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Brain metastases (BMs) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but are only visible when large enough. Therapeutic decisions such as whole brain radiation therapy would benefit from patient-specific predictions of radiologically undetectable BMs. Here, we propose a mathematical modeling approach and use it to analyze clinical data of BM from NSCLC. Primary tumor growth was best described by a gompertzian model for the pre-diagnosis history, followed by a tumor growth inhibition model during treatment. Growth parameters were estimated only from the size at diagnosis and histology, but predicted plausible individual estimates of the tumor age (2.1–5.3 years). Multiple metastatic models were further assessed from fitting either literature data of BM probability (n = 183 patients) or longitudinal measurements of visible BMs in two patients. Among the tested models, the one featuring dormancy was best able to describe the data. It predicted latency phases of 4.4–5.7 months and onset of BMs 14–19 months before diagnosis. This quantitative model paves the way for a computational tool of potential help during therapeutic management.

BackgroundWe evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid–inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti–programmed death 1 antibody pembrolizumab (NCT03739138).Patients and methodsPatients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs.ResultsFifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines.ConclusionsPatients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit.Trial registrationClinicalTrials.gov, NCT03065023 and NCT03739138.

Background: Small-cell lung cancer (SCLC) represents one of the most aggressive forms of lung cancer. Despite the fair sensitivity of SCLC to chemotherapy and radiotherapy, the current standard treatment regimens have modest survival rates and are associated with potential life-threatening adverse events. Therefore, research into new optimised regimens that increase drug efficacy while respecting toxicity constraints is of primary importance. Methods: A PK/PD model for the combination of cisplatin and etoposide to treat extensive-stage SCLC patients was generated. The model takes into consideration both the efficacy of the drugs and their haematological toxicity. Using optimisation techniques, the model can be used to propose new regimens. Results: Three new regimens with varying timing for combining cisplatin and etoposide have been generated that respect haematological toxicity constraints and achieve better or similar tumour regression. The proposed regimens are: (1) Protocol OP1: etoposide 80 mg m −2 over 1 h D1, followed by a long infusion 12 h later (over 3 days) of 160 mg m −2 plus cisplatin 80 mg m −2 over 1 h D1, D1–D1 21 days; (2) Protocol OP2: etoposide 80 mg m −2 over 1 h D1, followed by a long infusion 12 h later (over 4 days) of 300 mg m −2 plus cisplatin 100 mg m −2 over 1 h D1, D1–D1 21 days; and (3) Protocol OP3: etoposide 40 mg m −2 over 1 h, followed by a long infusion 6 h later (3 days) of 105 mg m −2 plus cisplatin 50 mg m −2 over 1 h, D1–D1 14 days. Conclusions: Mathematical modelling can help optimise the design of new cisplatin plus etoposide regimens for managing extensive-stage SCLC patients.

Patients with advanced non–small-cell lung cancer with a PD-L1 expression level of 1% or more of tumor cells were randomly assigned to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Overall survival was significantly longer among the patients who received nivolumab plus ipilimumab than among those who received chemotherapy.

The purpose of this study was to determine the prognostic significance of a high pretreatment serum CYFRA 21-1 level (a cytokeratin 19 fragment) adjusted for the effects of well-known co-variables in non-small-cell lung cancer (NSCLC). This meta-analysis based on individual updated data gathered comprehensive databases from published or unpublished controlled studies dealing with the prognostic effect of serum CYFRA 21-1 level at presentation in NSCLC of any stage (nine institutions, 2063 patients). Multivariate regression was carried out with the Cox model. The proportional hazard assumption for each of the selected variables retained in the final model was originally checked by log minus log plots baseline hazard ratio. The follow-up ranged from 25 to 78 months. A total of 1616 events were recorded. In the multivariate analysis performed at the 1-year end point, a high pretreatment CYFRA 21-1 level was an unfavourable prognostic determinant in all centres except one (Hazard ratio (95% confidence interval): 1.88 (1.64–2.15), P <10 −4 ). Other significant variables were stage of the disease, age and performance status. Within the first 18 months, the procedure disclosed a nearly similar hazard ratio for patients having a high pretreatment serum CYFRA 21-1 level (1.62 (1.42–1.86), P <10 −4 ). For patients who did not undergo surgery, the hazard ratio during the first year of follow-up was 1.78 (1.54–2.07), P <10 −4 . Finally, in the surgically treated population, at the 2-year end point, a high pretreatment CYFRA 21-1 and a locally advanced stage remained unfavourable prognostic determinants. In conclusion CYFRA 21-1 might be regarded as a putative co-variable in analysing NSCLC outcome inasmuch as a high serum level is a significant determinant of poor prognosis whatever the planned treatment.

RET fusion–positive lung cancer accounts for 1 to 2% of non–small-cell lung cancers. Among previously treated patients with RET fusion–positive lung cancer, 64% of those who received selpercatinib, a RET kinase inhibitor, had a response, and among previously untreated patients, 85% had a response. Approximately one third of the patients had adverse events of grade 3 or higher.

BackgroundSuccessful immunotherapy is restricted to some cancers only, and combinatorial strategies with other drugs could help to improve their efficacy. Here, we monitor T cells in NSCLC model after treatment with cytotoxics (CT) and anti-VEGF drugs, to understand when immune checkpoint inhibitors should be best associated next.MethodsIn vivo study was performed on BALB/c mice grafted with KLN205 cells. Eight treatments were tested including control, cisplatin and pemetrexed as low (LD CT) and full (MTD CT) dose as single agents, flat dose anti-VEGF and the association anti-VEGF + CT. Full immunomonitoring was performed by flow cytometry on tumor, spleen and blood over 3 weeks.ResultsImmunomodulatory effect was dependent upon both treatments and time. In tumors, combination groups shown numerical lower Treg cells on Day 21. In spleen, anti-VEGF and LD CT group shown higher CD8/Treg ratio on Day 7; on Day 14, higher T CD4 were observed in both combination groups. Finally, in blood, Tregs were lower and CD8/Treg ratio higher, on Day 14 in both combination groups. On Day 21, CD4 and CD8 T cells were higher in the anti-VEGF + MTD CT group.ConclusionsAnti-VEGF associated to CT triggers notable increase in CD8/Tregs ratio. Regarding the scheduling, a two-week delay after using anti-VEGF and CT could be the best sequence to optimize antitumor efficacy.

Medullary thyroid cancer often develops in patients with somatic or germline mutations in RET . Selpercatinib is a novel RET inhibitor. In a phase 1–2 trial, a response to selpercatinib occurred in 38 of 55 previously treated patients (69%) and in 64 of 88 previously untreated patients (73%). Toxic effects were mainly low grade.

Sotorasib is a selective irreversible inhibitor of the G12C-activated KRAS oncogene, present in approximately 13% of non–small-cell lung cancers. In a single-group, phase 2 trial involving 126 patients with previously treated KRAS p.G12C–mutated NSCLC, 37% had a response (median duration, 11 months). One fifth of patients had grade 3 toxic effects, mainly liver-enzyme abnormalities and diarrhea.

In a randomized study involving 582 patients with advanced nonsquamous lung cancer that had progressed after primary treatment, nivolumab produced a higher response rate and longer overall survival than standard docetaxel. Effective options are limited for patients with nonsquamous non–small-cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy. Docetaxel was approved as a second-line treatment for advanced NSCLC on the basis of longer survival than that with best supportive care. 1 – 3 Newer agents, such as pemetrexed and erlotinib, which have a better side-effect profile than docetaxel, have either been shown to be noninferior to docetaxel or have failed to show superiority to docetaxel with respect to overall survival when they are used as second-line therapy. 4 , 5 The programmed death 1 (PD-1) receptor expressed on activated T cells is engaged by . . .