Diffusion weighted MRI and apparent diffusion coefficient as a prognostic biomarker in evaluating chemotherapy-antiangiogenic treated stage IV non-small cell lung cancer: A prospective, single-arm, open-label, clinical trial (BevMar).

PURPOSE: When treating Lung Cancer, it is necessary to identify early treatment failure to enable timely therapeutic adjustments. The Aim of this study was to investigate whether changes in tumor diffusion during treatment with chemotherapy and bevacizumab could serve as a predictor of treatment failure. MATERIAL AND METHODS: A prospective single-arm, open-label, clinical trial was conducted between September 2014 and December 2020, enrolling patients with stage IV non-small cell lung cancer (NSCLC). The patients were treated with chemotherapy-antiangiogenic combination. Diffusion weighted magnetic resonance imaging (DW-MRI) was performed at baseline, two, four, and sixteen weeks after initiating treatment. The differences in apparent diffusion coefficient (ADC) values between pre- and post-treatment MRIs were recorded as Delta values (ΔADC). We assessed whether ΔADC could serve as a prognostic biomarker for overall survival (OS), with a five year follow up. RESULTS: 18 patients were included in the final analysis. Patients with a ΔADC value ≥ -3 demonstrated a significantly longer OS with an HR of 0.12 (95 % CI; 0.03- 0.61; p = 0.003) The median OS in patients with a ΔADC value ≥ -3 was 18 months, (95 % C.I; 7-46) compared to 7 months (95 % C.I; 5-9) in those with a ΔADC value < -3. CONCLUSION: Our findings suggest that early changes in tumor ADC values, may be indicative of a longer OS. Therefore, DW-MRI could serve as an early biomarker for assessing treatment response in patients receiving chemotherapy combined with antiangiogenic therapy.

Cerebrospinal fluid as a liquid biopsy for molecular characterization of brain metastasis in patients with non-small cell lung cancer.

OBJECTIVES: Non-small cell lung cancer (NSCLC) with brain metastases (BM) is a challenging clinical issue with poor prognosis. No data exist regarding extensive genetic analysis of cerebrospinal fluid (CSF) and its correlation to associated tumor compartments. MATERIALS AND METHODS: We designed a study across multiple NSCLC patients with matched material from four compartments; primary tumor, BM, plasma and CSF. We performed enrichment-based targeted next-generation sequencing analysis of ctDNA and exosomal RNA in CSF and plasma and compared the outcome with the solid tumor compartments. RESULTS: An average of 105 million reads per sample was generated with fractions of mapped reads exceeding 99% in all samples and with a mean coverage above 10,000x. We observed a high degree of overlap in variants between primary lung tumor and BM. Variants specific for the BM/CSF compartment included in-frame deletions in AR, FGF10 and TSC1 and missense mutations in HNF1a, CD79B, BCL2, MYC, TSC2, TET2, NRG1, MSH3, NOTCH3, VHL and EGFR. CONCLUSION: Our approach of combining ctDNA and exosomal RNA analyses in CSF presents a potential surrogate for BM biopsy. The specific variants that were only observed in the CNS compartments could serve as targets for individually tailored therapies in NSCLC patients with BM.

Safety and efficacy of immune checkpoint blockade in patients with advanced nonsmall cell lung cancer and brain metastasis.

The presence of brain metastases (BM) is a negative prognostic factor for patients with advanced nonsmall cell lung cancer (NSCLC). Their incidence seems to be higher in patients with oncogene-driven tumours, especially those with EGFR-mutated or ALK-rearranged tumours. Although targeted treatments demonstrate significant efficacy regarding BM, they only apply to a minority of NSCLC patients. On the other hand, systemic therapies for nononcogenic-driven NSCLC with BM have shown limited clinical benefit. In recent years, immunotherapy alone or combined with chemotherapy has been adopted as a new standard of care in first-line therapy. This approach seems to be beneficial to patients with BM in terms of efficacy and toxicity. Combined immune checkpoint inhibition as well as the combination of immunotherapy and radiation therapy show promising results with significant, but overall acceptable toxicity. A pragmatic approach of allowing enrolment of patients with untreated or symptomatic BM in randomised trials evaluating immune checkpoint inhibitors strategies, possibly coupled with central nervous system-related endpoints may be needed to generate data to refine treatment for this patient population.

Plasma RNA profiling unveils transcriptional signatures associated with resistance to osimertinib in EGFR T790M positive non-small cell lung cancer patients.

Background: Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib. Methods: Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D. Results: Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P<0.15, and P(interaction) >0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR <3×10-10). When applied to the 40 individual, sample-specific gene sets, the NEA detected 16 immune-related gene sets (FDR <0.25, P(interaction) >0.05 and NEA z-score exceeding 3 in at least one sample). Conclusions: Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients.

Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer.

Treatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired following first-line treatment with other EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, or dacomitinib). However, patients treated with osimertinib have a high risk of developing resistance to the treatment. A substantial fraction of the mechanisms for resistance is unknown and may involve RNA and/or protein alterations. In this study, we investigated the full transcriptome of parental and osimertinib-resistant cell lines, revealing 131 differentially expressed genes. Knockdown screening of the genes upregulated in resistant cell lines uncovered eight genes to partly confer resistance to osimertinib. Among them, we detected the expression of Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) in plasmas sampled at baseline and at disease progression from EGFR-positive NSCLC patients treated with osimertinib. Both genes were upregulated in progression samples. Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). Combination of osimertinib with a FAK inhibitor resulted in synergistic toxicity in osimertinib-resistant cells, suggesting a potential therapeutic drug combination for overcoming resistance to osimertinib in NSCLC patients.

Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC. Methods: We combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial. Results: Various miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib. Conclusions: Our results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC.

Osimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone in oncogene-addicted lung adenocarcinoma: A case report.

BACKGROUND: Asian patients with metastatic non-small cell lung cancer (NSCLC) have a higher prevalence of epidermal growth factor receptor (EGFR) mutations compared to Caucasians, 30-50% and 15%, respectively. Osimertinib is a tyrosine kinase inhibitor approved as first-line therapy in patients with metastatic NSCLC harboring exon 19 or exon 21 EGFR mutations. CASE PRESENTATION: We report a 68-year-old treatment-naïve Asian male patient with metastatic NSCLC harboring an exon 19 deletion mutation of EGFR treated with osimertinib. The patient developed an osimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after approximately two months of therapy. Following fluid restriction and osimertinib discontinuation, the hyponatremia improved significantly within one week. The patient was started on second-line erlotinib without any signs of hyponatremia after treatment initiation. CONCLUSION: There is a lack of published data from randomized prospective clinical trials of osimertinib-induced SIADH in metastatic NSCLC. Further studies to evaluate the potential underlying mechanisms are warranted.

Patient-reported health-related quality of life from a randomized phase II trial comparing standard-dose with high-dose twice daily thoracic radiotherapy in limited stage small-cell lung cancer.

OBJECTIVES: In a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 fractions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years. MATERIALS AND METHODS: 170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of ≥10 was defined as clinically significant. RESULTS: Maximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales. CONCLUSION: TRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC. Trial reg Clinicaltrials.gov NCT0204184.

Complications following novel therapies for non-small cell lung cancer.

The emergence of tyrosine kinase inhibitors and immune checkpoint inhibitors has paved a new era for the management of non-small cell lung cancer, which has for many years lacked major clinical breakthroughs. Historically, 5-year overall survival remained below 5% in individuals with metastatic disease. These novel treatments have led to significant prolongation of survival in the locally advanced and metastatic setting, exceeding 25% in selected populations. However, they present new challenges to clinicians due to their inherently different spectrum of toxicity unique to each specific drug's pharmacodynamic profile. Internists commonly come across these side effects in their daily clinical practice. Their optimal recognition and management are of utmost importance, because it is associated with significant improvements in patient survival outcomes and their quality of life. The aim of this review is to summarize the complications following these novel treatments for non-small cell lung cancer.

Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

High Density of NRF2 Expression in Malignant Cells Is Associated with Increased Risk of CNS Metastasis in Early-Stage NSCLC.

Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining of NRF2 and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was correlated with a higher risk of central nervous system (CNS) relapse OR = 7.36 (95% CI: 1.64-33.06). The multivariate analysis showed an OR = 8.00 (95% CI: 1.70-37.60) for CNS relapse in NRF2+/CK+ high-density cases. The density of TrxR1+/CK+ cells failed to show any statistically significant risk of relapse. The OS analyses for NRF2+/CK+ and TrxR1+/CK+ cell density failed to show any statistical significance. This is the first study to report a correlation between NRF2+/CK+ cell density and the risk of CNS relapse in early-stage NSCLC. The results of our study may impact the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis.

Correlation of Clinical Parameters with Intracranial Outcome in Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Pd-1/Pd-L1 Inhibitors as Monotherapy.

There is a paucity of biomarkers for the prediction of intracranial (IC) outcome in immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients (pts) with brain metastases (BM). We identified 280 NSCLC pts treated with ICIs at Karolinska University Hospital, Sweden, and University Hospital of Heraklion, Greece. The inclusion criteria for response assessment were brain metastases (BM) prior to ICI administration, radiological evaluation with CT or MRI for IC response assessment, PD-1/PD-L1 inhibitors as monotherapy, and no local central nervous system (CNS) treatment modalities for ≥3 months before ICI initiation. In the IC response analysis, 33 pts were included. Non-primary (BM not present at diagnosis) BM, odds ratio (OR): 13.33 (95% CI: 1.424-124.880, p = 0.023); no previous brain radiation therapy (RT), OR: 5.49 (95% CI: 1.210-25.000, p = 0.027); and age ≥70 years, OR: 6.19 (95% CI: 1.27-30.170, p = 0.024) were associated with increased probability of IC disease progression. Two prognostic groups (immunotherapy (I-O) CNS score) were created based on the abovementioned parameters. The I-O CNS poor prognostic group B exhibited a higher probability for IC disease progression, OR: 27.50 (95% CI: 2.88-262.34, p = 0.004). Age, CNS radiotherapy before the start of ICI treatment, and primary brain metastatic disease can potentially affect the IC outcome of NSCLC pts with BM.

High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival. METHODS: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m2 or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m2 on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845. FINDINGS: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group). INTERPRETATION: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules. FUNDING: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.

Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc - effects and side effects.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting. MATERIAL AND METHODS: All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995-2012. RESULTS: We included 164 patients with 175 tumours located in the thorax (n = 86), the liver (n = 27) and the abdomen (n = 62) and treated with a median prescribed dose (BEDα/ß 10Gy) of 80 Gy (71.4-113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control - 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3-5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax. CONCLUSION: SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.

Effect of corticosteroids on the outcome of patients with advanced non-small cell lung cancer treated with immune-checkpoint inhibitors.

INTRODUCTION: We analysed patients with advanced non-small cell lung cancer (NSCLC) who were treated with immune-checkpoint inhibitors (ICIs) to address the effect of the timeline and reason for corticosteroid administration on survival outcomes. METHODS: We retrospectively collected clinical data of non-oncogenic driven, advanced NSCLC patients treated with ICIs at Karolinska University Hospital, including the timeline and reason for steroid administration. Steroid administration was defined as > 10 mg prednisolone equivalent for ≥10 days. We subcategorized patients based on the aetiology of steroid administration into three subgroups: a) steroids for supportive reasons but not for cancer palliation; b) steroids for the palliation of cancer-related symptoms; c) steroids for the management of immune-related adverse events (irAEs). Furthermore, to analyse the timeline, patients were categorised into two groups; those who received corticosteroids within 2 weeks before until 2 days after ICI initiation and those who received steroids later during their treatment course. RESULTS: Analysed data from 196 patients showed 46.3% of patients received corticosteroids. Steroid administration due to irAEs did not affect overall survival (OS) (p = 0.38) compared with the steroid naïve group. Only steroid administration for the palliation of cancer-related symptoms was an independent predictor for shorter OS (HR = 2.7; 95% CI, 1.5-4.9). The timeline of steroid administration did not affect OS (p = 0.456) in our cohort. CONCLUSIONS: Steroids due to irAEs do not appear to hamper ICI efficacy. However, the administration of high-dose steroids to palliate malignancy-associated symptoms might reflect the dismal prognosis of this patient group.

Treatment of rheumatic immune-related adverse events due to cancer immunotherapy with immune checkpoint inhibitors-is it time for a paradigm shift?

Immunotherapy has revolutionized cancer treatment during the last years. Several monoclonal antibodies that are specific for regulatory checkpoint molecules, that is, immune checkpoint inhibitors (ICIs), have been approved and are currently in use for various types of cancer in different lines of treatment. Cancer immunotherapy aims for enhancing the immune response against cancer cells. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events of autoimmune origin, often referred to as immune-related adverse events (irAEs), which limit the utility of these drugs. These irAEs are quite common and can affect almost every organ. The grade of toxicity varies from very mild to life-threatening. The pathophysiological mechanisms behind these events are not fully understood. In this review, we will summarize current evidence specifically regarding the rheumatic irAEs and we will focus on current and future treatment strategies. Treatment guidelines largely support the use of glucocorticoids as first-line therapy, when symptomatic therapy is not efficient, and for more persistent and/or moderate/severe degree of inflammation. Targeted therapies are higher up in the treatment pyramid, after inadequate response to glucocorticoids and conventional, broad immunosuppressive agents, and for severe forms of irAEs. However, preclinical data provide evidence that raise concerns regarding the potential risk of impaired antitumoral effect. This potential risk of glucocorticoids, together with the high efficacy and potential synergistic effect of newer, targeted immunomodulation, such as tumor necrosis factor and interleukin-6 blockade, could support a paradigm shift, where more targeted treatments are considered earlier in the treatment sequence.

Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a 'Real-Life' Setting.

There is lack of data addressing the intracranial (IC) efficacy of immune checkpoint inhibitors (ICIs) on brain metastases (BM) in non-small cell lung cancer (NSCLC). This patient category is underrepresented in randomized clinical trials. We retrospectively collected clinical data on patients with non-oncogenic driven NSCLC with BM who were treated with ICIs at two medical oncology institutes in Sweden and Greece from 2016 to 2019. IC efficacy was assessed in patients who had not received local treatment for BM less than three months prior to the initiation of ICIs and had adequate radiological evaluation. We screened 280 patients, of which 51 had BM. BM was an independent predictor for inferior PFS (HR = 2.27; 95% CI, 1.53-3.36) but not OS (HR = 1.58; 95% CI, 0.97-2.60) for the whole patient population. IC response assessment was done on 33 patients. IC objective response rate (ORR) was 24.2%. The presence of neurological symptoms related to BM did not affect IC ORR (p = 0.48). High PD-L1 levels from extracranial biopsies were not a predictive factor for IC ORR (p = 0.13). ICIs are active in NSCLC patients with BM regardless of the presence of neurological symptoms and can achieve durable IC disease stabilization in a subgroup of patients.

Randomized Phase II Study with Cetuximab in Combination with 5-FU and Cisplatin or Carboplatin vs. Cetuximab in Combination with Paclitaxel and Carboplatin for Treatment of Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial).

BACKGROUND: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression-free survival (PFS) with standard cetuximab and 5-FU/platinum-based chemotherapy. Standard chemotherapy treatment for SCCHN is related to severe toxicity and new, less toxic regimens are needed. METHODS: In this multicentre, randomized, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomized in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A) vs. cetuximab and paclitaxel/carboplatin (arm B). Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is significantly worse than PFS in arm A. RESULTS: Median PFS in arm A was 4.37 months (95% CI: 2.9-5.9 m) and 6.5 months (95% CI: 4.8-8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3-11.5 m) in arm A and 10.2 months (95% CI: 5.4-15 m) in arm B, (HR = 0.71; 95% CI: 0.43-1.16). PFS HR for arm B was not significantly worse than arm A (HR = 0.65; 95% CI: 0.41-1.03). Adverse events ≥ grade 3 were more frequent in arm A than arm B (60% vs. 40%; p = 0.034). CONCLUSION: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favorable alternative to standard therapy.

ALK-Brain Prognostic Index-Preliminary Study of a Prognostic Tool for Patients with ALK-Rearranged, Non-small Cell Lung Cancer and Brain Metastases.

BACKGROUND: Disease-specific Graded Prognostic Assessment (DS-GPA) is the most validated prognostic tool for patients with brain metastasized lung cancer. The Lung-molGPA scoring system was recently introduced for oncogenic-driven brain metastasized lung cancer, but has not yet been validated in cohorts including only ALK-translocated tumors. METHODS: We designed a retrospective cohort study consisting of 44 patients with brain metastasized ALK-positive, non-small cell lung cancer (NSCLC) who were treated between January 2009 and November 2019 at Karolinska University Hospital in Stockholm, Sweden. Information about demographics and clinicopathological parameters were collected. Predictors of overall survival (OS) were identified by Cox regression analyses. A bootstrap validation with 1000 samples was performed in order to compare the different prognostic scores. RESULTS: The variables found to independently influence OS in the multivariate analysis, i.e., PS, sex and brain metastases at diagnosis, were used as prognostic variables in our new prognostic index (ALK-BPI). Patients were divided into two prognostic groups. The median OS was 65.7 months for the good prognostic group and 22.7 months for the poor prognostic group (p = 0.0068). In the univariate analysis of the different prognostic scores, ALK-BPI performed better than the others (HR = 3.6; 95% CI: 1.3-9.9). The mean C-statistics of the different prognostic scores were compared to each other, and no significant difference was observed. CONCLUSION: We propose the ALK-BPI score as a new prognostic tool that can easily be applied for ALK-positive lung cancer patients with brain metastases in daily clinical practice, as it has at least the same prognostic value as Lung-molGPA.