Radiomic Parameters for the Evaluation of Response to Treatment in Metastatic Colorectal Cancer Patients with Liver Metastasis: Findings from the CAVE-GOIM mCRC Phase 2 Trial.

BACKGROUND: CAVE is a single arm, Phase 2 trial, that demonstrated anti-tumor activity of cetuximab rechallenge plus avelumab in patients with RAS wild type (wt) metastatic colorectal cancer (mCRC). OBJECTIVE: We conducted a post hoc analysis to identify potential radiomic biomarkers for patients with CRC liver metastasis (LM). PATIENTS AND METHODS: Patients with LM that could be measured by enhanced contrast phase computed tomography (CT) imaging at baseline and at first response evaluation were included. Multiple texture parameters were extracted with the LifeX Software. Delta-texture (D-TA) variations were calculated by comparing data at baseline and after treatment. RESULTS: Overall, 55/77 patients (71%) had LM; 39 met the inclusion criteria for the current analysis. The D-TA parameters that significantly correlated at univariate analysis with median progression-free survival (mPFS) were EntropyHistogram (p = 0.021), HomogeneityGLCM (p < 0.001) and Dissimilarity GLCM (p = 0.002). At multivariate analysis, only HomogeneityGLCM resulted significant for PFS (p = 0.001). Patients (19/39, 48.7%) with reduction of HomogeneityGLCM experienced better mPFS (4.6 vs 2.9 months; HR 0.45; 95% CI 0.23-0.88; p = 0.021) and median overall survival (mOS) (17.3 vs 6.8 months; HR 0.40, 95% CI 0.21-0.80; p = 0.010). A trend to better mPFS, was also observed in patients with RAS/BRAF wt circulating tumor DNA and reduction of HomogeneityGLCM. Overall survival was significantly better in this subgroup of patients with low HomogeneityGLCM: mOS was 17.8 (95% CI 15.5-20.2) versus 6.8 months (95% CI 3.6-10.0) (HR 0.34, 95% CI 0.14-0.81; p = 0.016). CONCLUSION: Reduction in the D-TA parameter HomogeneityGLCM by radiomic analysis correlates with improved outcomes in patients with LM receiving cetuximab rechallenge plus avelumab therapy. Larger prospective studies are needed to validate and confirm these findings.

Prognostic role of circulating cytokines and inflammation indexes for avelumab maintenance in metastatic urothelial carcinoma.

Background: Avelumab maintenance after first-line platinum-based chemotherapy represents a cornerstone for the treatment of metastatic urothelial carcinoma (mUC). However, identifying prognostic biomarkers is paramount for optimizing patients' benefits while minimizing toxicity. Cytokines represent circulating mediators of the complex interaction between cancer, the immune system, and inflammation. Inflammation, a hallmark of cancer, can be expressed by circulating factors. In different tumor subtypes, peripheral blood biomarkers, such as circulating cytokines, and systemic inflammatory indexes, have been addressed as potential prognostic factors for immune checkpoint inhibitors. However, their role in mUC still needs to be determined. Methods: Between February 2021 and April 2023, we prospectively collected plasma cytokines and inflammation indexes in 28 patients with mUC before starting avelumab as first-line maintenance. The primary endpoint was the relationship between baseline cytokines and inflammatory indexes with the clinical benefit (CB), defined as the number of Responders. Secondary endpoints included the correlation of baseline cytokines and inflammatory indexes with progression-free survival (PFS), overall survival (OS), and the number and grade of immune-related adverse events. Results: High pre-treatment levels of interferon (IFN)-γ and interleukin (IL)-2, and low levels of IL-6, IL-8, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and systemic-inflammation index (SII) were associated with clinical benefit and longer survival. In the multivariate analysis, low IL-8, NLR, and SII levels maintained a positive prognostic value for OS. Conclusion: Our data suggest that, in mUC patients receiving avelumab, pre-treatment levels of plasma cytokines and inflammatory indexes may serve as potential prognostic biomarkers for response and efficacy. In particular, patients with signs of pre-therapeutic inflammation showed a significantly lower response and survival to avelumab. On the contrary, low systemic inflammation and high levels of cytokines characterized responders and longer survivors.

Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.

BACKGROUND: Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. METHODS: Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). CONCLUSIONS: First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Importance: Immune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial. Objectives: To evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs. Data Sources: PubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023. Study Selection: Two authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1-positive and -negative tumors. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies. Main Outcomes and Measures: Primary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1-positive tumors and patients with PD-L1-negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1-positive and -negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials. Results: A total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1-positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1-positive tumors and 5.1% to 63.2% in patients with PD-L1-negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1-positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P < .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1-positive tumors and from 6.0 to 19.1 months in patients with PD-L1-negative tumors. The pooled HR showed a significant reduction for patients with PD-L1-positive tumors compared with those with PD-L1-negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P < .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response. Conclusions and Relevance: This systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Immune checkpoint inhibitors plus chemotherapy in first-line endometrial cancer treatment: Still the era of microsatellites?

OBJECTIVE: The combination of immune checkpoint inhibitors (ICIs) plus chemotherapy is currently being tested as the first-line treatment of advanced endometrial. We aimed to evaluate the efficacy and safety of this combination. DESIGN: We performed a meta-analysis of randomized clinical trials. POPULATION AND SETTING: Patients with advanced endometrial carcinoma receiving ICIs plus chemotherapy in the experimental arm, compared with chemotherapy plus placebo in the control arm, were included. METHODS AND OUTCOMES: We evaluated the progression-free survival (PFS) as an efficacy outcome and the number and grades of adverse events (AEs) for safety. Hazard ratios (HR) for PFS and risk ratios (RR) for AEs, with 95% confidence intervals (CI), were calculated. RESULTS: 1303 patients were treated in the included studies. Adding ICIs to chemotherapy significantly improved PFS in mismatch repair deficient (dMMR-HR 0.29; 95% CI, 0.20-0.42; p < 0.00001) and in mismatch repair proficient (pMMR-HR 0.64; 95% CI, 0.46-0.90; p = 0.01) patients. No difference emerged for all-grades AEs (RR 1.00; p = 0.98), but the risk of ≥G3 AEs was increased in the ICIs + chemotherapy group (RR 1.22; 95% CI, 1.11-1.34; p < 0.0001). CONCLUSIONS: Adding ICIs to chemotherapy significantly improves PFS in first-line endometrial cancer, regardless of MMR status.

Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study.

PURPOSE: The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS: In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS: Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION: The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial.

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Hematological Toxicity of PARP Inhibitors in Metastatic Prostate Cancer Patients with Mutations of BRCA or HRR Genes: A Systematic Review and Safety Meta-analysis.

BACKGROUND: PARP inhibitors (PARPis) are effective treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) as single agents or in combination with androgen receptor-targeted agents (ARTA). However, a clinically relevant adverse effect of these agents is hematological toxicity, a typical class adverse event (AE), which can lead to treatment modifications and discontinuations. OBJECTIVE: We aimed to analyze the risk of hematological AEs, including anemia, neutropenia, and thrombocytopenia secondary to PARPi treatments in mCRPC. PATIENTS AND METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases, the American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO) meeting abstracts for clinical trials concerning the use of PARPis, both as single agents and in combination, in patients with mCRPC. The search deadline was 30 June, 2023. We analyzed the pooled incidence of all grades of and ≥ G3 anemia, neutropenia, and thrombocytopenia. We subsequently calculated risk ratios (RRs) for all grades of and ≥ G3 AEs of PARPis versus non-PARPis from randomized clinical trials (RCTs). RESULTS: Eleven phase 2/3 trials with olaparib, niraparib, rucaparib, and talazoparib administered as single agents or combined with ARTA were selected. Anemia was the most common all grades (38.6%) and ≥ G3 AE (24.9%). In the analysis of relative risk, six RCTs were included. The administration of PARPis significantly increased the risk of developing all grades of anemia (RR = 2.44), neutropenia (RR = 3.15), and thrombocytopenia (RR = 4.66) compared with non-PARPis. Similarly, a significant increase in the risk of ≥ G3 anemia (RR = 5.73) and thrombocytopenia (RR = 5.44), and a not significant increased risk of neutropenia (RR = 3.41), were detected. CONCLUSIONS: In mCRPC, PARPis increase the risk of hematological toxicity compared with other treatments, both as single agents or combined with ARTA (high-quality evidence). Clinicians should be aware of this risk and the correct management, especially with the expected increased PARPis use in mCRPC.

Personalized medicine for metastatic prostate cancer: The paradigm of PARP inhibitors.

Despite remarkable progress in the last decade, metastatic prostate cancer (mPCa) remains incurable. The approval of PARP inhibitors (PARPis) represents a milestone in this field, which definitively enters the era of precision medicine, as mPCa is often enriched for defects of homologous recombination repair genes. PARPis are now used as single agents for patients with metastatic castration-resistant PCa. Moreover, combinations of PARPis plus androgen-receptor targeted agents and immune checkpoint inhibitors, and earlier applications of PARPis in the metastatic hormone-sensitive PCa are under evaluation, representing the possible upcoming applications of these agents. Mechanisms of sensitization and resistance have been only partially elucidated. In our review, we summarize the current clinical evidence regarding PARPis in mPCa and the future directions of these targeted agents.

Enfortumab vedotin in metastatic urothelial carcinoma: the solution EVentually?

Metastatic urothelial carcinoma (mUC) is an aggressive malignancy with a dismal prognosis. Enfortumab vedotin (EV) is an antibody-drug conjugate consisting of an antibody targeting Nectin-4. This protein is highly expressed in UC cells. After binding, monomethyl auristatin E is released into cells, causing UC cell death. EV has been approved as a single agent for pre-treated mUC, with interesting improvements in response rate and survival in a setting with limited treatment options. More recently, EV approval occurred in cisplatin-ineligible naïve mUC patients in combination with pembrolizumab. Our review aims to summarize the pharmacological properties, clinical studies, and future developments of EV in mUC.

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting.

Ovarian cancer (OC) is the eighth most common cancer among the female population and the most lethal of all the female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC in the maintenance setting post platinum-based chemotherapy. Niraparib is the first Food and Drug Administration (FDA)- and European Medical Agency (EMA)-approved PARPi as maintenance therapy for platinum-sensitive OC, regardless of BReast CAncer gene (BRCA) status, in first-line patients, with a recent restriction to germline BRCA mutations in second-line patients. In this review, we comprehensively summarized the pharmacological properties of niraparib, alongside the efficacy and safety data of the main trials leading to the current approvals, and discussed the future development of this agent.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Thoracic ultrasound combined with low-dose computed tomography may represent useful screening strategy in highly exposed population in the industrial city of Taranto (Italy).

Objectives: We validated a screening protocol in which thoracic ultrasound (TUS) acts as a first-line complementary imaging technique in selecting patients which may deserve a second-line low-dose high resolution computed tomography (HRCT) scan among a population of asymptomatic high-risk subjects for interstitial lung abnormalities (ILA) and lung cancer. Due to heavy environmental pollution burden, the district Tamburi of Taranto has been chosen as "case study" for this purpose. Methods: From July 2018 to October 2020, 677 patients aged between 45 and 65 year and who had been living in the Tamburi district of Taranto for at least 10 years were included in the study. After demographic, clinical and risk factor exposition data were collected, each participant underwent a complete TUS examination. These subjects were then asked to know if they agreed to perform a second-level examination by low-dose HRCT scan. Results: On a total of 167 subjects (24.7%) who agreed to undergo a second-level HRCT, 85 patients (50.9%) actually showed pleuro-pulmonary abnormalities. Interstitial abnormalities were detected in a total of 36 patients on HRCT scan. In particular, 34 participants presented subpleural ILAs, that were classified in the fibrotic subtype in 7 cases. The remaining 2 patients showed non-subpleural interstitial abnormalities. Subpleural nodules were observed in 46 patients. TUS showed an overall diagnostic accuracy of 88.6% in detecting pleuro-pulmonary abnormalities in comparison with HRCT scan, with a sensitivity of 95.3%, a specificity of 81.7%, a positive predictive value of 84.4% and a negative predictive value of 94.4%. The matched evaluation of specific pulmonary abnormalities on HRTC scan (i.e., interstitial abnormalities or pulmonary nodules) with determinate sonographic findings revealed a reduction in both TUS sensibility and specificity. Focusing TUS evaluation on the assessment of interstitial abnormalities, a thickened pleural line showed a sensitivity of 63.9% and a specificity of 69.5%, hypoechoic striae showed a sensitivity of 38.9% and a specificity of 90.1% and subpleural nodules showed a sensitivity of 58.3% and a specificity of 77.1%. Regarding to the assessment of subpleural nodules, TUS showed a sensitivity of 60.9% and a specificity of 81.0%. However, the combined employment of TUS examination and HRCT scans allowed to identify 34 patients with early subpleural ILA and to detect three suspicious pulmonary nodules (of which two were intraparenchymal and one was a large subpleural mass), which revealed to be lung cancers on further investigations. Conclusion: A first-line TUS examination might aid the identification of subjects highly exposed to environmental pollution, who could benefit of a second-line low-dose HRCT scan to find early interstitial lung diseases as well as lung cancer. Protocol registration code: PLEURO-SCREENING-V1.0_15 Feb, 17.

Olaparib and advanced ovarian cancer: Summary of the past and looking into the future.

Ovarian cancer (OC) is women's eighth most common cancer, bearing the highest mortality rates of all female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC as a maintenance post platinum-based chemotherapy. Olaparib is the first PARPi developed for this disease. Results from Study 42, Study 19, SOLO2, OPINION, SOLO1, and PAOLA-1 clinical trials, led to the FDA and EMA approval of olaparib for the maintenance treatment of women with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer without platinum progression: in the platinum-sensitive recurrent OC; in the newly diagnosed setting in case Breast Cancer (BRCA) mutations and, in combination with bevacizumab, in case of BRCA mutation or deficiency of homologous recombination genes. In this review, we synthetized olaparib's pharmacokinetic and pharmacodynamic properties and its use in special populations. We summarized the efficacy and safety of the studies leading to the current approvals and discussed the future developments of this agent.

Current practice of genomic profiling of patients with advanced solid tumours in Italy: the Italian Register of Actionable Mutations (RATIONAL) study.

BACKGROUND: The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid tumours. METHODS: The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified. RESULTS: Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing. CONCLUSION: The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients.

Comparison of Anti-Programmed Cell Death Ligand 1 Therapy Combinations vs Sunitinib for Metastatic Renal Cell Carcinoma: A Meta-analysis.

This meta-analysis of 3 randomized clinical trials evaluates the association of combined anti­PD-L1 agents with survival and response rate among patients with metastatic renal cell carcinoma.

Pretreatment Plasma Circulating Tumor DNA RAS/BRAF Mutational Status in Refractory Metastatic Colorectal Cancer Patients Who Are Candidates for Anti-EGFR Rechallenge Therapy: A Pooled Analysis of the CAVE and VELO Clinical Trials.

Rechallenge with anti-EGFR drugs represents a promising strategy in refractory RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC). We performed the pooled analysis of the CAVE and VELO studies to evaluate the percentage of patients with WT circulating tumor DNA (ctDNA) tumors and the association of mutational status with time from the last anti-EGFR drug administration. At baseline, 97/129 patients had RAS/BRAF WT plasma ctDNA, while 32/129 had RAS/BRAF mutated plasma ctDNA. Median anti-EGFR drug-free interval was 10.6 (CI 95%, 8.9-13.4) months in the plasma RAS/BRAF mutant group as compared to 13.0 (CI 95%, 11.1-16.6) months in RAS/BRAF WT group (p = 0.169). To investigate the time window of the RAS/BRAF mutant cancer cell clone disappearance, descriptive analysis using different time points was performed. No difference in the proportion of patients whose baseline plasma ctDNA was RAS/BRAF WT or mutated was found between 4 and 18 months since the last administration of anti-EGFR drugs. In contrast, 38/44 of patients with anti-EGFR drug-free interval of 18 months or more displayed a ctDNA RAS/BRAF WT status. Taken together, these results shows that the length of anti-EGFR free interval is not a sufficient criterion for patient selection, supporting the role of liquid biopsies for improving treatment efficacy.

Efficacy and safety of a biomarker-driven cetuximab-based treatment regimen over 3 treatment lines in mCRC patients with RAS/BRAF wild type tumors at start of first line: The CAPRI 2 GOIM trial.

Background: Monoclonal antibodies targeting EGFR such as cetuximab or panitumumab represent a major step forward in the treatment of RAS wild type (WT) metastatic colorectal cancer (mCRC). Unfortunately, primary and acquired resistance mechanisms occur, with a huge percentage of patients succumbing to the disease. In the last years, RAS mutation has been identified as the main molecular driver that determine resistance to anti-EGFR monoclonal antibodies. Liquid biopsy analysis allows to a dynamic and longitudinal assessment of mutational status during mCRC disease and has provided important information on the use of anti-EGFR drugs beyond progression or as rechallenge strategy in patients with RAS WT tumors. Methods: The phase II CAPRI 2 GOIM trial investigates the efficacy and safety of a bio-marker-driven cetuximab-based treatment regimen over 3 treatment lines in mCRC patients with RAS/BRAF WT tumors at start of first line. Discussion: The aim of the study is to identify patients with RAS/BRAF WT tumors defined as "addicted" to an-anti EGFR based treatment along three lines of therapy. Moreover, the trial will evaluate the activity of cetuximab re-introduction in combination with irinotecan as 3rd line therapy as rechallenge for patients that will be treated in second line with FOLFOX plus bevacizumab, having a RAS/BRAF mutant disease at progression after FOLFIRI plus cetuximab first line. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by a liquid biopsy assessment of RAS/BRAF status by a comprehensive 324 genes Foundation One Liquid assay (Foundation/Roche). Trial registration: EudraCT Number: 2020-003008-15, ClinicalTrials.gov identifier: NCT05312398.