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We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide. Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4 weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status). 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61 weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013–1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214–2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not. Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status. • Postoperative pre-radiotherapy enhancing tumour volume is associated with survival. • MGMT promoter methylation is significantly associated with better survival. • Irrespective of MGMT methylation status patients benefit from lower tumour burden. [ABSTRACT FROM AUTHOR]

Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS -mutated (NRAS mut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRAS mut patients and 41% [95% CI, 35–48] in NRAS -wild type (NRAS wt) patients; 2-year OS was 54% [95% CI, 48–61] in NRAS mut patients and 57% [95% CI, 50–64] in NRAS wt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRAS mut patients and 53% [95% CI, 41–67] in NRAS wt patients; 2-year OS was 58% [95% CI, 49–70] in NRAS mut patients and 62% [95% CI, 51–75] in NRA Swt patients). The ORR to anti-PD1 was 35% for NRAS wt patients and 26% for NRAS mut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (> 5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRAS wt and NRAS mut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status. • PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. • Similar response rates to anti-PD1-based ICI were seen for NRAS mut and NRAS wt patients. • There was no correlation between NRAS mutation status and programmed cell death ligand-1 expression. [ABSTRACT FROM AUTHOR]

Phase I trials historically involved heavily pretreated patients (pts) with no more effective therapeutic options available and with poor expected outcomes. There are scare data regarding profile and outcomes of pts enrolled into modern phase I trials. Here, we sought to provide an overview of pts' profile and outcome into phase I trials at Gustave Roussy (GR). This is a monocentric retrospective study, including all pts enrolled into phase I trials at GR from 2017 to 2021. Data regarding pts' demographics, tumour types, investigational treatments and survival outcomes were collected. In total, 9482 pts were referred for early phase trials; 2478 pts were screened, among which 449 (18.1%) failed screening; 1693 pts finally received at least one treatment dose as part of a phase I trial. Median age of pts was 59 years old (range, 18–88) and most common tumour types included gastrointestinal (25.3%), haematological (15%), lung (13.6%), genitourinary (10.5%) and gynaecologic cancers (9.4%). Amongst all pts treated and evaluable for response (1634 pts), objective response rate was 15.9% and disease control rate was 45.4%. Median progression-free survival and overall survival were, respectively, 2.6 months (95% confidence interval [95% CI], 2.3; 2.8) and 12.4 months (95% CI, 11.7; 13.6). As compared with historical data, our study shows that outcomes of pts included into modern phase I trials have improved and that these trials constitute nowadays a valid and safe therapeutic option. These updated data provide facts for adapting the methodology, role and place of phase I trials over the next years. • Overall, 15.9% objective response rate and 45.4% disease control rate in phase I trials. • mPFS and mOS, respectively, of 2.6 months and 12.4 months. • Phase I trials represent a valid option for patients in oncology. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) has become a standard of care in the treatment of recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). However, only a subset of patients benefit from treatment. Quantification of plasma circulating tumour DNA (ctDNA) levels and on-treatment kinetics may permit real-time assessment of disease burden under selective pressures of treatment. R/M HNSCC patients treated with systemic therapy, platinum-based chemotherapy (CT) or ICB, underwent serial liquid biopsy sampling. Biomarkers tested included ctDNA measured by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) and markers of host inflammation measured by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Among 53 eligible patients, 16 (30%) received CT, 30 (57%) ICB [anti-PD1/L1] monotherapy and 7 (13%) combination immunotherapy (IO). Median progression-free survival (PFS) and overall survival (OS) were 2.8 months (95% CI, 1.3–4.3) and 8.2 months (95% CI, 5.6–10.8), respectively. Seven (13%) patients experienced a partial response and 21 (40%) derived clinical benefit. At baseline, median ctDNA variant allele frequency (VAF) was 4.3%. Baseline ctDNA abundance was not associated with OS (p = 0.56) nor PFS (p = 0.54). However, a change in ctDNA VAF after one cycle of treatment (ΔVAF (T1–2)) was predictive of both PFS (p < 0.01) and OS (p < 0.01). Additionally, decrease in ΔVAF identified patients with longer OS despite early radiological progression, 8.2 vs 4.6 months, hazard ratio 0.44 (95% CI, 0.19–0.87) p = 0.03. After incorporating NLR and PLR into multivariable Cox models, ctDNA ∆VAF retained an association with OS. Early dynamic changes in ctDNA abundance, after one cycle of treatment, compared to baseline predicted both OS and PFS in R/M HNSCC patients on systemic therapy. • Baseline ctDNA was not associated with progression free or overall survival (OS). • A change in ctDNA after one cycle of treatment was predictive of survival. • A decrease in ctDNA (T1-2) corresponded with longer OS despite radiological progression. • Low NLR was associated with improved OS. [ABSTRACT FROM AUTHOR]

This multi-centre prospective cohort study aimed to investigate non-inferiority in patients' overall survival when treating potentially resectable colorectal cancer liver metastasis (CRLM) with stereotactic microwave ablation (SMWA) as opposed to hepatic resection (HR). Patients with no more than 5 CRLM no larger than 30 mm, deemed eligible for both SMWA and hepatic resection at the local multidisciplinary team meetings, were deliberately treated with SMWA (study group). The contemporary control group consisted of patients with no more than 5 CRLM, none larger than 30 mm, treated with HR, extracted from a prospectively maintained nationwide Swedish database. After propensity-score matching, 3-year overall survival (OS) was compared as the primary outcome using Kaplan-Meier and Cox regression analyses. All patients in the study group (n = 98) were matched to 158 patients from the control group (mean standardised difference in baseline covariates = 0.077). OS rates at 3 years were 78% (Confidence interval [CI] 68–85%) after SMWA versus 76% (CI 69–82%) after HR (stratified Log-rank test p = 0.861). Estimated 5-year OS rates were 56% (CI 45–66%) versus 58% (CI 50–66%). The adjusted hazard ratio for treatment type was 1.020 (CI 0.689–1.510). Overall and major complications were lower after SMWA (percentage decrease 67% and 80%, p < 0.01). Hepatic retreatments were more frequent after SMWA (percentage increase 78%, p < 0.01). SMWA is a valid curative-intent treatment alternative to surgical resection for small resectable CRLM. It represents an attractive option in terms of treatment-related morbidity with potentially wider options regarding hepatic retreatments over the future course of disease. • Similar 3-year overall survival with thermal ablation versus hepatic resection. • Treatment-related morbidity lower while options for retreatment higher. • Thermal ablation valid treatment for resectable colorectal cancer liver metastases. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes. We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen. We included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8–251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio [aHR] = 4.26, 95% confidence interval [CI]:1.85–9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76–14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949). Patients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination. [Display omitted] • The TMB stratifies the outcomes of dMMR/MSI-H mCRC receiving ICIs. • Patients with a low TMB has poor outcomes regardless of the ICI type. • Patients with the highest TMB have greater benefit from anti-CTLA-4 combos. • TMB could be used to drive future research projects and trials' design. [ABSTRACT FROM AUTHOR]

Acinic cell carcinomas (AciCCs) are malignant tumours of the salivary glands. The aim of this work was to analyse data from the national REFCOR multicenter cohort (i) to investigate the prognostic factors influencing survival outcomes in AciCC, (ii) to assess the impact on survival of postoperative radiotherapy (RT) in patients treated for AciCC without high-grade transformation and (iii) to explore the prognostic impact of prophylactic neck dissection (ND) in patients treated for AciCC of the major salivary glands. Data from all the patients treated for salivary AciCC between 2009 and 2020 were extracted from the REFCOR database. Survival outcomes and prognostic factors influencing Disease-Free Survival (DFS) and Overall Survival (OS) were investigated using univariate and multivariate analyses. Propensity score matching was used to assess the impact of postoperative RT and prophylactic ND on DFS. A total of 187 patients were included. After a median follow-up of 53 months, their 5-year OS and DFS rates were 92.8% and 76.2%, respectively. In multivariate analysis, male sex, older age, higher T and N status, and high grade were independently associated with a worse DFS. In the subpopulation analysed after propensity score matching, patients with cN0 AciCC without high-grade transformation who were treated by surgery and RT did not have an improved DFS compared to patients who were treated by surgery alone (hazard ratio (HR) = 0.87, p = 0.8). Factors associated with nodal invasion were T3–T4 status and intermediate/high histological grade. After propensity score matching, prophylactic ND was associated with a trend toward a better DFS (HR = 0.46, p = 0.16). These results suggest that (i) long-term follow-up (>5 years) should be considered in patients with AciCC, (ii) treatment by surgery alone could be an option in selected cN0 patients with AciCC without high-grade transformation and (iii) prophylactic ND may be considered preferentially in patients with T3–T4 status and/or intermediate/high histological grade. • The 5-year OS and DFS were 92.8% and 76.2%, respectively. • Male sex, higher T/N status, and high grade were independently associated with a worse DFS. • T3–T4 status and intermediate/high histological grade were associated with N+ status. • After PS matching, prophylactic ND was associated with a trend toward a better DFS. [ABSTRACT FROM AUTHOR]

Retrospective subgroup analyses of previous trials in the first-line therapy of RAS wt metastatic colorectal cancer (mCRC) suggested a predictive impact of primary tumour side on the efficacy of anti-epidermal growth factor receptor (EGFR) agents. Recently, new head-to-head trials of doublets/bevacizumab versus doublets/anti-EGFR, PARADIGM and CAIRO5 were presented. We searched for phase II and III trials comparing doublet chemotherapy plus an anti-EGFR or bevacizumab as the first-line treatment for RAS wt mCRC patients. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and radical resection rate result in the overall study populations and, according to the primary side, were pooled together in a two-stage analysis with random effects and fixed effect models. The interaction between sidedness and treatment effect was then analysed. We identified five trials (PEAK, CALGB/SWOG 80405, FIRE-3, PARADIGM and CAIRO5), including 2739 patients, 77% left- and 23% right-sided. Among patients with left-sided mCRC, the use of anti-EGFRs was associated with higher ORR (74% versus 62%, OR = 1.77 [95% confidence interval {CI} 1.39–2.26–0.88], p < 0.0001), longer OS (hazard ratio [HR] = 0.77 [95% CI 0.68–0.88], p < 0.0001) and not significantly longer PFS (HR = 0.92, p = 0.19). Among patients with right-sided mCRC, the use of bevacizumab was associated with longer PFS (HR = 1.36 [95% CI 1.12–1.65], p = 0.002) and not significantly longer OS (HR = 1.17, p = 0.14). A subgroup analysis confirmed a significant interaction effect between the primary tumour side and treatment arm in terms of ORR (p = 0.02), PFS (p = 0.0004) and OS (p = 0.001). No differences in the radical resection rate were found according to treatment and sidedness. Our updated metanalysis corroborates the role of the primary tumour location in the choice of the upfront therapy for RAS wt mCRC patients, leading to strongly recommend anti-EGFRs in left-sided tumours and to prefer bevacizumab in the right-sided. • Doublet/anti-epidermal growth factor receptor (EGFRs) or bevacizumab are both valuable first-line options for RAS wt metastatic colorectal cancer (mCRC). • Left-sided mCRC achieves a better overall survival and overall response rate benefit from anti-EGFRs versus bevacizumab. • Right-sided mCRC patients achieve better progression-free survival , with a trend for overall survivalwith bevacizumab. • Anti-EGFRs should be recommended only in the left-sided RAS wt mCRC. • Bevacizumab should be preferred in the right-sided RAS wt mCRC. [ABSTRACT FROM AUTHOR]

In the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported. Patients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups). In the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67–1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33–0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed. OS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC. • Median overall survival (OS) was 19.3 and 17.1 months for olaparib versus chemotherapy treatment of physician's choice (TPC), respectively. • Overall, 8.8% of patients received at least 3 years of study treatment in the olaparib arm versus no patients in the TPC arm. • In first-line, median OS was numerically longer for olaparib versus TPC (22.6 versus 14.7 months, respectively). • In first-line, the 3-year OS rate was 40.8% for olaparib versus 12.8% for TPC. • These data confirm previous findings and suggest a possible OS benefit for olaparib in the first-line metastatic breast cancer setting. [ABSTRACT FROM AUTHOR]

Imbalanced body composition is mechanistically connected to dysregulated immune activities. Whether overweight/obesity or sarcopenia has an impact on treatment results in cancer patients undergoing immune checkpoint inhibitor (ICI) therapy is currently under debate. We aimed to answer if survival rates and occurrence of immune-related adverse events (irAEs) were different in obese or sarcopenic patients. A systematic search was conducted in PubMed, Embase and CENTRAL for all records published until July 2022 using specific search terms for body composition in combination with terms for ICI regimens. Two authors screened independently. All studies that reported on body mass index or sarcopenia measures were selected for further analysis. 48 studies reporting on overweight/obesity comprising of 19,767 patients, and 32 studies reporting on sarcopenia comprising of 3193 patients fulfilled the inclusion criteria. In the entire cohort, overweight/obesity was significantly associated with better progression-free survival (PFS; p = 0.009) and overall survival (OS; p <0.00001). Subgroup analyses stratified by sex revealed that overweight/obese males had the strongest survival benefit (PFS: p = 0.05; OS: p = 0.0005), and overweight/obese female patients did not show any. However, overweight/obese patients of both sexes had a higher risk to develop irAEs grade ≥3 (p = 0.0009). Sarcopenic patients showed significantly shorter PFS (p <0.0001) and OS (p <0.0001). The frequency of irAEs did not differ between sarcopenic and non-sarcopenic patients. This meta-analysis suggests that body composition is associated in a sex-specific manner with survival and irAEs in cancer patients undergoing ICI treatment. • In Immune-checkpoint inhibitorimmunotherapy, overweight and obesity are associated with longer survival. • Overweight patients are at higher risk to develop any and grade ≥3 immune-related adverse events. • Obesity-associated survival benefits were most prominent in male patients. • Sarcopenia is associated with shorter survival without increased immunotoxicities. [ABSTRACT FROM AUTHOR]

Data on the role of the microbiota in cancer have accumulated in recent years, with particular interest in intratumoral bacteria. Previous results have shown that the composition of intratumoral microbiome is different depending on the type of primary tumour and that bacteria from the primary tumour could migrate to metastatic sites. Seventy-nine patients with breast, lung, or colorectal cancer and available biopsy samples from lymph node, lung, or liver site, treated in the SHIVA01 trial were analysed. We performed bacterial 16S rRNA gene sequencing on these samples to characterise the intratumoral microbiome. We assessed the association between microbiome composition, clinicopathological characteristics, and outcomes. Microbial richness (Chao1 index), evenness (Shannon index) and beta-diversity (Bray Curtis distance) were associated with biopsy site (p = 0.0001, p = 0.03 and p < 0.0001, respectively) but not with primary tumour type (p = 0.52, p = 0.54 and p = 0.82, respectively). Furthermore, microbial richness was inversely associated with tumour-infiltrating lymphocytes (TILs, p = 0.02), and PD-L1 expression on immune cells (p = 0.03), or assessed by Tumor Proportion Score (TPS, p = 0.02) or Combined Positive Score (CPS, p = 0.04). Beta-diversity was also associated with these parameters (p < 0.05). Patients with lower intratumoral microbiome richness had shorter overall survival (p = 0.03) and progression-free survival (p = 0.02) in multivariate analysis. Biopsy site, rather than primary tumour type, was strongly associated with microbiome diversity. Immune histopathological parameters such as PD-L1 expression and TILs were significantly associated with alpha and beta-diversity supporting the cancer-microbiome-immune axis hypothesis. • The composition of microbiota in metastases is tissue-rather than tumor-driven. • PD-L1 and tumor-infiltrating lymphocytes are associated with microbiome diversity. • This ancillary study supports the cancer-microbiome-immune axis hypothesis. [ABSTRACT FROM AUTHOR]

Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients. URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC -rearranged round cell sarcomas, (2) BCOR::CCNB3 -rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed. In total, 148 patients were identified [88/148 (60%) CIC -rearranged sarcoma (median age 32 years, range 7–78), 33/148 (22%) BCOR::CCNB3 -rearranged (median age 17 years, range 5–91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4–70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3- rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5–98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7–51.3) in CIC -rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1–90.6; p < 0.0001). This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype. • Undifferentiated small round cell sarcomas (URCS) represent a therapeutic challenge. • Pathological, clinical and molecular data of these ultra-rare sarcomas are provided. • CIC-rearranged tumours have poor survival compared to BCOR:CCNB3/unclassified URCS. • Translational research and RNA-seq findings are discussed. [ABSTRACT FROM AUTHOR]

We report long-term efficacy and overall survival (OS) results from a randomised, double-blind, phase 2 study (NCT02022098) investigating xevinapant plus standard-of-care chemoradiotherapy (CRT) vs. placebo plus CRT in 96 patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Patients were randomised 1:1 to xevinapant 200 mg/day (days 1–14 of a 21-day cycle for 3 cycles), or matched placebo, plus CRT (cisplatin 100 mg/m2 every 3 weeks for 3 cycles plus conventional fractionated high-dose intensity-modulated radiotherapy [70 Gy/35 F, 2 Gy/F, 5 days/week for 7 weeks]). Locoregional control, progression-free survival, and duration of response after 3 years, long-term safety, and 5-year OS were assessed. The risk of locoregional failure was reduced by 54% for xevinapant plus CRT vs. placebo plus CRT but did not reach statistical significance (adjusted hazard ratio [HR] 0.46; 95% CI, 0.19–1.13; P =.0893). The risk of death or disease progression was reduced by 67% for xevinapant plus CRT (adjusted HR 0.33; 95% CI, 0.17–0.67; P =.0019). The risk of death was approximately halved in the xevinapant arm compared with placebo (adjusted HR 0.47; 95% CI, 0.27–0.84; P =.0101). OS was prolonged with xevinapant plus CRT vs. placebo plus CRT; median OS not reached (95% CI, 40.3-not evaluable) vs. 36.1 months (95% CI, 21.8–46.7). Incidence of late-onset grade ≥3 toxicities was similar across arms. In this randomised phase 2 study of 96 patients, xevinapant plus CRT demonstrated superior efficacy benefits, including markedly improved 5-year survival in patients with unresected LA SCCHN. [Display omitted] • Xevinapant + CRT improved PFS after 3 years of follow-up • The risk of death was more than halved in the xevinapant arm compared with placebo • The incidence of late-onset grade ≥3 toxicities was similar across treatment groups [ABSTRACT FROM AUTHOR]

When analysing patient survival, one is often interested in cause of death. Little is known about the presence of population mortality in advanced melanoma patients. The aim of this study was to assess population mortality after different response states in advanced melanoma patients in the Netherlands, and analyse the contribution of disease and population mortality for different age groups. We selected patients diagnosed between 2013 and 2019 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. A multi-state model with response states integrating population mortality was fitted. One-year landmark analyses were performed to assess outcomes after each response state. Overall, 5119 patients were selected. Five-year probabilities of melanoma-related mortality in patients alive in complete response at one year after diagnosis increased with age, and was 17.2% (95% confidence interval: 13.0–21.4) for patients aged <65 years and 28.7% (95% confidence interval: 24.3–33.1) in patients aged ≥80 years. Population mortality only played a large role for older patients (75 years and above) alive at 1 year after diagnosis with a partial or complete response. Even though survival outcomes of advanced melanoma patients have improved over the last decade, the vast majority of patients still die due to melanoma-related mortality. • Melanoma-related mortality after tumour responses has not been studied so far. • Using multi-state models, the prognostic impact of response states was assessed. • Melanoma-related mortality dominates population mortality in advanced melanoma. • Population mortality plays a role in patients ≥75 years who respond to therapy. [ABSTRACT FROM AUTHOR]

Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects. The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS. gov, number NCT01077427. • First study in PDAC investigating hyperthermia added to adjuvant chemotherapy. • The study failed to improve disease-free survival as the primary endpoint. • Post-recurrence survival was improved with a trend of improved overall survival. • Toxicity compares favorably with a more intensive adjuvant chemotherapy. • The study offers new perspectives to gain perioperative benefit in PDAC. [ABSTRACT FROM AUTHOR]

The use of medical cannabis has rapidly increased among cancer patients worldwide. Cannabis is often administered concomitantly with cancer medications, including immune checkpoint inhibitors (ICIs). As the cannabinoid receptors are abundantly expressed and modulate immune cells, it has been hypothesised that cannabis may attenuate the activity of ICIs. We aimed to assess the effect of cannabis on ICIs' efficiency in patients having non-small cell lung cancer (NSCLC). The murine model of CT26 tumour-bearing mice treated with an anti-PD-1 antibody and Δ9-tetrahydrocannabinol (THC) was used to evaluate the interaction between THC and ICIs in vivo. Correlation between use of medical cannabis and clinical outcome was evaluated in a cohort of 201 consecutive metastatic NSCLC patients treated with monotherapy pembrolizumab as a first-line treatment. Median overall survival (OS) of the mice receiving a control vehicle, THC, anti-PD-1 antibody or their combination was 21, 24, 31 and 54 days, respectively (p < 0.05 for the combination treatment compared to a control vehicle), indicating that THC did not reduce the efficacy of anti-PD-1 therapy. Of 201 NSCLC patients treated with first-line monotherapy pembrolizumab for metastatic disease, 102 (50.7%) patients received licence for cannabis within the first month of treatment. Cannabis-treated patients were younger compared to the cannabis naïve patients (median age 68 versus 74, p = 0.003), with female predominance (62, 60.8% versus 34, 34.3%, p = 0.002) and with more prevailing brain metastasis (15.7% versus 5%, p = 0.013). Similar distribution of histology, smoking status, ECOG (Eastern Cooperative Oncology Group) and programmed death-ligand 1 expression was noted between the groups. Liver metastases were marginally significant (19.6% versus 10.1%, p = 0.058). The most common indication for cannabis was pain (71%) followed by loss of appetite (34.3%). Time to tumour progression was similar for cannabis-naive and cannabis-treated patients (6.1 versus 5.6 months, respectively, 95% confidence interval, 0.82 to 1.38, p = 0.386), while OS was numerically higher in the cannabis-naive group (54.9 versus 23.6 months) but did not reach statistical significance (95% confidence interval 0.99 to 2.51, p = 0.08). In multivariate analyses, we did not identify cannabis use as an independent predictor factor for mortality. Preclinical and clinical data suggest no deleterious effect of cannabis on the activity of pembrolizumab as first-line monotherapy for advanced NSCLC. The differences in OS can most likely be attributed to higher disease burden and more symptomatic disease in the cannabis-treated group. These data provide reassurance regarding the absence of a deleterious effect of cannabis in this clinical setting. • Cannabis might alter tumour's microenvironment and, hence, reduce the immune checkpoint inhibitors efficacy. • We investigate this theory in murine models and real-world data. • We found no determinantal effect of this combination in clinic or laboratory. • This conclusion has a great reassuring impact on our patients having non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-based combination therapy (ICI-based combination) is a new standard of care for metastatic clear cell renal cell carcinoma (mRCC) in the frontline setting. Patients with poor performance status (PS) (≥2) were excluded from pivotal trials. Hence, the activity and safety of ICI-based combination therapy in this group of patients is still unknown. We performed a multicentre retrospective study of PS ≥2 mRCC patients who received frontline ICI-based combination, either nivolumab-ipilimumab (NI) or pembrolizumab-axitinib (AP). Patients' characteristics, clinical outcomes, and toxicity were collected. We analysed overall response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS) and grade ≥3 adverse events (G ≥ 3AEs). The association between the predictive biomarker IPI (immune prognostic index) and ORR/PFS/OS was also evaluated. We identified 70 mRCC patients with PS ≥2 treated with ICI-based combination across 14 institutions between October 2017 and December 2021, including 45 and 25 patients were treated with NI and AP, respectively. Median age at diagnosis was 63 years, 51 (73%) were male, only 17 (24%) had prior nephrectomy, 50 (71%) had synchronous metastatic disease at diagnosis, and 16 (23%) had brain metastases. Sixty-one (87%) and 9 (13%) patients had ECOG (Eastern Cooperative Oncology Group) PS 2 and 3, respectively, and 25 (36%) and 45 (64%) patients were intermediate and poor International Metastatic RCC Database Consortium (IMDC) risk, respectively. Among all, 91% were clear cell RCC, 7 patients had sarcomatoid features. At the time of the analysis (median follow-up 11.1 months), 41% patients were dead. Median PFS and mOS in the entire cohort were 5.4 months and 16.0 months, respectively; ORR was 31%. No significant differences in ORR, PFS, OS, or G ≥3AEs were seen between NI and AP. The intermediate and poor IPI groups were significantly associated with reduced ORR and shorter PFS. We report the first cohort of PS ≥2 mRCC patients treated with frontline ICI-based combination therapy. The survival outcomes in our cohort were inferior to that reported in pivotal trials. No significant differences in ORR, PFS, OS or toxicity were seen between NI and AP. Prospective real-world studies are needed to confirm these results. • First cohort of poor PS mRCC treated with front line ICI-based combination therapy. • The survival outcomes were inferior to that reported in pivotal trials. • No significant differences in ORR, PFS or OS were seen between NI and AP. • Both NI and AP were well tolerated without significant differences between them. [ABSTRACT FROM AUTHOR]

Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI. Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1–4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression. 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated "possibly" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE. This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints. • Largest analysis to date of treatment-related toxicity with combined ICI and SBRT. • More than 90 % of patients treated with a biologically effective dose of ≥ 100 Gy. • Dual-agent ICI was more toxic than single-agent ICI. • Radiation-related factors were not significantly associated with toxicity. • Adverse events were not significantly associated with improved survival. [ABSTRACT FROM AUTHOR]

The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2–17.7) vs. 15.6 (60 %CI 14.3–18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91–1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9–10.2) vs. 11.1 (60 %CI 10.3–12.8) months; adjusted HR 1.71 (60 %CI 1.38–2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS. • Nelfinavir and high-dose chemoradiotherapy (CRT) are well tolerated. • No improvement in overall survival is seen with high versus standard dose CRT. • Nelfinavir does not improve outcomes when used concurrent with CRT. • CRT dose escalation may improve local tumour control. • Health-related quality of life is not impacted by CRT dose escalation or nelfinavir. [ABSTRACT FROM AUTHOR]

MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2 -altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2 -altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2 -altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. NCT03748641 (MAGNITUDE) • Baseline characteristic imbalances can cause reduced estimated treatment efficacy. • Robustness can be shown using multiple adjustment methods for baseline imbalances. • We used novel IPTW to assess time-to-event outcomes in the phase 3 MAGNITUDE trial. • Outcomes were consistent with the pre-specified MVA, with additional value shown. • This confirmed the clinical benefit of niraparib+AAP in BRCA1/2 -altered mCRPC. [ABSTRACT FROM AUTHOR]

We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16–63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3–4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma. OSAD93 used a 2 drugs neoadjuvant chemotherapy regimen in adult osteosarcoma. The primary endpoint (good histological response in >30 % of patients) was not met The long term (>25y) OS & DFS are high in this adult osteosarcoma series. Limited long-term toxicity and no cardiac toxicity was observed in cured patients. This protocol provides excellent long-term results, deserving further investigations. [ABSTRACT FROM AUTHOR]

The presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors. In this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors. Metastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07–1.28), increased PFS (HR 0.93, 95 % CI 0.87–0.996), and OS (HR 0.94, 95 % CI 0.89–0.99). When categorized, patients in the highest tertile TILs-WG score (15–100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores. In advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice. • TILs in pre-treatment metastatic melanoma slides are associated with ICI response. • These associations are independent of known clinical predictors. • TILs are easily scored on readily available H&E slides. [ABSTRACT FROM AUTHOR]

The prognosis of patients with advanced biliary tract cancer (BTC) is still poor, and new strategies improving patients' outcome are needed. In our trial we investigated safety and activity of nab-paclitaxel in combination with gemcitabine and oxaliplatin as first-line systemic treatment for patients with advanced BTC. In this investigator-initiated, multicenter, dose-escalation, single-arm phase I/II trial, patients were accrued into cohorts of 3 patients and dose escalation was performed following the standard 3 + 3 rule. Primary endpoint was the proportion of patients free from progression at 6 months. Secondary endpoints included safety and tolerability of the combination; progression-free survival (PFS); overall survival (OS); objective response rate (ORR); duration of response. Between July 2017 and December 2020, 67 patients were treated. Among the 10 patients in the phase I, no dose-limiting toxicity was observed, and dose level 2 was defined as recommended phase II dose for the phase II part. At data cutoff, the 6-month PFS rate was 49.1 % (95 % CI 40.8–57.5 %) with 28 patients out of 57 free from progression or death at 6 months. Median PFS was 6.3 months (95 % CI 3.6–10.1) and median OS was 12.4 months (95 % CI 8–23). ORR was 20.89 %. Most common grade 3 and grade 1–2 drug-related adverse events were neutropenia and peripheral neuropathy, respectively. Triple chemotherapy demonstrated a favorable safety profile. However, the study did not meet its primary endpoint. Future studies will clarify the benefit of chemotherapy combinations in different settings. This trial is registered with ClinicalTrials.gov, NCT03943043. • This is a phase I-II study of GEMOX and nab-paclitaxel in patients with BTC. • The phase I part showed no dose-limiting toxicity; dose level 2 was defined as RP2D. • The primary endpoint of 6-month PFS rate was 49.1 %. • Median PFS was 6.3 months, median OS 12.4 months, ORR 20.89 %. • The trial was negative as it did not meet its primary endpoint. [ABSTRACT FROM AUTHOR]

This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment. Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center. In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C -statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008). Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS. • Tumor total volume (TTV) is prognostic for survival outcomes in patients with CRLM. • 5-year survival is 72 % for baseline of TTV 3 mL, 7 % for a baseline TTV of 300 mL. • Change in TTV after systemic therapy is associated with survival, RECIST1.1 is not. • TTV may guide individualized therapeutic decision making in patients with CRLM. [ABSTRACT FROM AUTHOR]

Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) are recommended 1st line treatments in HR+HER2- metastatic breast cancer. However, the impact of prior CDK4/6i on the natural history of brain metastases (BM) is not well described. We reviewed retrospective data for 363 patients with HR+HER2- BM who received a CDK4/6i (CDK-Y) between 1 Jan 2015 to 31 July 2021 and 299 patients with HR+HER2- BM who did not receive a CDK4/6i (CDK-N) between 1 Jan 2010 to 31 Dec 2014. CNS PFS and OS were assessed in patients who received CDK4/6i after BM. OS from the time of BM development was assessed between patients who received CDK4/6i before BM and the CDK-N cohort In the CDK-Y cohort of 363 patients, 203 (56 %) received a CDK4/6i before BM, 133 (37 %) received a CDK4/6i only after BM and 27 (7 %) received a CDK4/6i both before and after BM. Median CNS PFS was 21.4 months for patients receiving a CDK4/6i only after BM and 9.4 months for patients who received CDK4/6i both before and after BM (p = 0.006). Median OS was 24.9 months for patients receiving a CDK4/6i only after BM and 12.1 months for patients who received CDK4/6i both before and after BM (p = 0.0098). Median OS from time of BM development for patients receiving a CDK4/6i before BM versus the CDK-N cohort was 4.3 months and 7.7 months respectively (p = 0.0082). CDK4/6i exposure prior to BM may lead to development of resistance mechanisms which in turn reduces CNS PFS and OS upon rechallenging with a CDK4/6i after BM development. This motivates investigation of biomarkers for patient selection. • Real world data of impact of CDK4/6i on breast cancer brain metastases outcomes. • Improved median overall survival if CDK4/6i received only after brain metastases. • Potential development of resistance mechanisms with CDK4/6i exposure. • Rechallenging with CDK4/6i after brain metastases results in reduced efficacy. [ABSTRACT FROM AUTHOR]

This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with MET ex14 mutations in German routine care. SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39–0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31–0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80–3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring MET ex14 mutations and its significant role in preventing the development of brain metastases. • RECAP study presents indirect comparison of capmatinib vs SOC in German practice. • Capmatinib shows a robust clinically meaningful benefit vs SOC in MET ex14-mutated NSCLC. • Capmatinib demonstrates significant efficacy vs SOC in preventing brain metastases. • This real-world study reinforces the high need of molecular testing in NSCLC. [ABSTRACT FROM AUTHOR]

We aim to compare the prognostic value of organ-specific dynamics with the sum of the longest diameter (SLD) dynamics in patients with metastatic colorectal cancer (mCRC). All datasets are accessible in Project Data Sphere, an open-access platform. The tumor growth inhibition models developed based on organ-level SLD and SLD were used to estimate the organ-specific tumor growth rates (KGs) and SLD KG. The early tumor shrinkage (ETS) from baseline to the first measurement after treatment was also evaluated. The relationship between organ-specific dynamics, SLD dynamics, and survival outcomes (overall survival, OS; progression-free survival, PFS) was quantified using Kaplan-Meier analysis and Cox regression. This study included 3687 patients from 6 phase III mCRC trials. The liver emerged as the most frequent metastatic site (2901, 78.7 %), with variable KGs across different organs in individual patients (liver 0.0243 > lung 0.0202 > lymph node 0.0127 > other 0.0118 [week−1]). Notably, the dynamics for different organs did not equally contribute to predicting survival outcomes. In liver metastasis cases, liver KG proved to be a superior prognostic indicator for OS and surpasses the predictive performance of SLD, (C-index, liver KG 0.610 vs SLD KG 0.606). A similar result can be found for PFS. Moreover, liver ETS also outperforms SLD ETS in predicting survival. Cox regression analysis confirmed liver KG is the most significant variable in survival prediction. In mCRC patients with liver metastasis, liver dynamics is the primary prognostic indicator for both PFS and OS. In future drug development for mCRC, greater emphasis should be directed towards understanding the dynamics of liver metastasis development. • Tumor lesions in the liver have the most significant impact on survival. • Liver KG surpasses the predictive performance of the SLD KG. • Organ-level TGI model may be a more suitable option for mCRC clinical trials. [ABSTRACT FROM AUTHOR]

Homologous Recombination Deficiency (HRD) status predicts response to treatment with poly(ADP-ribose) polymerase inhibitors in Ovarian Cancer (OC) patients. The Myriad myChoiceCDx Assay is approved by Food and Drug Agency for the HRD assessment. Here we compared the HRD status obtained by three commercial panels with the results from Myriad reference test. The HRD analysis was performed on DNA from formalin-fixed and paraffin-embedded tumor samples of 100 untreated OC patients for which Myriad assay results were available, using TruSight Oncology 500 HRD assay (Illumina), Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific) and SOPHiA DDM HRD solution panel (SOPHiA Genetics). A good overall concordance with the reference method was demonstrated at three different levels: BRCA mutational status (from 94.4 % to 97.7 %), the genomic instability value (from 88.2 % to 95.3 %) and for the HRD status (from 90.4 % to 97.6 %). Moreover, a trend in favour of HRD positive patients for response rate, progression-free survival and overall survival similar to Myriad was observed for all three tests. Our data suggest the feasibility of commercial testing for assessing HRD status, with a good concordance with the reference method and association with clinical outcome. • Harmonization of HRD assays is crucial for PARPi therapy in ovarian cancer. • HRD commercial assays have a good a good agreement rate with the reference test. • The commercial tests show a correlation with outcome similar to reference assay. • Discordance was observed in BRCA classification of variants. • Genomic instability scores close to cut-off should be discussed in the tumor board. [ABSTRACT FROM AUTHOR]

Sex and gender are modulators of health and disease and may have impact on treatment allocation and survival in patients with cancer. In this study, we analyzed the impact of sex and gender on treatment allocation and overall survival in patients with stage I-III pancreatic cancer. Patients with stage I-III pancreatic cancer diagnosed between 2015 and 2020 were selected from the nationwide Netherlands Cancer Registry. Associations between sex and gender and the probability of receiving surgical and/or systemic treatment were examined with multivariable logistic regression analyses. Overall survival was assessed with log rank test and multivariable Cox proportional hazard analysis. Among 6855 patients, 51.2 % were female. Multivariable logistic regression analyses with adjustment for known confounders (age, performance status, comorbidities, tumor location, tumor stage and previous malignancies) showed that females less often received systemic chemotherapy compared to males (OR 0.799, 95 %CI 0.703–0.909, p <.001). No difference was found in the probability for undergoing surgical resection. Furthermore, females had worse overall survival compared to males (median OS 8.5 and 9.2 months respectively, 95 %CI 8.669–9.731). This nationwide study found that female patients with stage I-III pancreatic cancer significantly less often received systemic treatment and had worse overall survival as compared to males. Disparities in pancreatic cancer care can be decreased by recognizing and resolving potential obstacles or biases in treatment decision-making. • Impact of sex and gender was investigated in patients with stage I-III pancreatic cancer • Females less frequently received systemic treatment compared to males • Sex and potentially gender may impact treatment and survival in stage I-III pancreatic cancer [ABSTRACT FROM AUTHOR]

This prospective pharmacokinetic (PK) ancillary study of the TEXCAN phase II GERCOR trial of patients with chemorefractory metastatic colorectal cancer and treated with regorafenib (REGO) investigated correlations between overall survival (OS) and concentrations (C) of REGO and its active metabolites, M-2 and M-5. 55 patients received REGO 160 mg/day for 21 days of a 28-day cycle (NCT02699073). REGO, M-2, M-5 were measured by liquid chromatography-mass spectrometry assay on day 15 of cycle 1 (C1) and 2 (C2). We studied the association between OS and Cmin of REGO, M-2 and M-5 at C1 and their accumulations between C1 and C2. Medians of C2/C1 M-2 and M-5 ratios were 0.82 (interquartile range 0.50–1.78) and 0.75 (interquartile range 0.41–1.93), respectively. Patients with C2/C1 M-2 ratio ≥ median had improved survival compared to those < median (12.6 versus 4.0 months, P = 0.023), corresponding to a 66% mortality risk reduction in multivariate analysis. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum; P = 0.006). Restricted cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio raises and when C1 Csum ranged between 2.5 and 5.5 mg/L. Patients within the Csum range had a reduced incidence of serious adverse events and improved OS. We identified PK parameters associated with a survival benefit in patients with metastatic colorectal cancer treated by REGO. OS and safety were favourable when C1 REGO+M-2+M-5 Csum ranged between 2.5 and 5.5 mg/L. These results pave the way for individual REGO dose modification strategies based on PK monitoring. NCT02699073 - Therapeutic monitoring of regorafenib in metastatic colorectal cancer is feasible. - We define a safe range of residual concentration regorafenib + M-2+M-5. - This range translates into a survival benefit and decreased serious adverse events. - Only one-third of the patients are within range at C1 D14. - Therapeutic monitoring of regorafenib may help to optimise its dose. [ABSTRACT FROM AUTHOR]

The Lung Immune Prognostic Index (LIPI) is associated with immune checkpoint inhibitors (ICI) outcomes across different solid tumors, particularly in non-small cell lung cancer. Data regarding the prognostic and/or predictive role of LIPI in metastatic renal cell carcinoma (mRCC) are still scarce. The aim of this study was to evaluate whether LIPI could be predictive of survival in mRCC patients. We used patient level data from three different prospective studies (NIVOREN trial: nivolumab; TORAVA trial: VEGF/VEGFR-targeted therapy (TT); CheckMate 214: nivolumab-ipilimumab vs sunitinib). LIPI was calculated based on a derived neutrophils/(leukocyte-neutrophil) ratio > 3 and lactate-dehydrogenase >upper limit of normal, classifying patients into three groups (LIPI good, 0 factors;LIPI intermediate (int), 1 factor;LIPI poor, 2 factors) and/or into two groups (LIPI good, 0 factors;LIPI int/poor, 1–2 factors) according to trial sample size. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). In the Nivolumab dataset (n = 619), LIPI was significantly associated with OS (LIPI-good 30.1 vs 13.8 months in the LIPI int/poor; HR= 0.47) and PFS (HR=0.74). In the VEGF/VEGFR-TT dataset (n = 159), only a correlation with PFS was observed. In the CheckMate214 dataset (n = 1084), LIPI was significantly associated with OS (nivolumab-ipilimumab OS LIPI good vs int/poor: HR=0.55, p < 0.0001; sunitinib: OS LIPI good vs int/poor: 0.38, p < 0.0001) in both treatment groups in univariate and multivariate analysis. Pretreatment-LIPI correlated with worse survival outcomes in mRCC treated with either ICI or antiangiogenic therapy, confirming LIPI's prognostic role in mRCC irrespective of systemic treatment used. • Largest study on the prognostic role of LIPI in metastatic renal cell carcinoma (mRCC). • First study evaluating LIPI in mRCC treated with either ICI or antiangiogenics. • Our findings confirm LIPI's prognostic role in mRCC regardless treatment type. • LIPI did not outperform the IMDC risk score. • Its predictive value for ICI versus antiangiogenics remains inconclusive. [ABSTRACT FROM AUTHOR]

To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT). Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method. Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001). Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups. • Teratoma negatively impacts 5y-OS in IGCCCG good prognosis patients. • Teratoma negatively impacts 5y-PFS in IGCCCG intermediate prognosis patients. • Teratoma does not impact survival in IGCCCG poor prognosis patients. [ABSTRACT FROM AUTHOR]

This retrospective study determined survival responses to immune checkpoint inhibitors (ICIs), comparing mono- (mono) and combo-immunotherapy (combo) in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) by analyzing quantitative imaging data and clinical factors. One hundred fifty patients were included from two centers and divided into training (n = 105) and validation (n = 45) cohorts. Radiologists manually annotated chest-abdomen-pelvis computed tomography and calculated tumor burden. Progression-free survival (PFS) was assessed, and variables were selected through Recursive Feature Elimination. Cutoff values were determined using maximally selected rank statistics to binarize features, forming a risk score with hazard ratio-derived weights. In total, 2258 lesions were annotated with excellent reproducibility. Key variables in the training cohort included: total tumor volume (cutoff: 73 cm3), lesion count (cutoff: 20), age (cutoff: 60) and the presence of peritoneal carcinomatosis. Their respective weights were 1.13, 0.96, 0.91, and 0.38, resulting in a risk score cutoff of 1.36. Low-score patients showed similar overall survival and PFS regardless of treatment, while those with a high-score had significantly worse survivals with mono vs combo (P = 0.004 and P = 0.0001). In the validation set, low-score patients exhibited no significant difference in overall survival and PFS with mono or combo. However, patients with a high-score had worse PFS with mono (P = 0.046). A score based on total tumor volume, lesion count, the presence of peritoneal carcinomatosis, and age can guide MSI-H mCRC treatment decisions, allowing oncologists to identify suitable candidates for mono and combo ICI therapies. • Identifying MSI-H mCRC patients benefiting from ICI combotherapy is critical. • 150 MSI mCRC patients were included in this study. • All visible tumor lesions (n = 2258) were annotated by radiologists. • Total tumor volume, among other factors, formed a radio-clinic risk score. • The score can guide the mono or combo immunotherapy choice for MSI-H mCRC patients. [ABSTRACT FROM AUTHOR]

The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27−85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1–17.9), median OS was 16.1 months (95% CI, 14.4–18.8) and PFS was 9.9 months (95% CI, 8.8–11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6–17.1). ORR was 43.4% (95% CI, 40.4–46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study. [Display omitted] • Chemo-immunotherapy is the standard front-line treatment for advanced non-squamous NSCLC. • Real-world data about platinum, pemetrexed and pembrolizumab regimen are needed. • We conducted a retrospective-prospective real-world study in 33 Italian Centers. • KEYNOTE-189 regimen was effective and safe in daily clinical practice. [ABSTRACT FROM AUTHOR]

The NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM). In this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10. 118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9–9.8) in arm A and 4.7 months (95%CI 3.9–7.0) in arm B (HR 1.01, 80%CI 0.75–1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7–15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0–6.8) in arm A and 2.9 months (95%CI 2.4–5.5) in arm B (HR 0.60, 80%CI 0.45–0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35–4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8–22.9), the OS was 15.4 months (95%CI 11.1–22.6) in arm A and 11.1 months (95%CI 8.8–18.1) in arm B, (HR 0.73, 80%CI 0.53–1.0, P = 0.197). The primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine. • The NIPU-trial is a multicentre open-label randomised phase 2 clinical trial. • 118 patients with mesothelioma progressing after first line were included. • Patients were randomised between ipi/nivo alone or with the telomerase vaccine UV1. • The primary end-point PFS by BICR did not differ between treatment arms. • Predefined analyses of ORR by BICR were in favour of the vaccine arm. [ABSTRACT FROM AUTHOR]

The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC. Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m2 / 125 mg/m2 (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy. Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3–5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months. In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m2 / 125 mg/m2) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile. • AFFECT was a phase Ib trial that investigated afatinib with gemcitabine/nabPaclitaxel. • Patients with initial diagnosis of metastatic pancreatic cancer were enrolled (n = 11). • Primary endpoint of this study was maximum tolerated dose (MTD). • Afatinib showed an acceptable safety profile of 30 mg daily with standard chemotherapy. [ABSTRACT FROM AUTHOR]

The Health outcomes and Understanding of MyelomA multi-National Study (HUMANS) was a large-scale, retrospective study conducted across Denmark, Finland and Sweden using linked data from national registries. We describe the characteristics, treatment patterns and clinical outcomes for patients with newly diagnosed multiple myeloma (NDMM) over 2010–2018. Patients with NDMM who received MM-specific, first-line treatments, were categorised by treatment (autologous stem cell transplantation [ASCT] or a combination chemotherapy regimen based on bortezomib, lenalidomide or melphalan-prednisolone-thalidomide). 11,023 patients received treatment over 2010–2018. Time between diagnosis and treatment was shortest in Denmark (0.9 months), then Sweden (2.9 months) and Finland (4.6 months). Around one third of patients underwent ASCT. Lenalidomide-based regimens were prescribed to 23–28% of patients in Denmark and Finland, versus 12% in Sweden. Patients receiving lenalidomide had the longest wait for treatment, from 3.2 months (Denmark) to 12.1 months (Sweden). Treatment persistence was highest among patients receiving melphalan-prednisolone-thalidomide (7–8 months) in Finland and Sweden and lowest among those receiving bortezomib (3.5 months) in Finland. Overall survival (OS) was longest among patients with ASCT (7–10 years). Among patients receiving chemotherapy, OS (from diagnosis/treatment initiation), varied between cohorts. In a sensitivity analysis excluding patients with smouldering MM, OS decreased for all; for patients receiving bortezomib or lenalidomide, OS from diagnosis was 40–49 and 27–54 months, respectively. This population-based study of patients with NDMM receiving first-line MM-specific treatment, provides real-world data on treatment patterns and outcomes to complement data from randomised clinical trials. • Nordic patient registry data provide real-world evidence on treatments and outcomes. • Over 11,000 patients treated for multiple myeloma (2010–2018) in Nordic countries. • Time from diagnosis to treatment was shortest in Denmark. • Treatment persistence was highest in patients on melphalan-prednisolone-thalidomide. • Longest overall survival seen in patients with autologous stem cell transplantation. [ABSTRACT FROM AUTHOR]

A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM). Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed. Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406–0.835; P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366–0.759; P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35–1.04; P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41–1.66; P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29–0.89; P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53–2.09; P = 0.8970). AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined. ClinicalTrials.gov, number NCT01715285 • AAP+ADT showed survival benefit in mCSPC men regardless of visceral disease status. • Men with liver metastases had a poorer prognosis than those with lung metastases. • A benefit in OS and rPFS was not seen in the small group of men with liver metastases. [ABSTRACT FROM AUTHOR]

Around 50% of cutaneous melanomas harbour therapeutically targetable BRAF V600 mutations. Reliable clinical biomarkers predicting duration of response to BRAF -targeted therapies are still lacking. Recent in vitro studies demonstrated that BRAF-MEK inhibitor therapy response is associated with tumour TERT promoter mutation status. We assessed this potential association in a clinical setting. The study cohort comprised 232 patients with metastatic or unresectable BRAF V600-mutated melanoma receiving combined BRAF/MEK inhibitor treatment, including a single-centre retrospective discovery cohort (N = 120) and a prospectively collected multicenter validation cohort (N = 112). Patients were excluded if they received BRAF or MEK inhibitors in an adjuvant setting, as monotherapy, or in combination with immunotherapy. Kaplan–Meier and univariate/multivariate Cox regression analyses were performed as appropriate. median age at first diagnosis was 54 years (range 16–84 years). The majority of patients were men 147/232 (63.4%). Most tumours harboured TERT promoter mutations (72%, N = 167). A survival advantage was observed in both progression-free survival (PFS) and overall survival (OS) for patients with TERT promoter-mutant versus wild-type tumours in both the discovery cohort (mPFS of 9.6 months [ N = 87] vs 5.0 months [ N = 33]; hazard ratio [HR] = 0.56 [95% confidence interval {CI} 0.33–0.96] and mOS of 33.6 months vs 15.0 months; HR = 0.47 [95%CI 0.32–0.70]) as well as the validation cohort (mPFS of 7.3 months [ N = 80] vs 5.8 months [ N = 32]; HR = 0.67 [95%CI 0.41–1.10] and mOS of 51.1 months vs 15.0 months; HR = 0.33 [95%CI 0.18–0.63]). In the pooled cohort of TERT promoter-mutant (N = 167) versus wild-type (N = 65) tumours, respectively, PFS was 8.9 versus 5.5 months, (HR = 0.62; 95%CI 0.45–0.87; P = 0.004), and OS was 33.6 versus 17.0 months, (HR = 0.51; 95%CI 0.35–0.75, P = 0.0001). In patients with melanoma receiving BRAF/MEK-targeted therapies, TERT promoter mutations are associated with longer survival. If validated in larger studies, TERT promoter mutation status should be included as a predictive biomarker in treatment algorithms for advanced melanoma. • TERT promoter mutations are associated with prolonged progression-free and overall survival in patients receiving MAPKi therapy. • TERT promoter mutations may serve as a biomarker for response to MAPKi ther apy. • In BRAF V600 mutant melanoma patients TERT promoter mutation status may be relevant for deciding which therapy to give. [ABSTRACT FROM AUTHOR]

This study investigated how material deprivation in Italy influences the stage of hepatocellular carcinoma (HCC) at diagnosis and the chance of cure. 4114 patients from the Italian Liver Cancer database consecutively diagnosed with HCC between January 2008 and December 2018 were analysed about severe material deprivation (SMD) rate tertiles of the region of birth and region of managing hospitals, according to the European Statistics on Income and Living Conditions. The main outcomes were HCC diagnosis modalities (during or outside surveillance), treatment adoption and overall survival. In more deprived regions, HCC was more frequently diagnosed during surveillance, while the incidental diagnosis was prevalent in the least deprived. Tumour characteristics did not differ among regions. The proportion of patients undergoing potentially curative treatments progressively decreased as the SMD worsened. Consequently, overall survival was better in less deprived regions. Patients who moved from most deprived to less deprived regions increased their probability of receiving potentially curative treatments by 1.11 times (95% CI 1.03 to 1.19), decreasing their mortality likelihood (hazard ratio 0.78 95% CI 0.67 to 0.90). Socioeconomic status measured through SMD does not seem to influence HCC features at diagnosis but brings a negative effect on the chance of receiving potentially curative treatments. Patient mobility from the most deprived to the less deprived regions increased the access to curative therapies, with the ultimate result of improving survival. • A Multicentre Italian study on the impact of material deprivation on hepatocellular carcinoma (HCC) outcome. • Patients were stratified according to the material deprivation rate of Italian regions. • HCC survival was better in less deprived Italian regions. • Migration from most to less deprived regions improved HCC survival. • Effect of deprivation was mainly because of different access to HCC curative treatments. [ABSTRACT FROM AUTHOR]

In the TAX 323 (EORTC 24971) phase III trial enrolling patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), the addition of docetaxel (T) to cisplatin and 5-fluorouracil (PF)-based induction chemotherapy prior to definite radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS). The data were updated for PFS, OS and treatment-related long-term side-effects. Baseline clinical and laboratory data of 17 variables were collected and subjected to univariate and multivariate prognostic factor analyses for OS. All 358 patients randomised between 1999 and 2002 were included in the long-term analysis with a median follow-up of 8.6 years. The primary end-point of PFS remained significantly improved with TPF compared with PF (adjusted hazard ratio [HR], 0.70; 95% CI, 0.56–0.88, p = 0.002), translating into a persisting benefit in OS (adjusted HR, 0.75; 95% CI, 0.60–0.95, p = 0.015). Long-term side-effects in the TPF/PF arms comprised tracheostomy (7%/5%), feeding tube dependency (3%/6%) and gastrostomy (11%/11%). Second malignancy occurred in 8%/3%, respectively. Out of 177 patients randomised to the TPF arm, 160 were included in the multivariate analysis. Grade 2 or more dysphagia (p = 0.002) and grade 2 or more pain (p = 0.004) at baseline were identified as independent negative prognostic factors. In addition, OS differed across primary tumour sites (p = 0.027) and was worse in patients with a higher N-stage (p = 0.025). In LA-SCCHN patients treated with sequential chemoradiotherapy, TPF induction chemotherapy demonstrated long-lasting efficacy, superior to the PF regimen. Higher-grade dysphagia and pain are unfavourable prognosticators. • TPF is the optimal induction chemotherapy before definitive locoregional treatment. • The survival benefit of TPF over PF was confirmed at median follow-up of 8.6 years. • Baseline symptoms have independent negative prognostic value for overall survival. • Overall survival depends on primary site (worse for hypopharynx and oral cavity). • Overall survival is also worse in patients with a higher nodal stage. [ABSTRACT FROM AUTHOR]

We investigate the prognostic value of tumour-infiltrating lymphocytes (TILs) based on the evaluation of the present frequency in patients with breast cancer rather than that of the density proposed in previous research. Multiphoton microscopy (MPM) was introduced to label-freely obtain TIL images from a total of 564 patients, and then TILs were redefined as TILs-1 to TILs-3 from MPM images according to the relative positions between TILs, tumour cells and collagen fibres. More seminally, a new method, which was based on the present frequency of TILs-1 to TILs-3, was presented for assessing the predictive ability of TILs, and then a tumour-infiltrating lymphocytes score (TILs-score) for each patient was obtained by ridge regression analysis. Data results from Cox proportional hazards regression analysis showed that the TILs-score was an independent prognostic factor for both disease-free survival (DFS) and overall survival (OS) in the complete cohort (n = 564), oestrogen receptor (ER)–positive subgroup (n = 352) and ER-negative subgroup (n = 212), but was more suitable for the ER-positive subgroup. Furthermore, the nomogram model combining the TILs-score with independent clinical factors further improved the predictive ability for the ER-positive subgroup: area under the curve (AUC) at 5-year DFS (OS) and hazard ratio (HR) for DFS (OS) in the training cohort increase from 0.735 (0.785) to 0.814 (0.830) and from 3.156 (5.845) to 4.643 (7.006), respectively, and in the validation cohort from 0.749 (0.748) to 0.804 (0.830) and from 3.104 (3.701) to 3.729 (5.132), respectively. The TILs-score is an independent prognostic factor and displays a strong prognostic value for ER-positive breast cancer. To our knowledge, this is the first time to use MPM for studying the prognostic value of TILs in breast cancer. • A new method is presented for tumour-infiltrating lymphocytes score (TILs-score). • The TILs-score is an independent prognostic factor. • The TILs-score is more suitable for oestrogen receptor-positive breast cancer. [ABSTRACT FROM AUTHOR]

Ipilimumab plus nivolumab (COMBO) is the standard treatment in asymptomatic patients with melanoma brain metastases (MBM). We report a retrospective study aiming to assess the outcome of patients with MBM treated with COMBO outside clinical trials. Consecutive patients treated with COMBO have been included. Demographics, steroid treatment, Central Nervous System (CNS)-related symptoms, BRAF status, radiotherapy or surgery, response rate (RR), progression-free (PFS) and overall survival (OS) have been analyzed. 376 patients were included: 262 received COMBO as first-line and 114 as a subsequent line of therapy, respectively. In multivariate analysis, Eastern Cooperative Oncology Group (ECOG) (≥1 vs 0) [HR 1.97 (1.46–2.66)], extracerebral metastases [HR 1.92 (1.09–3.40)], steroid use at the start of COMBO [HR 1.59 (1.08–2.38)], CNS-related symptoms [HR 1.59 (1.08–2.34)], SRS (Stereotactic radiosurgery) [HR 0.63 (0.45–0.88)] and surgery [HR 0.63 (0.43–0.91)] were associated with OS. At a median follow-up of 30 months, the median OS (mOS) in the overall population was 21.3 months (18.1–24.5), whilst OS was not yet reached in treatment-naive patients, steroid-free at baseline. In patients receiving COMBO after BRAF/MEK inhibitors(i) PFS at 1-year was 15.7%. The dose of steroids (dexamethasone < vs ≥ 4 mg/day) was not prognostic. SRS alongside COMBO vs COMBO alone in asymptomatic patients prolonged survival. (p = 0.013). Toxicities were consistent with previous studies. An independent validation cohort (n = 51) confirmed the findings. Our results demonstrate remarkable long-term survival in treatment-naïve, asymptomatic, steroid-free patients, as well as in those receiving SRS plus COMBO. PFS and OS were poor in patients receiving COMBO after progressing to BRAF/MEKi. • Median OS was not reached in asymptomatic/steroid free pts with MBM receiving COMBO. • Patients receiving COMBO after BRAF/MEKi show a poor prognosis. • The dose of steroids during COMBO is not prognostic. • SRS given during COMBO is associated with improved survival. • Long-lasting responses can be maintained after treatment interruption. [ABSTRACT FROM AUTHOR]

The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed. Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270). CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD. • Chemoimmunotherapy prolongs PFS compared to chemotherapy in METΔ14ex NSCLC. • IO monotherapy confer long responses and OS similar to that of CHT-IO. • PD-L1 expression does not correlate with immunotherapeutic efficacy. • TP53 mutations are linked to better IO outcomes and may assist therapeutic decisions. • The rate of second-line treatment in the real-world setting is approximately 50%. [ABSTRACT FROM AUTHOR]

Small intestinal adenocarcinomas (SIAs) are rare. Hence, randomized controlled trials are lacking and understanding of the disease features is limited. This nationwide cohort investigates incidence, treatment and prognosis of SIA patients, to improve disease outcome. Data of 2697 SIA patients diagnosed from January 1999 through December 2019 were retrieved from the Netherlands Cancer Registry and Pathology Archive. Incidence was calculated using the revised European Standardized Rate. The influence of patient and tumor characteristics on overall survival (OS) was studied using survival analyses. The age-standardized incidence rate almost doubled from 0.58 to 1.06 per 100,000 person-years, exclusively caused by an increase in duodenal adenocarcinomas. OS did not improve over time. Independent factors for a better OS were a younger age, jejunal tumors, Lynch syndrome and systemic therapy. Only 13.8% of resected patients was treated with adjuvant chemotherapy, which improved OS compared to surgery alone in stage III disease (HR 0.47 (0.35–0.61)), but not in the limited group of deficient mismatch repair (MMR) patients (n = 53, HR 0.93 (0.25–3.47)). In the first-line setting, CAPOX was associated with improved OS compared to FOLFOX (HR 0.51 (0.36–0.72)). For oligometastatic patients, a metastasectomy significantly improved OS (HR 0.54 (0.36–0.80)). The incidence of SIAs almost doubled in the past 20 years, with no improvement in OS. This retrospective non-randomized study suggests the use of adjuvant chemotherapy for stage III disease and first-line CAPOX for metastatic patients. For selected oligometastatic patients, a metastasectomy may be considered. MMR-status testing could aid in clinical decision-making. • A large nationwide cohort study of 2697 small intestinal adenocarcinomas (SIAs). • The incidence of duodenal adenocarcinomas almost doubled with no improvement in OS. • Despite adjuvant chemotherapy prolonging OS, only 13.8% of eligible patients were treated. • In the first-line setting CAPOX prolonged OS compared to FOLFOX and capecitabine. • A metastasectomy in patients with one distant metastasis was associated with OS. [ABSTRACT FROM AUTHOR]

The impact of immunosuppressive therapy (IST) on immune-checkpoint inhibition (ICI) is unclear. Patients with unresectable advanced melanoma (MM) treated with ICI in the years 2011–2020 were identified from the prospective multicenter German skin cancer registry ADOREG. Patients with IST within 60 days before, or within 30 days after start of ICI were compared to patients without IST. End points were disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) determined by Kaplan-Meier method. Prognostic factors were evaluated in a Cox regression model. Of 814 patients treated with ICI, 73 (9%) received concomitant IST, mainly steroids. Patients with brain metastases (BM) received IST more frequently (n = 34/130 patients; 26%), than patients without BM (39/684 patients; 6%). In patients without BM, IST initiated before, but not IST initiated after start of ICI was significantly associated with worse PFS (univariate hazard ratio (HR) 2.59, 95% confidence interval (95%-CI) 1.07–6.28, p = 0.035; multivariate HR 3.48, 95%-CI 1.26–9.6, p = 0.016). There was no association between IST and OS or DCR. In patients with BM, IST initiated before, but not after start of ICI was significantly associated with worse OS (univariate HR 2.06, 95%-CI 1.07–3.95, p = 0.031; multivariate HR 5.91, 95%-CI 1.74–20.14, p = 0.004). There was no association between IST and PFS or DCR. Patients receiving IST 60 days before start of ICI showed a tendency to an impaired therapy outcome. IST initiated within 30 days after start of ICI, mainly due to early side effects, did not affect the efficacy of ICI therapy. • Immunosuppressive drugs before start of ICI may negatively impact treatment efficacy. • This effect was seen in patients with and without brain metastases. • Immunosuppressive drugs given after start of ICI did not impact treatment efficacy. [ABSTRACT FROM AUTHOR]

To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity. Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the "Stichting Hemato-Oncologie voor Volwassenen Nederland" (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents' willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR). Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS. Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients. • Varied views about PFS among healthcare professionals and regulators impact toxicity trade-offs. • Views about PFS related to beliefs about surrogacy and intrinsic benefit of PFS. • Concerns about bias and communication raised for PFS by healthcare professionals and regulators. [ABSTRACT FROM AUTHOR]