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Background: Immune checkpoint inhibitors (ICIs) have become the standard of care in several solid tumours. Thus the action of ICIs may lead to the development of inflammatory damage in nontumoral tissues, defined as immune-related adverse events (irAEs). Scanty data describe upper gastrointestinal tract toxicity. Patients and methods: We conducted a monocentric retrospective study, enrolling patients with advanced cancer, who developed histology-proven immune-related oesophago-gastro-duodenitis, treated with at least one cycle of ICI between January 2016 and November 2022. Results: We identified six patients with upper gastrointestinal irAEs: four affected by metastatic melanoma (three treated with nivolumab and one with nivolumab plus ipilimumab), one by unresectable cutaneous squamous cell carcinoma (treated with cemiplimab), and one by metastatic non-small-cell lung cancer (treated with pembrolizumab). Proton pump inhibitors and oral corticosteroids have been the mainstay of the management, and thus one patient had to receive intravenous methylprednisolone with hospitalisation, fasting, and parenteral nutrition. Based on the literature and our experience, we proposed a classification of ICI-induced upper gastrointestinal toxicity, with symptom and endoscopic sign grading. Each step of severity has been also correlated with a proposed diagnosis and clinical management. Conclusions: During ICI treatment, upper gastrointestinal symptoms can be a red flag for developing severe oesophago-gastro-duodenal toxicity that can impact patients’ quality of life and therapeutic plan. We recommend carefully investigating these symptoms, choosing a multidisciplinary approach to decide if an oesophagogastroduodenoscopy with random biopsy is indicated. [18]-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography might represent a promising complementary diagnostic tool. Steroids still represent the cornerstone of treatment, as for other irAEs.

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30-90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored., Methods: We performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort., Results: In total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71-0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64-0.80)., Conclusion: LIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression., (© 2024. The Author(s).)

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is the standard of care for patients with advanced NSCLC and EGFR-sensitizing mutations. Both in osimertinib pivotal trials and in the post-marketing phase, asymptomatic creatinine phosphokinase elevation and clinically relevant muscle damage have been reported. However, the mechanisms underlying these conditions remain unclear. Herein, we report the first muscle biopsy description of osimertinib-induced myopathy and hypothesize that the mechanisms underpinning muscle toxicity could be driven by hyporegenerative mechanisms and mitochondrial dysfunction with subsequent reduced metabolic endurance, both directly linked to the inhibition of downstream molecular pathways mediated by EGFR in muscle cells., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We report the case of an 87-year-old female patient who was diagnosed with metastatic non-small-cell lung cancer harboring MET exon 14 skipping mutation ( MET ex14) and PD-L1 expression of 60%. A first-line treatment with atezolizumab was started with primary resistance. Then, a second-line treatment with capmatinib, a selective type Ib MET tyrosine kinase inhibitor, was started, achieving a partial response. The patient is still alive and on treatment with capmatinib 300 mg twice daily after 20 months, with a good tolerability and no evidence of disease progression.In summary, our patient experienced a long-lasting response (>18 months) with capmatinib as second-line treatment. Further analyses evaluating the efficacy and tolerability of MET tyrosine kinase inhibitors are warranted, especially in the elderly, a non-small-cell lung cancer population whose tumors could more frequently harbor MET ex14 mutation.

For years, adjuvant chemotherapy has been the only standard treatment for resected non-small cell lung cancer patients (NSCLC), offering a dismal survival improvement at 5 years. Following the outstanding results of the recent ADAURA trial, osimertinib has become a new standard treatment for resected epidermal growth factor receptor (EGFR)-mutant non-squamous NSCLC, regardless of the administration of chemotherapy. For patients whose disease relapses after completion of the adjuvant therapy, there is no consensus about the optimal treatment. Herein, we report the case of a 74-year-old woman diagnosed with stage IIIA non-squamous NSCLC, harboring the EGFR p.L858R mutation. After complete tumor resection, the patient received adjuvant chemotherapy with cisplatin and vinorelbine, followed by osimertinib 80 mg daily for 3 years within the ADAURA trial. Brain disease relapse was documented 18 months after treatment completion by computed tomography scans. The patient was then retreated with osimertinib obtaining a deep intracranial partial response, which is still lasting after 21 months. The retreatment with osimertinib in patients whose disease relapsed following adjuvant therapy with the third-generation EGFR inhibitor might be a valid option, especially in patients with intracranial disease relapse. Studies are warranted to confirm this finding and to define the impact of the disease-free interval in this regard., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Many patients with non-small cell lung cancer (NSCLC) derive poor benefit from immunotherapy (IO). For some of them, adding chemotherapy (CT) can improve the outcomes, but the reliability of programmed death-ligand 1 (PD-L1) expression as the only biomarker to distinguish these patients is unsatisfactory. We sought to detect clinicopathological and molecular predictive factors of survival that might be added to PD-L1 expression in the selection of patients who should receive IO alone or chemoimmunotherapy (CIT)., Methods: We conducted a systematic search of randomized controlled clinical trials investigating IO, alone or with CT, vs CT alone in treatment-naïve advanced NSCLC patients. Meta-analyses and meta-regression analyses were performed to investigate IO alone vs CT, CIT vs CT, and IO alone vs CIT., Results: A total of 14 367 patients with advanced NSCLC across 25 randomized controlled clinical trials were included. Squamous histology, male sex, current and former smoker status, PD-L1 expression of 50% or more, and high tumor mutational burden (TMB) correlated with improved survival with IO alone compared with CT. Conversely, female sex, no smoking history, negative PD-L1 expression, and low TMB correlated with unsatisfactory outcomes with IO alone vs CT but not with CIT vs CT. CIT improved survival vs IO alone in female patients, never smokers, those having a PD-L1 expression of 1% or more (but not with a PD-L1 of  ≥ 50%) or a low TMB and in patients with central nervous system metastasis., Conclusions: These findings suggest some clinicopathological and molecular features that, added to PD-L1 expression, could help in the selection of the most appropriate first-line IO-based treatment for advanced NSCLC patients., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The widespread use of more sensitive detection tools, such as next-generation sequencing, has increased the identification of a variety of BRAF mutations other than V600E/K in melanoma patients. However, there is a lack of established data regarding the efficacy of BRAF/MEK inhibitors and immune-checkpoint immune inhibitors (ICI) for these patients. We performed a retrospective study, including all the patients diagnosed with stage III or IV melanoma that were referred to the University Hospital of Bologna from 2011 to 2021, carrying a non-V600E or V600K mutation of BRAF and who were started on systemic treatment. We found 14 patients with stage III or IV melanoma harboring the following BRAF mutations: V600R, V600_K601delinsE, K601E, p.T599_V600insT, L597V, G466R, S467L, and A598T. Of note, G466R and A598T BRAF mutations have never been previously reported in melanoma. Four patients received combined BRAF/MEK inhibitors, two patients BRAF inhibitor monotherapy, and six patients were treated with ICI for advanced melanoma; four patients received adjuvant treatment with nivolumab. Given the few cases and the absence of randomized clinical trials, it is important to report clinical experiences, which can guide physicians in the treatment of melanomas harboring rare BRAF mutations., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The combination of immune-checkpoint inhibitors (ICI) and platinum-pemetrexed chemotherapy (CT) in first-line setting improved survival outcomes of advanced non-small cell lung cancer (NSCLC) patients. Among the various adverse events, renal toxicity can be a relevant safety issue., Materials and Methods: We conducted a single-center, observational retrospective study including consecutive patients treated with upfront CT-ICI for advanced nonsquamous NSCLC to investigate incidence and clinical characteristics of acute kidney injury (AKI) using 'Acute Kidney Injury Working Group of Kidney Disease: Improving Global Outcomes' (KDIGO) definition., Results: A total of 89 patients received a first-line CT/ICI. The median age was 69 years. 60.7 % were male, and 87.6 % had an ECOG PS of 0-1. 92.1 % had a baseline glomerular filtration rate of at least 60 ml/min. According to KDIGO criteria, 25 (28 %) patients developed AKI. Considering risk factors for AKI onset, patients receiving >10 cycles of CT/ICI were more likely to experience AKI (p < 0.001). No other associations were found with other variables, including concomitant medications. Any component of the treatment was discontinued (pemetrexed pembrolizumab or both) in 10 (40 %) patients, and 9 patients (36 %) were addressed to nephrological consultation. These patients had higher mean creatinine variation from baseline (1 vs 0.6 mg/dl, p = 0.025) and creatine level (1.8 vs 1.4 mg/dl, p = 0.015), but lower eGFR (35.7 vs 54.2 ml/min, p = 0.011) in comparison to patients not addressed. No patients had microscopic hematuria or pyuria, but mild proteinuria (<0.8 g/24 h) was found in 4 patients. A renal biopsy was performed on 3 patients, revealing acute tubule interstitial nephritis (ATIN), karyomegalic interstitial nephritis, and acute tubular necrosis (ATN)., Conclusion: Renal toxicity represents a challenging adverse event that could negatively impact outcomes of metastatic nonsquamous NSCLC patients receiving CT/ICI demanding a multidisciplinary approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: An acceptable risk-benefit ratio may encourage the prescription of immune checkpoint inhibitors (ICI) near the late stage of life. The lung immune prognostic index (LIPI) was validated in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. The palliative prognostic (PaP) score without clinical prediction of survival (PaPwCPS) predicts early mortality probability in terminal cancer patients. Methods: We performed a retrospective study including 182 deceased advanced NSCLC patients, treated with single-agent ICI at our Institution. Two prognostic categories of high and low mortality risk were identified through ROC curve analysis for PaPwCPS and LIPI scores. Results: Most were >65 years of age (68.3%) and received second-line ICI (61.2%). A total of 29 (15.9%) and 131 (72.0%) patients died within 30 and 90 days from treatment start, respectively. A total of 81 patients (44.5%) received ICI during the last month of life. Baseline PaPwCPS and LIPI scores were assessable for 78 patients. The AUC of ROC curves was significantly increased for PaPwCPS as compared with LIPI score for both 30-day and 90-day mortality. A high PaPwCPS score was associated in multivariate analysis with increased 30-day (HR 2.69, p = 0.037) and 90-day (HR 4.01, p < 0.001) mortality risk. A high LIPI score was associated with increased 90-day mortality risk (p < 0.001). Conclusion: We found a tendency towards ICI prescription near the late stage of life. The PaPwCPS score was a reliable predictor of 30- and 90-day mortality.

Introduction: Targeting Kirsten Rat Sarcoma (KRAS) has been deemed impossible for long time, but new drugs have recently demonstrated promising results. Evidence on the outcome of KRAS-mutant advanced-NSCLC treated with new standard regimens are still scarce. Thus, we aimed at assessing the incidence and clinical impact of KRAS mutations in a real-life population of advanced-NSCLC, exploring the prognostic significance of distinct alterations., Materials and Methods: The present multicenter retrospective study, conducted by 5 Italian Centers from January 2018 to February 2020, involved 297 advanced KRAS mutant NSCLC. Complete clinico-pathological data were evaluated., Results: Out of 297 patients, 130 carried KRAS&#95;G12C mutation, while 167 presented with mutations other than G12C. Within KRAS&#95;non-G12C group, 73%, 16.8% and 8.9% harboured G12X, codon 13 and Q61H alterations, respectively. No significant differences in survival outcome and treatment response were documented according to KRAS&#95;G12C versus non-G12C, nor KRAS&#95;G12C versus G12X versus other mutations. On univariate analysis ECOG PS, number and sites of metastatic lesions and PD-L1 status significantly impacted on survival. A clear trend towards worse prognosis was apparent in chemotherapy-treated patients, while immunotherapy-based regimens were associated to prolonged survival. Investigating the outcome of PD-L1 ≥ 50% population, we did not detect any significant difference between KRAS&#95;G12C and non-G12C subsets., Conclusion: Here, we report on real-life data from a large retrospective cohort of advanced NSCLC harbouring KRAS alterations, with particular attention to G12C mutation. Our study offers useful clues on survival outcome, therapeutic response and clinico-pathological correlations in KRAS-mutant setting, especially in the upcoming era of KRAS G12C targeting therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The impact of baseline versus intercurrent steroids on the efficacy of upfront chemotherapy plus pembrolizumab (CT-ICI) for advanced non-small cell lung cancer (NSCLC) patients is unclear. We conducted a retrospective study on metastatic NSCLC patients treated with upfront CT-ICI at our institution between March 2020 and December 2021. The use of steroids was considered as the administration of at least 10 mg of prednisone equivalent. Of 101 patients, 36 (35.6%) received steroid therapy at baseline, and 18 (17.8%) started steroids on treatment. Overall, median progression-free survival (mPFS) was 6.5 months (95% CI, 5.9−8.9) and median overall survival (mOS) was 18.2 months (95% CI, 8.9-NR). Patients taking baseline steroids had significantly shorter survival than those not taking them and those assuming intercurrent steroids (mPFS 5.0 vs. 9.2 vs. 7.3 months, p < 0.001; mOS 7.0 months vs. not reached, p < 0.001). Baseline steroids were significantly associated with poorer survival outcomes in the multivariate model (OS HR 2.94, p = 0.02; PFS HR 3.84, p > 0.001). Conversely, intercurrent prescription did not reach a significant value regardless of other pivotal variables included in the model. Baseline steroid administration was associated with a detrimental effect on survival outcomes in NSCLC patients treated with CT-ICI. The role of intercurrent steroid administration should be further explored in larger studies.

Background: In non-small cell lung cancer (NSCLC), BRAF class 1 alterations are effectively targeted by BRAF inhibitors. Conversely, targeted therapies have very low or absent activity in patients carrying class 2 and 3 alterations. The spectrum of BRAF alterations in NSCLC patients, and their accompanying clinical features, genomic landscape and treatment outcomes have been poorly reported., Patients and Methods: We identified BRAF alterations of defined functional class across different tumors through a systematic review. Then, we selected NSCLC patients carrying BRAF alterations, according to the systematic review, in the cBioPortal (cBioPortal cohort) to collect and analyze clinical, biomolecular and survival data. Finally, we identified NSCLC patients carrying BRAF non-V600 mutations enrolled in POPLAR and OAK trials (POPLAR/OAK cohort), extracting clinical and survival data for survival analyses., Results: 100 different BRAF non-V600 alterations were identified through the systematic review. In the cBioPortal cohort ( n = 139), patients harboring class 2 and 3 alterations were more frequently smokers and had higher tumor mutational burden compared to those carrying class 1 alterations. The spectrum of most frequently co-altered genes was significantly different between BRAF alterations classes, including SETD2, STK11, POM121L12, MUC16, KEAP1, TERT, TP53 and other genes. In the POPLAR/OAK cohort, patients carrying non-V600 BRAF alterations were characterized by poor prognosis compared to BRAF wild-type patients., Conclusions: Different classes of BRAF alterations confer distinctive clinical features, biomolecular signature and disease behavior to NSCLC patients. Non-V600 alterations are characterized by poor prognosis, but key gene co-alterations involved in cancer cell survival and immune pathways may suggest their potential sensitivity to tailored treatments.

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1-2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET -positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically 'cold' tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to off-target effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET -positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood-brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/06/dic.2022-1-5-COI.pdf, (Copyright © 2022 Andrini E, Mosca M, Galvani L, Sperandi F, Ricciuti B, Metro G, Lamberti G.)

Introduction: BRAF mutation involved 2-4% of lung adenocarcinoma. Differences in clinicopathologic features and patient outcome exist between V600E and non-V600E BRAF mutated NSCLC. Thus, we sought to assess the frequency and clinical relevance of BRAF mutations in a real-life population of advanced-NSCLC, investigating the potential prognostic significance of distinct genetic alterations., Materials and Methods: The present multicenter Italian retrospective study involved advanced BRAF mutant NSCLC. Complete clinicopathologic data were evaluated for BRAF V600E and non-V600E patients., Results: A total of 44 BRAF mut NSCLC patients were included (V600E, n = 23; non-V600E, n = 21). No significant differences in survival outcome and treatment response were documented, according to V600E vs. non-V600E mutations, although a trend towards prolonged PFS was observed in the V600E subgroup (median PFS = 11.3 vs. 6.0 months in non-V600E). In the overall population, ECOG PS and age significantly impacted on OS, while bone lesions were associated with shorter PFS. Compared to immunotherapy, first-line chemotherapy was associated with longer OS in the overall population, and especially in the BRAF V600E subtype., Conclusions: Here, we report on real-life data from a retrospective cohort of advanced-NSCLC harboring BRAF alterations. Our study offers relevant clues on survival outcome, therapeutic response, and clinicopathologic correlations of BRAF-mutant NSCLC.

The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.