Mehta-Shah N, Zinzani PL, Jacobsen ED
… +12 more, Zain J, Mead M, Casulo C, Gritti G, Pinter-Brown L, Izutsu K, Sidransky D, Bentur OS, Pro B, Fox CP, Brammer JE, Horwitz SM
PURPOSE: Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous, aggressive lymphomas. Five-year overall survival (OS) remains approximately 30%-40%, and most patients will develop relapsed or refractory (R/R) disea...PURPOSE: Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous, aggressive lymphomas. Five-year overall survival (OS) remains approximately 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 II PRIMO trial (ClinicalTrials.gov identifier: NCT03372057; Secura Bio, Inc) evaluating duvelisib monotherapy in R/R PTCL. METHODS: PRIMO was conducted in two phases (dose optimization and dose expansion [PRIMO-EP]) at 45 centers globally. Eligible patients were age 18 years and older, had histologically confirmed diagnosis of PTCL, and had received ≥2 cycles of one standard regimen for PTCL. Based on dose optimization results, the selected regimen for PRIMO-EP was 75 mg twice a day for two cycles (to maximize disease control) followed by 25 mg twice a day (to reduce late toxicities), continued until progressive disease or unacceptable toxicity. RESULTS: 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, median OS (mOS): 12.4 months, and median duration of response (mDOR): 7.9 months. In the angioimmunoblastic T-cell lymphoma (AITL) subgroup, outcomes were ORR: 62.2%, CRR: 51.4%, mPFS: 8.3 months, mOS: 18.1 months, and mDOR: 11.3 months. Treatment-emergent adverse events (TEAEs; any grade) occurred in 120 patients (97.6%), and 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, respectively. CONCLUSION: 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.
PURPOSE: 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...PURPOSE: 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). METHODS: 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. RESULTS: 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]; = .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]; = .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]; = .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 ( = .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 ( = .75). CONCLUSION: 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.
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...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 + non-small cell lung cancer (NSCLC). With longer follow-up, taletrectinib continued to demonstrate high and durable response rates in both TKI-naïve and crizotinib-pretreated patients, including IC activity and promising overall survival (OS). Among 103 TKI-naïve 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 + NSCLC.
Oberstein PE, Hecht JR, Raghav K
… +43 more, Pietrantonio F, Arnold D, Moreno V, Van Cutsem E, Malik RA, Hong YS, Lee MA, Yu-Li Su H, Lee J, Chandana S, Cruz-Correa M, Yuan Y, Ahmad A, Lai KM, Hsu HC, Chen EX, Elez E, Lin CC, Lopez C, Prenen H, Roselló-Keränen S, Velez H, Yeh YM, Heinemann V, Eng C, Beom SH, Tejpar S, Chowdhury S, Lyu X, Kamat M, Curtin JC, Patel B, Xie J, Bhattacharya R, Schnepp RW, Yilmaz E, Iwasawa R, Daksh M, Lorenzini P, Thayu M, Baig M, Kim HS, Han SW
J Clin Oncol
· 2026 Jun · PMID 42013403
·
Full text
PURPOSE: 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 can...PURPOSE: 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). METHODS: 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 // ectodomain wild-type status, without / 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. RESULTS: 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. CONCLUSION: 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.
Peters S, Piha-Paul SA, Sehgal K
… +18 more, Calvo E, Bockorny B, Galvao V, Dowlati A, Fontana E, Hernandez-Guerrero T, Rivera Herrero F, Kingsley E, Lopez JS, Patnaik A, Perez CA, Sanborn RE, Knowles S, Patilea-Vrana G, Li J, Wang T, Wang Y, Hollebecque A
J Clin Oncol
· 2026 Jun · PMID 42008777
·
Full text
PURPOSE: 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 c...PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
The phase II GeparNuevo trial investigated whether adding durvalumab to neoadjuvant chemotherapy (NACT) only in patients with early triple-negative breast cancer cT1b-cT4a-d would improve pathologic complete response (pC...The phase II GeparNuevo trial investigated whether adding durvalumab to neoadjuvant chemotherapy (NACT) only in patients with early triple-negative breast cancer cT1b-cT4a-d would improve pathologic complete response (pCR) rate and patient survival. Hundred and seventy-four patients were randomly assigned to receive durvalumab or placebo concurrently with nab-paclitaxel once per week and followed by dose-dense epirubicin and cyclophosphamide. With 86.4 months of median follow-up compared with the previously reported 43.7 months, durvalumab showed sustained significant improvements in long-term outcomes as defined by STEEP compared with placebo regarding not only invasive disease-free survival (iDFS; hazard ratio [HR], 0.56 [95% CI, 0.32 to 0.99]; stratified log-rank = .0431), but also distant disease-free survival (DDFS; HR, 0.41 [95% CI, 0.21 to 0.80]; = .0069) and overall survival (OS; HR, 0.33 [95% CI, 0.14 to 0.79]; = .0085). All analyses were stratified by stromal tumor-infiltrating lymphocytes (sTILs) at baseline (low [≤10%], intermediate [11%-59%], high [≥60%]). In exploratory subgroup analysis, patients with nodal involvement at baseline demonstrated a greater iDFS benefit (HR, 0.33 [95% CI, 0.144 to 0.771]; = .01; = 0.045). sTILs in residual disease (RD) could be assessed in 39/71 patients without pCR. Post hoc analyses by sTILs high (>10%) versus low (≤10%) in RD showed estimated 7-year iDFS rates of 92.3% (95% CI, 56.6 to 98.9) and 51.4% (95% CI, 29.2 to 69.7), respectively. Hence, adding durvalumab to dose-dense NACT without adjuvant continuation of checkpoint inhibition improved long-term survival outcomes, irrespective of the extent of pathologic response. This underscores the necessity to re-evaluate the adjuvant continuation of checkpoint inhibition.
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 ye...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.
PURPOSE: Body size is an established risk factor for several cancers, but associations with bladder cancer risk remain unclear. METHODS: We pooled data from 2,533,008 participants in 30 international cohort studies to as...PURPOSE: Body size is an established risk factor for several cancers, but associations with bladder cancer risk remain unclear. METHODS: We pooled data from 2,533,008 participants in 30 international cohort studies to assess associations of BMI, waist circumference, and height with bladder cancer risk. Multivariable Cox regression models, including smoking status, duration, and other confounders, were run separately by cohort and sex, and results combined by random-effects meta-analysis. RESULTS: Incident first primary bladder cancer was diagnosed in 15,259 males and 5,188 females. For males, overweight (BMI, 25.0-29.9 kg/m) and obesity (BMI, ≥30 kg/m) were associated with increased risk of bladder cancer, with hazard ratios (HRs) of 1.08 (95% CI, 1.04 to 1.12) and 1.16 (95% CI, 1.10 to 1.22), respectively, when compared with normal weight (BMI, 18.5-24.9 kg/m). The corresponding HR for females were 1.02 (95% CI, 0.95 to 1.09) and 1.04 (95% CI, 0.95 to 1.14), respectively. The HR per 5 kg/m increment was 1.07 (95% CI, 1.05 to 1.09) for males and 1.00 (95% CI, 0.97 to 1.04) for females. Higher waist circumference was also associated with increased risk of bladder cancer for males (HR per 10 cm increase 1.06 [95% CI, 1.03 to 1.08]) but not females (HR, 1.01 [95% CI, 0.97 to 1.04]). Results for height were largely consistent with those for BMI and waist circumference, with strong and consistent evidence for males, but not females. CONCLUSION: Larger body size is associated with increased risk of bladder cancer for males, but not females. Public health interventions to prevent overweight and obesity, along with smoking cessation and reduced occupational exposure to bladder carcinogens, are likely to reduce bladder cancer incidence worldwide.
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 experime...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 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.
The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001) demonstrated improved efficacy for lenalidomide plus rituximab (R) versus rituximab with placebo (R-placebo) in patients with relapsed or refractor...The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001) demonstrated improved efficacy for lenalidomide plus rituximab (R) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Here, we present the long-term follow-up results and prespecified subgroup analyses of patients with follicular lymphoma (FL), including those 70 years and older. Patients with R/R grade 1 to 3a iNHL were randomly assigned 1:1 to receive R or R-placebo. In this long-term follow-up report, progression-free survival (PFS) was assessed per the investigator. Secondary end points included overall survival (OS) and safety. Of the 358 randomly assigned patients (intent-to-treat [ITT] population), 295 had FL (≥70 years, n = 66). At long-term follow-up (median, 65.9 months), in the ITT iNHL population, PFS (hazard ratio [HR], 0.50 [95% CI, 0.38 to 0.66]) and OS (HR, 0.59 [95% CI, 0.37 to 0.95]) were improved with R versus R-placebo. Safety findings were consistent with the primary analysis. Improved long-term efficacy with R versus R-placebo and manageable safety with R were observed in patients with FL, including those 70 years and older. With a follow-up of >5 years, data from the AUGMENT trial continue to support the use of R as a standard of care for patients with R/R iNHL.
de la Fouchardière C, Zaanan A, de Montfort A
… +17 more, Cohen R, Le Sourd S, Tougeron D, Soularue E, Dubreuil O, Williet N, Samalin-Scalzi E, Piessen G, Hautefeuille V, Jary M, Ben Abdelghani M, Evesque L, Rochigneux P, Blanc E, Pérol D, Bibeau F, Coutzac C
PURPOSE: 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 appr...PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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 ( = .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). CONCLUSION: 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.
Wen PY, Berry DA, Buxton MB
… +30 more, Colman H, de Groot J, Lim M, Mellinghoff I, Perry JR, Weller M, Blondin NA, Butt OH, Damek DM, de la Fuente MI, Drappatz J, Dunbar E, Giglio P, Hyddmark EV, Iwamoto F, Jaeckle KA, Kim L, Kling HM, Lee EQ, Mantica M, Mikkelsen T, Nabors B, Newton HB, Olson JJ, Schiff D, Walbert T, Weathers SP, Cloughesy T, Lassman AB, GBM AGILE Regorafenib Study Group
PURPOSE: 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 (O...PURPOSE: 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. METHODS: 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 ≥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. RESULTS: 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. CONCLUSION: 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.
Chen B, Liu S, Zhu Y
… +18 more, Zhang J, Bao Y, Meng F, Zhang L, Cheng X, Xuzhang W, Chen B, Wang R, Li Z, Hu Y, Liu M, Lv Y, Li J, Dragomir MP, Chen M, Li Q, Yang H, Xi M
PURPOSE: To evaluate the efficacy and safety of adding tislelizumab to induction chemotherapy and concurrent chemoradiotherapy (CRT), with or without maintenance immunotherapy, in patients with unresectable locally advan...PURPOSE: To evaluate the efficacy and safety of adding tislelizumab to induction chemotherapy and concurrent chemoradiotherapy (CRT), with or without maintenance immunotherapy, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: This multicenter, randomized, open-label, phase II trial was conducted across four academic hospitals in China (ClinicalTrials.gov identifier: NCT05520619). Participants were adults age 18-70 years with newly diagnosed, unresectable, stage II to IVB ESCC. Patients were randomly assigned (1:1) to receive two cycles of paclitaxel/cisplatin induction chemotherapy followed by concurrent CRT in combination with tislelizumab for 16 cycles in group A (two induction, two concurrent, and 12 maintenance) or four cycles in group B (two induction and two concurrent). The primary end point was progression-free survival (PFS) in the intention-to-treat population, compared with historical control. RESULTS: Between October 2022 and October 2024, 114 patients were randomly assigned to group A (n = 57) or group B (n = 57). After a median follow-up of 22.7 months (IQR, 16.2-28.2), group B demonstrated significantly better PFS versus controls (1-year: 71.9% [95% CI, 61.1 to 84.6] 56.4% [95% CI, 44.7 to 71.1]; hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.94]), while group A showed no PFS benefit (1-year: 52.6% [95% CI, 41.4 to 67.3]; HR, 1.06 [95% CI, 0.67 to 1.68]). Overall survival was also significantly better in group B (HR, 0.42 [95% CI, 0.22 to 0.82]). Grade ≥3 adverse events occurred in 86.0% of group A and 80.7% of group B, with the most common being lymphopenia (77.2% and 73.7%, respectively). Comprehensive biomarker analyses revealed that PD-L1 expression, CD8 T-cell density, NRF2 pathway mutations, and dynamic changes in circulating tumor DNA were associated with treatment efficacy. CONCLUSION: The addition of tislelizumab to induction chemotherapy and concurrent CRT without maintenance immunotherapy demonstrated superior efficacy and manageable toxicity in locally advanced ESCC.
Rettinger E, Heckl D, Hutter M
… +15 more, Salzmann-Manrique E, Luedtke M, Huenecke S, Bremm M, Cappel C, Bug G, Greil J, Meisel R, Wagner-Drouet EM, Serve H, Güngör T, Klusmann JH, Klingebiel T, Bader P, Bonig H
J Clin Oncol
· 2026 May · PMID 41941697
·
Full text
PURPOSE: 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 knowledg...PURPOSE: 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. METHODS: 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%). RESULTS: 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. CONCLUSION: 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.