AcSé Pembrolizumab is a phase II, non-randomized parallel arm, open-label, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with rare cancers (NCT03012620). Here we report the results of pembrolizumab in the rare sarcoma cohort.
Selected histotypes were all rare sarcomas (incidence <0.2/100,000/year). Main inclusion criteria were age>18, PS≤1, and advanced disease resistant to standard treatment. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1. Secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. Five groups of patients were distinguished, namely chordoma, alveolar soft-part sarcoma (ASPS), desmoplastic small round cell tumor (DSRCT), smarca4-malignant rhabdoid tumor (SMBT) and the others.
80 patients with rare sarcomas, including 24 with chordoma, 13 ASPS, 6 DSCRCT, 6 SMBT and 31 with other histotypes, were included from July 2017 to February 2020. The median number of cycles was 5 (range, 1 to 33) with 54 (67.5%) patients who discontinued the trial after a median of 4 cycles. Twenty-eight patients died after a median of 3 cycles (linked to cancer 27, other 1). Best response was PR in 13 patients (16.25%, 95%CI: 8.9 to 26.2%), and SD in 29 (36.25%). The occurrence of best response depended on the histotype, with 2 (8%) responses in chordoma, 5 (39%) in ASPS, 1 (17%) in DSCRCT, 3 (50%) in SMBT, and 2 (6%) in other histotypes (p=0.010). At data cut off, the 1-year PFS rates of the five histotype groups were 35%, 58%, 0, 62.5%, and 8%, with median times of 5.7 months, 14 months, 5, not reached, and 2.7 months respectively (p= 0.00016), while 1-year OS rates were 72%, 90%, 50%, 83% and 40% (p= 0.02). Median survival were only reached for chordoma (20 months), DSRCT (7.4 months), and other histotype group (5.4 months).
Pembrolizumab shows high levels of prolonged activity in selected subtypes of rare sarcomas.
J-Y. Blay: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): BMS; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Astrazeneca. S. Chevret, N. Penel, F. Bertucci, E. Bompas, E. Saada-Bouzid, J-C. Eymard, J-P. Lotz, E. Coquan, R. Schott, P. Soulié, C. Linassier, A. Le Cesne, M. Brahmi, C. Simon, A. Lamrani-Ghaouti, C. Massard: Research grant/Funding (institution): MSD. I.L. Ray-Coquard: Honoraria (institution), Research grant/Funding (institution): MSD; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Astrazeneca; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Roche. All other authors have declared no conflicts of interest.
Trabectedin (T) activity is partly mediated by targeting tumor associated macrophages. We report results of a multicenter phase Ib study assessing safety and preliminary efficacy of T combined with the PDL1 inhibitor durvalumab (D) in patients (pts) with unresectable or metastatic STS and relapsed OC, focusing on the STS expansion cohort.
This trial followed a conventional 3+3 design and included two dose-expansion cohorts (STS and OC). Pts aged >18, with unresectable or metastatic pretreated STS or relapsed OC were eligible. Primary objective was to assess safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD) and recommended phase II dose of T given on day 1 as 3-hour infusion combined with D at fixed dose of 1120 mg on day 2, every 3 weeks. Three dose levels were investigated: 1 mg/m2, 1.2 mg/m2 and 1.5 mg/m2. Secondary objectives comprised antitumor activity of the combination in terms of objective response (OR) rate, 6-month progression-free rate (PFR), progression-free survival (as per RECIST v.1.1) and overall survival (OS), and to explore immune biomarkers of T+D activity on serial tumor biopsies and metabolomics on plasma samples. At least one OR was needed to consider the combination active.
Between October 2017 and November 2019, 40 pts were included: nine in the dose escalation phase (3 at 1.0 mg/m2 and 6 at 1.2 mg/m2), 15 in the OC cohort and 16 in the STS cohort. With one DLT (grade 4 ALT increase), 1.2 mg/m2 was considered the MTD of T combined with 1120mg/m2 of D. In the STS expansion cohort, median follow-up was 10.7 months (IC95%: 3.1-13.5). Overall, 16 patients were assessable for safety and 14 for efficacy. Most frequent related AE were grade 1-2 nausea (15.1%), grade 1-2 fatigue (11.3%) Eight patients (50%) had drug-related grade 3/4 adverse events (AEs), mostly being neutrophil count decreased (35.7%), and there were 2 grade 5 AE (multi-organ failure and febrile aplasia). Six patients (42.9%) experienced tumor shrinkage, resulting in one partial response (ORR = 7.1%; CI95%: 0.2 - 33.9).The 6-month PFR was 28.6% (CI95%: 8.4 - 58.1).
Combination of T+D has activity in STS. Updated efficacy and biomarker analyses will be presented at the meeting.
M. Toulmonde: Travel/Accommodation/Expenses: PharmaMar. A. Bessede: Officer/Board of Directors: Immusmol. J-Y. Blay: Advisory/Consultancy, Research grant/Funding (institution): PharmaMar. All other authors have declared no conflicts of interest.
REGOBONE is non-comparative phase II, double-blind, PL-controlled trial designed to evaluate the activity and safety of REG, in 5 independent cohorts of sarcoma originating in bone. We report here the ES cohort results.
Key-eligibility criteria were histologically confirmed diagnosis of bone ES, age ≥10 years, confirmed measurable PD not amenable to curative-intent, 1-2 previous chemotherapy (CT) regimens for metastatic disease, ECOG 0-1. Eligible ES pts were randomized (2:1) to receive either REG (160 mg/d, 21/28 d) or matched PL with optional cross-over at the time of centrally confirmed progressive disease (PD). 24 pts were planned in the REG arm based on a A'Hern's single-stage design for phase II trials (1-sided α=0.05, and 80% power) to detect a 27% improvement in the progression-free rate (PFR) at 8 weeks (P0=40%) as evaluated by central review per RECIST1.1. Secondary endpoints included PFS, OS and safety.
From September 2014 to November 2019, 41 ES pts were included. Five pts were not eligible for efficacy analysis. Of 36 efficacy-evaluable pts (13 in PL arm and 23 in REG arm); 28 were men, median age was 32 (16-59) years. 13/23 pts in REG arm (56.5%; one-sided CI95% = [37.5-[) were non-progressive at 8 weeks vs. 1/13 pts in PL arm (7.7%; CI95% = [0.4-[). Median PFS was 11.4 (CI95% = 4.6-22.9) vs. 3.9 (CI95%= 3.3-7.3) weeks for REG and PL arms, respectively. 5 (21.7%) partial responses were observed on REG. Median OS was 34.9 (CI95%=17.6-58.7) and 30.4 (CI95%=10.0-NE) weeks for REG and PL arms, respectively. Ten out of 13 pts crossed-over to REG after centrally-confirmed PD on PL. The most common ≥ Gr3 REG-related AEs during the double blind period were diarrhea (13%), hand-foot skin reaction (13%), asthenia (9%), thrombocytopenia (9%), mucosal inflammation (9%) and febrile neutropenia (9%), with one toxic death due to thrombocytopenia.
Despite a PFR at 8 weeks lower than expected, this randomized non comparative study shows a promising signal of benefit of REG in relapsed ES, with a median of PFS of 11.4 weeks, and a moderate toxicity.
EudraCT: 2013-003910-42; NCT02389244.
F. Duffaud: Advisory/Consultancy: Bayer; Travel/Accommodation/Expenses: Leo Pharma; Travel/Accommodation/Expenses: PharmaMar. J-Y. Blay: Honoraria (institution), Advisory/Consultancy: Bayer. O. Mir: Honoraria (self): Amgen; Honoraria (self), Honoraria (institution): Astra-Zeneca; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self): Bristol Myers-Squibb; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli-Lilly; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Shareholder/Stockholder/Stock options: Ipsen; Honoraria (self): Lundbeck; Honoraria (self): MSD; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Speaker Bureau/Expert testimony: Servier; Honoraria (self): Vifor pharma; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Honoraria (institution): PharmaMar; Research grant/Funding (institution): Agios pharmaceutical; Research grant/Funding (institution): Epizyme; Travel/Accommodation/Expenses: Amgen; Shareholder/Stockholder/Stock options: Amplitude surgical; Shareholder/Stockholder/Stock options: Transgene. C.M. Chevreau: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy: Novartis. P. Boudou Rouquette: Advisory/Consultancy, Travel/Accommodation/Expenses: Takeda; Advisory/Consultancy: BMS; Travel/Accommodation/Expenses: PharmaMar. N. Penel: Research grant/Funding (institution): Bayer HealthCare. C. Perrin: Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Daiichi; Travel/Accommodation/Expenses: Novartis. N. Gaspar: Advisory/Consultancy: Eisai; Advisory/Consultancy: Ipsen. All other authors have declared no conflicts of interest.
Ewing Sarcoma (ES) is a rare pediatric cancer with poor prognosis and high unmet need. Chimeric oncoproteins encoded by fusions of the EWS gene and one of five different ETS transcription factors are dominant drivers of the disease. TK216 was designed to bind ETS proteins directly, disrupt protein interactions, inhibit transcription factor function and cause apoptotic cell death. Notably, TK216 plus vincristine (VCR) was shown to exert synergistic activity (Zollner 2017). Here, we report the results of the phase I trial of TK216 in ES.
TK216 was administered by continuous IV infusion to adult and pediatric patients (pts) with relapsed / refractory ES in a phase I study using a 3+3 design. Dosing duration of 7 days was later extended to 10 and 14 days, with a 14-day break to complete a cycle (C). DLT was evaluated during C1, and efficacy was evaluated after completion of C2. VCR could be added to treatment after C2.
32 pts were enrolled into 9 dose and schedule escalation cohorts (Coh) of TK216 ranging from 18 to 288 mg/m2/day. The MTD for the 14-day infusion was 200 mg/m2/d, which was selected as the recommended phase II dose (RP2D). Treatments were manageable with DLTs of neutropenia/febrile neutropenia, and other AEs of thrombocytopenia, anemia and fatigue. Nine pts have been treated in the expansion Coh with TK216 at the RP2D plus VCR. No new toxicities were noted except neurotoxicity due to VCR. In total, 11 pts were treated with the RP2D, 3 in the final dose escalation Coh and 8 in the expansion Coh, as of May 11, 2020. Observed efficacy was partial response (PR) 18% (2/11), stable disease 45% (5/11), for an overall clinical benefit rate of 64% (7/11). 3 of the patients experienced PD before reaching C2 evaluation (overall PD 36% (4/11). The two clinical responses were notable. One pt had a PR with a regression of all target lung lesions after 2 cycles of TK216 alone. After 6 mos of TK216 +/- VCR therapy, a small residual lesion was removed, for a surgical CR, now continuing for 14+ mos. A second pt had a PR with 90% reduction of target lung lesions by RECIST 1.1 after 2 cycles of TK216 plus VCR.
TK216 was well tolerated and showed encouraging early evidence of anti-tumor activity in a patient population with limited or no treatment options.
N. Federman: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer. R.F. Riedel: Advisory/Consultancy, Research grant/Funding (institution): Oncternal. J. Toretsky: Shareholder/Stockholder/Stock options: Oncternal Therapeutics. X. Ianopulos, F.J. Hsu: Full/Part-time employment: Oncternal Therapeutics. J.B. Breitmeyer: Shareholder/Stockholder/Stock options, Officer/Board of Directors: Oncternal Therapeutics. All other authors have declared no conflicts of interest.