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.

Real-world analysis of MET exon 14 mutations in non-small cell lung cancer: a retrospective study from two Swedish hospitals.

BACKGROUND: Real-World evidence on mesenchymal-epithelial transition exon 14 skipping mutations (METex14) in lung cancer remains limited. With an incidence of 3-4% across histological subtypes, METex14 is now an actionable target for MET inhibitors (METi) in advanced lung cancer, demonstrating response rates between 30-70%. Yet, its role in early stages and sensitivity to immune checkpoint inhibitors (ICIs) is still under exploration. MATERIAL AND METHODS: We conducted a retrospective analysis of the clinical data of lung cancer patients presenting with METex14 across all stages. These patients were treated at two Swedish University Hospitals: Karolinska and Skåne, between the years 2014 and 2022. RESULTS: We identified a total of 63 patients, of which 50 met the inclusion criteria. The median overall survival (OS) with corresponding 95% confidence intervals (95% CI) according to the stage was not reached (NR) for stage I, NR for stage II, 15 months (95% CI, 5.4-24.6) for stage III, and 17 months (95% CI, 9.2-NR) for stage IV. The median OS for stage IV patients who received a METi was 17 months (95% CI, 9.5-NR) vs. 10 months (95% CI, 6.2-NR) in patients without METi (p = 0.92; Hazard Ratio [HR] = 1.07). The median OS for stage IV patients who received ICIs was 18 months (95% CI, 16.5-NR) vs. 6 months (95% CI, 2.5-NR) in patients without ICIs (p = 0.15; HR = 0.47). The median OS for stage IV patients who received chemotherapy was 17 months (95% CI, 9.7-NR) vs. 10 months (95% CI, 4.5-NR) in patients without (p = 0.97; HR = 0.98). CONCLUSIONS: Our data suggest limited survival benefits from METi, ICIs, and chemotherapy for METex14 lung cancer patients. While not statistically significant, these findings underscore the need for larger trials for validation. Identifying effective treatments for this challenging lung cancer subtype remains a priority.

Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: case report and systematic review of the literature.

Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events. As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions.Here, we report a rare case of early-onset, mild cytokine release syndrome (CRS) in a patient who received ICIs for a metastasized renal cell carcinoma, which led to treatment discontinuation.We further provide a systematic review of the literature of CRS and related life-threatening side effects of ICI treatment, such as hemophagocytic lymphohistiocytosis (HLH). We searched Medline, Embase and the Web of Science Core Collection from inception to October 2021 for reports on CRS, cytokine storm, macrophage activation syndrome, HLH, and related hyperinflammatory disorders in patients with solid cancers receiving ICIs. We found n=1866 articles, which were assessed for eligibility independently by two examiners. Of those, n=49 articles reporting on n=189 individuals were eligible for review. We found that the median time from last infusion to the occurrence of CRS/HLH was approximately nine days, while the onset of symptoms varied from immediately after infusion to one month after treatment. Most patients were treated with either corticosteroids or the anti-interleukin 6 (IL-6) antibody tocilizumab, and although the majority of patients recovered, a few cases were fatal. Concomitant IL-6 and ICI treatment were reported as beneficial for both the antitumoral effect and for limiting side effects. Data from international pharmacovigilance databases underscored that ICI-related CRS and HLH are rare events, but we identified significant differences in reported frequencies, which might suggest substantial under-reporting.The results from this first systematic review of CRS/HLH due to ICI therapy highlight that life-threatening systemic inflammatory complications of ICIs are rare and might be associated with fatal outcome in approximately 10% of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.

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.

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.

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.

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.

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.