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• Vemurafenib and dabrafenib showed relevant clinical activity in pre-treated NSCLC with BRAF V600E mutations • Dabrafenib/trametinib demonstrated its superiority in pre-treated and treatment-naïve BRAF V600E-mutant NSCLC • Available efficacy data on BRAF V600 non-E mutations suggests a comparable efficacy of BRAF/MEK inhibitors • Limited activity of BRAF/MEK inhibitors has been observed in BRAF non-V600E mutations Lung cancer harbouring BRAF mutations accounts for 4% of all non-small cell lung cancer (NSCLC) cases, identifying a relevant subset of patients that need to be promptly managed. Three subtypes of BRAF mutations have been described: class I (V600E), and class II and III (non-V600), with different prognostic and predictive outcomes. Pivotal phase II trials have demonstrated the efficacy of the double BRAF/MEK inhibition with dabrafenib plus trametinib in patients harbouring V600E mutations, making BRAF a mandatory requirement in the genetic portrait of advanced non-squamous lung cancer patients. However, non-V600 mutations represent around 50% of BRAF -mutant NSCLC patients, for which no specific targeted approaches are approved. A paradigm shift from the double BRAF/MEK inhibition to combinations with agents with distinct mechanisms of action, such as immune-checkpoint inhibitors, pan-RAF and selective ERK 1/2 inhibitors, is under investigation and may change the therapeutic landscape of BRAF -driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with BRAF mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: Radon represents the main risk factor of lung cancer in non-smokers and the second one in smoking patients. In Europe, there are several radon-prone areas, but regulatory policies may vary between countries. Radon causes DNA damage and high genomic tumor instability, but its exact carcinogenesis mechanism in lung cancer remains unknown. Molecular drivers in NSCLC are more often described in non-smoker patients and a potential association between radon exposure and oncogenic-driven NSCLC has been postulated. This is an updated review on indoor radon exposure and its role in lung cancer carcinogenesis, especially focusing on its potential relation with NSCLC with driver genomic alterations. We want to contribute to rising knowledge and awareness on this still silent but preventable lung cancer risk factor. Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations. [ABSTRACT FROM AUTHOR]

Durvalumab is the standard-of-care as consolidation therapy after chemo-radiotherapy in stage III unresectable non-small cell lung cancer (NSCLC); however, its activity across patients with NSCLC harbouring driver genomic alterations (dGA) is poorly characterised. Multicentre retrospective study including patients with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and October 2020 at 26 centres in Europe and America. Clinical and biological data were collected; dGA included: EGFR / BRAF / KRAS mutations (m) and ALK/ROS1 rearrangements (r). We evaluated progression-free survival (PFS) and overall survival (OS) based on dGA. Out of 323 patients included, 43 patients had one dGA: KRAS m (n = 26; 8 G12C), EGFR m (n = 8; 6 del19/ex21), BRAF m (n = 5; 4 V600E) and ALK r (n = 4). The median age was 66 years [39–84], gender ratio 1:1, with 98% performance status (PS) 0–1 and 19% non-smokers; 88% had adenocarcinoma. PD-L1 was positive in 85% (n = 4 missing). In the whole cohort, the median PFS was 17.5 months (mo.) (95% CI, 13.2–24.9) and median OS 47 mo (95%CI, 47-not reached [NR]). No statistically significant differences in terms of the median PFS were observed between patients with dGA vs. non-dGA: 14.9 mo (95% CI, 8.1-NR) vs. 18 mo. (95% CI, 13.4–28.3) (P = 1.0); however, when analysed separately: the median PFS was NR (11.3-NR) in the KRAS m G12C vs. 8.1 mo (5.8-NR) in the EGFR m del19/ex21 vs. 7.8 mo (7.7-NR) in the BRAF m V600E/ ALK r (P = 0.02). We observed limited activity of durvalumab consolidation in patients with stage III unresectable NSCLC with EGFR/BRAF m and ALK r but not for those harbouring KRAS m. Larger prospective studies are needed to confirm these findings. • Similar treatment outcomes to PACIFIC phase III trial. • Different benefits of durvalumab consolidation based on oncogenic alterations. • Significant increase in PFS with durvalumab in patients with KRAS mutations. • ALK- rearranged NSCLC seem to benefit the least to durvalumab consolidation. • Largest retrospective study evaluating durvalumab in oncogenic addicted stage III NSCLC. [ABSTRACT FROM AUTHOR]

• GEFTREM evaluates tremelimumab plus gefitinib in refractory EGFR -mutant NSCLC • Grade 3 TRAEs occurred in 81% patients, mostly diarrhoea and ALT/AST increase • SD was the best overall response in 72% patients, with a median PFS of 2.2 months • GEFTREM is the only study combining a first-generation EGFR-TKI with an anti-CTLA-4 • Toxicity and limited efficacy prevented further evaluation of tremelimumab plus gefitinib A phase I open-label multicentre study was initiated to evaluate the association of tremelimumab with gefitinib in EGFR -mutant NSCLC patients who progressed after first-generation EGFR-TKI. Here we provide the efficacy data from the entire cohort. Patients with advanced EGFR- mutant NSCLC with progression after response to EGFR-TKI were enrolled. Study treatment was gefitinib 250 mg daily and tremelimumab at 3 dose levels: 3, 6 and 10 mg/kg IV Q4W for 6 cycles followed by Q12W until progression or unacceptable toxicity. The primary objective was safety and tolerability, and to establish a RP2D. Between January 2014 and July 2015, 27 patients (21 in the escalating dose cohort and 6 in expansion cohort) received at least one dose of tremelimumab. DLTs occurred in 4 patients: 1 at 3 mg/kg (one grade 3 diarrhoea), 1 at 6 mg/kg (one grade 3 diarrhoea) and 2 at 10 mg/kg (one grade 3 diarrhoea and one grade 3 AST/ALT increase) of tremelimumab. Grade 3 TRAE occurred in 22 patients (81%), most frequently diarrhoea (30%) and ALT/AST increase (15%). Stable disease was the best overall response in 72% patients, with median PFS of 2.2 months (95% CI, 1.8–4.2). All patients discontinued treatment, most frequently due to disease progression (63% of patients). The recommended dose of tremelimumab in combination with gefitinib in EGFR -mutant NSCLC patients was 3 mg/kg. The gastrointestinal toxicity and the limited efficacy data prevented further evaluation of this combination. (GEFTREM; clinical trial number NCT02040064) [ABSTRACT FROM AUTHOR]

Background: Anti-PD-(L)1 blocking agents can induce immune-related adverse events (irAEs), which can compromise treatment continuation. Since circulating leukocyte–platelet (PLT) complexes contribute to inflammatory and autoimmune diseases, we aimed to analyze the role of these complexes as predictors of irAEs in non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1. Materials and methods: Twenty-six healthy donors (HD) and 87 consecutive advanced NSCLC patients treated with anti-PD-(L)1 were prospectively included. Percentages of circulating leukocyte–PLT complexes were analyzed by flow cytometry and compared between HD and NSCLC patients. The association of leukocyte–PLT complexes with the presence and severity of irAEs was analyzed. Results: NSCLC patients had higher percentages of circulating leukocyte–PLT complexes. Higher percentages of monocytes with bound PLT (CD14 + PLT +) were observed in patients who received prior therapies while CD4 + T lymphocytes with bound PLT (CD4 + PLT +) correlated with platelets counts. The CD4 + PLT + high percentage group presented a higher rate of dermatological irAEs while the CD4 + PLT + low percentage group showed a higher rate of non-dermatological irAEs (p < 0.001). A lower frequency of grade ≥ 2 irAEs was observed in the CD4 + PLT + high percentage group (p < 0.05). Patients with CD4 + PLT + low and CD14 + PLT + high percentages presented a higher rate of grade ≥ 3 irAEs and predominantly developed non-dermatological irAEs (p < 0.01). Conclusions: Our results suggest that circulating leukocyte–PLT complexes and the combination of CD4 + PLT + and CD14 + PLT + percentages can be used as a predictive biomarker of the development and severity of irAEs in advanced NSCLC patients receiving anti-PD-(L)1 agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICI) have the potential to induce serious and unpredictable immune-related adverse events (irAEs), the underlying mechanisms of which remain incompletely understood. In this study, we investigated the relationship between irAEs and the expression of IFN-inducible chemokines and cytokines in patients with solid tumours treated with PD-(L)1 inhibitors. We analysed plasma levels of various IFN-related cytokines at different time points in patients categorized by irAE development and severity. We found that patients with serious irAEs showed significant increases in CXCL9, CXCL10, CXCL11, IL-18 and IL-10 at the onset of the irAE compared to patients with mild irAEs and those without irAEs. Additionally, IL-18 emerged as a promising predictive biomarker for serious irAE development. In summary, this study provides valuable insights into the immune responses associated with irAEs and proposes potential predictive markers for their severity. Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity. [ABSTRACT FROM AUTHOR]

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4447 cancer patients treated with ICI antibodies, 37 (0.8%) (23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 years)) were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n = 20, 54.1%), followed by melanoma (n = 8, 21.6%). The most common ICI antibody inhibitors reported were nivolumab (n = 18, 48.6%), pembrolizumab (n = 16, 43.2%), and ipilimumab (n = 8, 21.6%). About half of the patients (n = 19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n = 10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit, all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting the treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected. [ABSTRACT FROM AUTHOR]

• Pleural effusion (PE) is associated with worse immunotherapy outcomes in NSCLC. • This negative impact was also observed in patients with ≥50 % PD-L1 tumors. • In patients with PE, combinations strategies should be explored. Pleural effusion (PE) is a common metastatic site of NSCLC, associated with poor outcomes. As very few data are available about immune checkpoint inhibitors (ICI) and PE, we aimed to assess the clinical outcome of PE in NSCLC treated with ICI. Multicenter international retrospective study of patients with metastatic NSCLC treated with ICI, between 2012 and 2019. Stratification according to the presence of PE at ICI baseline or appearance under ICI treatment (PE group) versus no history of PE (non-PE group). Primary endpoints were overall survival (OS) and early death rate (EDR, OS ≤ 3 months). A total of 538 patients were included: 196 in the PE group and 342 in the non-PE group. In the PE group, median age was 64, 31.6 % were female, 77.6 % had non-squamous histology, PD-L1 was ≥50 % in 38.6 % of cases (95 missing). PE was more likely associated with >2 metastatic sites (70.4 % vs. 50 %) and worse performance status (PS ≥ 2, 30.8 % vs 23.1 %). Globally, the overall median OS was 9.7 months [95 %CI: 8.1–11.8]; 6.3 [95 % CI: 4.0–8.6] in PE vs. 11.4 [95 %CI: 9.7–13.8] in the non-PE respectively, P = 0.002. Overall the EDR was 31.4 %; higher in the PE group (38.3 % vs. 27.5 %; OR 1.63, 95 %CI: 1.13−2.37, P = 0.01). In the PE PD-L1≥50 % group, EDR was 33.3 %. In multivariate analysis, after adjustment on PS, liver/intracranial/bone metastasis, ICI line and dNLR, PE remained an independent prognostic factor for OS [HR: 1.38, 95 %CI: 1.09–1.74, P = 0.007]. In the PE group, PE appeared under ICI for 31 patients (16.4 %). We observed lower EDR in this group compared to patients whom PE was already present (29.0 % vs 40.5 %, P = 0.2). PE is associated with worse immunotherapy outcomes in NSCLC treated with ICI, including in patients with ≥50 % PD-L1 tumors. Thus, in these patients, combination strategies should be explored. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, the introduction of immunotherapy radically changed the therapeutic algorithm of non-small-cell lung cancer as an upfront or secondary strategy. Unfortunately, the small amount of patient benefits from immune-checkpoint inhibitors (ICI) and the prognostic role of concomitant treatments are a burning open issue. The use of steroids was associated with poor outcomes during ICI. We investigated the impact of intercurrent steroids, according to clinical indication, which is actually unclear. Interestingly, the use of intercurrent steroids given for cancer-unrelated symptoms has no survival impact on our study cohort. Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1–12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9–1.5] and mOS [1.9 mo.; 95%CI, 1.5–2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2–5.6] and OS [HR 4.53; 95% CI, 1.8–11.1], both p < 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms. [ABSTRACT FROM AUTHOR]