Abstract Introduction: Despite major advances with immune checkpoint inhibitors (ICIs) in treatment of metastatic NSCLC, reliable biomarkers to predict who will benefit from therapy and monitor early treatment response remain limited. Thymidine kinase is an enzyme fundamental in the DNA synthesis, its activity reflects tumor cell proliferation and tumor aggressiveness. This study (NCT06823401) is the first to evaluate plasma TKa levels in NSCLC patients receiving immunotherapy (IT) or chemotherapy-IT (CHT-IT). The objectives were to determine whether baseline TKa levels can predict efficacy of IT and if early on-treatment changes in TKa levels reflect treatment response, thereby supporting TKa as a minimally invasive biomarker for patient therapy selection and early efficacy assessment. The capacity of TKa to evaluate cell proliferation is expected to reflect and predict successful T-cell activation of IT and prolonged efficacy. Methods: 94 patients (50 males, 44 females) with metastatic NSCLC, had plasma samples collected at baseline (pre-treatment) and at second treatment cycle of whom 93 received first-line systemic therapy. Circulating TKa was measured using the FDA cleared and CE marked DiviTum® TKa assay (Biovica, Sweden), with values reported in DiviTum units of activity (DuA). Analysis was performed blinded to clinical outcomes. TKa was evaluated for its association with response rate (RR), progression-free survival (PFS), overall survival (OS) and was also correlated to other biomarkers, including PD-L1 expression. Results: 65 pts (70%) received first-line CHT-IT, while 28 pts (30%) received IT alone. PD-L1 expression was <1% in 37 pts (40%), 1-49% in 17 pts (18%), ≥50% in 34 pts (36%), and unknown in 6 pts (6%). The median baseline TKa level was 203 DuA. The RR in the low (<203 DuA) and high-TKa group was 52% and 32% respectively (p = 0.80) while the mPFS was not reached in the low TKa group versus 7.3 mos in high TKa group (p = 0.13). The 1-year OS rate was similar between the two groups (69.9% vs 62.4%, p = 0.34). Using a TKa cutoff of 326 DuA, we observed a statistically significant difference in mPFS; 13.8 months in the low-TKa group (65 pts) versus 3.3 months in the high-TKa group (23 pts) (p = 0.004). The 1-year OS rate was 65.6% vs 53.3%, respectively (p = 0.18). Further data on patients treated with IT alone and with CHT-IT will be presented at the meeting. Conclusions: Our study shows a possible association between high plasma TKa levels and shorter PFS and OS in advanced NSCLC treated with first-line IT alone or combined with CHT, supporting the potential role in guiding treatment choice. Further studies are needed to validate the prognostic and predictive value of TKa in this setting. Citation Format: Maristella Giammaruco, Lorenza Landi, Mattias Bergqvist, Gabriele Minuti, Silvia Carpano, Francesca Fusco, Martina Brandi, Fabiana Letizia Cecere, Vincenzo Pio Di Noia, Livia Tosetto, Andrea Torchia, Corrado Orciuolo, Daniele Marinelli, Grisel Maver Militello, Diana Giannarelli, Federico Cappuzzo. Circulating thymidine kinase activity (TKa) as a predictive and dynamic biomarker in the metastatic non-small cell lung cancer (NSCLC): Immunoblood study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7753.

Introduction The aim of this study was to analyze real-life data from a cohort of adult patients receiving atezolizumab in combination with carboplatin and etoposide for first-line treatment of ES-SCLC, in order to assess relative dose intensity (RDI), time-to-treatment discontinuation (TTD), time-to-treatment failure (TTF), progression-free survival (PFS), overall survival (OS) of treatments as well as the correlation between these outcomes. Methods An observational retrospective study was conducted. All patients treated with atezolizumab combined with carboplatin and etoposide for first-line treatment of ES-SCLC were included. Median TTD, TTF, PFS and OS were calculated in our cohort of patient by the Kaplan Meier method. Results The curves obtained with the Kaplan Meier method of TTF and TTD are substantially similar, indicating a good concordance of the information extracted by the two different data sources. This tendency was confirmed also when the TTD versus PFS curves were compared. The median OS registered was 11.8 months. Patients with no liver metastases showed a longer median time of OS than patients with liver metastases. The mean value of RDI for the entire cohort was 87.4%. Conclusions Our study showed that TTD, calculated from the administration data is a useful proxy of TTF as registered in the clinical chart. TTD is a real-world outcome that can be used to demonstrate the efficacy of drugs used for administered therapies. It can be used as an end point for RWE studies, where the evaluation is less structured and standardized.

BACKGROUND:Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response. METHODS:Methods involved RNA-SEQ on NSCLC cells with depleted hMENA isoforms. A retrospective observational study assessed tissues from surgically treated N0 patients with NSCLC, using immunohistochemistry for tumoral and stromal hMENA isoforms, fibronectin, and TLS presence. ICB-treated patient tumors were analyzed using Nanostring nCounter and GeoMx spatial transcriptomics. Multiparametric flow cytometry characterized B cells and tissue-resident memory T cells (TRM). Survival and ICB response were estimated in the cohort and validated using bioinformatics pipelines in different datasets. FINDINGS:Findings indicate that hMENA11a in NSCLC cells upregulates the TLS regulator LTβR, decreases fibronectin, and favors CXCL13 production by TRM. Conversely, hMENAΔv6 in CAFs inhibits LTβR-related NF-kB pathway, reduces CXCL13 secretion, and promotes fibronectin production. These patterns are validated in N0 NSCLC tumors, where hMENA11ahigh expression, CAF hMENAΔv6low, and stromal fibronectinlow are associated with intratumoral TLS, linked to memory B cells and predictive of longer survival. The hMENA isoform pattern, fibronectin, and LTβR expression broadly predict ICB response in tumors where TLS indicates an anti-tumor immune response. INTERPRETATION:This study uncovers hMENA alternative splicing as an unexplored contributor to TLS-related Tumor Immune Microenvironment (TIME) and a promising biomarker for clinical outcomes and likely ICB responsiveness in N0 patients with NSCLC. FUNDING:This work is supported by AIRC (IG 19822), ACC (RCR-2019-23669120), CAL.HUB.RIA Ministero Salute PNRR-POS T4, "Ricerca Corrente" granted by the Italian Ministry of Health.

Oncogene-addicted NSCLC inevitably becomes resistant to targeted therapy by developing acquired resistance through on- or off-target mechanisms, potentially detectable by liquid biopsy. We present the first reported case of a patient with pretreated EGFRdel19/BRAFV600E lung adenocarcinoma and symptomatic leptomeningeal metastasis obtaining durable clinical benefit on osimertinib, dabrafenib, and trametinib treatment.

Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of Mitogen-Activated Protein Kinase Kinase 3 (MKK3), a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene expression profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the roles of MKK3 in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAFV600E CRC lines and derived dabrafenib-resistant (DABR) sublines. Dabrafenib treatments reduce MKK3 activation by inducing autophagy in parental but not DABR cells. The MKK3 knockdown induces cell death in DABR cells, whereas ectopic MKK3 expression reduces dabrafenib sensitivity in parental cells. Mechanistically, activated MKK3 interacts and co-localizes with c-Myc oncoprotein (MYC), sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding light on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAFV600E CRC.

Immunotherapy has radically changed the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). PD-L1 expression is generally associated with efficacy of immunotherapy, with PD-L1 overexpressing (PD-L1 >50%) NSCLC patients deriving the greatest benefit. However, a consistent proportion of positive cases do not respond to treatment, while some PD-L1 negative patients gain a significant survival benefit. Mechanisms underlying these different outcomes remain largely unknown. The development of antibodies directed against immune checkpoint inhibitors (ICIs) could affect sensitivity and tolerability to treatment. Aim of the present study was to investigate whether patients receiving ICIs develop antidrug antibodies and if this event impact on drug efficacy and/or toxicity.

Importance Gastrointestinal stromal tumor (GIST) follow-up is recommended by international guidelines, but data on the role of follow-up in patients with low relapse risk are missing. For these patients, the potential benefit of anticipating recurrence detection should be weighed against psychological burden and radiologic examination loads in terms of costs and radiation exposure. Objective To evaluate the outcomes of guideline-based follow-up in low-risk GIST. Design, Setting, and Participants This multi-institutional retrospective cohort study involving Italian Sarcoma Group reference institutions evaluated patients with GIST who underwent surgery between January 2001 and June 2019. Median follow-up time was 69.2 months. Data analysis was performed from December 15, 2022, to March 20, 2023. Patients with GIST at low risk according to Armed Forces Institute of Pathology criteria were included provided adequate clinical information was available: primary site, size, mitotic index, surgical margins, and 2 or more years of follow-up. Exposures All patients underwent follow-up according to European Society for Medical Oncology (ESMO) guidelines. Main Outcomes and Measures The primary outcome was the number of tests needed to identify a relapse according to ESMO guidelines follow-up plan. Secondary outcomes included relapse rate, relapse timing, disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), postrelapse OS, secondary tumor rates, and theoretical ionizing radiation exposure. An exploratory end point, new follow-up schedule proposal for patients with low-risk GIST according to the observed results, was also assessed. Results A total of 737 patients (377 men [51.2%]; median age at diagnosis, 63 [range, 18-86] years) with low-risk GIST were included. Estimated 5-year survival rates were 95.5% for DFS, 99.8% for GIST-SS, and 96.1% for OS. Estimated 10-year survival rates were 93.4% for DFS, 98.1% for GIST-SS, and 91.0% for OS. Forty-two patients (5.7%) experienced disease relapse during follow-up (9 local, 31 distant, 2 both), of which 9 were detected after 10 or more years. This translated into approximately 1 relapse detected for every 170 computed tomography scans performed, with a median radiation exposure of 80 (IQR, 32-112) mSv per patient. Nongastric primary tumor (hazard ratio [HR], 2.09; 95% CI, 1.14-3.83; P = .02), and KIT mutation (HR, 2.77; 95% CI, 1.05-7.27; P = .04) were associated with a higher risk of relapse. Second tumors affected 187 of 737 patients (25%), of which 56 were detected during follow-up and represented the primary cause of death in these patients. Conclusions and Relevance In this cohort study on patients affected by low-risk GISTs, the risk of relapse was low despite a follow-up across 10 or more years. These data suggest the need to revise follow-up schedules to reduce the anxiety, costs, and radiation exposure of currently recommended follow-up strategy.

BACKGROUND:Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA11a isoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA11a downregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA11a downregulation.METHODS:Effects of hMENA11a downregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort.RESULTS:Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA11a induces IFN pathway activation, the production of different inflammatory mediators including IFNβ via RIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA11a, high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy.CONCLUSIONS:Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA11a in modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC.

GISTs are rare soft tissue neoplasms harboring, in most cases, activating mutations in KIT and PDGFRA genes. The aim of this study is to describe the molecular characteristics of GIST samples from Regina Elena National Cancer Institute. We collected sequencing data from 153 samples from GIST patients between January 2017 and March 2023. Next generation sequencing was performed on samples derived from surgical excision or biopsy of the primary or metastatic lesions. The Ion AmpliSeq Cancer Hotspot panel V2 and the Oncomine Focus Assay (Thermofisher Scientific) were used. The analysis was performed with R-4.2.2 and oncokb-annotator. The top 5 mutated genes were KIT (69% of the cases), TP53 (63%), PDGFRA (20%), KDR (20%), and PIK3CA (17%); the median number of variants per sample was 3. The most affected exons in KIT were 11 (51%), 9 (13.9%), 10 (13.3%); exon 17 harbored 3.3% of the variants; exon 13 1.3%. The most affected exons in PDGFRA were 18 (36.6%) and 10 (34.1%); the mutations in exons 14 and 12 accounted, respectively, for 7.3% and 4.9% of the cases. We annotated the variants according to OncoKB Therapeutic Levels of Evidence V2: 74 out of 631 total variants (11.7%) were annotated as oncogenic, 86 (13.6%) as likely oncogenic, 14 (2.2%) as likely neutral and 457 (72.4%) as inconclusive or unknown. Among the 160 oncogenic or likely oncogenic variants, 103 (64.4%) had a therapeutic level 1, 18 (11.3%) level 2, 9 (5.6%) level R1, 5 (3.1%) level R2. As for the KIT gene, 90 of the 151 variants (59.6%) were annotated as oncogenic or likely oncogenic, all of them had a therapeutic level 1, 5 (3.3%) had level R2. Regarding the PDGFRA gene, 14 out of 41 variants (34.1%) were annotated as oncogenic or likely oncogenic, all but one had a therapeutic level 1, 14 level 2, 9 level R1. The remaining oncogenic or likely oncogenic variants affected the following genes: KDR (19.4%), TP53 (8.8%), CTNNB1, JAK2, FBXW7, GNAS, NF1, PIK3CA, RB1, RET; 2 of them had a therapeutic level 3B, 1 level 4. Most of the recorded variants were in KIT and PDGFRA genes. More than half of them are oncogenic and targetable. Notably, we found other oncogenic variants that can have a role in the development of the disease and in the onset of resistance to the treatment.

OBJECTIVES:Target therapy with BRAF/MEK inhibitors in metastatic melanoma is characterised by a high response rate; however, acquired resistance to treatment develops in many cases. We aimed to investigate if baseline total metabolic tumour volume (TMTV) and therapy-response assessment by [18F]FDG PET/CT have a prognostic role on progression-free survival (PFS) and overall survival (OS) in patients with metastatic melanoma receiving BRAF ± MEK inhibitors. METHODS:Fifty-seven patients who performed an [18F]FDG PET/CT at baseline and on treatment were retrospectively evaluated. A Cox proportional-hazard model was used to examine associations between OS and PFS with baseline clinical/PET parameters as well as for PET response. RESULTS:According to EORTC criteria, 34 patients were classified as responders (partial/complete metabolic response [PMR/CMR]) and 23 as non-responders (progressive/stable metabolic disease [PMD/SMD]). Baseline characteristics associated with a shorter PFS were more than two metastatic organ sites and TMTV > 56 cm3; the latter was the only independent feature at multivariate analysis. Patients achieving a CMR were associated with a prolonged PFS compared with those with PMR (median PFS 42.9 vs 8.8 months; p = 0.009). Disease progression occurred in new-onset disease sites in 87.5% of CMR, 7.1% of PMR and 34.8% of PMD/SMD (p < 0.001). High baseline TMTV and lack of treatment response were independent prognostic factors for OS, stratifying patients in three different prognostic classes (median OS 6.7, 18.3 and 102.2 months, respectively). CONCLUSIONS:Baseline TMTV and metabolic response may be useful prognostic indicators for PFS and OS in patients with advanced melanoma treated with BRAF/MEK inhibitors. KEY POINTS:• In a retrospective cohort of 57 metastatic melanoma patients treated with BRAF/MEK inhibitors, a TMTV > 56 cm3 at baseline [18F]FDG PET/CT was significantly correlated with a shorter PFS and OS. • The combined use of baseline TMTV along with PET response during treatment allowed for the identification of three groups of patients with very different median OS.

Human papillomaviruses (HPVs) are associated with invasive malignancies, including almost 100% of cervical cancers (CECs), and 35–70% of oropharyngeal cancers (OPCs). HPV infection leads to clinical implications in related tumors by determining better prognosis and predicting treatment response, especially in OPC. Currently, specific and minimally invasive tests allow for detecting HPV-related cancer at an early phase, informing more appropriately therapeutical decisions, and allowing for timely disease monitoring. A blood-based biomarker detectable in liquid biopsy represents an ideal candidate, and the use of circulating HPV DNA (ct-DNA) itself could offer the highest specificity for such a scope. Circulating HPV DNA is detectable in the greatest part of patients affected by HPV-related cancers, and studies have demonstrated its potential usefulness for CEC and OPC clinical management. Unfortunately, when using conventional polymerase chain reaction (PCR), the detection rate of serum HPV DNA is low. Innovative techniques such as droplet-based digital PCR and next generation sequencing are becoming increasingly available for the purpose of boosting HPV ct-DNA detection rate. We herein review and critically discuss the most recent and representative literature, concerning the role of HPV ctDNA in OPC and CEC in the light of new technologies that could improve the potential of this biomarker in fulfilling many of the unmet needs in the clinical management of OPC and CEC patients.

Small cell lung cancer (SCLC) is an aggressive disease, difficult to treat. There have been no significant therapeutic advances over platinum and etoposide chemotherapy in the last 20 years until the introduction of immunotherapy. In 2020 atezolizumab, an immune checkpoint inhibitor against PD-L1 was approved in Italy in combination with carboplatin and etoposide for the first-line treatment of patients with extensive stage disease (ES-SCLC), becoming the new standard treatment. On May 20, 2021, a virtual meeting, directed by profs. Federico Cappuzzo and Emilio Bria, was held in which 14 clinicians from different oncology centers in Lazio, Umbria and Sardinia discussed the issues of ES-SCLC patients treatment, after the advent of immunotherapy. The aim of the meeting was to share their clinical experience and to provide a series of practical indications that can support clinicians in the management of ES-SCLC patients in first-line with chemo-immunotherapy.

Introduzione. In Italia i due anticorpi monoclonali nivolumab e pembrolizumab, per l’indicazione “melanoma avanzato (non resecabile o metastatico) negli adulti”, sono sottoposti a registro di monitoraggio AIFA: hanno identici criteri di eleggibilità al trattamento e sono indicati fino a fallimento per progressione o tossicità; hanno inoltre subito modifiche di dosaggio passando dalla dose pro/kg alla dose flat. In questo studio osservazionale abbiamo voluto indagare la real world time to treatment discontinuation (rwTTD), che rappresenta il tempo tra la data di inizio e la data di fine di un trattamento, i trattamenti brevi, le sospensioni con ripresa di terapia e le modifiche di dose. Metodi. Sono stati arruolati i pazienti che hanno iniziato un trattamento con nivolumab o pembrolizumab afferenti agli Ambulatori di oncologia medica degli Istituti Fisioterapici Ospitalieri di Roma nel periodo compreso tra lo 01/01/2016 e il 31/12/2018. I pazienti in studio sono stati seguiti fino al 31/01/2021. I dati sono stati raccolti dal registro di monitoraggio dell’AIFA e dai software di gestione ed erogazione delle terapie. È stato utilizzato il metodo di Kaplan-Meier per la stima della rwTTD, e le differenze tra sottogruppi del campione sono state valutate mediante il Log-Rank Test. Risultati. I pazienti arruolati nel periodo in studio sono 123. La rwTTD è di 11,67 mesi (IC 95%: 7,93-17,27). In media circa un paziente su cinque ha interrotto la terapia prima dei 2 mesi. I trattamenti sospesi per almeno 45 giorni consecutivi e poi ripresi sono stati il 47,6%, con una rwTTD pari a 26,4 mesi (IC 95%: 17,3-43,6), significativamente superiore (p=0,008) rispetto ai trattamenti che hanno subito interruzioni minori o uguali a 45 giorni (rwTTD=8,4 mesi) (IC 95%: 4,3-17,1). I cambi di dosaggio di nivolumab da pro/kg a dose flat hanno riportato variazioni percentuali, in milligrammi/ciclo ricevuti dai pazienti rispetto alla precedente, comprese tra -23,8% e +56,9%, media +7,2%. Nel caso di pembrolizumab, il passaggio alla dose flat ha portato a variazioni comprese tra +22% e +81,8%, media +39,9%. Discussione e conclusioni. I pazienti che interrompono temporaneamente il trattamento risultano avere una rwTTD mediana tripla rispetto a quelli che interrompono definitivamente e che hanno almeno 45 giorni di terapia. In altri studi è stato supposto che i pazienti con una risposta immunologica ed effetti collaterali, presentano poi PFS e OS superiori a chi non presenta effetti collaterali. Si conferma l’importanza della gestione delle tossicità e la raccomandazione a riprendere poi il trattamento laddove possibile. È stato rilevato un notevole incremento della dose somministrata ai pazienti in base al passaggio alla dose flat, soprattutto per pembrolizumab.

Il carcinoma del polmone a piccole cellule (SCLC), o microcitoma, è una patologia estremamente aggressiva e difficile da trattare. Negli ultimi 20 anni non vi sono stati significativi avanzamenti terapeutici rispetto alla chemioterapia con platino ed etoposide, fino all’introduzione dell’immunoterapia. Nel 2020 atezolizumab, un immune checkpoint inhibitor contro PD-L1, è stato approvato in Italia in associazione a carboplatino ed etoposide per il trattamento di prima linea dei pazienti con malattia in stadio esteso (ES-SCLC), diventando lo standard di trattamento. Lo scorso 20 maggio 2021 si è svolto un meeting virtuale a cui hanno partecipato 14 clinici di diversi centri oncologici del Lazio, dell’Umbria e della Sardegna riguardante il trattamento dei pazienti con ES-SCLC con l’avvento dell’immunoterapia, diretto dai proff. Federico Cappuzzo ed Emilio Bria. L’obiettivo dell’incontro è stato quello di condividere la propria esperienza clinica e di fornire una serie di indicazioni pratiche che possano supportare il clinico nel trattamento chemio-immunoterapico di prima linea dello ES-SCLC.

INTRODUCTION:In Italy, the monoclonal antibodies nivolumab and pembrolizumab are subjected to the AIFA monitoring registries for the indication "advanced melanoma (unresectable or metastatic) in adults". These two drugs have the same eligibility criteria, and they are indicated until failure due to progression or toxicity; both of these drugs have also undergone dosage changes from pro/kg to flat dose. In this observational study, also based on clinical eligibility parameters, we wanted to investigate the rwTTD, definitive and temporary suspensions, as well as dose modifications.METHODS:We enrolled patients who started a treatment with nivolumab or pembrolizumab and were admitted to the Regina Elena National Cancer Institute in the period between 01/01/2016 and 31/12/2018. Treatments were followed up to 31/01/2021. Data were collected from the AIFA monitoring registries and from local therapy monitoring databases. We used the Kaplan-Meier method to estimate rwTTD, and the differences between sample subgroups were evaluated using the Log-Rank Test.RESULTS:In the 123 patients enrolled, the rwTTD was 11.67 months (IC 95%: 7,93-17,27). On average, about one out of five patients stopped the therapy before 2 months. The treatments suspended for at least 45 consecutive days and then resumed were 49 (47.6%) with rwTTD= 26.4 months (95% CI 17.3-43.6), significantly higher (p=0.008) compared to treatments suspended for less than or equal to 45 days (rwTTD= 8.4 months (95% CI 4.3-17.1). Dosage changes of nivolumab from pro/kg to flat dose ended in percentage ranging from -23.8% to +56.9%, mean +7.2%. In the case of pembrolizumab, the transition to the flat dose led to variations between +22% and +81.8%, average +39.9%.DISCUSSION AND CONCLUSIONS:Patients who temporarily stopped the treatment had a median rwTTD that is three times higher than patients who stopped permanently and had at least 45 days of therapy. Other studies suggest that patients who had immunological response and side effects, then had better PFS and OS than those without side effects. It is confirmed that it is therefore important to manage toxicities and then resume treatment, whenever possible. In patients who switched to a flat dose, there was an evident increase in the dose administered, especially for pembrolizumab.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2‐positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T‐DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5–24.9, 25–29.9, and 30.0–34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression‐free survival to first‐line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T‐DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

BACKGROUND:Immune checkpoint inhibitors (ICIs), by unleashing the anticancer response of the immune system, can improve survival of patients affected by several malignancies, but may trigger a broad spectrum of adverse events, including autoimmune hypophysitis. ICI-related hypophysitis mainly manifests with anterior hypopituitarism, while the simultaneous involvement of both anterior and posterior pituitary (i.e., panhypophysitis) has rarely been described.CASE PRESENTATION:In June 2015, a 64-year-old man affected by liver metastases of a uveal melanoma was referred to us due to polyuria and polydipsia. Two months prior, he had started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated (only mild asthenia and diarrhea were reported). A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine/daily), and polydipsia. Laboratory tests were consistent with adrenal insufficiency, hypothyroidism, and transient central diabetes insipidus. The pituitary MRI showed an enlarged gland with microinfarcts, while the hypophyseal stalk was normal, and the neurohypophyseal 'bright signal' in T1 sequences was not detected. The treatment included dexamethasone (then cortisone acetate at replacement dose), desmopressin, and levothyroxine. Within the next five days, the symptoms resolved, and blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges; desmopressin was discontinued while cortisone acetate and levothyroxine were maintained. The fourth ipilimumab dose was entirely administered in the absence of further side effects.CONCLUSION:As ICIs are increasingly used as anticancer agents, the damage to anterior and/or posterior pituitary can be progressively encountered by oncologists and endocrinologists in their clinical practice. Patients on ICIs and their caregivers should be informed about that risk and be empowered to alert the referring specialists early, at the onset of panhypopituitarism symptoms, including polyuria/polydipsia.

Background Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice. Methods We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS). Results In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCHmut/HR(mut)signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCHmut/HR(mut)genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCHmut/HR(mut)signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002). Conclusions Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.

Background: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy. Patients and methods: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study. Results: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes. Conclusions: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.