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PubMed2026

Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS: ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS: 36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION: The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING: National Cancer Institute of the National Institutes of Health.

Humans↗

PubMed2026

Risk-Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta-Analysis.

Phase 2 (and phase 1 dose expansion, which we label phase 2 for the purposes of this study) cancer trials are the first direct tests of a new drug's efficacy. Because efficacy evidence is lacking, the therapeutic status of drug administration during ethical review is uncertain. We compared the efficacy and safety of cancer monotherapies in phase 2 with phase 3, where clinical equipoise underwrites a therapeutic status for drug administration. In this systematic review and meta-analysis, we searched Clinicaltrials.gov for phase 2 and 3 investigational monotherapy drug trials in six solid malignancies, with primary completion dates 2015-2020, inclusive. Two independent reviewers completed data extraction. Effects were estimated using an inverse-variance weighted random-effects model meta-analysis of proportions using the R package meta. We analyzed 130 phase 2 and 52 phase 3 trial arms, enrolling 6665 and 18,694 patients. The pooled objective response rate was 7% (95% CI 5%-11%) in phase 2 versus 24% in phase 3 (95% CI 17%-31%; p < 0.0001). The median PFS and OS were shorter in phase 2 compared to phase 3 (3.23 vs. 5.43 months, p < 0.0001; 9.46 vs. 14.44 months, p = 0.0001). The pooled rate of drug-related grade 3-4 adverse events was 30% (95% CI 23%-37%) in phase 2 and 25% (95% CI 19%-32%) in phase 3. Monotherapies delivered in phase 2 cancer trials present diminished risk-benefit compared with phase 3 and align with historic estimates for phase 1. Though there may be exceptions, risks for drug administration in phase 2 should generally be justified by appeals to research rather than therapeutic value.

Humans↗

PubMed2026

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans↗

PubMed2026

Penpulimab and Gemcitabine With or Without Anlotinib in Metastatic Nasopharyngeal Carcinoma: A Randomized, Open-Label, Multicenter Phase 2 Study.

This prospective exploratory phase 2 study employed a three-cohort, two-phase design to evaluate the potential of anlotinib as a substitute for cisplatin in gemcitabine-penpulimab combinations for metastatic nasopharyngeal carcinoma (NPC) patients who were previously treated with cisplatin-based chemoradiotherapy. Patients enrolled in the study were randomized in a 1:1:1 ratio during the lead-in phase to one of three treatment arms: gemcitabine, cisplatin, penpulimab, and anlotinib (GP-PA, n = 8); gemcitabine, cisplatin, and penpulimab (GP-P, n = 6); or gemcitabine, penpulimab, and anlotinib (GAP, n = 6). The expansion phase enriched the optimal cohort, with stratification based on PD-L1 expression. The primary endpoints were safety and objective response rate (ORR), while the secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). In the lead-in phase, grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 87.5% (GP-PA), 100% (GP-P), and 66.7% (GAP) patients, predominantly hematologic toxicities. ORR/DCR were 62.5%/87.5% (GP-PA), 83.3%/100% (GP-P), and 100%/100% (GAP). At median 20.2-month follow-up, median PFS/OS were 4.1/18.4 months for GP-PA and not reached for GP-P/GAP. In the expansion phase, a total of 14 patients received GAP, with an ORR of 93.3% and grade ≥ 3 TEAEs in 71.4% of patients. At data cut-off point, the median PFS had not been reached, and the 12-month PFS and OS rates were 53.8% and 78.6%, respectively. The GAP regimen demonstrated a favorable safety and efficacy profile, compared to the GP-PA and GP-P regimens in patients with metastatic NPC. These findings suggest that substituting cisplatin with anlotinib may offer a viable therapeutic strategy for this patient population.

Humans↗

PubMed2026

Safety and immunogenicity of an mRNA COVID-19 vaccine administered to adults: A phase 2, randomized, active-controlled trial.

We conducted a phase 2, randomized, active-controlled, observer-blind study (NCT05960097) among healthy adults ≥18 y of age who completed a primary COVID-19 mRNA vaccination series, with or without a booster, ≥3 months earlier. Participants were randomized (1:1:1:1:1) to either receive an investigational bivalent mRNA COVID-19 vaccine encoding ancestral D614G and Omicron BA.4-5 spike proteins (CV0701 mRNA vaccine) at one of three dose levels, an investigational monovalent mRNA COVID-19 vaccine encoding the Omicron BA.4-5 spike protein (CV0601 mRNA vaccine), or a licensed Original Wuhan/Omicron BA.4-5 bivalent mRNA COVID-19 vaccine. The primary objectives were to evaluate reactogenicity, safety and immunogenicity post-vaccination. Secondary and tertiary objectives were to further evaluate humoral and cell-mediated immunity post-vaccination. In total, 425 participants were vaccinated and 381 were included in the Day 29 per-protocol immunogenicity analysis. Most solicited events were mild to moderate. No vaccine-related serious adverse events or myocarditis/pericarditis cases were reported. For the CV0701 mRNA vaccine, a dose-dependent increase in Day 29 neutralizing titers against ancestral D614G and Omicron BA.4-5 was observed. Neutralizing titers against ancestral D614G and Omicron BA.4-5 declined by Days 91 and 181, but remained above baseline. Similar immune responses were observed for the CV0601 mRNA vaccine. At Day 8, CD4+ T cells (Th1 profile) increased in all study groups and CD8+ T cells increased in all study groups, except the lowest CV0701 dose group. The CV0701 and CV0601 mRNA vaccines elicited robust humoral and cellular immunity with an acceptable safety profile, comparable to a licensed, bivalent mRNA vaccine. Clinical Trial Registration EU CT number: 2023-504596-25-00 ClinicalTrials.gov: NCT05960097.

Humans↗

PubMed2026

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans↗

PubMed2026

Efficacy and safety of infigratinib in patients with refractory advanced gastric or gastroesophageal junction adenocarcinoma harboring FGFR2 gene amplification: a single-arm, multicenter phase 2 trial.

BACKGROUND: FGFR2 has garnered attention as a promising therapeutic target for gastric cancer (GC) because of its role in GC progression. Infigratinib, an FGFR1-3 selective tyrosine kinase inhibitor, has shown potential in preclinical GC models. METHODS: Infigratinib was evaluated in a phase 2 trial for patients with FGFR2-amplified GC or gastroesophageal junction (GEJ) adenocarcinoma who had failed two or more lines of systemic treatment for locally advanced or metastatic disease. A total of 21 patients received 125 mg of infigratinib orally once daily on a "3 weeks on, 1 week off" schedule. RESULTS: Infigratinib showed preliminary antitumor activity in this molecularly selected population, as reflected by a confirmed objective response rate of 23.8% (95% CI, 8.2-47.2) with median progression-free survival of 3.4 months and median overall survival of 6.7 months. The most common grade 3-4 adverse events were elevated aspartate aminotransferase, decreased white blood cell count, and neutropenia. No treatment-related deaths occurred. Exploratory genomic analyses identified alterations in individual patients with disease progression that may be associated with resistance; however, these findings were based on a limited number of cases and should be interpreted as hypothesis-generating. CONCLUSIONS: The findings support continued investigation of FGFR-targeted strategies in FGFR2-amplified GC/GEJ adenocarcinoma, while underscoring the need for larger studies, refined biomarker selection, and deeper characterization of resistance mechanisms. TRIAL REGISTRATION: NCT05019794, Registered 28 July 2021, https://clinicaltrials.gov/study/NCT05019794 .

Humans↗

PubMed2026

Anifrolumab Treatment Leads to Rapid Reduction in Urinary Biomarkers of Intrarenal Inflammation in Lupus Nephritis: Results From the Phase 2 Randomized Trial.

OBJECTIVE: Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE) and is partially driven by type I interferon signaling. Anifrolumab, an approved treatment for patients with SLE, has been investigated in a phase 2 trial in patients with LN receiving standard therapy (TULIP-LN, ClinicalTrials.gov identifier NCT02547922). We studied the impact of anifrolumab treatment on urinary biomarker expression in patients with LN through proteomic analysis of samples from TULIP-LN. METHODS: Urine samples were collected at weeks 0, 12, and 48 from patients treated with the anifrolumab basic regimen (n = 35), intensified regimen (n = 42), or placebo (n = 35), in addition to standard therapy, and analyzed for the presence of 197 proteins. The impact of anifrolumab relative to placebo on prespecified biomarkers linked to histologic activity was assessed, and a comparison of responders versus nonresponders was conducted on proteins detected in ≥75% of samples. RESULTS: Anifrolumab treatment significantly reduced urinary CD163 and monocyte chemoattractant protein 1 expression at week 12 versus placebo, including in patients classified as proteinuric nonresponders across all regimens. By week 48, biomarker levels declined in all groups, indicating that standard therapy alone can eventually suppress intrarenal inflammation but with slower kinetics. Proteomic analyses further revealed that anifrolumab was superior to placebo in reducing the proteomic inflammatory signature, regardless of responder status. CONCLUSION: Compared with placebo, anifrolumab treatment significantly reduced urinary biomarkers of renal histologic activity in patients with LN, which may accelerate the resolution of intrarenal inflammation, potentially preventing damage accrual.

Humans↗

PubMed2024

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial.

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Humans↗

PubMed2026

Teclistamab versus lenalidomide-dexamethasone in high-risk smoldering multiple myeloma: a randomized phase 2 trial.

Teclistamab, a B cell maturation antigen-targeting bispecific antibody, has demonstrated substantial activity in relapsed multiple myeloma (MM), particularly in earlier lines of therapy, and may have higher efficacy in high-risk smoldering MM (HR-SMM) with a more functional immune system. In the randomized phase 2 ImmunoPRISM trial, we compared fixed-duration teclistamab with lenalidomide-dexamethasone (Rd) in HR-SMM. After a six-patient safety run-in, patients were randomized 2:1 to teclistamab or Rd. The primary endpoint was complete response (CR) rate. As of 26 May 2026, 59 patients were treated-45 received teclistamab and 14 received Rd. Teclistamab treatment induced a CR in 77.8% patients versus 0% with Rd, and minimal residual disease negativity at 10-5 in 82.2% patients. At a median follow-up of 24.5 months, 2-year progression-free survival was 92% with teclistamab versus 49% with Rd. Overall, response rates, duration of response and time to progression (TTP) were significantly improved in teclistamab compared to Rd. Toxicities in the teclistamab arm included grades 1-2 cytokine release syndrome, no neurotoxicity and no increase in grade 3 infections compared to Rd (20% versus 21%). No deaths occurred in either arm. Teclistamab represents a highly active immune-interception strategy for HR-SMM. ClinicalTrials.gov registration: NCT05469893 .

Journal Article↗

PubMed2025

A Single-Arm Phase 2 Study of Sotorasib Plus Carboplatin and Pemetrexed in Patients With Advanced Nonsquamous NSCLC With KRAS G12C Mutation (WJOG14821L, SCARLET).

INTRODUCTION: The efficacy and safety of sotorasib plus platinum doublet chemotherapy in KRAS G12C-mutated nonsquamous NSCLC (nonsq NSCLC) have been previously reported with a limited follow-up period. METHODS: SCARLET is a single-arm phase 2 study involving chemotherapy-naive patients with KRAS G12C-mutated nonsq NSCLC. The participants received 960 mg daily plus four cycles of carboplatin (area under the curve = 5)/pemetrexed 500 mg/m2, followed by sotorasib/pemetrexed until disease progression. The primary end point was the overall response rate (ORR) and the secondary end points were progression-free survival (PFS), overall survival, and safety. Using plasma samples, next-generation sequencing was performed at baseline, 3 weeks, and during disease progression (the Japan Registry of Clinical Trials number 2051210086). RESULTS: Thirty patients were enrolled between October 2021 and July 2022 with a median follow-up of 14.8 months. ORR was 88.9% (80% confidence interval [CI]: 78.5%-94.8%, 95% CI: 70.8%-97.6%), median PFS was 6.6 months (95% CI: 5.3-16.7 mo), and median overall survival was 20.6 months (95% CI: 8.1 mo-not estimated). Among patients with programmed death-ligand 1 expression levels of 1% or higher and less than 1%, the ORRs were 82.3 and 100%, respectively, and the median PFS was 7.6 and 9.7 months, respectively. Using plasma samples, patients without KRAS G12C at baseline, without KRAS-related pathway co-alterations, or who cleared KRAS G12C at 3 weeks had better median PFS (16.7, 13.9, 8.7 mo, respectively). Tumor protein 53 mutations and EGFR and MET amplification were detected as acquired resistance. CONCLUSIONS: In patients with KRAS G12C-mutated nonsq NSCLC, sotorasib plus carboplatin/pemetrexed reported favorable efficacy, particularly for patients with less than 1% programmed death-ligand 1, with manageable toxicity.

Humans↗

PubMed2026

A phase 2 study of encorafenib in combination with binimetinib for Chinese participants with BRAFV600E mutated metastatic non-small cell lung cancer: Results from the OCEAN II study.

PURPOSE: The ongoing OCEAN II study (ClinicalTrials.gov identifier: NCT05195632) evaluates encorafenib in combination with binimetinib (E+B) in Chinese participants with BRAFV600E-mutated metastatic non-small cell lung cancer (NSCLC). METHODS: Participants with metastatic unresectable stage IV BRAFV600E-mutated NSCLC (treatment-naïve or with prior systemic therapy excluding BRAF/MEK-inhibitors), were enrolled in a phase 2 study with two parts: safety lead-in (SLI) and pivotal part (PP). Participants received daily oral encorafenib (450mg) and twice daily oral binimetinib (90mg total). Primary endpoints were dose-limiting toxicities (DLT) during SLI and confirmed objective response rate by independent central review (cORR-ICR) during PP. Secondary endpoints were other measures of efficacy, safety, and pharmacokinetics. RESULTS: In total, 63 participants were enrolled. One DLT (non-serious Grade 3 lipase increased) during SLI considered possibly related to E+B resolved without intervention, supporting initiation of PP. Pre-defined statistical efficacy criteria on the first 50 participants were met. In the main analysis, cORR-ICRwas59% (95%CI 45-72). At a later ad hoc analysis, cORR-ICR was 61% (95%CI 47-74), disease control rate 87% (95%CI 75-95). Medians (95%CI) were, time-to-response 1.8 months, duration of response 17.5 months, progression-free survival 13.8 months (7.5-not estimable), overall survival 27.9 months (14.7-30.0). 98.4% of participants experienced ≥1 treatment-related TEAE, and 55.6% had any Grade ≥3 TEAE. Nine (14.3%) participants discontinued any drug due to adverse events. CONCLUSION: These data confirm the clinical benefit of E+B in Chinese participants with BRAFV600E-mNSCLC, a population with distinct genomic and disease characteristics. No new safety concerns were identified in Chinese participants.

Adult↗

PubMed2026

Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

Adult↗

PubMed2026

The glucagon and GLP-1 receptor dual agonist DD01 for metabolic dysfunction-associated steatotic liver disease and steatohepatitis (DD01-DN-02): 12-week results from a randomised, double-blind, multicentre, placebo-controlled, phase 2 trial.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS: DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS: Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION: In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING: D&D Pharmatech, Neuraly.

Humans↗

PubMed2026

Hyperprogression Upon Cemiplimab Alone or With Short Course Chemotherapy in PD-L1 ≥ 50% Non-small Cell Lung Cancer: A Biomarker Guided Multicenter International Phase 2 Trial-HYPERBOLIC Study.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS: HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION: to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

CD10↗

PubMed2026

Adjuvant apatinib therapy following concurrent chemoradiotherapy in patients with high-risk nasopharyngeal carcinoma: A multicenter, prospective phase 2 study.

PURPOSE: To assess the efficacy and safety of concurrent chemoradiotherapy (CCRT) combined with apatinib in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: This multicenter, prospective, phase II study enrolled patients with newly histologically confirmed LA-NPC, who were randomly assigned to receive CCRT followed by adjuvant apatinib (investigational arm) or CCRT alone (control arm). The investigational arm received 250 mg/day of oral apatinib administered every 28 days for up to six cycles after CCRT. The primary endpoint was 3-year progression-free survival (PFS) and secondary endpoints of overall survival (OS), distant metastasis-free survival (DMFS) and local recurrence-free survival (LRFS) of 3-year, and safety. RESULTS: From July 2018 to September 2020, 44 and 44 patients were randomized into the CCRT-alone and CCRT and apatinib groups, respectively. The median follow-up duration 56 (range: 40.0-58.6) months. The survival outcomes were the 3-year PFS, OS, and DMFS rates in the adjuvant apatinib following CCRT group were significantly higher than those observed in the CCRT-alone group((PFS, 78.6%vs. 54.5%, p = 0.027; OS, 88.1% vs. 75.0%, p = 0.029; DMFS, 85.4%vs. 59.1%, p = 0.009). The 3-year LRFS was similar between the groups. The grade 3-4 treatment-related adverse events(TRAEs) were higher in the former group than in the latter. The most common grade 3-4 non-hematology-related adverse events were hypertension (14.3%), hand-foot syndrome (9.5%), increased transaminase levels (7.1%), and headache (7.1%). CONCLUSION: Apatinib significantly improved the treatment effects of CCRT for high-risk LA-NPC patients. Therefore, CCRT and adjuvant apatinib may represent a promising option for this patient population.

Adjuvant therapy↗

PubMed2026

Final phase 2 study results of acalabrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia.

Acalabrutinib is a selective, covalent Bruton tyrosine kinase inhibitor approved for marketing in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report final, long-term phase 1/2 study results in 99 patients with treatment-naive (TN) and 134 with relapsed/refractory (R/R) CLL/SLL. At final data cutoff, 71% and 31% of patients in the TN and R/R cohorts, respectively, remained on acalabrutinib treatment (median follow-up of 73.7 and 52.6 months). Among the events of clinical interest (any grade) in the TN and R/R cohorts, atrial fibrillation was reported in 6.1% and 9.0%, hypertension in 29.3% and 23.1%, other malignancies (excluding nonmelanoma skin cancer) in 14.1% and 17.2%, and major bleeding in 8.1% and 8.2% of patients, respectively. The incidence of the most common adverse events decreased over time. Overall response rates were 97.0% and 94.8% in the TN and R/R cohorts, respectively, with similar response findings among patients with standard and high-risk genomic features. In the TN cohort, median progression-free survival (PFS) was not reached and the 72-month PFS rate was 86.7% (95% confidence interval [CI], 77.0-92.5). For the R/R cohort, median PFS was 66.1 months (range, 0.4-87.8) and the 72-month PFS rate was 45.1% (95% CI, 35.6-54.1). This final analysis extends the duration of benefit observed with acalabrutinib, demonstrates that no new safety signals are apparent with longer follow-up, and confirms the safety and tolerability of acalabrutinib monotherapy for patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Humans↗

PubMed2026

Clinical and molecular prognostic factors in newly diagnosed pediatric T-cell lymphoblastic lymphoma: a prospective, multicenter, single-arm phase 2 clinical trial.

BACKGROUND: Poor early treatment response in T-cell lymphoblastic lymphoma (T-LBL) is associated with an unfavorable prognosis. This multicenter prospective study evaluated the efficacy of the response-adjusted Chinese Children's Cancer Group (CCCG-LBL-2016) protocol for pediatric T-LBL and examined clinical and molecular prognostic factors. METHODS: Clinical and laboratory data from seven pediatric oncology centers were analyzed. A sub-cohort of 23 patients underwent exploratory integrated genomic analysis, including targeted next-generation sequencing, RNA sequencing, and copy-number array analysis. Survival was evaluated using the Kaplan-Meier method, and prognostic factors were analyzed using multivariable Cox proportional hazards regression. RESULTS: A total of 163 patients (median age: 108 months; 116 males, 47 females) were enrolled, most with advanced disease (stage III: 81.0%; stage IV: 17.8%). Patients were stratified into the low-risk (R1, n = 2) and intermediate-risk groups (R2, n = 161); thirty one patients in the R2 group were escalated to the high-risk intensified regimen (R3) due to poor early response. The 3-year overall survival (OS) was 78.6% ± 3.3% and event-free survival (EFS) was 73.9% ± 3.5%. Outcomes differed by risk group (P < 0.05), with 3-year OS and EFS of 100% and 100% in R1, 82.6% ± 3.4% and 79.5% ± 3.4% in R2, and 58.6% ± 9.1% and 48.3% ± 9.1% in R3. Progression or recurrence occurred in 42 patients (median: 7 months; 3-year OS: 17.1% ± 6.3%). Clinical risk factors included R3 assignment and elevated lactate dehydrogenase. In the exploratory molecular sub-cohort, recurrent alterations included CDKN2A (39.1%), NOTCH1 (26.1%), FBXW7 (21.7%), and MTAP/PIK3R1/NRAS (13.0%). Exploratory multivariable Cox regression analysis identified that CDKN2A alteration was associated with an increased risk of progression or recurrence (hazard ratio = 35.89, 95% confidence interval: 3.07-419, P = 0.004). CONCLUSIONS: Adjusting the risk stratification based on treatment response significantly improved the overall prognosis of T-LBL. However, survival rates remain very low among patients who experience disease progression or recurrence. The preliminarily explored molecular genetic risk factors might contribute to further risk stratification and provide potential therapeutic targets.

Humans↗