465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site's independent ethics committee

Infiltration de la plèvre viscérale par les adénocarcinomes bronchiques de stade IB (rôle pronostique ?)

La chimiothérapie adjuvante des CBNPC de stade II et IIIA est admise au vu de l'amélioration de la survie montrée dans plusieurs essais randomisés. Pour les stades IB, l'intérêt de ce traitement reste à établir. Cette étude a analysé le rôle pronostique de l'infiltration de la plèvre viscérale pour statuer sur son intérêt en tant que nouveau critère décisionnel de réalisation d une chimiothérapie adjuvante. Une série nantaise de 73 patients porteurs d adénocarcinomes de stades pT1 à pT3N0M0 réséqués entre le 01/01/1999 et le 01/01/2005 a été étudiée. La survie à 5 ans des stades pT2a (>3 et <=5cm) est statistiquement meilleure en l absence d infiltration de la plèvre viscérale (81,8% versus 37,5%, p<0,028). Les tumeurs pT2 <=3cm ont le même pronostic que les pT1 et doivent donc être traités comme tels. Ces résultats ouvrent la voie à une étude prospective testant, chez les patients porteurs d'adénocarcinomes classés pT2N0M0, l'impact d'une chimiothérapie adjuvante.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study

Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study (ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry. PD-L1-positive patients had membranous PD-L1 expression in >= 1% of tumor and associated inflammatory cells or positive staining in stroma. Response was assessed by investigator per Response Evaluation Criteria in Solid Tumors version 1.1 every 8 weeks for the first 6 months and every 12 weeks thereafter. Adverse events (AEs) were reported per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Primary end points were safety, tolerability, and objective response rate (ORR). Secondary end points included progression-free survival, overall survival, and duration of response. Results Twenty-four patients with PD-L1-expressing SCLC were enrolled and received at least one pembrolizumab dose. At the data cutoff date (June 20, 2016), the median follow-up duration was 9.8 months (range, 0.5 to 24 months). All 24 patients experienced AEs; the most common were asthenia (n = 7), fatigue (n = 7), and cough (n = 6). Two patients experienced grade 3 to 5 treatment-related AEs: one patient had elevated bilirubin, and one patient had asthenia, grade 5 colitis, and intestinal ischemia. One patient had a complete response, and seven patients had partial responses, resulting in an ORR of 33% (95% CI, 16% to 55%). Conclusion The safety of pembrolizumab was consistent with the known safety profile in other tumor types. Pembrolizumab demonstrated promising antitumor activity in patients with pretreated, PD-L1expressing SCLC. (C) 2017 by American Society of Clinical Oncology

Prognostic Impact of TP53 Mutations in Metastatic Nonsquamous Non–small-cell Lung Cancer

International audienceBackground: The prognostic impact of TP53 mutations in advanced or metastatic nonsquamous non-small-cell lung cancer (nsNSCLC) patients treated with chemotherapy and/or immune checkpoint inhibitors (ICI) remains unclear.Materials and methods: We retrospectively collected data from patients with nsNSCLC treated in the first line from January 2018 to May 2021. The patient was separated into 2 groups according to their TP53 mutation status (wt vs. mut). Survival was estimated through the Kaplan-Meier method and compared by log-rank test.Results: Of 220 patients included, 126 were in the mutTP53 group, and 94 were in the wtTP53wt group. Median OS (mOS) was not significantly different between the mutTP53 and wtTP53 groups [17.5 months (95% confidence interval (CI), 11.3-21.5) vs. 9.5 months (95% CI, 7.4-14.2), (P = .051)]. In subgroup analyses, the mutTP53 group treated with ICI had a significantly improved mOS compared to the wtTP53 group [(24.7 months (95% CI, 20.8-not reach) vs. 12.0 months (95% CI, 4.7-not reach), (P = .017)] and mPFS [(9.6 months (95% CI, 5.8-not reach) vs. 3.2 months (95% CI, 1.3-13.8) (P = .048)]. There was no difference in terms of mOS and mPFS between the mutTP53 and the wtTP53 group treated by chemotherapy alone or combined with ICI.Conclusion: TP53 mutation had no survival impact in the overall population, but is associated with better outcomes with ICI alone. These results suggest that patients with TP53 mutations could be treated with ICI alone, and wild-type patients could benefit from the addition of chemotherapy

Phase I dose-escalation trial of afatinib, an irreversible ErbB family blocker, in combination with gemcitabine or docetaxel in patients with relapsed or refractory solid tumors

IF 3.502International audienceBackground Afatinib, an irreversible ErbB family blocker, has shown synergistic antitumor activity and manageable tolerability in combination with chemotherapy. This phase I study assessed oral afatinib plus intravenous gemcitabine or docetaxel in patients with relapsed/refractory solid tumors. Methods Patients received afatinib (30, 40, or 50 mg) plus gemcitabine (1000 or 1250 mg/m2) or docetaxel (60 or 75 mg/m2). Dose escalation proceeded via a 3 + 3 design until the maximum tolerated dose (MTD) was reached. Adverse events (AEs), pharmacokinetics and antitumor activity were also assessed. Results Dose-limiting toxicities during Cycle 1 were reported in 6/39 patients receiving afatinib/gemcitabine (most commonly diarrhea, thrombocytopenia and vomiting) and 16/54 patients receiving afatinib/docetaxel (most commonly febrile neutropenia and stomatitis). The MTDs were established as afatinib 40 mg/gemcitabine 1000 mg/m2 and afatinib 30 mg/docetaxel 60 mg/m2. The most common drug-related AEs were diarrhea, asthenia and rash with afatinib/gemcitabine, and diarrhea, asthenia and stomatitis with afatinib/docetaxel. No relevant pharmacokinetic interactions were observed for either combination. Both combinations demonstrated clinical activity and durable disease control at the MTDs. Compared with the MTD, higher response rates were achieved with afatinib 30 mg/docetaxel 75 mg/m2 (28% vs 6%); however, this regimen was associated with problematic febrile neutropenia, an expected AE with docetaxel, that is often managed with growth factor support. Conclusions Afatinib/gemcitabine and afatinib/docetaxel demonstrated manageable safety profiles, with evidence of clinical efficacy at the MTDs. For afatinib/docetaxel, a dose level of afatinib 30 mg/docetaxel 75 mg/m2 produced higher response rates. Trial registration: NCT01251653 ( ClinicalTrials.gov )

A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers

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