👤 Rastilav Bahleda

This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549. Show less

Despite efficacy of approved FGFR inhibitors, emergence of polyclonal secondary mutations in the FGFR kinase domain leads to acquired resistance. KIN-3248 is a selective, irreversible, orally bioavailable, small-molecule inhibitor of FGFR1-4 that blocks both primary oncogenic and secondary kinase domain resistance FGFR alterations. A first-in-human, phase I study of KIN-3248 was conducted in patients with advanced solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). The primary objective was determination of MTD/recommended phase II dose (RP2D). Secondary and exploratory objectives included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular response by circulating tumor DNA (ctDNA) clearance. Fifty-four patients received doses ranging from 5 to 50 mg orally daily across six cohorts. Intrahepatic cholangiocarcinoma (48.1%), gastric (9.3%), and urothelial (7.4%) were the most common tumors. Tumors harbored FGFR2 (68.5%) or FGFR3 (31.5%) alterations-23 (42.6%) received prior FGFR inhibitors. One dose-limiting toxicity (hypersensitivity) occurred in cohort 1 (5 mg). Treatment-related, adverse events included hyperphosphatemia, diarrhea, and stomatitis. The MTD/RP2D was not established. Exposure was dose proportional and concordant with hyperphosphatemia. Five partial responses were observed; 4 in FGFR inhibitor naïve and 1 in FGFR pretreated patients. Pretreatment ctDNA profiling confirmed FGFR2/3 alterations in 63.3% of cases and clearance at cycle 2 associated with radiographic response. The trial was terminated early for commercial considerations; therefore, RP2D was not established. Preliminary clinical data suggest that KIN-3248 is a safe, oral FGFR1-4 inhibitor with favorable pharmacokinetic parameters, though further dose escalation was required to nominate the MTD/RP2D. KIN-3248 was a rationally designed, next generation selective FGFR inhibitor, that was effective in interfering with both FGFR wild-type and mutant signaling. Clinical data indicate that KIN-3248 is safe with a signal of antitumor activity. Translational science support the mechanism of action in that serum phosphate was proportional with exposure, paired biopsies suggested phospho-ERK inhibition (a downstream target of FGFR2/3), and ctDNA clearance may act as a RECIST response surrogate. Show less

Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912. Show less

We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4 Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered. Show less