Rectal cancer treatment in Nordic countries has traditionally differed, especially regarding neoadjuvant treatment. The aim of this review is to give an overview of the current rectal cancer guidelines in the Nordics and compare these to international guidelines. Oncologists and colorectal surgeons from the Nordic countries (Denmark, Finland, Norway, and Sweden) and the Netherlands were invited to participate in this narrative review. Two consensus meetings were held to agree on the content. All authors provided recommendations from their national guidelines. In addition, recommendations from the European Society of Medical Oncology (ESMO) and from the US National Comprehensive Cancer Network (NCCN) guidelines were extracted. Several differences between the included guidelines were identified. The radiological "sigmoid take-off" definition for the upper margin of the rectum has been adapted in Denmark and the Netherlands, whereas the other guidelines rely on distance from the anal verge on rigid sigmoidoscopy. Indications for direct surgery vary considerably, where the NCCN guidelines recommend more aggressive neoadjuvant treatment, primarily total neoadjuvant therapy (TNT), the Nordic and European guidelines open for direct surgery more often, and reserve especially TNT for high-risk cases. European countries more often recommend short-course radiotherapy, whereas NCCN maintains chemoradiotherapy as the mainstay. Whereas intentional and opportunistic organ preservation is an established part of the Dutch, NCCN, and ESMO guidelines, its use is mostly restricted to clinical trials in the Nordics. The Nordics and the Netherlands are restrictive in terms of adjuvant treatment, which is frequently recommended in ESMO and NCCN. Whereas neoadjuvant immunotherapy is recommended for mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) rectal cancer in NCCN, this use is off-label in Europe and not routinely recommended. Although all guidelines rely on the same evidence, there are considerable differences, especially in the indications and type of oncologic treatment, both in the neoadjuvant and in the adjuvant setting.
MORPHEUS-UC (NCT03869190) is a signal-seeking, global, phase Ib/II, open-label, multicenter, randomized, umbrella study in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). Patients were randomly assigned to one of seven atezolizumab (anti-programmed death-ligand 1)-based treatment combinations or atezolizumab monotherapy. We report efficacy and safety results for atezolizumab + sacituzumab govitecan (trophoblast cell surface antigen-2-directed antibody conjugate) versus atezolizumab alone. Eligible patients were checkpoint inhibitor-naïve and experienced disease progression or recurrence during or after ≤1 platinum-containing regimen. Primary endpoints were investigator-assessed objective response rate (ORR) and safety. Secondary efficacy endpoints included investigator-assessed progression-free survival (PFS), duration of response, disease control rate, and overall survival (OS). Fifteen patients received atezolizumab + sacituzumab govitecan; 30 received atezolizumab alone. The best confirmed ORR was 6.7% with atezolizumab + sacituzumab govitecan and 27.6% with atezolizumab. No improvement in ORR, PFS, or OS was seen with the addition of sacituzumab govitecan to atezolizumab. Most frequent treatment-related adverse events (TRAEs) were anemia, neutropenia, pruritus, nausea, and alopecia with atezolizumab + sacituzumab govitecan, and pruritus, decreased appetite, rash, and fatigue with atezolizumab. No grade 5 TRAEs occurred. The atezolizumab + sacituzumab govitecan efficacy and safety results suggest limited rationale for further development of this combination in platinum-experienced patients with locally advanced or mUC.
Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after anthracycline-based chemotherapy versus 78% after intensified alkylating chemotherapy with autologous stem cell rescue (IACT) in a post-hoc analysis of an earlier randomised controlled trial. In this study, we aimed to prospectively assess 4-year overall survival with IACT and establish whether this approach remains superior to a contemporary HRD-targeting regimen in patients with HER2-negative breast cancer with HRD. This open-label, randomised, controlled, phase 3 trial included patients from eight hospitals and one cancer centre in the Netherlands and one cancer centre in France. Newly diagnosed patients aged between 18-66 years with stage IIIA-C, HER2-negative, HRD breast cancer without distant metastases who had a pathogenic germline BRCA1/2 mutation or evidence of a HRD tumour on testing were randomly assigned (1:1) to receive IACT or conventional chemotherapy using interactive response technology. IACT comprised dose-dense alkylating chemotherapy (ddAC; four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks intravenously), supported by 6 mg prophylactic pegfilgrastim subcutaneously every 2 weeks. 2 weeks after stem cell mobilisation, patients received two IACT cycles 3 weeks apart (3000 mg/m2 cyclophosphamide on day 1, 250 mg/m2 thiotepa on day 2, and 400 mg/m2 carboplatin intravenously on days 1 and 2), followed by autologous stem cell transplantation. Conventional chemotherapy comprised four ddAC cycles, followed by four cycles of intravenous carboplatin area under the curve 6 every 3 weeks, and 80 mg/m2 paclitaxel every week for 12 weeks (carboplatin-paclitaxel intravenously), followed by 1 year of oral olaparib (300 mg twice daily). All patients proceeded to surgery and radiotherapy according to local practice. Stratification factors were treatment centre, age, stage, and oestrogen receptor status. The primary endpoint was overall survival in the intention-to-treat population (all randomly allocated patients). The trial was registered at ClinicalTrials.gov, NCT02810743, and is ongoing, but is closed for inclusion. From Jan 25, 2017, through to Oct 5, 2023, 356 patients were screened for eligibility, and 174 patients were randomly assigned to receive IACT (n=87) or olaparib (n=87). All patients were female, and median age was 42 years (IQR 37-50). We did not ask explicit informed consent for collecting data on ethnicity of patients, because we focused on a very rare patient subgroup and therefore used pragmatic eligibility criteria following standard General Data Protection Regulation. 28 (32%) in the IACT group and 22 (25%) patients in the olaparib group had germline BRCA1/2 mutations. With a median follow-up of 41 months (IQR 27-59), the 4-year overall survival was 77·0% (95% CI 67·7-87·7 in the IACT group and 76·4% (66·9-87·4) in the olaparib group (hazard ratio for death 1·11 [95% CI 0·57-2·17]; p=0·37).The most common grade 3-4 adverse events were platelet count decreased (80 [99%] in the IACT group vs 18 [19%] in the olaparib group), neutrophil count decreased (77 [95%] in the IACT group vs 56 [61%] in the olaparib group), and anaemia (50 [62%] in the IACT group vs 37 [41%] in the olaparib group). Treatment-emergent serious adverse events occurred in 38 (47%) of 81 patients in the IACT group versus 24 (26%) of 91 patients in the olaparib group. Febrile neutropenia was the most common serious adverse event in both groups (36 [44%] in the IACT group; 11 [12%] in the olaparib group). No treatment-related deaths were reported. These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib. Dutch Cancer Society, the Dutch Ministry of Health, the Netherlands Organization for Health Research and Development, A Sister's Hope, [Z]aan de Wandel, AstraZeneca, MSD, and Eurocept Pharmaceuticals.
Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([177Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs. This phase 3, open-label, superiority trial included patients aged 18 years or older with treatment-naive or previously treated unresectable or metastatic (or both) grade 1-2 GEP NETs. Patients were enrolled from 49 specialist neuroendocrine tumour treatment centres across 14 countries in Africa, Europe, North America, and Oceania and randomised (2:1) to intravenous [177Lu]Lu-edotreotide (7·5 ± 0·7 GBq every 3 months, maximum four cycles) or oral everolimus (10 mg/day) for up to 30 months. Random assignment was via a central, web-based randomisation system (block size of 6) and stratified by primary tumour origin and previous therapy. The primary endpoint was progression-free survival, assessed via blinded independent central review in all randomly assigned patients at 30 months. Harms were assessed in all enrolled patients who received at least one dose of a study drug. This study was registered with ClinicalTrials.gov (NCT03049189) and is no longer recruiting. Between April 13, 2017, and June 20, 2022, 324 patients were enrolled and 309 patients (including 168 [54%] male patients and 141 [46%] female patients) were randomly assigned to treatment: 207 to the [177Lu]Lu-edotreotide group and 102 to the everolimus group. The median follow-up for progression-free survival was 27·5 months (IQR 19·6-30·4) for the [177Lu]Lu-edotreotide group and 21·2 months (8·9-29·4) for the everolimus group. Median progression-free survival was significantly longer with [177Lu]Lu-edotreotide versus everolimus (23·9 months [95% CI 18·7-30·0] vs 14·1 months [9·2-20·9]; stratified hazard ratio 0·67 [95% CI 0·48-0·95]; p=0·022). Treatment-related adverse events occurred in 178 (82%) of 217 patients in the [177Lu]Lu-edotreotide group and 96 (97%) of 99 patients in the everolimus group. 40 (18%) patients in the [177Lu]Lu-edotreotide group and 40 (40%) in the everolimus group had at least one treatment-related grade 3-4 adverse event. The most common treatment-related adverse events in the [177Lu]Lu-edotreotide group were diarrhoea and nausea (both 79 [36%] patients) and asthenia (66 [33%] patients), whereas those in the everolimus group were diarrhoea (45 [45%] patients), asthenia (36 [36%] patients), and anaemia (27 [27%] patients). No treatment-related deaths occurred in either study group. [177Lu]Lu-edotreotide led to statistically significant and clinically meaningful improvements in progression-free survival. Efficacy and harms results support the use of [177Lu]Lu-edotreotide in early lines of therapy in patients with advanced, progressive GEP NETs. ITM Solucin.
The ABC-06 trial established FOLFOX as the reference second-line regimen for patients diagnosed with advanced biliary tract cancer (ABC). Here we analysed the prognostic role of tumour markers carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA125) and the impact of FOLFOX on quality of life (QoL). Patients diagnosed with ABC were randomly assigned (1:1) to second-line active symptom control (ASC) + modified FOLFOX or ASC alone. Tumour markers (CA19-9, CEA, and CA125) were measured and QoL (EORTC QLQ-C30, QLQ-BIL21) and value of health (EuroQol EQ-5D) questionnaires were completed at baseline and during follow-up. The prognostic value of baseline tumour markers, CA19-9 dynamics (week 4 change), time to deterioration of QoL (TTD; ≥10-point decline in global health status), and QoL changes over time (month 4 status) were assessed. Paired baseline and week 4 CA19-9 data were available for 37 patients in the ASC + FOLFOX arm. Stable/decreasing CA19-9 was associated with a numerically longer median radiological progression-free survival (PFS) and overall survival (OS; P values >0.05). Baseline CA19-9 data were available for 135 of 162 patients: 92 (68.1%) high, 43 (31.9%) low. High baseline CA19-9 was associated with shorter unadjusted OS [4.4 versus 6.4 months; hazard ratio (HR) 1.97, 95% confidence interval (CI) 1.33-2.93, P < 0.001] and unadjusted PFS (3.2 versus 5.0 months; HR 1.53, 95% CI 1.05-2.23, P = 0.027) in the FOLFOX arm. In 120 patients with baseline data for all markers available (CA19-9, CEA, and CA125), each marker independently predicted OS in the multivariable analysis: adjusted HR (aHR) 1.56 (95% CI 1.03-2.35, P = 0.003), aHR 1.60 (95% CI 1.06-2.43, P = 0.026), and aHR 1.70 (95% CI 1.13-2.56, P = 0.011) for CA19-9, CEA, and CA125, respectively. In addition, median OS decreased from 8.9 months (no markers elevated) to 3.2 months (all three elevated). QoL analysis (n = 76) showed no significant difference in TTD between arms (aHR 0.97, 95% CI 0.48-1.97, P = 0.94). FOLFOX did not worsen global, physical, social, or symptom QoL scores, whereas patients receiving ASC recorded declines across several domains. In the setting of second-line FOLFOX for ABC, elevated tumour markers impacted on prognosis and could be utilised as stratification factors in future clinical trials. The addition of FOLFOX did not imply QoL deterioration, and did, in fact, preserve some of the status in several domains.
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer characterized by features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). As cHCC-CCA prognosis often falls between HCC and CCA or resembles CCA, we compared the outcomes of durvalumab plus gemcitabine-cisplatin (GCD) in patients with cHCC-CCA and CCA in a real-world setting. This retrospective multicenter study included patients with histologically confirmed unresectable or metastatic CCA or cHCC-CCA who underwent first-line GCD at four centers in Taiwan between 2021 and 2025. Outcomes included overall survival (OS), progression-free survival (PFS), tumor response, and safety. Propensity score matching (PSM) was performed to balance baseline characteristics. Among the 175 patients, 154 had CCA and 21 had cHCC-CCA. Before matching, patients with cHCC-CCA more frequently had elevated α-fetoprotein levels and poor biliary drainage; however, these imbalances were resolved after PSM. Before PSM, patients with CCA and cHCC-CCA had median OS of 13.3 months [95% confidence interval (CI) 9.5-17.1] and 13.8 months (95% CI 2.1-25.6, P = 0.60) and median PFS of 5.1 months (95% CI 4.7-5.5) and 5.3 months (95% CI 3.1-7.5, P = 0.40), respectively. After PSM, both OS and PFS rates were similar between the groups. The objective response rate was higher in the cHCC-CCA group (38.1% versus 23.4% before PSM, P = 0.15; 38.1% versus 23.8% after PSM, P = 0.24), whereas the disease control rates were identical (66.7% after PSM). The most common toxicities were hematologic events, with both groups demonstrating similar rates of anemia, thrombocytopenia, leukopenia, and neutropenia. This study demonstrates that patients with cHCC-CCA derive comparable clinical benefit from GCD as those with CCA in terms of efficacy and safety. These findings support the incorporation of immunochemotherapy into the treatment framework for cHCC-CCA and provide a rationale for its use in clinical practice.
∼60%-70% of patients with metastatic non-small cell lung cancer (NSCLC) have relatively low tumor mutational burden (TMB), with limited biomarker-guided immunotherapy options beyond programmed death-ligand 1 (PD-L1) expression. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) mutational signatures, defined by characteristic genomic footprints, are associated with higher TMB and a better response to immune checkpoint inhibitors (ICIs). However, whether APOBEC independently predicts ICI response in TMB-low tumors has not been established. We analyzed 857 ICI-treated and 1328 ICI-untreated TMB-low (<10 mut/Mb) patients with metastatic NSCLC from the MSK-CHORD cohort. APOBEC status was classified using MESiCA, a machine-learning algorithm for mutational signature detection from targeted gene panels. Predictive value was established through treatment interaction testing, multivariate adjustment, propensity score weighting, and landmark analyses. External validation included 82 TMB-low patients from published whole-exome sequencing studies. APOBEC-positive patients (n = 52, 6.1%) had significantly improved overall survival [median 33.7 versus 17.4 months; hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.42-0.85, P = 0.004]. No such benefit was observed in ICI-untreated patients (HR 0.98, P = 0.85), with significant treatment interaction (P = 0.032), confirming a predictive rather than prognostic effect. APOBEC remained independently predictive after adjustment for PD-L1 status and age (adjusted HR 0.57, P = 0.002). The benefit was particularly pronounced in PD-L1-negative ICI-treated patients (HR 0.51, P = 0.002). The effect was robust across propensity score, landmark, and bootstrap analyses. External validation confirmed independent APOBEC benefit (adjusted HR 0.23, P = 0.020). APOBEC mutational signatures represent a robust predictive biomarker for ICI response in TMB-low metastatic NSCLC, identifying responders particularly among PD-L1-negative patients where biomarker guidance is most needed, detectable from targeted gene panels used in routine clinical practice.
The Trop-2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown significant benefit in metastatic triple-negative breast cancer (mTNBC) in clinical trials. However, evidence about its effectiveness and safety in real-world heterogeneous patient populations is limited. This multicenter study, including the largest European and second-largest worldwide real-world cohort of SG-treated patients with mTNBC, offers valuable insights for its use in routine clinical practice. This analysis included 256 women with mTNBC treated with SG across 17 Italian oncology centers, consisting of 217 retrospectively identified patients and 39 prospectively enrolled patients. Treatment activity and safety were assessed according to RECIST v1.1 and Common Terminology Criteria for Adverse Events del National Cancer Institute (NCI-CTCAE) v5.0 criteria. Median patient age was 54 years (range 26-80), and 70.7% had TNBC at initial diagnosis. The median interval from metastatic diagnosis to SG initiation was 16 months (range 0-115), with a median of two prior treatment lines (range 0-7). Frequent metastatic sites were lymph nodes (60.9%), bone (43.0%), lung (42.6%), liver (33.2%), and brain (26.2%). Overall, 37.5% achieved complete or partial response, 27.7% had stable disease, and 31.2% experienced progression. At a median follow-up of 17.4 months, 202 patients had progressed, and 139 had died. Median real-world progression-free survival was 6.4 months [95% confidence interval (CI) 5.3-7.3] and median real-world overall survival was 13.6 months (95% CI 11.5-15.5). The most common treatment-related adverse events were alopecia (69.1%), neutropenia (57.0%), nausea (49.6%), anemia (46.9%), and diarrhea (36.7%). Grade 3-4 neutropenia occurred in 18.0% and 5.9%, respectively. Dose reductions were required in 36.5%, and 2.7% discontinued treatment. SG demonstrated durable clinical benefit and manageable toxicity in patients with mTNBC, highlighting the importance of optimized adverse-event management. The size and heterogeneity of the study population, including the largest reported cohort of patients with central nervous system metastases, support the robustness of these findings.
Artificial intelligence (AI) is increasingly integrated into oncological imaging, but its ability to predict detailed histopathological features from standard mammography remains understudied in ductal carcinoma in situ (DCIS). This study aimed to evaluate the performance of a large language model (ChatGPT-4, Open AI, May 2025) in predicting nuclear grade, architectural subtype, comedo necrosis, and stromal invasion from specimen mammography. Materials and Methods: We conducted a retrospective and methodological study of 29 patients with histologically confirmed DCIS or invasive carcinoma with DCIS components. Our clinical protocol is based on NCCN/ESMO guidelines of treatment ductal carcinoma in situ. Preoperatively, all patients with confirmed disease benefited from wire guide localization of the breast lesion. Patients were then submitted to surgical excision (lumpectomy) and surgical specimen mammography to confirm the complete macroscopic excision. For each of these cases, mammographic specimens were analyzed using an AI model designed to extract and process radiomic features. AI-model reports were compared with histopathological reports which served as the gold standard. Diagnostic performance was evaluated for four parameters: DCIS nuclear grade, architectural subtype, comedo necrosis, and stromal invasion. Accuracy, sensitivity, specificity, precision, and F1 scores were computed. Results: The size of mammographic lesions ranged from 1.2 to 10.0 mm (mean Ã+- SD: 4.46 Ã+- 2.25 mm). Histopathological diagnoses included pure DCIS (n = 17), invasive NST carcinoma with DCIS (n = 10), and mixed histologies (n = 2). The AI model achieved 65.5% accuracy for detecting comedo necrosis (sensitivity 75.0%, specificity 53.8%) and 72.4% accuracy for detecting stromal invasion (specificity 94.1%, sensitivity 41.7%). Nuclear grade classification matched histopathology in 20.7% of cases, while architectural subtype classification achieved 17.2% agreement. Multiclass predictions showed low F1 scores for most categories. Although the AI model demonstrated acceptable utility for detection of comedo necrosis and excluding stromal invasion, it faced several difficulties regarding nuclear grading and architectural subtype classification. Although limited by the small sample size and 2D imaging, this methodological study provides an insight for future AI and radiomics approaches in breast tumor characterization.
ORCHARD (NCT03944772) was an open-label, phase 2 platform study that evaluated resistance mechanisms and post-progression treatments in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) with progressive disease (PD) on first-line osimertinib. We report final data from the module investigating durvalumab plus etoposide-platinum in patients with neuroendocrine transformation to small cell lung cancer or large cell neuroendocrine carcinoma. Patients received durvalumab 1,500 mg intravenously every three weeks (Q3W) plus etoposide-platinum Q3W for up to four cycles. Durvalumab continued until PD, unacceptable toxicity or another discontinuation criterion was met. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Fourteen patients received treatment and were evaluable for efficacy/safety (data cutoff: January 21, 2025). Confirmed ORR was 43 % (80 % confidence interval [CI]: 24-63) (six partial responses). Median duration of response was 4.3 months (95 % CI: 3.0-not calculable); one patient had a response lasting 10 months. Progression-free survival (PFS) events were observed in 13 patients (93 %) and 11 patients (79 %) died. Median PFS was 4.2 months (95 % CI: 3.0-5.6) and median overall survival was 10.2 months (95 % CI: 4.3-16.8). Nine patients (64 %) reported grade ≥3 adverse events (AEs), most commonly neutropenia and decreased neutrophil count (four patients each), and one patient discontinued all three study drugs due to an AE (not treatment-related). Durvalumab plus etoposide-platinum demonstrated a modest treatment response in neuroendocrine-transformed EGFR-mutated NSCLC. AEs were concordant with the known safety profiles of the combination, and no new safety signals were observed. ClinicalTrials.gov, NCT03944772.
Hypoxic microenvironments throughout tumors contribute to proliferation and resistance to chemoradiotherapy. Copper-64 diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) is a first-in-class drug enabling hypoxia-targeting radioligand therapy with β- particles and high-linear energy transfer Auger electrons, originally employed for positron emission tomography imaging. We report the first-in-human study of 64Cu-ATSM therapy in patients with recurrent brain tumors. This phase I dose-escalation trial (STAR-64, jRCT2091220362) evaluated intravenous 64Cu-ATSM administered four times at 30, 60, 99, or 150 MBq/kg weekly in patients with recurrent malignant brain tumors, using the 3 + 3 design. Primary objectives were to assess dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD). Secondary objectives included efficacy, pharmacokinetics, and organ dosimetry. Eighteen patients received 64Cu-ATSM: grade 3 glioma (anaplastic astrocytoma and anaplastic oligodendroglioma) 27.8%, grade 4 glioma (glioblastoma) 50%, malignant meningioma 11.1%, and metastatic brain tumors 11.1%. DLTs, consisting only of grade 3 lymphopenia, were observed in four patients: one at 60 MBq/kg, one at 99 MBq/kg, and two at 150 MBq/kg. The MTD was established as 99 MBq/kg. Two patients had a radiographic complete response by RECIST v1.1 with long-term survival: ≥45 months for a patient with anaplastic oligodendroglioma (60 MBq/kg) and ≥23 months for a patient with glioblastoma (99 MBq/kg). The 1-year and median overall survival (OS) were 76.6% and 29.4 months, respectively, in all 18 patients; 12 patients (66.7%) were long-term survivors of ≥12 months. Among nine patients with glioblastoma, the 1-year and median OS were 64.8% and 17.7 months, respectively, suggesting favorable preliminary outcomes compared with historical references. Pharmacokinetic and dosimetry analyses revealed a clinically favorable distribution and organ radiation doses of 64Cu-ATSM, supporting the selected dosing regimen and schedule. 64Cu-ATSM therapy was well tolerated and demonstrated preliminary efficacy in patients with recurrent malignant brain tumors, particularly glioblastoma, supporting further evaluation in an ongoing phase III study (STEP-64, jRCT2031240090).
JCOG1212 is a multi-institutional prospective single-arm trial evaluating the efficacy and safety of superselective intra-arterial cisplatin infusion with concomitant radiotherapy (RADPLAT) for locally advanced maxillary sinus squamous-cell carcinoma (MS-SCC). We previously reported the results for the T4aN0M0 cohort (n = 64), in which RADPLAT was shown to be feasible and to provide favorable survival outcomes. This report presents the results for the T4bN0M0 cohort. Patients with previously untreated T4bN0M0 MS-SCC received weekly intra-arterial cisplatin (100 mg/m2) for seven cycles in combination with radiotherapy (70 Gy in 35 fractions). The primary endpoint was 3-year overall survival (OS), with a predefined efficacy threshold of 35% and a one-sided alpha of 5%. Secondary endpoints included event-free survival (EFS), local EFS (LEFS), clinical response, and toxicity. Sixty-four patients were enrolled from 20 institutions. The 3-year OS was 68.8% [90% confidence interval (CI) 58.1% to 77.2%], exceeding the efficacy threshold. The clinical complete response rate was 54.7%. The 3-year EFS and LEFS was 51.6% (95% CI 38.8% to 63.0%) and 57.8% (95% CI 44.8% to 68.8%), respectively. With regard to acute adverse events, neutropenia ≥ grade 3 (18.0%), mucositis ≥ grade 3 (23.0%), hearing impairment ≥ grade 2 (3.3%), and stroke ≥ grade 2 (1.6%) were observed. No grade 2 ≥ creatinine increase was observed. There were no treatment-related deaths. RADPLAT achieved favorable survival outcomes with acceptable toxicity in patients with T4bN0M0 MS-SCC. These results establish RADPLAT as a feasible and effective organ-preserving treatment and demonstrate the potential of intra-arterial chemoradiotherapy for unresectable MS-SCC.
The current standard of care for resectable locally advanced colon cancer (LACC) is based on upfront surgery followed by adjuvant chemotherapy (AC). This study aimed to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) in this setting. ELECLA is a multicenter, randomized, open-label, phase II controlled trial conducted across 12 hospitals in Spain between March 2017 and June 2024. This report presents the results of a preplanned interim analysis conducted after early termination of recruitment following the loss of clinical equipoise. Patients with radiologically defined LACC (T3 > 5 mm/T4, any N, and M0) and proficient mismatch repair status, were randomly assigned at a 1:1 ratio to receive either NAC (three cycles of CAPOX or five of FOLFOX), surgery, and AC (investigational group) or upfront surgery followed by AC (control group). The primary endpoint was 2-year disease-free survival. A total of 120 patients were included. The NAC completion rate was 94.2%, with a nonsignificant trend toward a reduced surgical complication rate compared with controls (17.3% versus 22.1%; P = 0.52). In the investigational group, a favorable radiologic tumor downstaging was achieved, with a tumor volume reduction of 65.4% (P < 0.001), and a tumor regression grading of 0-2 in 51.2% of assessable patients. An R0 resection was achieved in all patients within the NAC group. A relevant reduction in classical histological adverse prognostic features, including lymphatic invasion (21.5% versus 44.1%; P = 0.009), tumor budding (23.3% versus 58.5%; P = 0.002), and incomplete resections (0% versus 7.4%; P = 0.068) was observed in the NAC group. The 2-year disease-free survival rate was 88.9% [95% confidence interval (CI) 75.2% to 95.2%] in the intervention group and 83.3% (95% CI 70.9% to 90.7%) in the control group (P = 0.34). NAC is safe, feasible, and associated with improved tumor downstaging and favorable pathologic features without increased perioperative morbidity. These findings support the use of NAC as a safe and efficient therapeutic option in patients with LACC.
PADMA is a prospective, randomized, open-label, multicenter phase IV study comparing palbociclib and endocrine therapy (ET) with mono-chemotherapy (CT) +/- maintenance ET (at the discretion of the treating physician) as first-line therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (mBC). Patients were randomly assigned 1:1 to receive first-line treatment with palbociclib + ET or investigator-selected CT (capecitabine, epirubicin, paclitaxel, or vinorelbine) +/- maintenance ET. The primary endpoint was time-to-treatment failure (TTF). Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and treatment adherence. One hundred twenty patients, of whom 106 (88.3%) were postmenopausal, were randomly assigned and started treatment (palbociclib + ET, n = 61; CT, n = 59). Most patients in the CT group received capecitabine (n = 40, 67.8%) or paclitaxel (n = 17, 28.8%). In 13 patients (22%), CT was followed by maintenance ET. At a median follow-up of 36.8 months, the median TTF was 17.2 months with palbociclib + ET versus 6.1 months with CT [hazard ratio 0.46, 95% confidence interval (CI) 0.31-0.69, P < 0.001]. The TTF benefit in subgroups, including AKT signaling alterations or g/tBRCA1/2 mutations, was consistent with that in the overall population. Median PFS was 18.7 months with palbociclib + ET versus 7.8 months with CT (hazard ratio 0.45, 95% CI 0.29-0.70, P < 0.001). OS did not differ significantly between the study arms (P = 0.494). Hematologic toxicity was significantly higher in the palbociclib + ET arm than in the CT-based arm (96.8% versus 70.7%; P < 0.001), although nonhematological toxicity was comparable in both arms. PADMA is the first randomized multicenter study to show that palbociclib + ET as first-line treatment compared with CT also leads to improvements in TTF and PFS in predominantly postmenopausal patients with HR-positive/HER2-negative mBC.
Neoadjuvant radiotherapy (NRTX) is recommended for soft tissue sarcomas (STS) by current European Society of Medical Oncology (ESMO) guidelines. Histological response to preoperative treatment (including NRTX) is a well-established prognostic parameter in patients with osteosarcoma and Ewing sarcoma. In patients with STS, however, the relevance of histological - and radiological - necrosis rate following neoadjuvant treatment is less well known. We conducted a systematic PubMed search and obtained 2,433 potentially relevant entries, of which 30 original articles were finally included. Histological and radiological tumour necrosis following NRTX of STS was systematically studied, as was the potential association between the histological necrosis rate and oncological outcome (local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS)) using random-effects meta-analysis. Information on 2,346 patients (1,257 males; 53.6%) of whom 2,228 (95.0%) had received NRTX was summarised. Most STS were located in the extremities (n = 2016; 85.9%). A histological necrosis rate of ≥90% was present in 22.8%. On imaging, the mean necrosis rate ranged between 14.7 and 67.7%. There was a significant association between higher histological necrosis rate and improved DMFS (HR = 0.29; 95% CI: 0.12-0.71; P = 0.018), while no associations for LRFS (HR = 0.54; 95% CI: 0.06-5.17; P = 0.181) or OS (HR = 0.60; 95% CI: 0.10-3.64; P = 0.437) were found. Tumour necrosis is frequently observed following NRTX in STS. Higher histological necrosis seems to be associated with improved DMFS. Overall, varying reporting of the histological and radiological necrosis rate following NRTX in STS calls for improved estimation of treatment response, considering histological and radiological features alike.
Heterodimeric IL-15 (NIZ985) shows rapid and indirect effects on different myeloid cells but may upregulate PD-1 (programmed cell death-protein 1) on CD8 + T cells, limiting its therapeutic potential. Combining IL-15 with an anti-PD-1 antibody is known to enhance antitumor immune response and prolong survival in mice. This was a phase I/Ib, open-label, multicenter study (NCT04261439) of NIZ985 single agent (SA) or with an anti-PD-1/CPI agent in patients with advanced solid tumors or lymphoma (responded and progressed on prior anti-PD-1) in a dose escalation (SA/with spartalizumab) and a dose expansion (with tislelizumab) arm. Primary objectives were to assess safety and tolerability including DLTs in cycle 1, adverse events (AEs) and serious AEs, dose interruptions, reductions, and dose intensity of NIZ985 SA and combination therapy. The recommended dose for expansion (RDE) for further investigations was determined. NIZ985 was safe and well-tolerated, with a safety profile consistent with a previous investigation. Most common AEs with SA were injection site reaction, pyrexia, and transaminase increase. With combination therapy, AEs leading to dose adjustment/interruption were higher with NIZ985 16mg/kg compared to 8mg/kg and 12 mg/kg. NIZ985 exposure after the first dose increased with dose increases and was not affected by concomitant administration of CPIs. The RDE was determined to be 12 µg/kg NIZ985 QW (3 weeks on-1week off). While NIZ985 is safe to use in combination with PD-1 inhibitors and showed biological activity, preliminary antitumor efficacy was limited in patients who previously progressed on an anti-PD-1/CPI agent.
Phase III randomised controlled trials often support FDA approval of new anticancer drugs, but trial quality reporting and clinical relevance vary. We assessed the risk of bias and clinical benefit of phase III randomised trials supporting FDA approvals of new anticancer drugs. Cross-sectional study of pivotal phase III randomised trials supporting initial FDA approvals of anticancer drugs (January 1, 2018-May 15, 2025). Risk of bias was assessed using Cochrane Risk-of-Bias Tool 2.0 (low, some concerns, high), and clinical benefit with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (substantial, intermediate, low). Among 43 indications supported by randomised trials, 21 (51%) were open-label. Overall survival benefit was demonstrated in 10 (23%) studies and quality of life improved in 6 (14%). Using a combined assessment incorporating publications and FDA regulatory documents, 13 trials (30%) were judged to be at low risk of bias, 24 (56%) raised some concerns, and 6 (14%) were at high risk of bias. Source-specific assessments differed: 19/42 trials (45%) were classified as high-risk based on published reports alone, versus 7/43 (17%) when assessed using FDA review documents alone. Substantial clinical benefit was observed in 14/43 (33%), but only 4 (9%) combined low risk of bias with substantial benefit. Among the 16 trials (37%) with low clinical benefit, 12 (75%) had methodological concerns or high risk of bias. Risk of bias was inconsistently associated with clinical benefit, overall survival, or quality-of-life outcomes. Recent FDA approvals of anticancer drugs frequently rely on trials with methodological limitations and limited clinical benefit. Integrating risk-of-bias and clinical benefit assessments may strengthen pre-approval evaluation and post-approval oversight, support patient communication, and inform value-based pricing decisions.
The phase III JBCRG-M06/EMERALD study was the first to show noninferior progression-free survival (PFS) of eribulin to taxane, combined with dual human epidermal growth factor receptor 2 (HER2) blockade (trastuzumab plus pertuzumab), as a first-line treatment for HER2-positive locally advanced breast cancer or metastatic breast cancer (LABC/MBC). We report final survival outcomes and biomarker analyses of the EMERALD trial. Patients with HER2-positive LABC/MBC were randomly assigned 1:1 to either eribulin or physician-choice taxane (docetaxel or paclitaxel), both combined with trastuzumab plus pertuzumab, as first-line chemotherapy. PFS and overall survival (OS) were assessed through 30 June 2023 for PFS and 31 December 2024 for OS. Survival outcomes were compared between the eribulin and taxane groups and according to circulating tumor DNA (ctDNA) detection of PIK3CA mutations (PIK3CAm+; E542K, E545K, H1047R, and N345K single nucleotide variants) or HER2 amplification (HER2 amp+; ERBB2 copy number >2.5). Median OS was 78.5 months [95% confidence interval (CI) 64.3-not reached (NR)] for eribulin and was NR for taxane, with a hazard ratio of 1.25 (95% CI 0.92-1.71, log-rank P = 0.19). The 60-month OS rates were 59.7% and 65.2% for eribulin and taxane, respectively. Median OS and 60-month OS rates were numerically lower in ctDNA PIK3CAm+ patients, and greater in ctDNA HER2 amp+ patients for all patients and with stratification by treatment group. There were no statistical interactions between treatment group with either ctDNA PIK3CAm or ctDNA HER2 amp status. Similar patterns were observed for PFS. Final survival analysis revealed that median OS exceeded 6 years with eribulin or physician-choice taxane, combined with trastuzumab plus pertuzumab, as first-line chemotherapy for HER2-positive LABC/MBC, with no significant differences between the two groups. ctDNA PIK3CAm+ status was a poor prognostic factor. ctDNA HER2 amp+ was associated with longer survival.
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Avelumab first-line maintenance is the recommended treatment option for patients with advanced urothelial carcinoma (UC) without progression following platinum-based chemotherapy (PBC), based on the phase III JAVELIN Bladder 100 trial. High body mass index (BMI; ≥30 kg/m2) and diabetes mellitus (DM) are risk factors for bladder cancer. We report exploratory analyses from JAVELIN Bladder 100 in patients with high BMI or documented controlled DM at the time of random assignment. JAVELIN Bladder 100 enrolled patients with advanced UC without progression after first-line PBC, who were randomly assigned to receive avelumab plus best supportive care (BSC; n = 350) or BSC alone (n = 350). The primary endpoint was overall survival (OS) from the time of random assignment. Overall, 122 patients (17.4%) had high BMI and 114 (16.3%) had DM. After a median follow-up of ≥38 months in both arms, hazard ratios for OS with avelumab plus BSC versus BSC alone were 0.77 [95% confidence interval (CI) 0.49-1.21] in patients with high BMI and 0.60 (95% CI, 0.37-0.95) in patients with DM. Long-term safety of avelumab maintenance in these subgroups was generally consistent with that of the overall population. Exploratory analyses support the use of avelumab first-line maintenance in patients with advanced UC without progression following PBC, including those with high BMI or DM.