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Cancer progression is driven in part by genomic alterations

Background: Metastatic triple-negative breast cancer (mTNBC) is the most aggressive and heterogeneous breast cancer subtype, with limited therapeutic options. Immune-checkpoint inhibitors (ICI) with chemotherapy are approved as first-line therapy in mTNBC for patients with PD-L1+tumors. The generation of immunosuppressive extracellular adenosine in the tumor microenvironment by the overexpression of ectoenzyme CD73 is a mechanism that could impair ICI and chemotherapy activity. The SYNERGY trial investigates if the addition of an anti-CD73 monoclonal antibody, oleclumab, increases the clinical benefit (CB) to the combination of chemotherapy with an anti-PD-L1 antibody, durvalumab, in previously untreated patients with advanced or mTNBC. Here we present data from a primary analysis including the first 68 evaluable patients. Methods: Patients with previously untreated inoperable locally advanced or mTNBC were randomized between carboplatin AUC 1.5 and paclitaxel 80 mg/m2 q1w x 12 in combination with durvalumab 1500 mg q4w with (Arm A) or without (Arm B) oleclumab 3000 mg q2w x5 followed by 3000 mg q4w according to the recommended phase 2 dose. Maintenance with immunotherapy was continued after chemotherapy. The primary hypothesis is that the addition of oleclumab increases the clinical benefit rate (CBR) at week 24 defined as complete response, partial response or stable disease according to RECIST 1.1. by 20% (1-sided α=0.1 and 80% power with 68 pts/arm; 150 pts to be enrolled). Patients were stratified by PD-L1 status and CD73 immunohistochemistry (IHC) expression assessed on baseline tumor tissue by a central lab. Using the Lan-Demets approach, the stopping boundary was z test < 0.074, p=0.464. Data from this primary analysis for safety and futility were reviewed by an independent data monitoring committee ( IDMC). Results: The 68th evaluable patient reached week 24 on the 2nd Apr 2021. Patients’ baseline characteristics were well balanced between both arms. Grade 3-4 adverse events (AE) occurred in 28/33 patients (84.9%) in Arm A and 21/35 patients (60.0%) in Arm B (p=0.03). Most common grade 3-4 AE were hematological toxicities with neutropenia (Arm A 17/33 [51.5%]; Arm B 12/35 [34.3%], and anemia (Arm A 5/33 [15.2%]; 1/35 [2.9%] in Arm B). There was no increase of immune-related AEs in the arm A with oleclumab. In Arm A, 15/33 patients (45%) met the CB criterion vs. 17/35 patients (49%) in Arm B. The futility boundary was crossed with z-value = -0.2574, p=0.69 (one-sided Fisher's exact). No significant difference in CBR was observed when patients were stratified according to PD-L1 status or CD73 IHC expression. Based on these results, the IDMC recommended to stop further recruitment. Patients under treatment are allowed to continue with durvalumab and oleclumab after being informed of these preliminary results. Of note, at the moment of interim analysis, long-lasting responses were observed with immunotherapy maintenance in both arms. Conclusion: The addition of oleclumab to the combination of chemotherapy by carboplatin and paclitaxel with durvalumab as first-line therapy for advanced or mTNBC did not significantly increase CBR at 6 months. Thus, in arm A the CBR was 45% in the overall population with long-lasting responses and an acceptable toxicity profile. Longer follow-up to evaluate the survival benefit is required. Further investigations evaluating the heterogeneity of this disease using blood and tissue samples collected during trial will shed light on the mechanisms associated with response and resistance to the trial regimens and help to define specific subgroups of patients with TNBC who could benefit from ICI and adenosine targeting agents. Citation Format: Veronique Debien, Christian Maurer, Philippe Aftimos, Florian Clatot, Delphine Loirat, Kevin Punie, François Ghiringhelli, Anhony Gonçalves, Donatienne Taylor, Tom Van den Mooter, Jean-Marc Ferrero, Hervé Bonnefoi, Jean-Luc Canon, François Duhoux, Renaud Poncin, Fernando Bazan, Nicolas Isambert, Philippe Barthelemy, Mariana Brandão, Paulus Kristanto, Michail Ignatiadis, Martine Piccart, Laurence Buisseret. First-line chemo-immunotherapy with durvalumab, paclitaxel and carboplatin with or without anti-CD73 antibody oleclumab in advanced or metastatic triple-negative breast cancer: Preliminary results of the randomized phase II SYNERGY trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-02.

Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical.This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia's incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule.A population PK/PD model was developed to describe absolute neutrophil counts' (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G-CSF. Final model estimates were used to calculate neutropenia's incidence following different G-CSF dosing schedules for 1000 virtual subjects.The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G-CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia.Simulations showed a single G-CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin-induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence.Eudract 2015-001753-32, 2015/01/26.

Introduction: Soft tissue sarcomas (STSs) are a rare and heterogenous group of tumors, with poor prognostic, judging from their frequency to relapse. Few drugs are available after the conventional first-line regimen. Since 2007, trabectedin got approval after failure of anthracyclines and ifosfamide, for advanced or metastatic STS. This led to a FDA approval in 2015, but real-world evidence is still required, complementary to the pivotal phase II and III trials. Methods: One hundred twenty-six patients with STS, treated by trabectedin between 2002 and 2019, were analyzed in this retrospective study, in two French centers. The effects of trabectedin on survival, response, and toxicity were described. All patients were tested for toxicities, and efficacy was assessed in patients exposed to at least 2 cycles of trabectedin. Results: Three median cycles were administered per patient (1–79). Among the 113 patients analyzed for efficacy, the median progression-free survival was 3.0 months (95% CI: 2.3–4.8), with an overall survival of 12.3 months (95% CI: 10.2–16.9). The rate of disease control was 46% at the end of treatment. Myxoid liposarcoma (n = 11) was the histology subtype that benefited most from this chemotherapy with median progression-free survival and overall survival of 13.3 months (95% CI: 2.3–18.7) and 27.8 months (95% CI: 3.2–64.7), respectively. Adverse events were manageable. Discussion and Conclusion: Efficacy of trabectedin is confirmed in terms of clinical benefit and low toxicity, especially for myxoid liposarcoma. Combinatory regimens are under clinical trials to optimize the place of this chemotherapy.

PDF file - 60K, Biological pathways overrepresented in "REARRANGED" LMS and LMS of the extremities

Correlation analysis between pharmacodynamic and pharmacokinetic findings in part 1

PDF file - 23K, Kaplan-Meier curves of metastasis-free survival (A) and overall survival (B) for the overall population

Mean paclitaxel plasma concentrations following nab-paclitaxel administration alone or with CC-486 in part 1 arm B

Purpose: Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.Experimental Design: From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.Results: Median age was 59 years (range, 21–98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59–67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.Conclusion: Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients. Clin Cancer Res; 19(5); 1190–6. ©2013 AACR.

Table S1. CC-486 Plus Carboplatin Dose Levels in Part 1 Arm A Table S2. CC-486 Plus nab-Paclitaxel Dose Levels in Part 1 Arm B Table S3. CC-486 Dose Levels in Part 1 Arm C Table S4. Number of Patients With Treatment Emergent Adverse Events for Part 1 Table S5. Number of Patients With Treatment-Emergent Adverse Events in Any Treatment Arm in Part 2 Table S6. Mean CC-486 Plasma Pharmacokinetic Parameters Table S7. Efficacy of CC-486 Alone or in Combination With Carboplatin or nab-Paclitaxel in Part 2 Table S8. Prior Treatment History of NPV Patients

Mean total carboplatin plasma concentration following carboplatin administration alone or with CC-486 in part 1 arm A

PDF file - 66K, Significant Prognostic Factors for Metastasis-free Survival (MFS) and Overall survival (OS) (univariate analysis)

PDF file - 55K, Kaplan-Meier curves of metastasis-free survival according to tumor site (A), tumor size (B), tumor location (C) and tumor grade (D)

Supplementary Figure S3. Platelet Count Over Time in Response to CC-90011 at the RP2D (A), MTD (B), and NTD (C). Error bars indicate range. C, cycle; D, day; MTD, maximum tolerated dose; NTD, nontolerated dose; RP2D, recommended phase 2 dose. Data cutoff: 3 May 2019.

SUPPLEMENTARY TABLES AND FIGURES

Supplementary methods and results

Purpose:Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).Patients and Methods:CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25–120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics.Results:Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22–75). Patients received a median of three (range, 1–9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma.Conclusions:CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.

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PDF file - 61K, Clinical characteristics of the molecular cohort (N=73)

PDF file - 60K, Biological pathways dysregulated in metastatic LMS

Pharmacodynamic Assessments

Purpose:CDKN2A loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss.Patients and Methods:This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1.Results:As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1–2 adverse events (AEs) and 12 patients (41.4%) grade 3–4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance.Conclusions:Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A–deleted GIST refractory to imatinib and sunitinib.

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.

PDF file - 68K, Individual median of free to VEGF-bound aflibercept Ctrough ratio observed from cycle.

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m2) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.

PDF file - 52K, Kaplan-Meier curves of overall survival according to age (A), tumor size (B), tumor location (C) and tumor grade (D)

PDF file - 197K, Supplemental Table 1. Characteristics of GIST patients for the immunohistochemistry study. Supplemental Table 2. Characteristics of GIST and STS patients studied in flow cytometry. Supplemental Table 3: Antibodies for flow cytometry and IHC. Supplemental Figure 1. Correlation between T and NK cell infiltrates and the 3-digit Miettinen score. Supplemental Figure 2. GIST TIls are mainly composed of CD4+ T cells.

Background: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal–epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. Methods: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. Results: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast), respectively, with no change in Cmax. Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. Conclusion: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Background The phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. Objective We investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methods Copanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 on days 8, 15, and 22, and weekly thereafter). Results Three patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response. Conclusion Copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients. Trial registration NCT02822482, Date of registration: June 2016.

Adenocarcinoma esofàgic; Bintrafusp Alfa Adenocarcinoma Esofágico; Bintrafusp Alfa Esophageal Adenocarcinoma; Bintrafusp Alfa Background Esophageal adenocarcinoma patients have limited treatment options. TGF-β can be upregulated in esophageal adenocarcinoma, and blocking this pathway may enhance clinical response to PD-(L)1 inhibitors. Bintrafusp 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. Objective The objective of this study was to investigate the efficacy and safety of bintrafusp alfa in patients with advanced, post-platinum esophageal adenocarcinoma, unselected for PD-L1 expression. Patients and Methods In this phase 1 study, patients with post-platinum, PD-L1–unselected esophageal adenocarcinoma received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was confirmed best overall response per RECIST 1.1 by independent review committee (IRC). Results By the database cutoff of 24 August 2018, 30 patients (80.0% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks. The confirmed objective response rate (ORR) per IRC was 20.0% (95% CI 7.7–38.6); responses lasted 1.3–8.3 months. Most responses (83.3%) occurred in tumors with an immune-excluded phenotype. Investigator-assessed confirmed ORR was 13.3% (95% CI 3.8–30.7). Nineteen patients (63.3%) had treatment-related adverse events: seven patients (23.3%) had grade 3 events; no grade 4 events or treatment-related deaths occurred. Conclusions Bintrafusp alfa showed signs of clinical efficacy with a manageable safety profile in patients with heavily pretreated, advanced esophageal adenocarcinoma. This trial was funded by Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA and GlaxoSmithKline. Merck KGaA provided the study drug and worked with investigators on the trial design and plan, collection and analysis of data, and interpretation of results. Funding for a professional medical writer with access to the data was provided by Merck KGaA and GlaxoSmithKline.

We report the clinical activity, safety, and identification of a predictive biomarker for bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβRII (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1, in patients with advanced triple-negative breast cancer (TNBC).In this expansion cohort of a global phase 1 study, patients with pretreated, advanced TNBC received bintrafusp alfa 1200 mg every 2 weeks intravenously until disease progression, unacceptable toxicity, or withdrawal. The primary objective was confirmed best overall response by RECIST 1.1 assessed per independent review committee (IRC).As of May 15, 2020, a total of 33 patients had received bintrafusp alfa, for a median of 6.0 (range, 2.0-48.1) weeks. The objective response rate was 9.1% (95% CI, 1.9%-24.3%) by IRC and investigator assessment. The median progression-free survival per IRC was 1.3 (95% CI, 1.2-1.4) months, and median overall survival was 7.7 (95% CI, 2.1-10.9) months. Twenty-five patients (75.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 patients (15.2%); no patients had a grade 4 TRAE. There was 1 treatment-related death (dyspnea, hemolysis, and thrombocytopenia in a patient with extensive disease at trial entry). Responses occurred independently of PD-L1 expression, and tumor RNAseq data identifiedBintrafusp alfa showed clinical activity and manageable safety in patients with heavily pretreated advanced TNBC.NCT02517398.