Introduction: Immune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, MET-, and RET-NSCLC in a real-world setting.Methods: In this retrospective, multicenter study in ICItreated BRAF-, HER2-, MET-or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS).Results: There were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were neversmokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval [CI]: 12.6-not reached [NR]) months, 4.7 (95% CI: 2.3-7.4) months, and 16.2 (95% CI: 12.0-24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF-non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2-NR) and 4.3 (95% CI: 2.1-8.5) months, respectively, and OS was 11.7 (95% CI: 4.1-NR) and 35.8 (95% CI: 9.0-35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three. Conclusions:In this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed.

PurposeWe prospectively evaluated whether a strategy using point spread function (PSF) reconstruction for both diagnostic and quantitative analysis in non-small cell lung cancer (NSCLC) patients meets the European Association of Nuclear Medicine (EANM) guidelines for harmonization of quantitative values.MethodsThe NEMA NU-2 phantom was used to determine the optimal filter to apply to PSF-reconstructed images in order to obtain recovery coefficients (RCs) fulfilling the EANM guidelines for tumour positron emission tomography (PET) imaging (PSFEANM). PET data of 52 consecutive NSCLC patients were reconstructed with unfiltered PSF reconstruction (PSFallpass), PSFEANM and with a conventional ordered subset expectation maximization (OSEM) algorithm known to meet EANM guidelines. To mimic a situation in which a patient would undergo pre- and post-therapy PET scans on different generation PET systems, standardized uptake values (SUVs) for OSEM reconstruction were compared to SUVs for PSFEANM and PSFallpass reconstruction.ResultsOverall, in 195 lesions, Bland-Altman analysis demonstrated that the mean ratio between PSFEANM and OSEM data was 1.03 [95 % confidence interval (CI) 0.94–1.12] and 1.02 (95 % CI 0.90–1.14) for SUVmax and SUVmean, respectively. No difference was noticed when analysing lesions based on their size and location or on patient body habitus and image noise. Ten patients (84 lesions) underwent two PET scans for response monitoring. Using the European Organization for Research and Treatment of Cancer (EORTC) criteria, there was an almost perfect agreement between OSEMPET1/OSEMPET2 (current standard) and OSEMPET1/PSFEANM-PET2 or PSFEANM-PET1/OSEMPET2 with kappa values of 0.95 (95 % CI 0.91–1.00) and 0.99 (95 % CI 0.96–1.00), respectively. The use of PSFallpass either for pre- or post-treatment (i.e. OSEMPET1/PSFallpass-PET2 or PSFallpass-PET1/OSEMPET2) showed considerably less agreement with kappa values of 0.75 (95 % CI 0.67–0.83) and 0.86 (95 % CI 0.78–0.94), respectively.ConclusionProtocol-optimized images and compliance with EANM guidelines allowed for a reliable pre- and post-therapy evaluation when using different generation PET systems. These data obtained in NSCLC patients could be extrapolated to other solid tumours.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-013-2391-1) contains supplementary material, which is available to authorized users.

Background: BRAF mutations occurring in 1%e5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. Patients and methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after 1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was 30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%e54.8%]. The ORR had a 99.9% probability of being 30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8e6.8), and OS was 10 months (95% CI 6.8e15.7). The vemurafenib safety profile was consistent with previous publications. Conclusion:Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations. Trial registration: ClinicalTrials.gov identifier: NCT02304809.

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IntroductionRandomized prospective studies on patients with metastatic non‐small‐cell lung cancers (NSCLCs) showed that anti‐programmed death‐1 (PD‐1) agents notably improved 2‐year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing.MethodsWe retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes.ResultsAmong 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra‐ or extracranial irradiation courses, any‐grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune‐related AE (IRAE). Respective 1‐ and 2‐year OS rates were 48.8% and 29.1%, while 1‐ and 2‐year progression‐free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS.ConclusionRadiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities.