 pts with stage II CRC screened for CIRCULATE between 2020 and 2024. Blood samples were collected within 5-60 days post tumor resection in stabilizing tubes (Streck or PaxGene). Samples were analyzed for postop. cfDNA concentration and tumor-informed ctDNA in plasma samples by an error-reduced Next-Generation Sequencing (NGS) approach [Stasik S Front Genet. 2022]. Results: Plasma cfDNA concentrations (measured by qPCR for beta-globin gene) ranged from 0.02 to 20.32 ng/µL (mean: 0.689 ng/µL; median: 0.360 ng/µL). The highest cfDNA levels were observed within 2 weeks after surgery (mean: 1.079 ng/µL; median: 0.540 ng/µL), with a significant decrease in samples collected > 3 weeks postop. (mean: 0.631 ng/µL; median: 0.355 ng/µL; p < 0.0001), suggesting an impact of surgical trauma and subsequent cfDNA release from normal tissue. In ctDNA-neg. pts, cfDNA concentrations stabilized between 0.405 and 0.449 ng/µL during weeks 4-8. In contrast, ctDNA-pos. pts had significantly elevated cfDNA levels at 2 months post-surgery (mean: 0.972 ng/µL; p = 0.419), indicating ongoing tumor-specific DNA shedding associated with recurrent disease. Variant allele frequencies (VAFs) in ctDNA-pos samples were negatively correlated with cfDNA concentrations, particularly in early postop. samples (Spearman r = -0.508), suggesting a dilution effect of ctDNA post-surgery. This correlation diminished at later time points, supporting the potential advantage of later sampling to improve ctDNA sensitivity. Despite temporal variations in cfDNA concentrations, ctDNA positivity was consistent across all sampling intervals (i.e. week 1: 4.1%; week 6-8: 5.64%), demonstrating the assay's robust sensitivity. Conclusions: We observed a significant variation in cfDNA levels depending on the timing of postop. sampling. Different kinetics, such as cfDNA release from normal tissue and tumor shedding, may influence cfDNA levels and the sensitivity to ctDNA detection. Nonetheless, our assay demonstrates consistent and reliable sensitivity for ctDNA detection across all postop. sampling time points. Clinical trial information: NCT04089631 .
