Search

Purpose: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non–small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. Patients and Methods: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150–wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. Results: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. Conclusions: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Background Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. Patients and methods In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000mg/m2 (arm 2a) or 500mg/m2 (arm 2b), followed by GDC-0575 (45 or 80mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. Results Of 102 patients treated, 70% were female, the median age was 59years (range 27–85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2hours of dosing, and half-life was ∼23hours. No pharmacokinetic drug–drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. Conclusion GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. Clinical trial number NCT01564251.

Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors. Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses. Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2. Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin. Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR.

58 Background: It is estimated that more than 40% of patients with mCRPC have functional loss of phosphatase and tensin homolog (PTEN) tumor suppressor gene, which is associated with unfavorable prognosis and reduced response to androgen receptor-targeting therapy. We describe patient characteristics and survival outcomes by PTEN LOF status among patients with mCRPC in real-world clinical practice. Methods: We conducted a retrospective cohort study using data from the nationwide Flatiron Health-Foundation Medicine mCRPC Clinico-Genomic database (FH-FMI CGDB), a de-identified database linking data derived from electronic health records with genomic data derived from FMI comprehensive genomic profiling (CGP) tests. The study included patients ≥18 years old, with a primary diagnosis of mCRPC between 1/1/2013 and 6/30/2019 who underwent FMI CGP testing and who had a valid PTEN LOF status. Patients were included if their PTEN report date and mCRPC diagnosis date occurred before death or censoring. PTEN LOF status was identified via FMI’s CGP testing. Kaplan-Meier (KM) methods assessed overall survival (OS) by PTEN LOF status from the date of mCRPC diagnosis (later of metastasis and castration resistance) until death or end of study follow-up. A stratified Cox regression model was used to estimate the hazard of death. The Cox model was adjusted for age, race and sequence of metastasis/CRPC diagnoses, and was stratified by the year of mCRPC diagnosis. Adjustments to account for left-truncation and survivorship bias were made in the KM analysis and the Cox regression model. Results: Among the 458 patients who met the eligibility criteria, 174 (38%) had PTEN LOF. The majority of the study sample (76%) was diagnosed with castration-resistance after metastasis. The PTEN LOF group had a higher percentage of white patients (80% vs. 68%; p= 0.01) compared to the PTEN non-LOF group. The mean age of the study sample was 68 years, and there was no difference in mean age at diagnosis by PTEN LOF status ( p= 0.17). Based on the KM estimates adjusted for left-truncation, the median OS was 14.3 months (95% confidence interval [CI]: 11.1-19.7) in the PTEN LOF group compared to 18.3 months (95%CI: 15.5-21.5) in the PTEN non-LOF group (log-rank p= 0.049). In the multivariable Cox model, the PTEN LOF group had numerically 30% higher risk of death compared to the PTEN non-LOF group (hazard ratio = 1.30; 95% CI: 0.99-1.71; p= 0.057). Conclusions: Among real-world patients with mCRPC in the CGDB, PTEN LOF could be associated with poorer survival outcomes, potentially highlighting the unmet need among these patients. Additional studies with larger cohorts are needed to better evaluate the survival outcomes of patients with PTEN LOF. Therapeutic agents acting on the PTEN/PI3K/AKT/mTOR pathway are being tested in clinical trials, and could potentially improve outcomes in this subgroup of patients with mCRPC.

Background: Hormone receptor-positive (HR+) breast cancer (BC) comprises 60-65% of all BC. Activating mutations in PIK3CA are the most common oncogenic alteration in HR+ BC, yet little is known about the prognostic utility of single (SM) and multiple (MM) PIK3CA mutations. A novel database with next-generation sequencing (NGS) data from Foundation Medicine, Inc. (FMI) linked to electronic health records-derived clinical data from Flatiron Health allows investigation of the prognostic utility of genomic alterations including PIK3CA. Using this database, this study seeks to understand HR+/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC (mBC) patient (pt) testing behavior, characteristics, and survival according to PIK3CA mutation status. Methods: Pt-level data from US pts diagnosed with HR+/HER2- mBC from January 1, 2011 to December 31, 2018 were selected from the de-identified Flatiron Health-FMI Clinico-Genomic Database (CGDB). Kaplan-Meier methods were used to estimate median (95% confidence interval [CI]) survival time, defined as time from mBC diagnosis to death. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. Index date was mBC diagnosis date, but adjustments were made in survival analyses to account for delayed dataset entry due to FMI results date occurring after mBC diagnosis date. Descriptive statistics and chi-square and Kruskal-Wallis tests for significance were used to compare pt characteristics. Results: Of 1349 HR+/HER2- mBC pts included in this study, 807 pts (60%) were wild-type (WT) for PIK3CA, 436 (32%) were SM, and 106 (8%) were MM. Only 2% of pts had an FMI results date before mBC diagnosis date. Most pts had an FMI results date either during (26%) or after (59%) first-line treatment. Median time from mBC diagnosis to FMI results date was longer for MM (19 mo) vs. SM (13 mo) and WT (13 mo) pts (p=0.15). SM and MM pts were older than WT pts at mBC diagnosis (median: 59.9 yr [MM] vs. 59.6 yr [SM] vs. 56.2 yr [WT], p Conclusions: These data showed that PIK3CA mutations were not associated with survival in this patient population and underscore the utility of linked clinical and genomics data for understanding the relationship between genetic alterations and patient outcomes. The majority of HR+/HER2- mBC pts received FMI results more than a year after mBC diagnosis, suggesting that NGS testing is used to guide decisions after pts have failed standard therapy. Additional studies with larger sample sizes and longer follow-up are needed to confirm these observations. Citation Format: Mary K. Downer, Peter Lambert, Sami Mahrus, Katherine E. Hutchinson, Patricia Luhn, Jennifer L. Schutzman. Utility of novel clinico-genomic data to understand patient characteristics, treatments, and outcomes according to PIK3CA mutation status among hormone receptor-positive metastatic breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 29.

Background Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. Methods This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. Results Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. Conclusions Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. Trial registration ClinicalTrials.gov identifier: NCT02048709.

105 Background: GDC-0919, a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), reduces tryptophan catabolism and kynurenine production within the tumor microenvironment that may promote normal effector T cell activity and an immunogenic state. IDO1 inhibition may complement targeting of PD-L1 with atezolizumab. Methods: A Phase Ib, open-label, study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity (RECIST v1.1) of GDC-0919 and atezolizumab in pts with locally advanced or metastatic solid tumors. Pts were given escalating doses of GDC-0919 (50-1000 mg orally twice daily, for 21 days) and atezolizumab (1200 mg IV, every 3 weeks) using a standard 3+3 design. Results: As of 14Dec2016, 52 pts were treated in 6 cohorts of GDC-0919 plus atezolizumab. The median number of prior systemic therapies was 3 (range 1-9); 2 pts received prior immunotherapy. Pts received a median of 4 cycles of GDC-0919 and atezolizumab (range 1-17). No MTD was identified. Across all dose levels, 1 DLT was observed (Grade [G] 3 sepsis syndrome at GDC-0919 200 mg); no G4/5 AEs were attributed to study treatment. G3+ AEs, regardless of causality were reported in 34 (65%) pts. Related G3 AEs were reported in 7 (13%) pts, included nausea, rash, sepsis syndrome, fatigue, and pneumonitis. Two pts (4%) had AEs leading to treatment discontinuation, related in 1/2 (G3 pneumonitis). Combination PK was consistent with single agent observations and supports BID dosing of GDC-0919. Peripheral PD showed dose-dependent decreases in plasma kynurenine, consistent with systemic modulation of IDO1. Preliminary efficacy data from 45 pts with ≥ 1 on-treatment tumor assessments included 4 patients (9%) with partial response and 11 (24%) pts with stable disease. Conclusions: The combination of GDC-0919 and atezolizumab was generally well-tolerated and demonstrated peripheral IDO1 modulation and preliminary efficacy in a heterogeneous patient population during dose escalation. The study is currently enrolling pts with select tumor types in expansion cohorts to assess tumor PD and combination efficacy. Clinical trial information: NCT02471846.

Background: Checkpoint kinase 1 (Chk1) acts at S and G2/M checkpoints to allow time for high-fidelity DNA replication and repair before cell cycle progression. Chk1 inhibition converts a transient genotoxic insult from chemotherapy into a cytotoxic event by overriding cell cycle arrest, allowing cells mitosis with DNA damage. GDC-0425 is an oral, selective Chk1 inhibitor. GDC-0425 enhances gemcitabine (gem) efficacy in tumor xenograft models. Greater chemopotentiation is observed in cancer cell lines lacking p53 activity. Methods: A phase I dose-escalation trial (3+3+3 design) included patients (pts) with refractory solid tumors and ECOG performance status (PS) ≤ 1. Pts received a single dose of GDC-0425 on day -7 for PK evaluation followed by 21-day cycles of gem on Days 1 and 8 and GDC-0425 on Days 2 and 9 at gem (mg/m2) + GDC-0425 (mg) dose levels of 750 + 60, 1000 + 60, and 1000 + 80. p53 was evaluated in archival tumor tissue by gene sequencing, immunohistochemistry, and gene expression signature. Safety, pharmacokinetics (PK), pharmacodynamics, and tumor response were investigated. Results: Of 40 pts treated, 55% were female, median age was 56 years (range 33-82), and 68% had ECOG PS 0. Most common tumor types were breast (n = 10), non-small cell lung (n = 5), and cancer of unknown primary (CUP, n = 4). Maximum concentrations of GDC-0425 were achieved within 4 hours of dosing and its half-life was approximately 16 hours. Target exposures associated with checkpoint abrogation and anti-tumor activity in preclinical models were exceeded at 60 mg. No PK interaction was observed with GDC-0425 and gem. Dose escalation was halted at GDC-0425 80 mg with gem 1000 mg/m2 as 3 of 6 pts experienced Grade 4 thrombocytopenia as a dose-limiting toxicity (DLT); 1 pt also had Grade 3 neutropenia that delayed Cycle 2 (DLT). Blood counts recovered with treatment interruption and supportive care. The maximum tolerated dose of GDC-0425 was 60 mg with gem 1000 mg/m2. The most frequent adverse events (AEs) (all grades) related to GDC-0425 and/or gem were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). Serious AEs related to GDC-0425 and/or gem occurred in 8 pts: neutropenia and thrombocytopenia (n = 2 each); leukopenia, ALT/AST/GGT increased, pyrexia, rash, dyspnea, gastric ulcer, and gastroenteritis (n = 1 each). Median number of administered cycles was 3.5 (range 1-14). There were 3 partial responses in pts with triple-negative breast cancer (TNBC, TP53 mutated), melanoma, and CUP (n = 1 each). Conclusions: It is safe and feasible to administer GDC-0425 with a standard dose of gem. At the doses assessed, bone marrow suppression is common but manageable and exposures exceed those predicted by preclinical models to inhibit Chk1. Clinical activity was observed, including 1 patient with TP53 mutated TNBC. Citation Format: Jeffrey R. Infante, Antoine Hollebecque, Sophie Postel-Vinay, Todd Bauer, Beth Blackwood, Marie Evangelista, Sami Mahrus, Frank Peale, Xuyang Lu, Srikumar Sahasranaman, Rui Zhu, Yuan Chen, Xiao Ding, Elaine Murray, Jennifer Schutzman, Jennifer Lauchle, Jean-Charles Soria, Patricia LoRusso. Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT139. doi:10.1158/1538-7445.AM2015-CT139

Meeting abstracts Indoleamine 2, 3-dioxygenase (IDO1) is a cytosolic enzyme catalyzing the oxidation of tryptophan to kynurenine. IDO1 plays an important role in modulating immune responses in cancer, where increasing evidence suggests that IDO1 expression by dendritic cells (DCs) and other antigen