Signal Transduction and Targeted Therapy最新文献

The randomized phase 3 CHART trial (NCT03520478) revealed that rezvilutamide (REZ) plus androgen deprivation therapy (ADT) in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC) significantly enhanced radiographic progression-free and overall survival than bicalutamide (BIC)-ADT. Accordingly, we examined patient-reported outcomes (PROs) results, which were exploratory endpoints in the CHART trial. The patients were randomly allocated to receive REZ-ADT or BIC-ADT in a 1:1 ratio. The PROs were evaluated with the Brief Pain Inventory-Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaires. Both study groups displayed comparable baseline pain scores and functional status. Patients administered REZ-ADT had an extended time to progression of worst pain intensity in comparison to those treated with BIC-ADT (25th percentile, 9.2 [95% CI 7.4–16.6] vs. 6.4 months [95% CI 5.5–8.3]; HR 0.75 [95% CI 0.57–0.97]; p = 0.026). Similarly, patients received REZ-ADT exhibited a delayed time to progression of pain interference in comparison to those receiving BIC-ADT (25th percentile, 20.2 [95% CI 12.9–31.3] vs. 10.2 months [95% CI 7.4–11.1]; HR 0.70 [95% CI 0.52–0.93]; p = 0.015). Additionally, the REZ-ADT group demonstrated a prolonged delay in the deterioration of the total score on the FACT-P questionnaire (25th percentile, 12.8 [95% CI 7.4–20.3] vs. 6.0 months [95% CI 4.6–9.2]; HR 0.66 [95% CI 0.50–0.86]; p = 0.002), as well as most of the FACT-P subscale scores, in comparison to the BIC-ADT group. In conclusion, REZ-ADT is superior to BIC-ADT regarding the pain alleviation and enhancement of functional scales for high-volume mHSPC.

In a recent study published in Science, Liu and colleagues used computational ultra-large library docking to discover new chemotypes acting as positive allosteric modulators (PAM) of the Calcium-Sensing Receptor (CaSR),¹ which bind the receptor with very high affinity and shows evidence of biased signaling, i.e. the preferential activation of one signaling pathway over others, compared to the receptor’s natural ligands. Importantly, the in vivo test of one substance (‘54159) did not induce hypocalcemia, which is an advantage over FDA-approved calcimimetics, which are limited in clinical practice due to their potential to disrupt calcium homeostasis and cause hypocalcemia.

This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β, in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment for unresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologically confirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients received SHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m²) intravenously on day 1, along with oral capecitabine (1 g/m² twice daily) on days 1–14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenance therapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival (PFS) was 10.3 months (95% CI: 8.3–13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated 12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% of patients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that high tumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactate dehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safety profile and potent antitumor activity in unresectable mCRC.

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). In spite of durable responses in some patients, many patients develop early disease progression during the ICI treatment. Thus, early identification of patients with no durable benefit would facilitate the clinical decision for these patients. In this prospective, multicenter study, 101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients. At the date of cutoff, 83 patients were eligible for ICI efficacy evaluation, with 56 patients having progress-free survival (PFS) over 6 months, which was defined as durable clinical benefit (DCB). A multimodal model was established by integrating normalized bTMB, early dynamic of ctDNA and the first RECIST response. This model could robustly predict DCB with area under the curve (AUC) of 0.878, sensitivity of 79.2% at 86.4% specificity (accuracy = 80.0%). This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887, sensitivity of 94.7% at 85.3% specificity (accuracy = 90.3%). Patients with higher predict scores had substantially longer PFS than those with lower scores (training cohort: median PFS 13.6 vs 4.2 months, P < 0.001, HR = 0.24; validation cohort: median PFS 11.0 vs 2.2 months, P < 0.001, HR = 0.17). Taken together, these results demonstrate that integrating early changes of ctDNA, normalized bTMB, and the first RECIST response can provide accurate, noninvasive, and early prediction of durable benefits for NSCLC patients treated with ICIs. Further prospective studies are warranted to validate these findings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.

In an article published in Cell in September 2024, Baldwin and colleagues present a bone marrow stromal cell (BMSC) based mitochondrial transfer platform to combat mitochondrial dysfunction or scarcity in human T cells ex-vivo.¹ This thorough and methodically diverse investigation results in a promising technology at a time when adoptive T cell therapies seem to run against a wall of T cell exhaustion and dysfunction in treatments targeting solid tumors.²

Correction to: Signal Transduction and Targeted Therapy (2024) 9:327; https://doi.org/10.1038/s41392-024-02058-x; Article published online 20 November 2024

Advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) have poor prognoses and limited treatment options. Here, we conducted this first-in-class phase II study to evaluate the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment (trial registration: ChiCTR2000037927). Among 51 enrolled patients, the BTC cohort showed an objective response rate (ORR) of 28% (including 2 complete responses) and a disease control rate (DCR) of 80%, with a median progression-free survival (mPFS) of 5.1 months and a median overall survival (mOS) of 16.0 months. In the PDAC cohort, the ORR was 15% (2 complete responses), with a DCR of 60%, and the mPFS and mOS were 2.1 months and 5.3 months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 29.4% of patients, with no grade 5 TRAEs reported. Exploratory analyses revealed that primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits. An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously.

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Correction to: Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-024-01914-0, published online 08 August 2024

Previous studies showed encouraging efficacy of alternating FOLFOX/FOLFIRI for metastatic colorectal cancer (mCRC). This phase 2 trial (NCT04324476) aimed to evaluate efficacy and safety of alternating modified CAPOX (capecitabine and oxaliplatin)/modified CAPIRI (capecitabine and irinotecan) plus bevacizumab (anti-VEGF-A antibody) in untreated unresectable mCRC. Induction treatment included capecitabine 1000 mg/m² bid D2–8 and D16–22, oxaliplatin 85 mg/m² D1, irinotecan 150 mg/m² D15, and bevacizumab 5 mg/kg D1 and 15 for 28-day cycles (up to six cycles). Capecitabine 1000 mg/m² bid D2–15 and bevacizumab 7.5 mg/kg D1 for 21-day cycles were used as maintenance treatment. 52 patients were included. Median follow-up was 25.0 months. Median progression-free survival (PFS; the primary endpoint) was 11.0 months (95% CI 9.0–12.4). Subgroup analyses showed patients with neutrophil-to-lymphocyte ratio<5 or RAS wild-type disease had longer PFS (both P < 0.05). Objective response and disease control were obtained in 38 (73%; 95% CI 59%–84%) and 49 (94%; 95% CI 84%–99%), respectively. Mean depth of response, conversion and no evidence of disease rates were 46.0% ± 26.3%, 23% and 19%, respectively. Median overall survival was 28.1 months (18.4–34.0). Grade 3–4 treatment-related adverse events (TRAE) occurred in 17 (33%) patients. No treatment-related death was reported. The most common grade 3–4 TRAE were hypertension (13 [25%]), neutrophil count decreased (three [6%]), and hand-foot syndrome (two [4%]). In addition, grade 3–4 TRAE of diarrhea reported in one [2%] patient and no grade 3–4 peripheral neuropathy occurred. Thus, alternating modified CAPOX/CAPIRI plus bevacizumab had promising efficacy and acceptable safety. The regimen may be a novel option for untreated unresectable mCRC.