José Manuel Pérez García

Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor–positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed.

3020 Background: CB-103 selectively inhibits the CSL-NICD interaction leading to down-regulation of CSL-NICD mediated oncogenic pathway activation downstream of NOTCH receptor/ligand signaling, and has shown potent anti-cancer activity as single agent and in combination with targeted/chemotherapies in preclinical models. The aim of this dose escalation/expansion phase 1/2a study is to assess safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), preliminary activity, pharmacokinetics and pharmacodynamics of CB-103. Methods: Eligible were adult patients (pts) with advanced or recurrent selected solid tumors. Tumor tissue, where available, was retrospectively tested for NOTCH pathway activating mutations and surrogate tissues were evaluated for gene expression of related target genes. CB-103 was given orally in 28 days cycles at escalating doses until disease progression or toxicity. In a dose confirmatory cohort, NOTCH activation will be prospectively assessed to determine eligibility. Results: Forty-one pts (19 adenoid cystic carcinoma (ACC), 16 colorectal and 4 breast cancer, 2 prostate cancer) were assigned to increasing dose levels starting from 15mg once daily (OD). Median age was 55 years (range 25-76). Median number of prior lines of therapy was 2 (range 0-7). Thirty-two pts in 8 escalation groups completed the 28-day DLT window. One DLT (asymptomatic grade (G) 3 GGT increase) was observed at the highest dose (600mg). Related treatment emergent adverse events (AE) occurring in >10% of pts were nausea (24%), diarrhea (20%), dyspepsia (15%), fatigue (12%) and vision blurred (12%), all G 1/2. No discontinuations occurred due to treatment-related AEs. The MTD has not been reached. Several pts reported vision changes that improved over time and were fully reversible after stopping the drug. Median time on treatment for all pts was 52 days (range 5-249). Best response was stable disease (SD). For ACC pts, preliminary median PFS was 21.7 weeks (95% confidence interval (CI) 13.7-22.4 weeks) and disease control rate (DCR) was 79% at week 8 and 58 % at week 20. Three pts with ACC harboring activating NOTCH alterations had radiologically confirmed stable disease (SD) > 6 months. Importantly, in 3 pts with NOTCH positive disease a temporary stop of tumor growth was observed. One pt showed a reduction in size of a liver lesion up to 25% before progression due to new lesions. Mechanistically, strong on-treatment downregulation of NOTCH target genes was observed. The dose of 600mg CB-103 OD was declared the RP2D. Conclusions: CB-103 is the first drug to effectively control the CSL-NICD transcription complex. CB-103 is well tolerated in pts with advanced tumors and, as expected on the basis of mechanistic studies, in the absence of the typical toxicities associated with Notch targeting GSIs or mABs. The RP2D has been established for advancing clinical development into phase 2. Clinical trial information: NCT03422679.