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Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is the most common cause of brain metastasis (BM). Little is known about immune checkpoint inhibitor activity in the central nervous system, especially in patients receiving monotherapy for tumors with a tumor proportion score (TPS) ≥ 50%. This noninterventional, retrospective, multicenter study, conducted with the GFPC, included treatment-naïve patients strongly positive for PD-L1 (TPS ≥ 50%) with BM receiving first-line single-agent pembrolizumab treatment between May 2017 and November 2019. The primary endpoints were centrally reviewed intracranial overall response rates (ORRs), centrally reviewed intracranial progression-free survival (cPFS), extracranial PFS, and overall survival were secondary endpoints. Forty-three patients from five centers were included. Surgical or local radiation therapy was administered to 31 (72%) patients, mostly before initiating ICI therapy (25/31). Among 38/43 (88.4%) evaluable patients, the intracranial ORR was 73%. The median PFS was 8.3 months. The cerebral and extracerebral median PFS times were 9.2 and 5.3 months, respectively. The median OS was 25.5 months. According to multivariate analysis, BM surgery before ICI therapy was the only factor significantly associated with both improved PFS (HR = 0.44) and OS (HR = 0.45). This study revealed the feasibility and outcome of front-line pembrolizumab treatment in this population with BM. [ABSTRACT FROM AUTHOR]

Data regarding characteristics, safety and survival outcomes of patients aged 80 or older treated with immune checkpoint inhibitors (ICI) in routine oncology practice are limited. We retrospectively collected data of patients aged 80 and older with advanced non-small cell lung cancer (NSCLC) or melanoma treated with anti-PD1, anti-PD-L1 or anti-CTLA-4 regardless of the treatment line, in 14 institutions, between January 2014 and June 2017. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan Meier method. Toxicity was assessed according to CTCAE 5.0. Multivariate analyses were performed with the Cox model. Eighty-two patients were included (36 with NSCLC, 45 with melanoma). Their median age was 82 years (range 80–93). Nivolumab and pembrolizumab were mainly used. In the NSCLC group, median PFS and OS were 2.3 months (95%CI 1.8–6.1) and 8.8 months (95%CI 5.5–18.1), respectively. In the melanoma group, median PFS and OS were 10.2 months (95%CI 4.5–20.0) and 24.5 months (95%CI 14.1–NR), respectively. The albumin level was found to be independently associated with a better OS in both groups. Grade 3–4 toxicities occurred in 15 patients (18.5%). One patient died from ICI-induced pulmonary toxicity. Our study findings suggest that treatment with ICI in elderly patients with NSCLC and melanoma has a risk-benefit ratio that supports its use. However, we report in this cohort that one in five patients has a grade 3–4 IRAEs leading to treatment discontinuation. Geriatric assessment prior to initiation of therapy and during therapy should be routine in patients aged 80 years and older. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are currently recommended as first-line treatment for advanced non-small-cell lung cancer (NSCLC) with EGFR -activating mutations. Third-generation (3rd G) EGFR-TKIs, including osimertinib, offer an effective treatment option for patients with NSCLC resistant 1st and 2nd EGFR-TKIs. However, the efficacy of 3rd G EGFR-TKIs is limited by acquired resistance that has become a growing clinical challenge. Several clinical and preclinical studies are being carried out to better understand the mechanisms of resistance to 3rd G EGFR-TKIs and have revealed various genetic aberrations associated with molecular heterogeneity of cancer cells. Studies focusing on epigenetic events are limited despite several indications of their involvement in the development of resistance. Preclinical models, established in most cases in a similar manner, have shown different prevalence of resistance mechanisms from clinical samples. Clinically identified mechanisms include EGFR mutations that were not identified in preclinical models. Thus, NRAS genetic alterations were not observed in patients but have been described in cell lines resistant to 3rd G EGFR-TKI. Mainly, resistance to 3rd G EGFR-TKI in preclinical models is related to the activation of alternative signaling pathways through tyrosine kinase receptor (TKR) activation or to histological and phenotypic transformations. Yet, preclinical models have provided some insight into the complex network between dominant drivers and associated events that lead to the emergence of resistance and consequently have identified new therapeutic targets. This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies. [ABSTRACT FROM AUTHOR]

The incidence rate of tuberculosis in developed countries is low. The most common presentation of this disease is its pulmonary form but with the increasing use of immunosuppressive drugs, extra-pulmonary tuberculosis is re-emerging. Nevertheless, sternal bone involvement is uncommon. We report the case of an eighty-three-year-old man who presented a painful sternal mass which progressed towards cutaneous ulceration. The first diagnostic hypothesis was neoplasia. The pathological and microbiological diagnosis of tuberculosis was achieved after surgical biopsy. The patient received treatment against tuberculosis for nine months enabling recovery without surgery. This case illustrates the importance of having a diagnosis prior to any kind of treatment facing any voluminous parietal thoracic lesions. This diagnosis is made possible by surgical samples and interdisciplinary teamwork. This case underlines that tuberculosis remains a differential diagnosis that must be evoked in case of unusual bone mass. [ABSTRACT FROM AUTHOR]

In the management of cystic fibrosis, treatments against Staphylococcus aureus and Haemophilus influenzae such as amoxicillin or cotrimoxazole have to be prescribed and the antibiotherapy's efficacy may be linked to the concentration that reaches the infected site. As cystic fibrosis patients present disturbed pharmacokinetics parameters, drug monitoring would be relevant to assess the lung distribution of antibiotics and to optimize dosing regimens. In this context, the aim of the study was to develop and validate HPLC‐based methods for the determination of both antibiotics in bronchial sputum from cystic fibrosis patients, in order to assess the distribution of the drugs into the lungs. Plasma proteins were precipitated by acetonitrile and amoxicillin concentrations in sputum were determined by HPLC coupled with tandem‐mass spectrometry. Following liquid extraction with ethyl acetate, cotrimoxazole was quantified by HPLC using ultraviolet detection. Both methods were rapid, specific, accurate and reproducible. The method was applied to patient samples. In three treated patients, concentrations of amoxicillin in sputum were similar and below the lower limit of quantification (0.1 μg/g) and in six patients, sputum concentrations up to 11.1 and 6.4 μg/g were measured for sulfamethoxazole and trimethoprim, respectively. [ABSTRACT FROM AUTHOR]

Pembrolizumab plus chemotherapy is currently used in the first-line treatment of advanced non-small-cell lung cancer without EGFR mutations or ALK rearrangements, regardless of PD-L1 expression status. A study comparing chemotherapy plus pembrolizumab versus pembrolizumab alone has never been performed in patients with PD-L1 ≥50%. The aim of this trial is to perform such a comparison as first-line treatment in patients not eligible for locally advanced treatment who have expression of PD-L1 on ≥50% of tumor cells. The expected results are a reduction in the risk of early progression. A higher objective tumor response is also expected with the combination of chemotherapy and pembrolizumab compared with pembrolizumab alone. The study will allow a direct comparison of the proportion of patients who derive long-term benefit from the treatment. Clinical trial number: EudraCT (2020-002626-86); ClinicalTrials.gov (NCT04547504). [ABSTRACT FROM AUTHOR]

Background: The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM. Methods: This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin–pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life [ClinicalTrials.gov identifier: NCT02162537]. Results: The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% versus 20%; p < 0.001); there were no significant differences between BR and ChT arms for median PFS: 4.7, 95% confidence interval (CI):3.4–7.5 versus 4.8, 95% CI: 2.4–6.5 months, for median OS: 8.5, 95% CI:.6–11.1 versus 8.3, 95% CI:4.5–11.5 months, cerebral and extra-cerebral ORR (27% versus 13%, p = 0.064, and 30% versus 41%, p = 0.245, respectively). The ChT arm had more grade 3/4 neutropenia than the BR arm (13% versus 6%, p = 0.045); others toxicities were comparable. Conclusion: The significant BR rate difference between the two arms suggests that upfront BR is not mandatory in aNSCLC with aBM but this trial failed to show that deferring BR for aBM is superior in terms of PFS from upfront BR. [ABSTRACT FROM AUTHOR]

• Immune related encephalitis is a rare but serious complication of anti–PD-1/PD-L1 immunotherapy. • Characteristics from NSCLC patients presenting immune related encephalitis, were evaluated retrospectively. • Prognosis is good when management, particularly corticosteroids, are started early. Using immune-checkpoint inhibitors (ICIs) to manage cancer is associated with various immune-related adverse events. Central and/or peripheral neurological disorders are rare and potentially serious. We analyzed the characteristics of non-small–cell lung cancer (NSCLC) patients who developed immune-related encephalitis under anti–programmed-death protein-1 or its ligand (PD-1/PD-L1). Clinical, biological and radiological characteristics of ICI-treated NSCLC patients with immune-related encephalitis, from 6 centers, were evaluated retrospectively. The 6 centers included 9 patients: all men, all smokers, median (range) age 67 (48–77) years, 78% adenocarcinomas, first- or second-line ICI for 5 and 4 patients, respectively. Two patients had non-active cerebral metastases at ICI onset. A median of 5 (1–22) ICI infusions preceded neurological symptoms, the most frequent being confusion (78%), fever (45%) and cerebellar ataxia (33%). CSF analyses revealed a median white blood cell count of 22/mm3 (1–210/mm3), with hyperlymphocytosis in 8 patients and high protein levels in all. All bacteriological and virological analyses were negative. Cerebral MRI was considered normal for 5 patients; 4 patients had FLAIR hypersignals consistent with brain parenchyma inflammation. Three patients required intensive care. All patients received corticosteroids (different doses), a median of 8.5 (6–18) days post-onset. Corticosteroids achieved rapid symptom regression without sequelae in 8 patients. The last patient, with the longest time until corticosteroid introduction, died. ICIs were never restarted in any patient. Immune encephalitis, a rare but serious complication of anti–PD-1/PD-L1 therapy, carries a good prognosis when managed with early corticosteroids. [ABSTRACT FROM AUTHOR]

Lung cancer prognosis has improved in the last decade, including in patients with brain metastasis. However, few of these patients who receive corticosteroids have a primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP). We report the case of an 80-yearold man diagnosed with non-small cell lung cancer and concomitant symptomatic brain metastases, treated with 50 mg/day of prednisolone without any prophylaxis, who presented an acute PJP. After 72 hours of unsuccessful treatment of PJP, the patient died. In our review of this case and the existing literature, we emphasise the importance of a wide use of prophylaxis for PJP, especially in advanced lung cancer treated with corticosteroid therapy. We discuss this issue and report current evidence for primary prophylaxis by trimethoprim–sulfamethoxazole. [ABSTRACT FROM AUTHOR]