National Cancer Institute and Merck KGaA.

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-β (TGF-β) "trap."Experimental Design: In the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. Results:Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions STATEMENT OF TRANSLATIONAL RELEVANCEExcitement surrounding the durable benefits associated with PD-1/PD-L1-targeted therapy has been tempered somewhat by responses being confined to only a subset of patients.To increase the rate of response, many ongoing trials are evaluating anti-PD-1/PD-L1 agents in combination with other immunotherapies; however, these combination strategies have limitations and novel approaches are required. M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β "trap." We report the first clinical data for M7824 -including pharmacokinetics, safety, and efficacy findings -which derive from a phase 1 dose-escalation study in patients with advanced solid tumors. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β throughout the dosing period at a dose >1 mg/kg. M7824 appeared to have a manageable safety profile and early evidence of clinical efficacy -including 1 ongoing confirmed complete response and 2 durable confirmed partial responses -was demonstrated.

BackgroundCheckpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.MethodsEligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.ResultsSeventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.ConclusionsDurvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.Trial registrationClinicalTrials.gov identifier: NCT02484404.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0463-2) contains supplementary material, which is available to authorized users.

PURPOSE We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.MethodsIn these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.ResultsAs of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.ConclusionBintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

515 Background: Tolerability and efficacy of CaboNivo and CaboNivoIpi were demonstrated in the initial phase I cohort, prompting longer follow-up and the addition of expansion cohorts to further evaluate both combinations Methods: Phase I cohort had 7 dose levels (DL). Recommended phase 2 doses for CaboNivo=Cabo 40mg/Nivo 3mg/kg (DL2) & CaboNivoIpi=Cabo 40mg/Nivo 3mg/kg/Ipi 1mg/kg (DL6) (Nadal ESMO 2017).In expansion cohorts, pts were treated: [1] DL8: Cabo 40mg/Nivo 1mg/kg/Ipi 3mg/kg; [2]DL2: mUC, metastatic renal cell carcinoma (mRCC), adenocarcinoma bladder (AcB): post-PD-1-PDL1 inhibitor mUC (p-mUC), and [3] DL6 mRCC. Objectives: safety, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) & overall survival (OS). Results: 75 pts enrolled. Median age 59 yo. 83% male, 17% female. 47 treated with CaboNivo (mUC n=24; AcB n= 9; germ cell tumor (GCT) n= 5; castrate-resistant prostate cancer (CRPC) n= 4; bladder squamous cell carcinoma (SCC) n= 2; penile n=1; mRCC n= 7). 28 treated with CaboNivoIpi: (mUC n=8; penile n=3; CRPC n=7; Sertoli n=1; mRCC n=6; bladder small cell carcinoma n=1; renal medullary carcinoma (RMC) n=2). Any grade (G) adverse events (AEs) (CaboNivo 96% & CaboNivoIpi 96%)/G3–4 AEs (CaboNivo 62% & CaboNivoIpi 71%). Most common any G, CaboNivo: fatigue 70%, diarrhea 60%, AST/ALT 60%, hypophosphatemia (hypoP) 45% & CaboNivoIpi: fatigue 71%, diarrhea 68%, hypoP 50%, AST/ALT 43%. Most common G3-4, CaboNivo: lipase 17%, hypoP 15%, fatigue 6% & CaboNivoIpi: hypoP 21%, AST/ALT 14%, lipase 14%. Selected irAs: colitis (2.6%), hepatitis (2.6%), pneumonitis (2.6%), aseptic meningitis (1.3%). ORR: 36%; 3CR (2mUC, 1SCC) & 20PR (5mUC, 2SCC, 7mRCC, 2Penile, 2AcB, 1CRPC, 1RMC). mDOR: 24.1 mo [95% CI: 14.7-NR], mPFS: 7.2 mo [95%CI: 5.1-18.4], mOS:18.8 mo [95%CI: 10.6-NR]. OS 6/12 mo: 83%/61%. Cohort of p-mUC pts(n=5):1PR/3SD/1PD Conclusions: Updated results from phase I and expanded cohorts confirm initial safety findings and promising antitumor activity for both combinations in mUC, mRCC, and rare GU malignancies Clinical trial information: NCT02496208.

Purpose The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine. Experimental Design Human dendritic cells (DCs) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses. Results MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro. No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤ grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients. Conclusions The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned.

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