KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.

BACKGROUND: Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. METHODS: The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data. RESULTS: An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours. CONCLUSIONS: KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.

Real-world data for precision cancer medicine-A European perspective.

Leveraging real-world data (RWD) for drug access is necessary to overcome a key challenge of modern precision oncology: tackling numerous low-prevalence oncogenic mutations across cancers. Withholding a potentially active medication in patients with rare mutations for the sake of control chemotherapy or "best" supportive care is neither practicable nor ethically justifiable anymore, particularly as RWD could meanwhile be used instead, according to scientific principles outlined by the US Food and Drug Administration, European Medicines Agency and other stakeholders. However, practical implementation varies, with occasionally opposite recommendations based on the same evidence in different countries. In the face of growing need for precision drugs, more transparency of evaluation, a priori availability of guidance for the academia and industry, as well as a harmonized framework for health technology assessment across the European Union (EU) are imperative. These could in turn trigger infrastructural changes in national and pan-European registries, cancer management guidelines (e.g., frequency of routine radiologic restaging, inclusion of patient-reported outcomes), and the health data space, to ensure conformity with declared standards and facilitate extraction of RWD sets (including patient-level data) suitable for approval and pricing with minimal effort. For an EU-wide unification of precision cancer medicine, collective negotiation of drug supply contracts and funding solidarity would additionally be required to handle the financial burden. According to experience from pivotal European programs, off-label use could potentially also be harmonized across EU-states to accelerate availability of novel drugs, streamline collection of valuable RWD, and mitigate related costs through wider partnerships with pharmaceutical companies.

Impact of molecular alterations on quality of life and prognostic understanding over time in patients with incurable lung cancer: a multicenter, longitudinal, prospective cohort study.

PURPOSE: The purpose of this study is to investigate changes over time in quality of life (QoL) in incurable lung cancer patients and the impact of determinants like molecular alterations (MA). METHODS: In a prospective, longitudinal, multicentric study, we assessed QoL, symptom burden, psychological distress, unmet needs, and prognostic understanding of patients diagnosed with incurable lung cancer at the time of the diagnosis (T0) and after 3 (T1), 6 (T2) and 12 months (T3) using validated questionnaires like FACT-L, National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT), PHQ-4, SCNS-SF-34, and SEIQoL. RESULTS: Two hundred seventeen patients were enrolled, 22 (10%) with reported MA. QoL scores improved over time, with a significant trend for DT, PHQ-4, and SCNS-SF-34. Significant determinants for stable or improving scores over time were survival > 6 months, performance status at the time of diagnosis, and presence of MA. Patients with MA showed better QoL scores (FACT-L at T1 104.4 vs 86.3; at T2 107.5 vs 90.0; at T3 100.9 vs 92.8) and lower psychological distress (NCCN DT at T1 3.3 vs 5; at T2 2.7 vs 4.5; at T3 3.7 vs 4.5; PHQ-4 at T1 2.3 vs 4.1; at T2 1.7 vs 3.6; at T3 2.2 vs 3.6), but also a worsening of the scores at 1 year and a higher percentage of inaccurate prognostic understanding (27 vs 17%) compared to patients without MA. CONCLUSION: Patients with tumors harboring MA are at risk of QoL deterioration during the course of the disease. Physicians should adapt their communication strategies in order to maintain or improve QoL.

Major clinical benefit from adjuvant chemotherapy for stage II-III non-small cell lung cancer patients aged 75 years or older: a propensity score-matched analysis.

BACKGROUND: Data are currently insufficient to support the use of adjuvant chemotherapy (ACT) after surgical resection for stage II or III non-small cell lung cancer (NSCLC) in patients aged ≥ 75 years. In this study we evaluated efficacy and safety profile of ACT in this population. METHODS: We retrospectively evaluated 140 patients ≥ 75 years who underwent curative surgical resection for stage II-III NSCLC from 2010 to 2018 with an indication to ACT according to current guidelines. A propensity score-matched analysis was performed to avoid cofounding biases. RESULTS: Thirty of 140 patients (21%) received ACT. Most patients (n = 24, 80%) received carboplatin in combination with vinorelbine, while 5 patients (17%) received cisplatin plus vinorelbine and one patient (3%) carboplatin plus gemcitabine. The occurrence of adverse events led to treatment discontinuation in 8 (27%) cases, while 19 (63%) patients completed 4 chemotherapy cycles. Common reported adverse events with ACT were anemia (n = 20, 67%), neutropenia (n = 18, 60%), thrombocytopenia (n = 9, 30%), renal impairment (n = 4, 13%) and transaminase elevation (n = 4, 13%). No toxic deaths occurred. The median follow-up was 67 months (IQR: 53-87). ACT was associated with a significant benefit in both relapse-free survival (median 36 vs. 18.5 months, p = 0.049) and overall survival (median not reached [NR] vs. 33.5 months, p = 0.023) in a propensity score-matched analysis which controlled for cofounders. CONCLUSION: ACT confers a survival benefit after curative resection of stage II-III NSCLC in selected patients aged 75 years or older with a manageable toxicity profile.

First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations.

BACKGROUND: The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. MATERIALS AND METHODS: 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016-2022 were analyzed. RESULTS: Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270). CONCLUSION: CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.

Pembrolizumab Alone or With Chemotherapy for 70+ Year-Old Lung Cancer Patients: A Retrospective Study.

OBJECTIVE: First-line pembrolizumab alone, as approved for PD-L1 ≥50%, or with chemotherapy was analyzed in older non-small-cell lung cancer (NSCLC) patients, for whom evidence is scarce. MATERIALS AND METHODS: A total of 156 consecutive ≥70 year-old patients treated between January 2016 and May 2021 were retrospectively analyzed. Tumor progression was verified through radiologic review, while toxicity was captured from records. RESULTS: Pembrolizumab plus chemotherapy (n = 95) caused higher rates of adverse events (91% vs. 51%, P < .001), treatment discontinuation (37% vs. 21%, P = .034), and hospitalization (56% vs. 23%, P < .001), but similar rates of immune-related adverse events (irAEs, mean 35%, P = .998) compared to pembrolizumab monotherapy (n = 61). Progression-free (PFS) and overall survival (OS) were similar between the 2 groups (7 vs. 8 months, and 16 vs. 14 months in median, P > .25). Occurrence of irAEs was associated with longer survival in a 12-week landmark analysis (median PFS 11 vs. 5 months, hazard ratio [HR] 0.51, P = .001; median OS 33 vs. 10 months, HR 0.46, P < .001), but occurrence of other AEs not (both P > .35). A worse ECOG performance status (PS) ≥2, presence of brain metastases at diagnosis, squamous histology and lack of tumor PD-L1 expression were independent predictors of shorter PFS and OS in multivariable analysis (HR 1.6-3.9 for PFS and OS, all P < .05). CONCLUSION: Chemoimmunotherapy increases the rate of adverse events and hospitalization without prolonging PFS or OS in newly diagnosed NSCLC patients aged 70 years or older compared to pembrolizumab monotherapy. ECOG PS 2, presence of brain metastases at diagnosis, squamous histology and PD-L1 negativity are associated with poor outcome.

Recent advances in small cell lung cancer: the future is now?

Small cell lung cancer is a relevant clinical issue as it is a highly malignant cancer, often diagnosed in advanced stage. Similarly to non-small cell lung cancer, tobacco smoking is currently the main risk factor. Its incidence, at least in males, has declined over the past decades, due to the worldwide decreased percentage of active smokers. The typical small cells of this tumor type are characterized by a high Proliferation Index, chromosomal deletions such as 3p(14-23) involving the tumor-suppressor gene FHIT, alterations of the MYC or Notch family proteins and the frequent expression of neuroendocrine markers. The combination of thoracic radiotherapy and chemotherapy is the standard treatment for limited stage disease, while platinum-based chemotherapy is the most effective choice for extensive stage disease. Unfortunately, whatever chemotherapy is used, the results are disappointing. No regimen has proved to be effective in the long run, indeed small cell lung cancer rapidly progresses after a frequent initial strong response, and the mortality rate remains still high. The advent of immunotherapy is actually changing the landscape in oncology. As well as in other cancers, recent trials have demonstrated the efficacy of the combination of immune checkpoint inhibitors and chemotherapy, opening new perspectives for the future of our patients.

Combination of Crizotinib and Osimertinib in T790M+ EGFR-Mutant Non-Small Cell Lung Cancer with Emerging MET Amplification Post-Osimertinib Progression in a 10-Year Survivor: A Case Report.

Tyrosine kinase inhibitors (TKIs) represent the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The duration of the response is, however, limited in time owing to the development of resistance mechanisms to both first- and second-generation agents such as MET oncogene amplification. This report describes the successful results obtained with the combination of the third-generation TKI osimertinib with the multitargeted TKI and MET inhibitor crizotinib in a patient with EGFR-mutant NSCLC with emerging MET amplification with a tolerable toxicity profile.

Autoimmune-related encephalitis during treatment with nivolumab for advanced head and neck cancer: a case report.

INTRODUCTION: Head and neck cancer represents a variety of tumors involving different organs in the cervical district, burdened by poor prognosis when diagnosed in an advanced stage. Immunotherapy with both anti-PD-1 nivolumab and pembrolizumab has the aim of increasing overall survival for patients with this malignancy. We report the first case of immune-related encephalitis caused by nivolumab in this setting of disease and present a brief review of the literature. CASE DESCRIPTION: A 60-year-old woman had been treated with concomitant chemoradiotherapy for a locally advanced human papillomavirus-negative squamous cell carcinoma of the tonsil. After local recurrence, she was treated with platinum-based first-line chemotherapy, followed by nivolumab at further progression within 6 months. Nivolumab was administered for 19 weeks, then discontinued due to the occurrence of immune-related hypothyroidism and grade 2 diarrhea. A month after the onset of the endocrinopathy, the patient also developed steroid-responsive encephalitis, considered as a consequence of anti-PD-1 therapy. One year after discontinuation of immunotherapy, toxicities have resolved and the patient is maintaining a complete radiologic response. CONCLUSIONS: Immunotherapy is a relatively new and promising therapy in the field of oncology. Its mechanism of action, which aims to stimulate the immune system against cancer cells, is not comparable to systemic and cytotoxic chemotherapy, which directly attacks and destroys malignant cells. Despite these differences, immunotherapy is not to be considered free from side effects, sometimes life-threatening.

Durvalumab in frail and elderly patients with stage four non-small cell lung cancer: Study protocol of the randomized phase II DURATION trial.

BACKGROUND: Elderly patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, but they are still underrepresented in clinical trials. In particular, data regarding efficacy and safety in frail or elderly patients with respect to immunotherapy are lacking. Importantly, immunosenescence in elderly patients might interfere with activities of immune-modulating drugs such as PD-1/PD-L1 inhibitors. Thus, there is an urgent need to assess safety and efficacy of such inhibitors in this group. METHODS/DESIGN: This prospective, open label, treatment stratified, randomized phase II study will enroll 200 patients with stage IV NSCLC amenable at least to single-agent chemotherapy (CT). Eligible patients must be aged 70 years or older and/or "frail" (Charlson Comorbidity Index > 1) or have a restricted performance status (Eastern Cooperative Oncology Group, ECOG > 1). Patients are stratified according to modified Cancer and Age Research Group (CARG) score: "fit" patients are allocated to combination CT (carboplatin/nab-paclitaxel) and "less fit" patients receive single-agent CT (gemcitabine or vinorelbine). After allocation to strata, patients are randomized 1:1 to receive either four cycles of CT or two cycles of CT followed by two cycles of durvalumab and subsequent maintenance treatment with durvalumab every 4 weeks. The primary endpoint is the rate of treatment-related grade III/IV adverse events (Common Terminology Criteria for Adverse Events (CTCAE) V4.03). As secondary endpoints, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, response rate (RR), overall survival (OS), descriptive subgroup analyses according to PD-L1 expression, and quality of life are addressed. Geriatric screening assessments and functional tests will be performed to complete the phenotyping of a potential "frail" and "elderly" patient cohort. The trial is accompanied by a biomaterial repository to explore potential biomarkers. DISCUSSION: The DURATION trial will prospectively investigate the safety and tolerability of anti-PD-L1 treatment with durvalumab after chemotherapy in elderly and frail patients and thereby provide new insights into the effect of PD-L1 blockade and the impact of immunosenescence in this cohort of patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03345810; initially registered on 17 November 2017. Eudra-CT, 2016-003963-20; initially registered on 3 January 2017.

Corrigendum: PTX3 Intercepts Vascular Inflammation in Systemic Immune-Mediated Diseases.

[This corrects the article DOI: 10.3389/fimmu.2019.01135.].

PTX3 Intercepts Vascular Inflammation in Systemic Immune-Mediated Diseases.

PTX3 is a prototypic soluble pattern recognition receptor, expressed at sites of inflammation and involved in regulation of the tissue homeostasis. PTX3 systemic levels increase in many (but not all) immune-mediated inflammatory conditions. Research on PTX3 as a biomarker has so far focused on single diseases. Here, we performed a multi-group comparative study with the aim of identifying clinical and pathophysiological phenotypes associated with PTX3 release. PTX3 concentration was measured by ELISA in the plasma of 366 subjects, including 96 patients with giant cell arteritis (GCA), 42 with Takayasu's arteritis (TA), 10 with polymyalgia rheumatica (PMR), 63 with ANCA-associated systemic small vessel vasculitides (AAV), 55 with systemic lupus erythematosus (SLE), 21 with rheumatoid arthritis (RA) and 79 healthy controls (HC). Patients with SLE, AAV, TA and GCA, but not patients with RA and PMR, had higher PTX3 levels than HC. PTX3 concentration correlated with disease activity, acute phase reactants and prednisone dose. It was higher in females, in patients with recent-onset disease and in those with previous or current active vasculitis at univariate analysis. Active small- or large- vessel vasculitis were the main independent variables influencing PTX3 levels at multivariate analysis. High levels of PTX3 in the blood can contribute to identify an increased risk of vascular involvement in patients with systemic immune-mediated diseases.

Plasma levels of M-CSF are increased in ANCA-associated vasculitides with active nephritis.

Anti-Neutrophil Cytoplasmic Antibodies (ANCA)-associated vasculitides (AAV) are characterized by small vessel injury and in some cases granulomatous lesions and glomerular inflammation. The pathogenic bases of these clinical phenotypes are incompletely understood, but evidence from patients with AAV and other inflammatory diseases suggest a role for monocyte/macrophages in the perpetuation of tissue injury. Macrophage colony stimulating factor (M-CSF) is a promoter of monocyte recruitment and macrophage proliferation, involved in mesangial cell proliferation and experimental nephritis development. Serum concentrations of M-CSF mark and herald the onset of lupus nephritis. Plasma samples from 29 patients with AAV (18 granulomatosis with polyangiitis, GPA, 6 eosinophilic granulomatosis with polyangiitis, EGPA, and 5 microscopic polyangiitis, MPA) and from 10 healthy controls were collected together with clinical data. Patients with AAV had higher levels of M-CSF when compared to controls. M-CSF levels correlated positively with the BVAS, serum C-reactive protein and erythrocyte sedimentation rate, while haemoglobin correlated inversely with M-CSF. Patients with active renal disease had significantly higher levels of M-CSF when compared to the other subgroups. M-CSF levels did not differ between ANCA subserotypes and were not associated with the involvement of other organs. In conclusion, M-CSF is higher in patients with AAV and active nephritis and could contribute to the pathogenesis of these diseases. In addition, M-CSF could behave as a useful marker of renal involvement in AAV.