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• Efficacy and safety of necitumumab combined with pembrolizumab was assessed in advanced NSCLC. • Pretreated NSCLC population had relatively high proportion of PDL1 negative patients. • Modest benefits of combined necitumumab and pembrolizumab seen in patients with NSCLC. • Safety corresponded to individual profiles of both drugs, with no additive toxicities. Efficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. This single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR). In 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %–35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4–6.9 months) and OS at 6 months was 74.7 % (61.5%–83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5–75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. Results suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities. [ABSTRACT FROM AUTHOR]

• Adapting maintenance according to response to chemo (SD/OR) doesn't improve survival. • Doublet with G or P, have equivalent efficacy in contrast to the JMDB trial. • Chemo remains the reference in case of contra-indication/failure of immunotherapy. • Toxicities of the two doublets are quite similar during induction/maintenance phase. Benefit from maintenance in advanced non-squamous non-small cell lung cancer (NS-NSCLC) might favor switch maintenance after disease stabilization (SD) and continuation after objective response (OR). This trial assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG) with G continuation for patients with OR or switch to pemetrexed (P) for patients with SD as compared with a control arm based on the Paramount regimen. Eligibility criteria: age 18–70 years, ECOG PS 0–1, untreated stage IV NS-NSCLC without EGFR or ALK alteration, ineligibility to bevacizumab. Patients were randomized 1:1 to receive either CG (4 cycles) followed by G maintenance in case of OR followed by P at progression, or switch to P for patients with SD, or 4 cycles of CP followed by P (control arm). Primary endpoint: overall Survival. Between 2012 and 2016, 932 patients were randomized (CG: 467, CP: 465) with well-balanced characteristics. 257 patients (56.7%) in the CG arm received maintenance (G: 142, P: 113) versus 277 patients (59.7%) in the CP arm. Median number of maintenance cycles was 5 for G and P (CG induction) and 4 for P (CP induction). OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p = 0.71) with a median of 10.9 months (CG) versus 10.4 (CP). HR for PFS was 0.95 (95% CI 0.83, 1.09; p = 0.45) with a median of 4.8 months for CG versus 4.5 for CP. Safety profile was as expected. Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome. Clinical trial information: NCT01631136. [ABSTRACT FROM AUTHOR]

• We report the first case of prolonged complete tumor response to immunotherapy in an ALK-rearranged NSCLC patient. • This case supports the idea that some ALK rearranged NSCLC could durably benefit from immunotherapy. • This case highlights the need for further studies to identify predictive factors of response to ICI in this population. Immune checkpoint inhibitors (ICI) have become a major treatment in advanced non small cell lung cancer (NSCLC). However, some patients do not benefit from ICI, especially those harboring an ALK rearrangement. Here, we report a case of prolonged complete tumor response to immunotherapy in an ALK-rearranged NSCLC patient. We verify ALK expression and rearrangement on formalin-fixed paraffin-embedded tumor samples of the patient by Immunohistochemistry and Fluorescence In Situ Hybridization analysis. The patient provided written informed consent authorizing publication of clinical case. We report the case of 48 years old man with a ALK-rearranged NSCLC. This patient displayed a complete response for 16 months under nivolumab therapy in third line setting after ceritinib and platin based chemotherapy. This is the first case of complete and prolonged response to ICI in ALK rearranged NSCLC. This case supports the idea that some ALK rearranged NSCLC could durably benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

• Brigatinib is efficient in ALK + NSCLC pretreated with crizotinib or other ALK TKIs. • Real-world data on the efficacy of brigatinib remain rare. • Brigatinib is efficient after progression with ALK TKIs in early access program. • Dose reduction rate in real-world setting was 8.8%. Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib. This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors (mainly crizotinib then ceritinib). At brigatinib initiation, 59.1% had performance status 0–1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (95% CI, 0.06–20.7) months. Median PFS was 6.6 (4.8–9.9) months for the entire population. For patients who received 2, 3–4 and >4 lines of treatment before brigatinib, PFS was 4.3 (2.5–8.9), 10.4 (5.9–13.9) and 3.8 (0.8–7.4) months, respectively. In the 91 evaluable patients, disease control rate was 78.2%. From brigatinib start, median overall survival was 17.2 (11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Median OS from the diagnosis of NSCLC was 75.3 (38.2–174.6) months. These real-world results confirm the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC. [ABSTRACT FROM AUTHOR]

• NRAS mutated NSCLC are mostly found in men with smoking history. • NRAS mutated NSCLC are characterized by a high frequency of codon 61 mutations. • Efficacy of immunotherapy combined with chemotherapy needs further investigation. • NRAS codon 61 mutation should be considered in targeted therapy development. NRAS mutations are observed in less than 1% of non-small cell lung cancer (NSCLC). Clinical data regarding this rare subset of lung cancer are scarce and response to systemic treatment such as chemotherapy or immune checkpoint inhibitors (ICI) has never been reported. All consecutive patients with an NRAS mutated NSCLC, diagnosed between August 2014 and November 2020 in 14 French centers, were included. Clinical and molecular data were collected and reviewed from medical records. Out of the 164 included patients, 106 (64.6%) were men, 150 (91.5%) were current or former smokers, and 104 (63.4%) had stage IV NSCLC at diagnosis. The median age was 62 years, and the most frequent histology was adenocarcinoma (81.7%). NRAS activating mutations were mostly found in codon 61 (70%), while codon 12 and 13 alterations were observed in 16.5% and 4.9% of patients, respectively. Programmed death ligand-1 expression level <1%/1–49%/≥50% were respectively found in 30.8%/27.1%/42.1% of tumors. With a median follow-up of 12.5 months, median overall survival (OS) of stage IV patients was 15.3 months (95% CI 9.9–27.6). No significant difference in OS was found according to the type of mutation (codon 61 vs. other), HR = 1.12 (95% CI 0.65–1.95). Among stage IV patients treated with platinum-based doublet (n = 66), ICI (n = 48), or combination of both (n = 10), objective response rate, and median progression free survival were respectively 45% and 5.8 months, 35% and 6.9 months, 70% and 8.6 months. NRAS mutated NSCLC are characterized by a high frequency of smoking history and codon 61 mutations. Further studies are needed to confirm the encouraging outcome of immunotherapy in combination with chemotherapy. [ABSTRACT FROM AUTHOR]

Highlights • Efficacy of osimertinib in real-world setting and in clinical trials was comparable. • Osimertinib was efficient in patients with brain metastasis. • Osimertinib was efficient in second or more lines in T790 M EGFR-mutated patients. • EGFR exon 19 deletion had a better susceptibility to osimertinib. Abstract Objectives The efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR T790 M resistance mutation was demonstrated in clinical trials. However, data on efficacy of osimertinib in real world remain rare. Materials and methods This retrospective multicentric study analyzed T790M-positive advanced NSCLC patients enrolled in French early access program for osimertinib. Patients were pretreated with first- or second-generation EGFR tyrosine-kinase inhibitor and for a majority with chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. Results 205 patients (mean age, 69.5 years; female, 68.8%; adenocarcinoma, 97.5%, never-smokers, 71.5%) were analyzed. Osimertinib was used in second and third line in 18.0% and 82.0% of patients, respectively. Median PFS was 12.4 (95% CI, 10.1–15.1) months. In patients with and without cerebral metastasis, PFS was 9.7 (7.7–13.5) and 15.1 (12.0–17.1) months (p = 0.21), respectively. PFS in second and third line or more was 12.6 (6.7–17.5) and 12.4 (9.7–15.3) months, respectively. Median PFS in patients with EGFR exon 19 deletion and exon 21 mutation was 13.5 (10.1–16.0) and 9.7 (7.4–13.2) months, respectively (p = 0.049). Median OS since osimertinib initiation was 20.5 (16.9–24.3) months: 23.1 (18.6–27.8) and 18.0 (12.2–22.2) months in patients without and with cerebral metastasis (p = 0.11); 17.5 (11.6–27.8) and 21.7 (17.3–24.3) months as second or third line of treatment or more (p = 0.46), respectively. Median OS in patients with EGFR exon 19 deletion and exon 21 mutation was 23.1 (18.6–25.7) and 15.3 (11.6–21.7) months, respectively (p = 0.03). Osimertinib dosage was modified in 8.0% of patients and definitively discontinued for adverse events in 5.9%. Fifty patients benefited from rebiopsy (persistence of T790 M mutation, 44.7%; C797S mutation, 21.1%; cMET amplification, 8.0%). Conclusion In pretreated patients with T790M-mutated advanced NSCLC, the efficacy of osimertinib appears similar in real-world setting to that of clinical trials. [ABSTRACT FROM AUTHOR]

Highlights • MET amplification enhances proliferation of EGFR mutated NSCLC cells in vitro. • MET amplification also promotes cell migration and EMT phenotype. • In vivo , MET amplification increases tumor growth and metastatic spread. Abstract Background Five to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) through MET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown. Methods We investigated, in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression. Results MET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo , MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification. Conclusion MET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification. [ABSTRACT FROM AUTHOR]

Objectives Although nivolumab has shown efficacy against non–small-cell lung cancers (NSCLCs), patients with active brain metastases (BMs) were excluded from pivotal clinical trials. Hence, data regarding nivolumab intracerebral activity and safety in NSCLC patients with BMs are scarce. Materials and methods We conducted a retrospective multicenter study on NSCLC patients with BMs treated with nivolumab. The primary endpoint was intracerebral objective response rate (IORR), according to RECIST criteria. Secondary endpoints included intracerebral control rate, intracerebral and general progression-free survival (PFS), overall survival (OS) and tolerance. Results and conclusion Forty-three patients were included. BMs were locally pretreated in 34 (79%) patients and active in 16 (37%) patients. Median follow-up was 5.7 (95% CI: 2.7–8.4) months. IORR and extracerebral response rate were, respectively, 9% (95% CI: 3–23%) and 11% (95% CI: 4–26%). Intracerebral control rate was 51% (95% CI: 37–66%). Median intracerebral and general PFS lasted 3.9 (95% CI: 2.8–11.1) and 2.8 (95% CI: 1.8–4.6) months, respectively. Median OS was 7.5 (95% CI: 5.6–not reached) months. Five neurological adverse events occurred, including 1 grade-4 transient ischemic attack of uncertain imputability and 1 grade-3 neurological deficit; neither required nivolumab discontinuation. Nivolumab intracerebral activity was similar to its reported extracerebral efficacy, with an acceptable safety profile. Prospective and controlled data are needed to determine nivolumab’s place in treatment of NSCLC patients with BMs. [ABSTRACT FROM AUTHOR]

Objectives The receptor tyrosine kinase MET is essential to embryonic development and organ regeneration. Its deregulation is associated with tumorigenesis. While MET gene amplification and mutations leading to MET self-activation concern only a few patients, a high MET level has been found in about half of the non-small cell lung cancers (NSCLCs) tested. How this affects MET activation in tumors is unclear. Also uncertain is the prognostic value, in cancer, of a phenomenon well described in cell models: MET shedding, i.e. its cleavage by membrane proteases leading to release of a soluble fragment into the medium. Materials and methods A prospective cohort of 39 NSCLC patients was constituted at diagnosis or soon after. Normal tissues, tumor tissues, and blood samples were obtained. This allowed, for the same patient, synchronous determination of (i) the MET level in the tumor, (ii) receptor phosphorylation, and (iii) the concentration of soluble MET fragment (sMET) in the serum. Results After confirming the adequacy of an ELISA for measuring the serum level of sMET, we found no correlation between this level and the concentration of MET in tumors, as evaluated by immunohistochemistry and western blotting. Nevertheless, all but one tumor displaying a high MET level also displayed receptor phosphorylation, restricted to a small number of tumor cells. Conclusion Our results thus demonstrate that the serum level of sMET is not indicative of the amount of MET present in the tumor cells and cannot be used as a biomarker for therapeutic purposes. However, MET scoring of tumor biopsies could be a first step prior to determination of MET receptor activation in high-MET tumors. [ABSTRACT FROM AUTHOR]

Abstract: Background: Combination of bevacizumab and weekly paclitaxel showed synergitic effects, anti-tumor efficacy and a good toxicity profile for patients with breast cancer but has never been evaluated in non small cell lung cancer (NSCLC). We retrospectively reviewed safety and efficacy of this regimen in metastatic non-squamous NSCLC as fourth-line therapy or beyond. Methods: Patients were identified from a prospective database. Treatment consisted in paclitaxel 80mg/m2 on days 1, 8 and 15 and bevacizumab 15mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity. Results: Twenty patients were included in this study. Objective response rate at first evaluation was 40% (8/20), confirmed response rate was 15% (3/20) and disease control rate was 75% (15/20). The median progression-free survival and overall survival were 6.4 months (CI95% 4.1–9) and 9.6 months (CI95% 7–19.7). Grade 3–4 adverse events included neutropenia (4/20), onycholysis (2/20) and infection (2/20). One patient died from a bowel perforation and another one died from unknown cause. Prolonged responses were observed in a patient who had received bevacizumab as part of first-line chemotherapy and in another one who harbored an ALK rearrangement. Conclusions: In our experience, combination of bevacizumab and weekly paclitaxel exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond for non-squamous NSCLC patients, supporting further evaluation in larger prospective studies. [Copyright &y& Elsevier]