Opinion statement
Targeted therapies and more recently immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced NSCLC. Clinical trials investigating immune checkpoint ...inhibitors (ICI) have usually excluded patients with oncogenic drivers, so that the outcome of these agents in this population is poorly known. In patients with oncogenic addiction, targeted therapy remains clearly the best option, and the place of immunotherapy in this population has not been clearly defined yet.
Based on available data, we suggest that (i) immunotherapy single agent should be proposed only after exhaustion of more validated treatments, (ii) combinations of immunotherapy with targeted therapies are of interest provided that we can manage toxicity and find the best sequence, (iii) a combination of immunotherapy with chemotherapy may be appealing in patients pretreated with targeted agents. The best way to opt in for the best strategy will depend upon the identification of adequate biomarkers. New basic and clinical research is awaited in this field.
Introduction
Mini-invasive bronchoscopic techniques (such as radial endobronchial ultrasonography (rEBUS) and electromagnetic navigation (EMN)) have been developed to reach the peripheral lung but ...result in small samples. The feasibility of an adequate molecular testing from these specimens has been very little studied.
Methods
We retrospectively reviewed EMN and rEBUS procedures performed in patients diagnosed with lung cancer in our institution in 2017 and 2018. We analysed the sensitivity for rEBUS and EMN and each sampling method, and the feasibility of a comprehensive molecular testing.
Results
In total, 317 rEBUS and 14 EMN were performed. Median sizes of tumours were 16 and 32 mm for EMN and rEBUS, respectively. Overall sensitivity for rEBUS and EMN was 84.3%. Cytology was found to be complementary with biopsies, with 13.3% of cancer diagnosed on cytology while biopsies were negative. Complication rate was 2.4% (pneumothorax 1.5%, mild haemoptysis 0.9%). Genotyping (immunohistochemistry for
ROS1
and
ALK
followed by fluorescence
in situ
hybridisation if positive and hybrid capture next-generation sequencing covering 48 genes), when ordered (n=188), was feasible in 69.1% (
EGFR
17.7%,
KRAS
31.7%,
BRAF
4.8%,
ALK
1.2%,
MET
3.1%,
HER2
0.8%). PD-L1 (programmed death-ligand 1) expression, when ordered (n=232), could be analysed in 94% of cases. Overall, 56.9% (33 out of 58) of patients for whom genotyping was not feasible underwent a second sampling (12 pretreatment, 21 at progression), allowing for the detection of six actionable genotypes (five
EGFR
, one
MET
).
Conclusion
rEBUS and EMN are sensitive and safe procedures that result in limited samples, often not suitable for genotyping, highlighting the importance of integrating liquid biopsy in routine testing.
KRAS mutation is the most frequent molecular alteration found in advanced NSCLC; it is associated with a poor prognosis without available targeted therapy. Treatment options for NSCLC have been ...recently enriched by the development of immune checkpoint inhibitors (ICIs), and data about its efficacy in patients with KRAS-mutant NSCLC are discordant. This study assessed the routine efficacy of ICIs in advanced KRAS-mutant NSCLC.
In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and with available molecular analysis between April 2013 and June 2017. Analysis of programmed death ligand 1 (PD-L1) expression was performed if exploitable tumor material was available.
A total of 282 patients with ICI-treated (in the first line or more) advanced NSCLC (all histological subgroups) who were treated with ICIs (anti–programmed death 1, anti–PD-L1, or anti–cytotoxic T-lymphocyte associated protein 4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations, and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression of 1% or more and 50%, respectively (49.5% and 21.2%, respectively, in the case of the 85 patients with KRAS-mutant NSCLC). No significant difference was seen in terms of objective response rates, progression-free survival, or overall survival between KRAS-mutant NSCLC and other NSCLC. No significant differences in overall survival or progression-free survival were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRAS-mutant NSCLC, unlike in non–KRAS-mutant NSCLC, the efficacy of ICIs is consistently higher, even though not statistically significant, for patients with PD-L1 expression in 1% or more of tumor cells than for those with PD-L1 expression in less than 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥50%).
For patients with KRAS-mutant NSCLC (all mutational subtypes), the efficacy of ICI is similar to that for patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICIs in KRAS-mutant NSCLC than it is in other types of NSCLC.
Anatomically complex airway stenosis (ACAS) represents a challenging situation in which commercially available stents often result in migration or granulation tissue reaction due to poor congruence. ...This proof-of-concept clinical trial investigated the feasibility and safety of computer-assisted designed (CAD) and manufactured personalised three-dimensional (3D) stents in patients with ACAS from various origins. After CAD of a virtual stent from a CT scan, a mould is manufactured using a 3D computer numerical control machine, from which a medical-grade silicone stent is made. Complication rate, dyspnoea, quality of life and respiratory function were followed after implantation. The congruence of the stent was assessed peroperatively and at 1 week postimplantation (CT scan). The stent could be implanted in all 10 patients. The 3-month complication rate was 40%, including one benign mucus plugging, one stent removal due to intense cough and two stent migrations. 9 of 10 stents showed great congruence within the airways, and 8 of 10 induced significant improvement in dyspnoea, quality of life and respiratory function. These promising outcomes in highly complex situations support further investigation on the subject, including technological improvements.Trial registration number NCT02889029.
New 3D technologies are rapidly entering into the surgical landscape, including in interventional pulmonology. The transition of 2D restricted data into a physical model of pathological airways by ...three-dimensional printing (3DP) allows rapid prototyping and fabrication of complex and patient-specific shapes and can thus help the physician to plan and guide complex procedures. Furthermore, computer-assisted designed (CAD) patient-specific devices have already helped surgeons overcome several therapeutic impasses and are likely to rapidly cover a wider range of situations. We report herein with a special focus on our clinical experience: i) how additive manufacturing is progressively integrated into the management of complex central airways diseases; ii) the appealing future directions of these new technologies, including the potential of the emerging technique of bioprinting; iii) the main pitfalls that could delay its introduction into routine care.
Thymic epithelial tumors (TETs) are rare malignancies that may be aggressive and difficult to treat. In the advanced setting, systemic treatments may be delivered as primary therapy before surgery or ...definitive radiotherapy, as exclusive treatment when no focal treatment is feasible, or in the setting of recurrences. Réseau tumeurs THYMIques et Cancer (RYTHMIC) is the nationwide network for TETs in France. The objective of the study was to describe the modalities and analyze the efficacy of systemic treatments for patients with advanced TETs included in the RYTHMIC prospective database hosted by the French Thoracic Cancer Intergroup.
All consecutive patients for whom systemic treatment was discussed at the RYTHMIC multidisciplinary tumor board from 2012 to 2015 and who received at least one cycle of treatment were included. The main end points were objective response and progression-free survival (PFS).
A total of 236 patients were included in this analysis. Of those 236 patients, 91 received primary chemotherapy, leading to response rates of 83% for thymomas and 75% for thymic carcinomas and a median PFS of 23.2 months. A strong predictor of longer PFS was histologic type of thymoma (p < 0.001). Exclusive chemotherapy was delivered to 54 patients. The response rates were 31% for thymomas and 37% for thymic carcinomas. The median PFS was 6.2 months, and it was correlated to response rate (p = 0.001). Systemic therapy for a first, second, third, and fourth recurrence was delivered to 114, 81, 51, and 27 patients, respectively. The response rates ranged between 15% and 39% for thymomas and 4% to 21% for thymic carcinomas. The median PFS times were 7.7, 6.2, 5.9, and 6.5 months, respectively.
Patients with advanced thymic malignancies may receive multiple lines of systemic therapy, with an opportunity for clinically relevant PFS rates for which objective response may be a surrogate. Our real-life study provides landmark efficacy data that are needed when designing clinical trials to assess innovative agents.
Endobronchial localizations of inflammatory myofibroblastic tumors are very unusual. We report the multimodal, bronchoscopic management of 3 cases, offering durable local control in all cases ...(including 2 patients who were definitively cured). Although surgery is usually considered the gold standard, therapeutic bronchoscopy should probably be considered as a frontline option for proximal lesions with limited base (< 10 mm2) because of uncommon metastatic spread and delayed local recurrence. Of note, 1 of our cases is a rare airway case after allograft hematopoietic stem cell transplant.
Interventional bronchoscopy has a predominant role in the management of both early and advanced-stage airway tumors. Given the very poor prognosis of lung cancer, there is a need for new tools to ...improve early detection and bronchoscopic treatment of endo-bronchial precancerous lesions. In more advanced stages, interventional bronchoscopy plays an important role, as nearly a third of lung cancers lead to proximal airway obstruction. This will cause great discomfort or even life-threatening symptoms related to local extension, such as dyspnea, post-obstructive pneumonia, and hemoptysis. Surgery for very locally advanced disease is only effective for a limited number of patients and the effects of conventional antitumor therapies, like radiation therapy or chemotherapy, are inconstant and are too delayed in a palliative context. In this review, we aim to provide pulmonologists with an exhaustive technical overview of (I) the bronchoscopic management of benign endobronchial lesions; (II) the bronchoscopic management of malignant tumors, including the curative treatment of localized lesions and palliative management of malignant proximal airway stenosis; and (III) descriptions of the emerging endoscopic techniques used to treat peripheral lung tumors.
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