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Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel–bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19–82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2–9.6] and 10.8 [IQR: 5.3–19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI−): 7.0 [IQR: 4.2–11.0] versus 5.2 [IQR: 2.9–8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0–1. Only a performance status of 0–1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Non-small-cell lung cancers (NSCLC) represent 85% of all lung cancers, with adenocarcinoma as the most common subtype. Since the 2000's, the discovery of molecular alterations including epidermal growth factor receptor ( ) mutations and anaplastic lymphoma kinase ( ) rearrangements together with the development of specific tyrosine kinase inhibitors (TKIs) has facilitated the development of personalized medicine in the management of this disease. This review focuses on the biology of molecular alterations in NSCLC as well as the diagnostic tools and therapeutic alternatives available for each targetable alteration. Rapid and sensitive methods are essential to detect gene alterations, using tumor tissue biopsies or liquid biopsies. Massive parallel sequencing or Next Generation Sequencing (NGS) allows to simultaneously analyze numerous genes from relatively low amounts of DNA. The detection of oncogenic fusions can be conducted using fluorescence hybridization, reverse-transcription polymerase chain reaction, immunohistochemistry, or NGS. mutations, and rearrangements, (MET proto-oncogenereceptor tyrosine kinase), (B-Raf proto-oncogen serine/threonine kinase), (neurotrophic tropomyosin receptor kinase , and (ret proto-oncogene) alterations are described with their respective TKIs, either already authorized or still in development. We have herein paid particular attention to the mechanisms of resistance to EGFR and ALK-TKI. As a wealth of diagnostic tools and personalized treatments are currently under development, a close collaboration between molecular biologists, pathologists, and oncologists is crucial.

Background We describe a case of pemetrexed toxicities related to reabsorption by an ileal neobladder, which caused prolonged hematotoxicity and nephrotoxicity. Case presentation A 59-year-old white man was diagnosed with metastatic wild-type adenocarcinoma of the upper lobe of his right lung. After a first cycle of cisplatin and pemetrexed, he had unusually prolonged aplasia and acute kidney injury. The prolonged aplasia was caused by pemetrexed reabsorption by the ileal mucosa of the neobladder as pemetrexed was eliminated renally in an active form and is partly lipophilic. Conclusions Pemetrexed may be reabsorbed by the ileal mucosa of the neobladder because of its hydrophobic structure and renal excretion in its active form. Acute urinary retention may maintain this phenomenon. Published data excluded a potential role for cisplatin in this toxicity; furthermore, we could not assess pemetrexed concentrations in the blood or urine as these assay techniques are not validated. Thus, care is needed when giving chemotherapy to patients with a neobladder.

Background Nivolumab, a monoclonal antibody targeting the programmed death-1 receptor, is indicated in locally advanced or metastatic non-small cell lung cancer, with progression after platinum-based chemotherapy. Up-to-now, few data are available concerning brain activity of this treatment and concomitant use of corticosteroids. Case presentation A 64-year-old caucasian man with a pulmonary adenocarcinoma associated with brain metastases received four courses of nivolumab in concomitance with a high dose of corticosteroids for his neurologic symptoms. He experienced a partial response in his brain and chest with an improvement in his general condition. Nivolumab was effective in shrinking symptomatic brain metastases, and metastases at other sites, in a patient with non-small cell lung cancer and first-line chemotherapy failure. The effect of nivolumab was obtained despite concomitant high-dose corticosteroid therapy. Combined nivolumab and high-dose corticosteroid therapy did not induce unexpected adverse events. Conclusion Nivolumab and concomitant high-dose corticosteroid therapy was found to be efficient and well tolerated.

BackgroundFew real-world data are available in patients with advanced metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy, particularly in those with brain metastases at treatment initiation.MethodsThis was a national, retrospective, multicenter study that consecutively included all patients with PD-L1-positive (tumor proportion score ≥ 50%) advanced NSCLC who initiated first-line treatment with pembrolizumab as a single agent between May 2017 (date of availability of pembrolizumab in this indication in France) to November 22, 2019 (approval of the pembrolizumab-chemotherapy combination). Data were collected from medical records with local response assessment.ResultsThe cohort included 845 patients and 176 (20.8%) had brain metastases at diagnosis. There were no significant differences in outcomes for patients with and without brain metastases: 9.2 (95% CI 5.6–15) and 8 (95% CI 6.7–9.2, p = 0.3) months for median progression-free survival (PFS) and, 29.5 (95% CI 17.2–NA) and 22 (95% CI 17.8–27.1, p = 0.3) months for median overall survival (OS), respectively. Overall response rates were 47% and 45% in patients with and without cerebral metastases. In multivariate analysis, performance status 2–4 vs. 0–1 and neutrophil-to-lymphocyte ratio ≥ 4 vs. < 4 were the main independent negative factors for OS; brain metastasis was not an independent factor for OS.ConclusionIn this large multicenter cohort, nearly 20% of patients initiating pembrolizumab therapy for advanced NSCLC had cerebral metastases. There was no significant difference in response rates, PFS and OS between patients with and without brain metastases.

Background Few data are available on the impact of venous thrombotic events (VTE) in patients with metastatic non-small cell lung cancer (mNSCLC) treated with immunotherapy. Methods This is a secondary analysis of the ESKEYP study, a national, retrospective, multicenter study that consecutively included all PD-L1 ≥ 50% mNSCLC patients who initiated first-line treatment with pembrolizumab monotherapy. From May 2017 to November 2019, 845 patients were included (from availability of pembrolizumab in this indication in France to the authorization of the combination with chemotherapy). Impact of VTE and patient characteristics were analyzed. Results Of the 748 patients (88.5%) with available data, the incidence of VTE was 14.8% (111/748). At pembrolizumab initiation, Khorana score was ≥ 2 for 55.0% (61/111) of them. Recurrence of VTE was reported for 4 of the 111 patients and 5 had bleeding complications. Patients with VTE were significantly younger, had more frequently long-term corticosteroids treatment and more often liver metastases. Progression-free survival (PFS) was significantly shorter in patients with VTE compared to patients without VTE: 6.1 (95% CI 4.1–9.0) months vs. 8.3 (6.9–10.3) months (p = 0.03). VTE did not significantly impact overall survival (OS): 15.2 (10.0–24.7) months with VTE and 22.6 (18.4–29.8) months without VTE (p = 0.07). In multivariate analysis for PFS and OS, HRs for VTE were 1.3 (0.99–1.71), p = 0.06 and 1.32 (0.99–1.76), p = 0.05. Conclusion The incidence of VTE appears to be as high with in first-line immunotherapy as with chemotherapy in patients with mNSCLC, with in patient with VTE, a no significant trend for lower PFS and OS in multivariate analysis. more marked impact on PFS than on OS.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second-or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in thirdline (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.