To investigate the preclinical characterization of dirozalkib, a novel anaplastic lymphoma kinase (ALK) inhibitor, and its safety, pharmacokinetics, and preliminary antitumor activity in advanced non-small cell lung cancer (NSCLC).

The phase 3 KEYNOTE-522 study in high-risk early-stage triple-negative breast cancer (TNBC) showed significantly improved efficacy outcomes with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy alone. We present findings from the KEYNOTE-522 Japan subgroup. Eligible participants (aged ≥ 18 years) with untreated locally advanced TNBC (stage T1c N1-2 or T2-4 N0-2) were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo plus chemotherapy every 3 weeks for 8 cycles followed by surgery and adjuvant pembrolizumab or placebo for ≤ 9 cycles. Primary endpoints were pathologic complete response (pCR; ypT0/Tis ypN0) at the time of surgery and event-free survival (EFS). Of 76 participants enrolled in Japan, 45 were randomized to the pembrolizumab arm and 31 to the placebo arm. Median time from randomization to data cutoff (March 22, 2024) was 76.3 months. Twenty-four participants (53%) in the pembrolizumab arm and 15 (48%) in the placebo arm achieved pCR (between-treatment arm difference, 4.9%; 95% CI, -17.6% to 27.1%); findings were similar regardless of PD-L1 expression. Rates of EFS at 60 months were 84% and 73%, respectively (HR, 0.54; 95% CI, 0.20-1.50). Grade 3 or 4 treatment-related AEs occurred in 37 of 45 participants (82%) treated with pembrolizumab and 23 of 30 participants (77%) treated with placebo; there were no grade 5 AEs. In conclusion, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab showed improved efficacy outcomes and manageable safety versus neoadjuvant chemotherapy alone in Japanese participants, supporting the use of this regimen in Japanese patients with high-risk early-stage TNBC. Trial Registration: The study (ClinicalTrials.gov, NCT03036488) was conducted in compliance with local and/or national regulations and International Council for Harmonization Good Clinical Practice guidelines and in accordance with the ethical principles originating from the Declaration of Helsinki.

Although immune checkpoint inhibitor therapies have revolutionized oncology, many cancers are unresponsive or develop resistance that involves transforming growth factor-β1 (TGFβ1). This multicenter, open-label, phase 1 study (DRAGON trial, SRK-181-001) evaluated safety, pharmacokinetics, pharmacodynamics, predictive biomarkers and efficacy of linavonkibart, a first-in-class fully human selective anti-latent TGFβ1 antibody with anti-programmed cell death protein 1 (PD-1) therapy. The DRAGON trial was divided into three treatment parts: part A1 (dose-escalation cohorts with single-agent linavonkibart), part A2 (dose-escalation cohorts with the combination treatment of linavonkibart and pembrolizumab) and part B (dose-expansion cohorts with the combination treatment). The primary objective of the study was to determine the safety and tolerability of linavonkibart alone and in combination with pembrolizumab. Secondary objectives included evaluation of linavonkibart pharmacokinetics for each treatment paradigm, assessment of anti-linavonkibart antibody development (parts A and B) and measurement of antitumor activity (part B) after treatment. All primary and secondary objectives were met in the study. Overall, linavonkibart had a manageable safety profile, and combined therapy with pembrolizumab was generally consistent with that of pembrolizumab monotherapy. Dermatological reactions were the only additional risk identified. Neither cytokine release syndrome nor infusion interruption was observed in any patient enrolled in DRAGON. In part A (n = 34), no dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred (linavonkibart; ≤3,000 mg once every 3 weeks (Q3W) and 2,000 mg once every 2 weeks (Q2W)). In part B (n = 78), patients progressing on prior anti-PD-1 therapy received linavonkibart (1,500 mg Q3W/1,000 mg Q2W) with pembrolizumab (200 mg Q3W). This combination demonstrated confirmed objective response rates of 20.0%, 18.2%, 9.1% and 9.1% in anti-PD-1-resistant patients with clear cell renal cell cancer (ccRCC), melanoma, head and neck squamous cell cancer and urothelial cancer, respectively. Biomarker data provide proof of mechanism and a potential ccRCC patient selection strategy. ClinicalTrials.gov identifier: NCT04291079 .

Chemoradiotherapy (CRT) combined with anti-PD-1 for locally advanced esophageal squamous cell carcinoma (ESCC) has shown promising efficacy but lack the predictive biomarkers to identify patients who could benefit from this therapy. The predictive value of serum cytokines in ESCC patients remains unclear. We aimed to identify cytokine-based biomarkers for treatment response and survival in this setting.

SCT510 is a proposed biosimilar of bevacizumab (Avastin®), a monoclonal antibody that targets vascular endothelial growth factor.

Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear.

Protein kinase B (AKT)-directed therapies offer promise for patients with cancers harboring germline and somatic phosphatase and tensin homolog (PTEN) mutations. TAS-117 is an oral, selective, non-adenosine triphosphate-competitive allosteric AKT inhibitor that showed encouraging antitumor activity in a phase I study. This phase II study aimed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAS-117 in patients with advanced/metastatic solid tumors, including those harboring germline PTEN-inactivating mutations (EudraCT: 2020-004770-22).

Standardized chemotherapy-induced nausea and vomiting (CINV) prevention in HEC is critical, yet NK1RAs remain inaccessible for some patients due to cost and availability. Our prior study demonstrated HXZQ + 5HT3RAs + dexamethasone's superior efficacy; this phase III trial aimed to validate this regimen.

To assess efficacy and safety in subgroups of patients treated with Melphalan/Hepatic Delivery System (melphalan/HDS), a drug/device combination for liver-directed treatment of metastatic UM (mUM) patients. Previously reported FOCUS study results indicated melphalan/HDS treatment provides a clinically meaningful response rate and favorable benefit-risk ratio in patients with unresectable mUM.

Immune checkpoint inhibitors (ICIs) are a leading immunotherapy. However, their application has not universally translated into significant benefits. A substantial number of patients either show resistance or relapse post-initial response, which emphasizes the need for more sophisticated therapeutic approaches. The drug combination is one promising route. The cancer-immunity cycle reveals the anti-tumor immune-related rate limiting steps of tumors. Theoretically, focusing on different phases of the cancer-immunity cycle can enhance therapeutic results. However, combination therapy includes a higher risk of adverse effects, which demand careful consideration.

Clinical development of crizotinib in children with ALK-positive anaplastic large cell lymphoma (ALCL) was advanced in the US but not in Japan. The objectives of phase 1 part of a clinical study in Japan were to assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of crizotinib in children with relapsed/refractory (R/R) ALK-positive ALCL or neuroblastoma (NB). Two dose levels (165 and 280 mg/m2 twice daily (BID)) were planned to be evaluated. The aim of phase 2 part of the study was to assess the antitumor activity of crizotinib at the RP2D in children with R/R ALK-positive ALCL. Seven patients were eligible for phase 1 part, 5 with ALCL and 2 with NB. All 7 patients received crizotinib at a starting dose of 165 mg/m2 BID, with 1 dose-limiting toxicity observed (grade 3 gamma-glutamyltransferase increased). The most common grade 3 or 4 adverse event was neutropenia (71%). The steady-state Cmax and AUCtau of crizotinib at 165 mg/m2 BID were higher than expected. Considering the risk of a greater incidence of severe neutropenia, we decided that the 165 mg/m2 BID be the RP2D without evaluation at 280 mg/m2 BID. A total of 11 patients with ALK-positive ALCL were enrolled in the phase 2 part. The objective response rate was 72.7% (90% CI, 43.6%-92.1%). One patient permanently discontinued crizotinib due to disease progression. Crizotinib at 165 mg/m2 BID was well tolerated and showed favorable antitumor activity in children with R/R ALK-positive ALCL. Trial Registration: UMIN-CTR: UMIN000028075.

It has been hypothesized that sequencing antigen-directed immunotherapy with immune checkpoint inhibitors could prime a tumor for immune response to immune checkpoint inhibitors.

Chemotherapy-induced side effects can diminish physical and psychological well-being for women with breast cancer. Although nutrition and exercise improve quality of life (QoL) posttreatment, their ability to attenuate treatment-related declines in QoL during chemotherapy remains underexplored.

Chemotherapy, with or without immunotherapy, is a standard of care for first-line treatment of locally advanced or metastatic oesophageal cancer. However, outcomes remain poor. We aimed to evaluate the activity and safety of tiragolumab, an anti-TIGIT monoclonal antibody, plus atezolizumab, an anti-PD-L1 monoclonal antibody, and chemotherapy in treatment-naive locally advanced unresectable or metastatic oesophageal cancer.

The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours.

Patients with platinum-resistant/refractory ovarian cancer (PROC) experience suboptimal outcomes, highlighting an immediate need for novel therapies. This phase 1b study investigated the safety and efficacy of botensilimab (BOT), a fragment crystallizable (Fc)-enhanced anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action from first-generation CTLA-4 inhibitors, plus balstilimab (BAL; anti-programmed cell death protein 1 antibody), in an expanded cohort of patients with treatment-refractory ovarian cancer.

In the randomized phase III CheckMate 77T study, perioperative nivolumab showed statistically significant and clinically meaningful improvement in event-free survival (EFS) vs. placebo in patients with resectable, non-metastatic non-small cell lung cancer (NSCLC). Here, we report efficacy and safety outcomes in the Japanese subpopulation. Adults with resectable stage IIA-IIIB NSCLC were randomized 1:1 to neoadjuvant nivolumab plus chemotherapy or chemotherapy plus placebo every 3 weeks for ≤ 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for ≤ 13 cycles. Assessments included EFS (primary endpoint), pathological complete response (pCR), major pathological response (MPR), and safety. A total of 68 Japanese patients were randomized to perioperative nivolumab (n = 40) or placebo (n = 28). At 24.9 months' median follow-up, median EFS was not reached (NR; 95% CI: 21.4-NR) with perioperative nivolumab vs. 12.1 (95% CI: 8.1-NR) months with placebo (hazard ratio, 0.46 [95% CI: 0.22-0.95]); 18-month EFS rates were 76.6% vs. 42.9%, respectively. The pCR rate (95% CI) was 42.5% (27.0%-59.1%) with perioperative nivolumab vs. 0% (0%-12.3%) with placebo (odds ratio [OR], not available); MPR rate (95% CI) was 52.5% (36.1%-68.5%) vs. 7.1% (0.9%-23.5%), respectively (OR, 14.37; 95% CI: 3.00-68.82). Grade 3-4 treatment-related and surgery-related adverse events with perioperative nivolumab vs. placebo occurred in 55.0% vs. 39.3% and 16.7% vs. 19.2% of patients. Consistent with the global population, perioperative nivolumab improved EFS, pCR, and MPR vs. placebo in the Japanese subpopulation, with no new safety signals reported, supporting its use in Japanese patients with resectable NSCLC. Trial Registration: ClinicalTrials.gov identifier, NCT04025879.

To assess the benefits of the traditional Chinese medicine (TCM) Qufenghuoxue formula, on the treatment of chemotherapy-induced peripheral neuropathy (CIPN) in patients with lung cancer receiving paclitaxel (PTX).

APX3330 is an oral agent targeting the redox signaling activity of APE1/Ref-1 (Ref-1), a key regulator of transcription factors involved in inflammation and tumorigenesis. APX3330 selectively inhibits Ref-1's redox function without affecting its DNA repair role. This Phase 1, multicenter, open-label, dose-escalation study in advanced solid tumors was aimed at determining the recommended Phase 2 dose (RP2D) while assessing safety, pharmacokinetics, and biomarker evidence of target engagement.

Programmed cell death protein-1 inhibitors have improved metastatic non-small cell lung cancer (NSCLC) prognosis. Stereotactic ablative body radiation therapy (SABR) may enhance immunity. This study evaluated the activity and safety of adding SABR to first-line immunotherapy post chemotherapy with nivolumab for metastatic NSCLC.