搜索结果：Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Cord blood transplantation (CBT) is limited by delayed hematopoietic recovery leading to frequent use of double-unit grafts. This phase II study evaluated the safety of adding dilanubicel, a cryopreserved, cord blood (CB)-derived, non-human leukocyte antigen-matched expanded progenitor cell product generated from pooled donors to single-unit CBT. Between March 2022 and July 2025, we enrolled 28 patients with hematologic malignancies in this single-center phase II trial. The infusion of a matched single CB unit was followed by a target dose of 800 × 106 CD34+ cells of dilanubicel. All patients received a myeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine and mycophenolate mofetil. The median age was 36 years (range, 10-63). Underlying diagnoses included acute leukemias (n = 25) and other hematologic malignancies (n = 3). All patients engrafted neutrophils (median, 18 days; range, 14-30) and platelets (median, 31 days; range, 26-43). Dilanubicel induced transient myelomonocytic recovery, peaking on day 7 and absent by day 14. An early lymphocyte expansion, derived exclusively from the CB graft, occurred by day 9 and peaked by day 11. No grade 3 to 4 acute or chronic GVHD was observed. At a median follow-up of 1.4 years, 27 patients remain alive and disease-free. When evaluated alongside a contemporaneous institutional cohort receiving standard single- or double-unit CBT, patients treated with dilanubicel demonstrated faster hematopoietic recovery and a markedly lower incidence of severe acute GVHD. The addition of dilanubicel to single-unit CBT demonstrated a favorable safety profile, with no severe acute or chronic GVHD, and was associated with excellent clinical outcomes. These findings support further investigation of this strategy.

To evaluate the efficacy and safety of adjuvant hepatic arterial infusion (HAI) of oxaliplatin combined with intravenous (IV) fluorouracil/leucovorin (LV5FU2) after curative-intent surgery of ≥4 colorectal liver metastases (CRLM). Patients with an Eastern Cooperative Oncology Group performance status 0-1, who underwent resection or ablation of ≥4 CRLM after preoperative IV chemotherapy were enrolled. Patients were randomly assigned (1:1) to receive adjuvant oxaliplatin via HAI (HAI group, n = 50) or IV infusion (IV group, n = 49), both combined with IV LV5FU2 for at least 3 months. The primary end point was hepatic recurrence-free survival (h-RFS). Secondary end points included RFS, overall survival (OS), safety, and feasibility. After a median follow-up of 59 months (IQR, 45-71), the median h-RFS was 25 (95% CI, 16 to 37) months in the HAI group versus 12 (95% CI, 8 to 19) months in the IV group (hazard ratio [HR], 0.63 [95% CI, 0.40 to 0.99]; P = .047). Median RFS was 14 months (95% CI, 10 to 20) in the HAI group versus 9 months (95% CI, 7 to 11) in the IV group (HR, 0.63 [95% CI, 0.41 to 0.97]; P = .03). Median OS was 74 months (95% CI, 51 to not defined) in the HAI group versus 57 months (95% CI, 37 to 69) in the IV group (HR, 0.61 [95% CI, 0.33 to 1.12]; P = .11). Five-year OS was 62% in the HAI arm compared with 47% in the IV arm. Grade 3 to 4 adverse events occurred in 58% of HAI patients and 32% of IV patients (P = .02). No treatment-related deaths were reported. Four or more cycles of adjuvant chemotherapy were delivered in 81% of patients in the HAI group and 78% in the IV group (P = .75). Adjuvant oxaliplatin HAI plus LV5FU2 improves h-RFS after curative-intent surgery of CRLM in high-risk patients, with an acceptable safety profile. These results support further evaluation in a phase III trial.

Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancers (CRC). We aimed to assess efficacy and tolerance of perioperative pembrolizumab in dMMR/MSI CRC. The prospective multicenter phase II trial IMHOTEP enrolled patients with localized resectable dMMR/MSI CRC to receive one or two cycles of IV pembrolizumab 400 mg once every 6 weeks before surgery and 1-year total duration thereafter. The primary end point was pathologic complete response (pCR) rate (ypT0N0). Secondary objectives included safety, event-free survival, and overall survival. IMHOTEP enrolled 81 patients with dMMR/MSI CRC who received at least one cycle of pembrolizumab from November 26, 2021, to February 22, 2023: median age was 66 (21-89) years, 46 (52%) were women, and 63 (71%) had clinical stage III disease at baseline. Out of the 72 patients included in the efficacy population, 38 patients (52.7% [95% CI, 41.4 to 63.9]) achieved a pCR. The exploratory post hoc analysis showed a pCR rate increased from 46% (23/50) after one cycle to 68.2% (15/22) after two cycles of neoadjuvant pembrolizumab (P = .0125). With a median follow-up of 24.5 (95% CI, 23.3 to 25.6) months, three disease recurrences occurred. Grade ≥3 immune-related toxicities were reported in 14 (15.7%) patients including one grade 5 (myasthenia). The IMHOTEP trial showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC. To our knowledge, this prospective study is the first to demonstrate the feasibility and the safety of perioperative pembrolizumab.

Overall survival (OS) should be evaluated in all randomized cancer trials, even when not the primary end point, as it is clinically meaningful and measures both safety and efficacy. Crossover from the control to experimental arms in randomized trials may be incorporated to allow access to promising investigational treatments after progression on a control arm. The results of Study LIBRETTO-431, an ex-US multiregional, open-label, randomized, active-controlled trial of selpercatinib versus platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with treatment-naïve advanced rearranged during transfection fusion-positive non-small cell lung cancer, highlight the challenges of interpreting OS in trials with high crossover rates and variable postprogression therapies. Trial results demonstrated a large improvement in progression-free survival with an acceptable safety profile, but were accompanied by an immature OS analysis with a hazard ratio of 1.26, favoring the chemoimmunotherapy arm. Regardless of the position of OS in the end point hierarchy, it is critical that OS analyses include prespecified plans for data collection and analytical methods to account for the potential impact of postprogression therapies on the interpretation of study results.

Chronic graft-versus-host disease (cGVHD) is a multisystem alloimmune disorder associated with abnormal B-cell biology and aberrant antibody responses. As B-cell-directed therapy can effectively treat established cGVHD, we tested whether prophylactic B-cell depletion could prevent the development of corticosteroid-requiring cGVHD following allogeneic transplantation. We performed a randomized, placebo-controlled, and blinded trial comparing four doses of the B-cell-depleting antibody obinutuzumab (1,000 mg once on days 90, 180, 270, and 365 after transplantation) with placebo in transplant recipients receiving tacrolimus-based GVHD prevention at higher risk of cGVHD. The primary end point was the 1-year incidence of corticosteroid-requiring cGVHD. We measured antibody responses against Y chromosome-encoded minor histocompatibility (H-Y) antigens and correlated their occurrence with corticosteroid-requiring cGVHD incidence. One hundred seventy-eight participants were analyzed. The prophylactic administration of obinutuzumab resulted in profound B-cell depletion, a significant reduction in the incidence of steroid-requiring cGVHD at 1 year (13.3% v 35.2%; P = .0005), and an improvement in immunosuppression-free, relapse-free survival (48% v 34% at 2 years; P = .02). Neutropenia was more common in the obinutuzumab arm, but nonrelapse mortality was not different. In participants without preformed H-Y antibodies at the time of study intervention, obinutuzumab resulted in the most significant reduction in steroid-requiring cGVHD at 12 months (8.6%) compared with obinutuzumab participants with H-Y antibodies (40%) or placebo participants regardless of antibody status (41% with antibodies, 57% without antibodies). In allogeneic transplant recipients at higher risk of cGVHD, early B-cell depletion results in a significant reduction in the incidence of corticosteroid-requiring cGVHD.

Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous, aggressive lymphomas. Five-year overall survival (OS) remains ∼30-40%, and most patients will develop relapsed or refractory (R/R) disease. Duvelisib is an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms. Here, we report on the final analysis of the phase 2 PRIMO trial (NCT03372057; Secura Bio, Inc.) evaluating duvelisib monotherapy in R/R PTCL. PRIMO was conducted in 2 phases (Dose Optimization and Dose Expansion [PRIMO-EP]) at 45 centers globally. Eligible patients were ≥18 years of age, had histologically confirmed diagnosis of PTCL, and had received ≥2 cycles of 1 standard regimen for PTCL. Based on Dose Optimization results, the selected regimen for PRIMO-EP was 75 mg BID for 2 cycles (to maximize disease control) followed by 25 mg BID (to reduce late toxicities), continued until progressive disease or unacceptable toxicity. PRIMO-EP (N=123) outcomes included Independent Review Committee-assessed objective response rate (ORR): 48.0%, complete response rate (CRR): 33.3%, median progression-free survival (mPFS): 3.4 months, mOS: 12.4 months, median duration of response (mDOR): 7.9 months. In the AITL subgroup, outcomes were ORR: 62.2%, CRR: 51.4%, mPFS: 8.3 months, mOS: 18.1 months, mDOR: 11.3 months. Treatment-emergent adverse events (TEAEs) (any grade) occurred in 120 patients (97.6%), TEAEs grade ≥3 occurred in 91 patients (74.0%). TEAEs resulting in dose hold or dose reduction occurred in 44.7% and 9.8% of patients. The PRIMO study demonstrates significant activity and tolerability of duvelisib in patients with R/R PTCL, most notably in the AITL subgroup. This provides strong rationale for further development in PTCL, and more specifically in the subgroup of nodal T-follicular helper cell lymphoma.

Integrin beta-6 (IB6) is highly expressed in non-small cell lung cancer (NSCLC) and other solid tumors and potentially associated with poor outcomes. Sigvotatug vedotin (SV), a novel IB6-directed antibody-drug conjugate, demonstrated acceptable safety and encouraging antitumor activity in dose escalation. We report updated results for dose-expansion regimens in advanced NSCLC (aNSCLC). SGNB6A-001 is an open-label, multicenter, dose-escalation/dose-expansion phase I study evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of SV in patients with select advanced solid tumors. After dose escalation, dose expansion further explored three regimens: 1.25 mg/kg total body weight (TBW) on Days 1 and 8 of a 21-day cycle, 1.5 mg/kg TBW on Days 1 and 15 of a 28-day cycle (once every 2 weeks), and 1.8 mg/kg adjusted ideal body weight (AiBW) once every 2 weeks. Eligible patients had prior chemotherapy and immunotherapy or targeted therapy if indicated. Primary end points were safety and determination of an optimal dosing schedule. Secondary end points were antitumor activity, PK, and immunogenicity. As of November 26, 2024, 117 patients with aNSCLC were treated in the above cohorts. Any-grade and grade ≥3 treatment-emergent adverse events occurred in 98% and 48% of all patients, respectively, and in 94% and 35% of patients receiving SV 1.8 mg/kg AiBW once every 2 weeks. Modeling revealed that the AiBW regimen resulted in lower PK variability than TBW regimens. The objective response rate and median duration of response were 19% and 11.3 months in the overall population, respectively, and 29% and 12.8 months in patients with nonsquamous, taxane-naïve NSCLC. SV demonstrated a manageable safety profile and promising antitumor activity with durable responses in aNSCLC. PK and clinical data support further investigation with the recommended 1.8-mg/kg AiBW once every 2 weeks dosing regimen.

Patients with high-risk (HR) leukemia remain at substantial risk of early relapse, treatment-related toxicity, and poor survival, underscoring the need for effective relapse prevention therapies. To our knowledge, this first-in-human, disease burden-guided study evaluated the feasibility, safety, and efficacy of donor-derived allogeneic interleukin-15-activated cytokine-induced killer cells (IL15-CIK) combining T-cell and natural killer cell properties for post-transplant disease control. In a prospective, multicenter phase I/II trial (EudraCT 2013-005446-11) and an identically designed pilot study, 53 adult and pediatric patients with HR leukemia received 56 courses of IL15-CIK monotherapy after human leukocyte antigen (HLA)-matched or HLA-mismatched transplantation. Treatment intent was categorized as consolidation (13%), preemptive (61%), or salvage (27%) with 169 infusions administered as a single dose (29%) or according to adaptable dose-escalation regimens (71%). Acute graft-versus-host disease (GVHD) grades 1-2 and grade 3 occurred in 27% and 4% of cases, respectively; no extensive chronic GVHD or treatment-related mortality was observed. IL15-CIK-associated adverse events were predominantly mild. Disease clearance, assessed by the cumulative incidence of complete molecular remission, peaked at day 700, reaching 74% in the preemptive and 13% in the salvage setting. The five-year progression-free survival was 50% overall and highest (69%) in pediatric acute myeloid leukemia. The five-year overall survival (OS) was 71% in the consolidation, 61% in the preemptive, and 20% in the salvage setting. Multivariable analysis demonstrated significantly lower relapse rates with Campath compared with ATG, superior OS in myeloid malignancies, and reduced IL15-CIK efficacy in advanced disease. The median follow-up was 7.3 years. IL15-CIK monotherapy is feasible and safe and demonstrates promising relapse-preventive activity after hematopoietic stem-cell transplantation. Clinical outcomes are strongly influenced by disease burden at treatment initiation and previous serotherapy, supporting optimized patient selection and timing in future post-transplant immunotherapeutic strategies.

The diagnosis and treatment of hematologic malignancies has undergone significant advancements over the past few decades, resulting in enhanced outcomes. For hematologic malignancies diagnosed during pregnancy, this poses new questions. As possibilities continue to expand and the rising global incidence results in an increasing number of diagnoses within the pregnant population, there is a pressing need to gain a deeper understanding of the potential options for pregnant women and the impact on the newborn. As knowledge of the effects of cancer treatment increases, more women are receiving adequate cancer diagnosis and treatment during pregnancy. This paper presents an expert opinion on the use of diagnostic modalities and treatment options, including chemotherapy, radiation therapy, and immunotherapy, for acute leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloproliferative neoplasms, aplastic anemia, and multiple myeloma during pregnancy.

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, is approved in non-small cell lung cancer (NSCLC). Effective treatments are limited for chemorefractory metastatic colorectal cancer (mCRC). OrigAMI-1 (ClinicalTrials.gov identifier: NCT05379595) is a phase Ib/II study evaluating amivantamab monotherapy in chemorefractory (2-3 prior lines) mCRC. Participants had centrally confirmed RAS/BRAF/EGFR ectodomain wild-type status, without ERBB2/HER2 amplification. Participants with left-sided mCRC without (cohort A) or with (cohort B) prior anti-EGFR antibody treatment, or right-sided mCRC (cohort C) regardless of prior anti-EGFR treatment, received intravenous amivantamab 1,050 mg (1,400 mg for ≥80 kg) once every 2 weeks. The primary end point was objective response rate (ORR) per RECIST v1.1. By October 31, 2024, 94 participants received amivantamab monotherapy (median follow-up, 11.9 months). The median age was 60 years, and 65% of participants were male, with a median of 2 prior lines (94%, prior bevacizumab). In left-sided cohorts, the ORR was 29% (5 of 17) in cohort A and 19% (10 of 54) in cohort B; the median duration of response (DoR) was 9.0 months and 6.1 months, and the median progression-free survival (PFS) was 5.7 months and 4.6 months, respectively. In the right-sided cohort, the ORR was 22% (10 of 23; 43% had prior anti-EGFR), the median DoR was 9.8 months, and the median PFS was 3.7 months. Most frequent treatment-related grade ≥3 adverse events (AEs) were rash (7%), dermatitis acneiform (4%), and hypoalbuminemia (4%). One participant discontinued amivantamab because of a treatment-related AE. Amivantamab monotherapy demonstrated promising, durable antitumor activity in chemorefractory mCRC, regardless of prior anti-EGFR therapy and the primary tumor location. The amivantamab safety profile in mCRC is consistent with experience in NSCLC. Amivantamab plus chemotherapy is currently being explored in two phase III studies in first-line and second-line mCRCs.

GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was &#x2265;98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

BRAF V600 mutations are tumor-agnostic oncogenic drivers whose targeted inhibition is challenged by therapeutic resistance. Mosperafenib is a novel paradox breaker and brain-penetrant BRAF inhibitor (BRAFi), tested in this study for safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary clinical activity. This phase Ia/b study was conducted in patients with advanced solid tumors harboring a BRAF V600 mutation (ISRCTN13713551). The modified continuous reassessment method guided dose escalation of mosperafenib, which was given orally up to 3,600 mg once daily in 28-day cycles. The primary objective was to estimate the MTD and/or recommended phase II dose(s). Eighty patients (60% BRAFi-exposed)-63 with colorectal cancer (CRC), 13 with melanoma, and 4 with other solid tumors-received &#x2265;1 dose of mosperafenib as a single agent for a median of 3.7 months (range, 0.2-28.6). Two dose-limiting grade 3 toxicities of rash and rash maculopapular were reported. MTD was not reached. Grade 3 to 4 treatment-related adverse events (TRAEs) occurred in 13 patients (16.3%); no grade 5 TRAEs events were reported. Two patients (2.5%) discontinued study treatment due to TRAEs. There were no reports of palmar-plantar erythrodysesthesia or keratoacanthoma. Linear and time-independent PK was demonstrated across the tested dose range, achieving exposure levels with sustained PK-derived pERK inhibition &#x2265;90%. An exposure-response relationship was observed. Overall response rate was 24.2%, including two complete responses and 14 partial responses. Median progression-free survival was 6.4 months in patients with CRC (200 mg once daily-1200 mg three times a day) and 3.5 months in patients with melanoma (200 mg once daily-800 mg twice a day). Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-na&#xef;ve and BRAFi-exposed patients.

To provide evidence-based recommendations on the use of systemic therapy in different types of thyroid cancers. The American Society of Clinical Oncology convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. The literature search included studies published between January 1, 2000, and November 5, 2025, and comprised systematic reviews, meta-analyses, randomized controlled trials, and observational studies. Outcomes of interest included overall survival, disease-free survival, and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. A total of 66 publications were identified to inform the evidence base for this guideline. Evidence-based recommendations address the use of systemic therapy in patients with well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer.Additional information is available at https://ascopubs.org/topics/asco-guidelines/head-neck-cancer.

The antibody-drug conjugate Temab-A comprises the c-Met-targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload, adizutecan. A first-in-human phase I study (ClinicalTrials.gov identifier: NCT05029882) of Temab-A in patients with advanced solid tumors whose disease has progressed is currently ongoing. We report results from all patients in the dose escalation and the monotherapy metastatic colorectal cancer (mCRC) dose expansion. Temab-A was administered intravenously once every 3 weeks as a monotherapy starting at 1.6 mg/kg in dose escalation. In mCRC dose expansion, patients with confirmed BRAF wild-type, microsatellite stable/mismatch repair-proficient mCRC were randomly assigned to 1.6 mg/kg, 2.4 mg/kg, or 3.0 mg/kg Temab-A once every 3 weeks. Primary end points included safety, pharmacokinetics, recommended phase II dose of Temab-A monotherapy, and Temab-A efficacy in patients with mCRC. In total, 57 patients received &#x2265;1 dose of Temab-A in dose escalation; 3.0 mg/kg once every 3 weeks was established as the maximum tolerated dose. Collectively, in dose escalation and dose expansion, 122 patients with mCRC received Temab-A (dose escalation, N = 29; randomized dose optimization expansion, N = 93). All patients experienced &#x2265;1 treatment-emergent adverse event; the most frequent were gastrointestinal (78%) and hematologic (71%) toxicities. Treatment-related discontinuations and deaths were infrequent (10% and 3%, respectively). Across all doses in patients with mCRC, overall response rate was 15.6% (95% CI, 9.6 to 23.2), disease control rate was 74.6% (95% CI, 65.9 to 82.0), and duration of response was 5.9 months (95% CI, 4.1 to 10.5); responses were more frequent at doses of 2.4 mg/kg and 3.0 mg/kg once every 3 weeks. Median progression-free survival was 4.6 months (95% CI: 4.0, 5.4), and median overall survival was 10.4 months (95% CI, 8.9 to 13.1). Temab-A at 2.4 mg/kg once every 3 weeks has a tolerable and manageable safety profile, with promising antitumor activity.

The evaluation of novel health technologies is increasingly complicated by a landscape of pervasive social media influence and intense product marketing, factors that may distort evidence appraisal and contribute to suboptimal medical decision-making and patient outcomes. Within this context, interest in histotripsy, a novel technology approved for the treatment of liver tumors, has expanded rapidly. This accelerated adoption has outpaced the available evidence, challenging established principles of safety, efficacy, and appropriate patient selection and has generated substantial debate within the oncologic community. In this editorial, we provide an overview of the technology and available data, examine the external forces contributing to its accelerated application, and propose a well established, structured, evidence-based framework to guide its rigorous evaluation, responsible adoption, and optimal clinical implementation.

Cascade genetic testing in families with hereditary cancer syndromes is an important strategy to reduce the burden of cancer, but testing of relatives is low. Direct engagement of relatives through cancer survivors is a promising approach to bridge this gap. We conducted a population-based cluster-randomized clinical trial (Genetic Information and Family Testing [GIFT]) of an online, direct-to-family, cancer genetic education and communication tool including the offer of home testing to adult relatives of cancer survivors diagnosed in 2018-2019 who carried a pathogenic variant. We selected patients through SEER and surveyed them for eligibility followed by a trial invitation. Two features were randomized: assistance from a human navigator (yes, no) and testing cost (free v $50). We hypothesized that the fraction of relatives tested in a family (primary outcome) would be higher with a navigator and free testing. Four thousand three hundred patients were surveyed and 2,285 responded (53.1%); 2,006 eligible respondents were invited (87.8%) and 414 enrolled (20.6%). Enrolled patients reported a total of 4,946 first- and second-degree relatives (mean, 12.3; standard deviation [SD], 8.6); they invited 948 relatives (19.2%) and 303 enrolled (32.0%). Most enrolled relatives ordered testing (267, 91.3%); more than double were tested in the free versus $50 arm (odds ratio [OR], 2.5 [1.6-3.9]), but the baseline fraction tested was low at 0.03 and thus the absolute increase was modest (0.04 [95% CI, 0.02 to 0.05]). We did not find evidence for increased testing in the navigation arm (OR, 1.3 [0.8-2.1]). GIFT is a promising blueprint for online cascade genetic education and testing. Results suggest that a low-cost, population-level intervention could be deployed without a human navigator. Additional intervention strategies are needed to increase the modest invitation and testing uptake observed in this study.

Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. Unsupervised clustering identified nine entities with distinct genomic features and outcomes (P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts (P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population (P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.

Taletrectinib is a next-generation, CNS-active, selective ROS1 tyrosine kinase inhibitor (TKI) with activity against the ROS1 G2032R resistance mutation. Initial data from the TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) demonstrated high response rates and intracranial (IC) activity, with promising durability, in Chinese patients with advanced ROS1+ non-small cell lung cancer (NSCLC). With longer follow-up, taletrectinib continued to demonstrate high and durable response rates in both TKI-na&#xef;ve and crizotinib-pretreated patients, including IC activity and promising overall survival (OS). Among 103 TKI-na&#xef;ve patients who started taletrectinib at 600 mg once daily (median follow-up, 51.0 months), the objective response rate (ORR) was 90.3% (95% CI, 82.9 to 95.3), the median duration of response (DOR) and median progression-free survival (PFS) exceeded 4 years (49.7 months and 49.6 months, respectively), and median OS was not reached. Among 66 crizotinib-pretreated patients (median follow-up, 45.2 months), the ORR was 51.5%, the median DOR was 13.2 months, the median PFS was 7.6 months, and the median OS was 25.6 months. The safety profile remained consistent with prior reports, and no new safety signals were identified. Overall, taletrectinib demonstrated durable long-term efficacy and a manageable safety profile in patients with advanced ROS1+ NSCLC.