Alice P. Chen

Purpose: Preclinical data suggest that the anti-cancer efficacy of ATR inhibitors can be synergistically enhanced by low-dose gemcitabine. To test the clinical feasibility of this regimen, we conducted a phase 1 trial of low-dose gemcitabine combined with the ATR inhibitor elimusertib (BAY1895344). Patients and Methods: This phase 1 study evaluated the combination of gemcitabine and elimusertib in patients with previously treated, incurable solid tumors. The primary objective was to assess the safety and tolerability of this regimen and to determine the maximum tolerated dose (MTD). Secondary objectives included assessment of objective response rate (ORR) per RECIST v.1.1 and characterization of the pharmacokinetic (PK) profile. Results: Fourteen patients were enrolled; most patients had pancreatic cancer (n=6) or ovarian cancer (n=6). The median age was 63.5 years of age, and the median number of prior therapies was 2. The regimen caused significant toxicity, and four patients (28%) discontinued the trial due to treatment-related adverse events. The trial was stopped prior to establishing an MTD due to the pharmaceutical company's decision to halt development of the agent. A confirmed partial response was observed in one patient with platinum-refractory ovarian cancer harboring a gain in CCNE1. Another patient with pancreatic adenocarcinoma harboring biallelic ATM loss remained on trial for 9.5 months with stable disease, with an 85% decrease in CA19-9. Conclusions: The combination of low-dose gemcitabine combined with elimusertib was not tolerable. Although evidence of anti-tumor activity was observed, significant improvements in tolerability are required for future ATR inhibitor combinations to be clinically feasible.

Supplementary Tables including study representativeness table.

Purpose: Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on the RAF–MEK–ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations. Patients and Methods: In this single-arm study, patients with BRAF non-V600 mutations or BRAF fusions were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: Of the 34 eligible patients, the median age was 66.5; 50% were women; and 88%, 9%, and 3% were White, Black, and Asian, respectively. Seventy-four percent of patients had an Eastern Cooperative Oncology Group performance status of 1. The median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer (n = 3), and melanoma (n = 3). No patients achieved complete response or partial response, resulting in an ORR of 0%. Stable disease was the best response in 7 of 26 centrally confirmed cases. The median PFS was 1.7 months [90% confidence interval (CI), 1.1–2.2]; the 6-month PFS rate was 5% (90% CI, 0.6%–17.7%); and the median OS was 3.5 months (90% CI, 1.9–5.4). Twenty (57%) patients had grade 3 toxicity, and 1 (3%) patient had grade 4 toxicity as their worst toxicity; there was no grade 5 toxicity. Conclusions: Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions or non-V600E/non-V600K BRAF mutations.

While most gastrointestinal stromal tumors are driven by oncogenic mutations in KIT or PDGFRA , 10–15% exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess methylation in SDH-deficient gastrointestinal stromal tumors disrupts genomic insulators, inducing aberrant expression of oncogenic ligands FGF3 , FGF4 , and activating an autocrine signaling loop mediated through FGFR1. We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST. The primary objective was to estimate objective response rate. Secondary objectives were to estimate progression-free survival (PFS) and assess safety and tolerability. Exploratory objectives were to evaluate serial measurements of FGF3 and FGF4 and fibroblast growth factor receptors in serial biopsies, to perform whole-exome sequencing in serial biopsies and to explore rogaratinib exposure with pharmacodynamic effects. Twenty-four patients received rogaratinib and ten experienced partial responses for an objective response rate of 41.7%. Median PFS was 31.0 months (95% confidence interval 20.2–not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7–97.1). Toxicities were manageable and included hyperphosphatemia, fatigue and diarrhea. Elevations in phosphorous were seen across the cohort, consistent with target engagement of FGFR1. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes ( SDHx ) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: NCT04595747 .

Subprotocol C1: Adverse Events Related to Treatment.

Subprotocol C1 co-occurring mutation plot

Subprotocol C1: Details on Cases with Confirmed PR or PFS >6 months

Subprotocol C2 co-occurring mutation plot

Subprotocol C2: Adverse Events Related to Treatment