Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Computational markers for personalized prediction of outcomes in non-small cell lung cancer patients with brain metastases.

Intracranial progression after curative treatment of early-stage non-small cell lung cancer (NSCLC) occurs from 10 to 50% and is difficult to manage, given the heterogeneity of clinical presentations and the variability of treatments available. The objective of this study was to develop a mechanistic model of intracranial progression to predict survival following a first brain metastasis (BM) event occurring at a time [Formula: see text]. Data included early-stage NSCLC patients treated with a curative intent who had a BM as the first and single relapse site (N = 31). We propose a mechanistic mathematical model able to derive computational markers from primary tumor and BM data at [Formula: see text] and estimate the amount and sizes of (visible and invisible) BMs, as well as their future behavior. These two key computational markers are [Formula: see text], the proliferation rate of a single tumor cell; and [Formula: see text], the per day, per cell, probability to metastasize. The predictive value of these individual computational biomarkers was evaluated. The model was able to correctly describe the number and size of metastases at [Formula: see text] for 20 patients. Parameters [Formula: see text] and [Formula: see text] were significantly associated with overall survival (OS) (HR 1.65 (1.07-2.53) p = 0.0029 and HR 1.95 (1.31-2.91) p = 0.0109, respectively). Adding the computational markers to the clinical ones significantly improved the predictive value of OS (c-index increased from 0.585 (95% CI 0.569-0.602) to 0.713 (95% CI 0.700-0.726), p < 0.0001). We demonstrated that our model was applicable to brain oligoprogressive patients in NSCLC and that the resulting computational markers had predictive potential. This may help lung cancer physicians to guide and personalize the management of NSCLC patients with intracranial oligoprogression.

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study.

BACKGROUND: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials. METHODS: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments. RESULTS: The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0-48.0]) for a median duration of 4.9 months (95% CI 4.5-5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4-2.3]). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: [29.9-31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI [42.3-50.9]) and 21.2% (95% CI [17.7-24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0-5.4]), 37.5% (95% CI [33.3-41.7]) and 15.2% (95% CI [12.2-18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0-13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1-21.5]). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news. CONCLUSIONS: IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.

Immunologic constant of rejection as a predictive biomarker of immune checkpoint inhibitors efficacy in non-small cell lung cancer.

BACKGROUND: Anti-PD1/PDL1 immune checkpoint inhibitors (ICI) transformed the prognosis of patients with advanced non-small cell lung cancer (NSCLC). However, the response rate remains disappointing and toxicity may be life-threatening, making urgent identification of biomarkers predictive for efficacy. Immunologic Constant of Rejection signature (ICR) is a 20-gene expression signature of cytotoxic immune response with prognostic value in some solid cancers. Our objective was to assess its predictive value for benefit from anti-PD1/PDL1 in patients with advanced NSCLC. METHODS: We retrospectively profiled 44 primary tumors derived from NSCLC patients treated with ICI as single-agent in at least the second-line metastatic setting. Transcriptomic analysis was performed using the nCounter® analysis system and the PanCancer Immune Profiling Panel. We then pooled our data with clinico-biological data from four public gene expression data sets, leading to a total of 162 NSCLC patients treated with single-agent anti-PD1/PDL1. ICR was applied to all samples and correlation was searched between ICR classes and the Durable Clinical Benefit (DCB), defined as stable disease or objective response according to RECIST 1.1 for a minimum of 6 months after the start of ICI. RESULTS: The DCB rate was 29%; 22% of samples were classified as ICR1, 30% ICR2, 22% ICR3, and 26% ICR4. These classes were not associated with the clinico-pathological variables, but showed enrichment from ICR1 to ICR4 in quantitative/qualitative markers of immune response. ICR2-4 class was associated with a 5.65-fold DCB rate when compared with ICR1 class. In multivariate analysis, ICR classification remained associated with DCB, independently from PDL1 expression and other predictive immune signatures. By contrast, it was not associated with disease-free survival in 556 NSCLC TCGA patients untreated with ICI. CONCLUSION: The 20-gene ICR signature was independently associated with benefit from anti-PD1/PDL1 ICI in patients with advanced NSCLC. Validation in larger retrospective and prospective series is warranted.

Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC.

INTRODUCTION: Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). METHODS: Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. RESULTS: Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30). CONCLUSIONS: In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.

Immunoscore immune checkpoint using spatial quantitative analysis of CD8 and PD-L1 markers is predictive of the efficacy of anti- PD1/PD-L1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking. METHODS: Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic test, was used on 471 routine single FFPE-slides, and the duplex-immunohistochemistry CD8 and PD-L1 staining was quantified using digital-pathology. Analytical validation was performed on two independent cohorts of 206 NSCLC patients. Quantitative parameters related to cell location, number, proximity and clustering were analysed. The Immunoscore-IC was applied on a first cohort of metastatic NSCLC patients (n = 133), treated with anti-PD1 or anti-PD-L1 mAbs. Another independent cohort (n = 132) served as validation. FINDINGS: Anti-PDL1 clone (HDX3) has similar characteristics as anti-PD-L1 clones (22C3, SP263). Densities of PD-L1+ cells, CD8+ cells and distances between CD8+ and PD-L1+ cells were quantified and the Immunoscore-IC classification was computed. Using univariate Cox model, 5 histological dichotomised variables (CD8 free of PD-L1+ cells, CD8 clusters, CD8 cells in proximity of PD-L1 cells, CD8 density and PD-L1 cells in proximity of CD8 cells) were significantly associated with Progression-Free Survival (PFS) (all P < 0.0001). Immunoscore-IC classification improved the discriminating power of prognostic model, which included clinical variables and pathologist PD-L1 assessment. In two categories, the Immunoscore-IC risk-score was significantly associated with patients' PFS (HR = 0.39, 95% CI (0.26-0.59), P < 0.0001) and Overall Survival (OS) (HR = 0.42, 95% CI (0.27-0.65), P < 0.0001) in the training-set. Further increased hazard ratios (HR) were found when stratifying patients into three-category Immunoscore-IC (IS-IC). All patients with Low-IS-IC progressed in less than 18 months, whereas PFS at 36 months were 34% and 33% of High-IS-IC patients in the training and validation sets, respectively. INTERPRETATION: Immunoscore-IC is a powerful tool to predict the efficacy of immune-checkpoint inhibitors (ICIs) in patients with NSCLC. FUNDING: Veracyte, INSERM, Labex Immuno-Oncology, Transcan ERAnet European project, ARC, SIRIC, CARPEM, Ligue Contre le Cancer, ANR, QNRF, INCa France, Louis Jeantet Prize Foundation.

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.

Atezolizumab with or without bevacizumab and platinum-pemetrexed in patients with stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies: A multicentre phase II open-label non-randomised study GFPC 06-2018.

BACKGROUND: Previous reports showed limited efficacy of immune checkpoint inhibitors as single-agent treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation or ALK/ROS1 fusion. We aimed at evaluating the efficacy and safety of immune checkpoint inhibitor combined with chemotherapy and bevacizumab (when eligible) in this patient subgroup. METHODS: We conducted a French national open-label multicentre non-randomised non-comparative phase II study in patients with stage IIIB/IV NSCLC, oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine kinase inhibitor and no prior chemotherapy. Patients received platinum, pemetrexed, atezolizumab, bevacizumab (PPAB cohort) or, if not eligible to bevacizumab, platinum-pemetrexed-atezolizumab (PPA cohort). The primary end-point was the objective response rate (RECIST v1.1) after 12 weeks, evaluated by blind independent central review. RESULTS: 71 patients were included in PPAB cohort and 78 in PPA cohort (mean age, 60.4/66.1 years; women 69.0%/51.3%; EGFR mutation, 87.3%/89.7%; ALK rearrangement, 12.7%/5.1%; ROS1 fusion, 0%/6.4%, respectively). After 12 weeks, objective response rate was 58.2% (90% confidence interval [CI], 47.4-68.4) in PPAB cohort and 46.5% (90% CI, 36.3-56.9) in PPA cohort. Median progression-free survival and overall survival were 7.3 (95% CI 6.9-9.0) months and 17.2 (95% CI 13.7-NA) months in PPAB cohort and 7.2 (95% CI 5.7-9.2) months and 16.8 (95% CI 13.5-NA) months in PPA cohort, respectively. Grade 3-4 adverse events occurred in 69.1% of patients in PPAB cohort and 51.4% in PPA cohort; Grade 3-4 atezolizumab-related adverse events occurred in 27.9% and 15.3%, respectively. CONCLUSION: Combination approach with atezolizumab with or without bevacizumab and platinum-pemetrexed achieved promising activity in metastatic EGFR-mutated or ALK/ROS1-rearranged NSCLC after tyrosine kinase inhibitor failure, with acceptable safety profile.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion-positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion-positive NSCLC.

Revisiting metronomic vinorelbine with mathematical modelling: a Phase I trial in lung cancer.

BACKGROUND: A phase Ia/Ib trial of metronomic oral vinorelbine (MOV) driven by a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Disease Control Rate, progression free survival, toxicity and PK/PD were the main endpoints. METHODS: Best MOV scheduling was selected using a simplified phenomenological, semi-mechanistic model with a total weekly dose of 150-mg vinorelbine. Computation of individual PK parameters was performed using population approach. RESULTS: The mathematical model proposed the following metronomic schedule for a 150-mg weekly dose of vinorelbine: 60 mg D1, 30 mg D2, 60 mg D4. A total of 37 heavily pre-treated patients (30 evaluable) were enrolled. Grade III/IV neutropenia was observed in 30% patients. Median PFS was 11 weeks. Disease Control Rate was 73% (i.e.; 13% partial response and 60% stable disease). A large variability in drug exposure (AUC0-24 h: 53%) and PK parameters (Cl: 83%) were observed among patients. Simulated trough levels after D2 and D4 showed similarly 56-73% variability among patients. Drug exposure was not associated with efficacy, but neutropenia was more frequent in patients with AUC > 250 ng/ml.h. Tumor burden, performance status and neutrophils-to-lymphocyte ratio (NLR) were associated with PFS, suggesting that MOV would be indicated in selected patients. We built a composite score to predict efficacy, mixing baseline tumor size and NLR showing 84% selectivity and 75% specificity. CONCLUSIONS: MOV was characterized by important variability in drug exposure among patients. However, and despite being all heavily pre-treated, 73% of disease control rate and 11 weeks PFS were achieved with manageable toxicities. PK/PD relationships yielded conflicting results depending on the initial tumor burden and BSA, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker suggests immunomodulating features with MOV.

Nivolumab plus ipilimumab in malignant pleural mesothelioma.

INTRODUCTION: Unresectable pleural mesothelioma is a poor prognosis disease. Improvement in overall survival (OS) has been shown with PEMETREXED combined with CISPLATIN. BEVACIZUMAB combined with chemotherapy is associated with an improvement in OS, compared to chemotherapy alone, but is not supported by health insurance everywhere. AREAS COVERED: Immune Checkpoint Inhibition (ICI) monotherapy seemed to be promising but is controversial. ICI combination showed significant results. NIVOLUMAB, an anti-Programmed-Death-receptor 1, associated with IPILIMUMAB, an anti-Cytotoxic-T-Lymphocyte-Associated-protein 4, was evaluated in two phase II trials and a phase III trial, recently published. This combination led to a significant benefit in survival in first line compared to chemotherapy (OS 18.1 months (95%CI (16.8-21.4)) vs 14.1 (95%CI (12.4-16.2) HR 0.74 (95%CI 0.6-0.91) p = 0.002). EXPERT OPINION: These results represent a big step in unresectable pleural mesothelioma. The benefit in non-epithelioid subtype is impressive (OS 18.1 months (95%CI 12.2-22.8) vs 8.8 months 95%CI (7.4-10.2) HR 0.46 (95%CI (0.31-0.68))). Benefit in epithelioid subtype (OS 18.7 months 95%CI (16.9-22) vs 16.5 95%CI (14.9-20.5) HR 0.86 95%CI (0.69-1.08)) is similar to the benefit of the combination of BEVACIZUMAB and chemotherapy. Identification of predictive biomarkers is needed to identify patients who are most likely to benefit from each therapeutic strategy.

Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial.

PURPOSE: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. PATIENTS AND METHODS: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). RESULTS: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 <1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; Pinteraction = 0.036). CONCLUSIONS: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Molecular profiling of non-small-cell lung cancer patients with or without brain metastases included in the randomized SAFIR02-LUNG trial and association with intracranial outcome.

INTRODUCTION: Lung cancer remains the most frequent cause of brain metastases (BMs) and is responsible for high morbidity and mortality. Intracranial response to systemic treatments is inconsistent due to several mechanisms: genomic heterogeneity, blood-tumor barrier, and the brain-specific microenvironment. We conducted a study using data from the SAFIR02-LUNG trial. The primary objective was to compare the molecular profiles of non-small-cell lung cancer (NSCLC) with or without BMs. The secondary objective was to explore central nervous system (CNS) outcomes with various maintenance treatment regimens. METHODS: In total, 365 patients harboring interpretable molecular data were included in this analysis. Clinical and biological data were collected. Genomic analyses were based on array-comparative genomic hybridization and next-generation sequencing (NGS) following the trial recommendations. RESULTS: Baseline genomic analyses of copy number variations identified a 24-gene signature specific to lung cancer BM occurrence, all previously known to take part in oncogenesis. NGS analysis identified a higher proportion of KRAS mutations in the BM-positive group (44.3% versus 32.3%), especially G12C mutations (63% versus 47%). Protein interaction analyses highlighted several functional interactions centered on EGFR. Furthermore, the risk of CNS progression was decreased with standard pemetrexed maintenance therapy. The highest rate of CNS progression was observed with durvalumab, probably because of the specific intracranial immune microenvironment. CONCLUSION: This work identified a 24-gene signature specific to lung cancer with BM. Further studies are needed to precisely determine the functional implications of these genes to identify new therapeutic targets for the treatment of lung cancer with BM.

Acceptance, efficacy, and safety of COVID-19 vaccination in older patients with cancer.

PURPOSE: The COVID-19 vaccination campaign began in December 2020, in France, and primarily targeted the oldest people. Our study aimed to determine the level of acceptance of vaccination in a population of older patients with cancer. METHODS: From January 2021, we offered vaccination with the BNT162b2 COVID-19 vaccine to all patients 70 years and older referred to our geriatric oncology center in Marseille University Hospital (AP-HM) for geriatric assessment before initiation of an oncological treatment. Objectives were to evaluate acceptance rate of COVID-19 vaccination and to assess vaccine safety, reactogenicity, and efficacy two months after the first dose. RESULTS: Between January 18, 2021 and May 7, 2021, 150 older patients with cancer were offered vaccination after a geriatric assessment. The majority were men (61.3%), with a mean age of 81 years. The two most frequent primary tumors were digestive (29.4%) and thoracic (18%). The vaccine acceptance rate was 82.6% and the complete vaccination rate (2 doses) reached 75.3%. Among the vaccinated patients, 15.9% reported mild side effects after the first dose and 23.4% after the second dose, mostly arm pain and fatigue. COVID-19 cases were observed in 5.1% of vaccinated patients compared with 16.7% in unvaccinated patients. Of the 22 vaccinated patients who agreed to have their serum tested, 15 had antibodies against the spike protein at day 21 after the first dose. CONCLUSION: Our study showed a high acceptance rate of COVID-19 vaccination, with good tolerance in this frail population. These results highlight the benefits of organizing vaccination campaigns at the very beginning of oncological management in older patients. CLINICAL TRIAL REGISTRATION: This study was registered May 23, 2019 in ClinicalTrials.gov (NCT03960593).

Clinical Impact of High Throughput Sequencing on Liquid Biopsy in Advanced Solid Cancer.

BACKGROUND: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. METHODS: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. RESULTS: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. CONCLUSIONS: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient's outcomes was shown in this unselected pan-cancer study.

Effects of Ethnicity on Outcomes of Patients With EGFR Mutation-Positive NSCLC Treated With EGFR Tyrosine Kinase Inhibitors and Surgical Resection.

INTRODUCTION: In addition to the higher prevalence of EGFR mutations found among lung cancer cases in East Asian patients, it is unclear whether there are differences in treatment outcomes by ethnicity-that is, East Asian versus non-East Asian. METHODS: Patients diagnosed with EGFR-mutant lung cancer between January 2004 and October 2014 at a single center were reviewed. Data captured included demographics, tumor and treatment information, and survival. Survival of patients of East Asian and non-East Asian ancestry was compared, including in the subgroup that received EGFR tyrosine kinase inhibitor (TKI) for advanced disease and in those with early-stage disease that underwent surgical resection. RESULTS: A total of 348 patients with EGFR-mutant NSCLC were identified. There was a higher proportion of nonsmokers among those of East Asian ethnicity. No significant difference in survival was seen between patients of East Asian and non-East Asian ethnicity, median 6.7 years (95% confidence interval [CI]: 5.4-not applicable) and 5.4 years (95% CI: 4.1-7.2), respectively (p = 0.09). Among 196 patients that received treatment with EGFR TKI, the median survival from TKI initiation was also similar for those of East Asian and non-East Asian ethnicity, 3.0 years (95% CI: 2.1-3.5) and 2.7 years (95% CI: 2.2-3.5), respectively. Among the early-stage patients that underwent surgical resection (n = 163), those of East Asian ethnicity had similar median recurrence-free survival from surgery compared with non-East Asian patients, 5.3 years (95% CI: 3.5-not applicable) and 5.1 years (95% CI: 3.3-7.2), respectively. CONCLUSIONS: In a cohort of patients with EGFR-mutant lung cancer with access to uniform standards of care, East Asian ethnicity was not associated with improved survival after treatment with EGFR TKI or surgical resection.

Functional status in older patients with lung cancer: an observational cohort study.

PURPOSE: An assessment of the impact of functional status (FS) evaluated using a combination of Activities of Daily Living (ADL) and the short version of the Instrumental Activities of Daily Living (IADL), on 3- and 6- month mortality and on 3-month unplanned hospitalizations in older patients treated for lung cancers. METHOD AND OBJECTIVES: This observational retrospective study was conducted between September 2015 and January 2019 at Marseille University Hospital (AP-HM). During this period, all consecutive outpatients aged 70 years or older referred for a comprehensive geriatric assessment (CGA) before the initiation of lung cancer treatment were enrolled. RESULTS: Two hundred twenty-seven patients were analyzed: the median age was 78.7 years and 74.0% were male. Almost half of the patients were metastatic (45.4%). Concerning FS, 41.9% of patients had no ADL-IADL impairment, 30.0% had either IADL or ADL impairment, and both ADL-IADL were impaired for 28.1%. Impaired ADL-IADL was associated with poor nutritional status, depression, mobility, and cognitive disorders. In a logistic regression model, ADL or IADL impairment (aOR = 2.1; 95% CI [1.0-4.2]; p = 0.037) and impaired ADL-IADL (aOR = 2.6; 95% CI [1.2-5.3]; p = 0.012) were independently associated with a higher risk of unplanned hospitalizations within 3 months. In the multivariate Cox model, 6-month mortality risk was independently associated with impaired ADL-IADL (aHR = 2.3; 95% CI [1.3-4.4]; p = 0.008). CONCLUSION: The combination of ADL and IADL scales to assess FS is a prognostic marker of the mortality risk at 6 months in older patients with lung cancer and should be more largely used by oncologists in treatment decision making.

Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

INTRODUCTION: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. METHODS: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. RESULTS: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). CONCLUSION: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

Machine Learning for Prediction of Immunotherapy Efficacy in Non-Small Cell Lung Cancer from Simple Clinical and Biological Data.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are now a therapeutic standard in advanced non-small cell lung cancer (NSCLC), but strong predictive markers for ICIs efficacy are still lacking. We evaluated machine learning models built on simple clinical and biological data to individually predict response to ICIs. METHODS: Patients with metastatic NSCLC who received ICI in second line or later were included. We collected clinical and hematological data and studied the association of this data with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Multiple machine learning (ML) algorithms were assessed for their ability to predict response. RESULTS: Overall, 298 patients were enrolled. The overall response rate and DCR were 15.3% and 53%, respectively. Median PFS and OS were 3.3 and 11.4 months, respectively. In multivariable analysis, DCR was significantly associated with performance status (PS) and hemoglobin level (OR 0.58, p < 0.0001; OR 1.8, p < 0.001). These variables were also associated with PFS and OS and ranked top in random forest-based feature importance. Neutrophil-to-lymphocyte ratio was also associated with DCR, PFS and OS. The best ML algorithm was a random forest. It could predict DCR with satisfactory efficacy based on these three variables. Ten-fold cross-validated performances were: accuracy 0.68 ± 0.04, sensitivity 0.58 ± 0.08; specificity 0.78 ± 0.06; positive predictive value 0.70 ± 0.08; negative predictive value 0.68 ± 0.06; AUC 0.74 ± 0.03. CONCLUSION: Combination of simple clinical and biological data could accurately predict disease control rate at the individual level.