scholarly journals AKT Inhibition in Solid Tumors With AKT1 Mutations

2017 ◽  
Vol 35 (20) ◽  
pp. 2251-2259 ◽  
Author(s):  
David M. Hyman ◽  
Lillian M. Smyth ◽  
Mark T.A. Donoghue ◽  
Shannon N. Westin ◽  
Philippe L. Bedard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Human Cancer ◽  
Neutral Loss ◽  
Evaluation Criteria ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Pi3k Pathway ◽  
Genomic Context ◽  
Biomarker Analysis

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K–mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor–positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K–mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9011-9011
Author(s):  
Ross A. Soo ◽  
Jean-Francois Martini ◽  
Anthonie J. van der Wekken ◽  
Shunsuke Teraoka ◽  
Alice T. Shaw ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Similar Response ◽  
Dna Dynamics ◽  
Paired Samples ◽  
Biomarker Analysis ◽  
Alk Positive ◽  
Ctdna Analysis

9011 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival (PFS) and overall/intracranial responses vs crizotinib in patients (pts) with previously untreated ALK-positive advanced non-small cell lung cancer (NSCLC) in the ongoing randomized Phase 3 CROWN study (NCT03052608). To identify whether additional molecular biomarker analysis correlated with efficacy, we evaluated early ctDNA dynamics compared with clinical outcomes. Methods: Plasma samples were prospectively collected at screening (SC), week 4 (cycle 2, day 1 [C2D1]), week 24 (C7D1), and end of treatment for ctDNA analysis. ctDNA was analyzed using Guardant360CDx (Guardant Health, Inc., Redwood City, CA, USA). Mean variant allele fraction (VAF) of ALK alterations (fusions and/or mutations) and overall detected alterations at each time point and longitudinal mean change (dVAF) as (VAFC2D1) – (VAFSC) were calculated; dVAF <0 indicated decreased ctDNA at week 4. Objective tumor response and PFS were evaluated according to dVAF. These analyses were repeated vs ctDNA results at week 24. Additional correlation analyses between depth of molecular response and/or ctDNA clearance and clinical outcomes are ongoing. Results: Paired samples were available at SC and week 4 from 232 of 255 pts included in the ctDNA analysis: 118/130 (90.8%) in the lorlatinib arm and 114/125 (91.2%) in the crizotinib arm. ALK alterations were detected in 122/232 (52.6%) pts at SC (62/118 [52.5%] from the lorlatinib arm) but only 19/232 (8.2%) at week 4 (8/118 [6.8%] from the lorlatinib arm). Mean VAF of ALK alterations at week 4 was significantly decreased compared with SC in both treatment arms (lorlatinib -1.54, crizotinib -1.25; both P<0.0001; P=0.4239 between arms). In the lorlatinib arm, mean VAF at week 4 was significantly decreased compared with SC in pts with a complete or partial response (dVAF -1.53; n=47; P<0.0001), or stable disease (dVAF -1.37; n=12; P=0.0304). Similar results were observed in the crizotinib arm. In pts with dVAF <0 for ALK alterations, mean percent change from screening in tumor size was -40.8% with lorlatinib (n=59) and -38.7% with crizotinib (n=58). Only 2 pts had dVAF ≥0, both from the crizotinib arm. Median PFS for pts with dVAF <0 for ALK alterations was not reached in the lorlatinib arm (n=62), and was 7.4 months (95% CI, 7.2–9.3) in the crizotinib arm (n=58). Similar response and PFS data were observed in the analysis of dVAF for ALK alterations at week 24. Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. Reference: Shaw AT, et al. N Engl J Med. 2020;383:2018-2029. Clinical trial information: NCT03052608.

Phase II trial of volasertib (BI 6727) versus chemotherapy (CT) in platinum-resistant/refractory ovarian cancer (OC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5504-5504 ◽  
Author(s):  
Eric Pujade-Lauraine ◽  
Beatrice E. Weber ◽  
Isabelle Ray-Coquard ◽  
Ignace Vergote ◽  
Frédéric Selle ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Demographic Data ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Overall Response ◽  
Platinum Resistant ◽  
Measurable Disease ◽  
Platinum Refractory

5504 Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study investigated V vs CT as 3rd- or 4th-line therapy in patients (pts) with platinum-refractory or resistant OC. Methods: Pts were randomized to V 300 mg IV Q3W or investigator’s choice single-agent CT (pegylated liposomal doxorubicin, topotecan, paclitaxel, gemcitabine) until progression or intolerance. Primary endpoint was 24-wk disease control rate (DCR; % of pts with complete/partial response [PR] or stable disease [SD]). Secondary endpoints included safety, progression-free survival (PFS), best overall response (RECIST 1.1) and explorative biomarkers. Results: 109 pts received V (n=54) or CT (n = 55) for a median (range) of 95 (22–716) and 114 (7–351) days, respectively. Demographic data were balanced between the treatment arms. Overall, median age was 62.0 yr; ECOG PS 0–1: 103 pts; 2 prior CTs: 51 pts; ≥3 prior CTs: 57 pts; platinum-resistant: 78 pts; platinum-refractory: 31 pts; measurable disease: 89 pts. 24-wk DCR (95% CI) for V vs CT was 31% (18–43) vs 43% (30–57), and median PFS was 13.1 vs 20.6 wks (HR = 1.01; 95% CI: 0.66–1.53). Six V pts vs 0 CT pts are ongoing for PFS 1 yr after randomization. Best overall response in pts with measurable disease (V/CT) was: PR, 7/8 pts; SD, 24/24 pts. Adverse events (AEs) led to discontinuation in 20 pts (V, n = 5; CT, n = 15); no V pts and 8 CT pts discontinued due to treatment-related AEs (including neuropathy in 3 CT pts). Most frequent all grade AEs (% of pts) regardless of relatedness were neutropenia (61%), anemia (54%), thrombocytopenia (46%), nausea (37%) and asthenia (33%) with V, and asthenia/nausea (47% each), abdominal pain (38%), anemia (36%) and neutropenia/vomiting (31% each) with CT. There were 3 fatal AEs per arm. Conclusions: Single-agent V showed antitumor activity in OC in a range similar to CT. AEs with V were mainly hematologic and manageable, with fewer non-hematologic AEs than CT. Exploration of potential predictive biomarkers for V activity is ongoing. Clinical trial information: NCT01121406.

scholarly journals The efficacy and adverse events of anlotinib plus PD-1 inhibitor for metastatic solid tumors

2021 ◽  
Author(s):  
Hao Lin ◽  
Tao Liu ◽  
Xinli Zhou ◽  
Xiaohua Liang
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Kaplan Meier ◽  
Hemorrhagic Events ◽  
Tumor Immune Microenvironment

Abstract Background Several antiangiogenic tyrosine kinase inhibitors (TKIs) have the potential to modulate the tumor immune microenvironment and improve immunotherapy effect Of these, anlotinib has demonstrated antitumor efficacy in clinical trials. However, its role in immune regulation and the potential synergistic antitumor effect of its combination with PD-1 inhibitor remain unclear. This study investigated the efficacy and adverse events (AEs) of the combination of anlotinib and PD-1 inhibitor for solid tumors in real-world settings. Methods This retrospective study included patients with metastatic solid tumors treated with anlotinib plus PD-1 inhibitor at Huashan hospital, Fudan University between October 1, 2018 and August 31, 2020. The objective response rate was assessed using the response evaluation criteria in solid tumors v1.1. Descriptive statistics were performed using the Kaplan–Meier method, and any AEs were noted. Results Partial response was achieved in 13 patients, and 8 patients showed stable disease, representing a response rate of 43.3% and a disease control rate of 70%. The median progression-free survival was 3.8 months. Although AEs were observed in 50% of patients, most of them were Grades 1–2 and well tolerated. The most common AEs were thrombocytopenia (16%), thromboembolic or hemorrhagic events (16%), and rash (13%). Conclusions Anlotinib plus PD-1 inhibitor is an alternative salvage treatment choice in metastatic solid tumors with Favorable efficacy and tolerable toxicities.

Beyond the bevacizumab resistance, combined effects of erlotinib in heavily pretreated patients with recurrent ovarian cancers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16505-e16505
Author(s):  
Yoshihiro Kikuchi ◽  
Masashi Takano ◽  
Yuji Ikeda ◽  
Ryoko Kikuchi ◽  
Kazuya Kudoh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Solid Tumors ◽  
Synergistic Effects ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Ovarian Cancers ◽  
Heavily Pretreated ◽  
Pretreated Patients

e16505 Background: In heavily pretreated ovarian cancer patients, bevacizumab (B) combined with conventional chemotherapy has been reported to improve the response. However, responses to B are usually transient and resistance inevitably develops. The vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) are valid targets in many solid tumors, and their inhibitors have synergistic effects in preclinical studies. Methods: In 13 patients with heavily pretreated ovarian cancers, after development of B resistance erlotinib (E) (150 mg/day, 3 week, one week rest) and B (2 mg/kg/week, 3 week, one week rest) were administered with cytotoxic agents until development of disease progression or unmanageable adverse effects (AE). The primary endpoint in this study was response rate (RR) and progression-free survival (PFS). Results: Of 13 patients, 3 patients were not evaluable for response evaluation criteria in solid tumors (RECIST). Of 10 patients, 3 (30%) patients had partial responses (PR), 4 (40%) had stable diseases (SD), resulting in 70% clinical benefit rate (CBR). The PFS lasts more than 6 months in 4 (40%) patients. Although main AEs by E were rash, diarrhea and mucositis, all cases were manageable and tolerable. Conclusions: E administration after development of B resistance can reverse effects of B in 70% of heavily pretreated patients with recurrent ovarian cancers. AE of E was manageable and tolerable. These results warrant further studies in such clinical settings.

Phase II study of afatinib in recurrent and/or metastatic esophageal squamous cell carcinoma (R/M ESCC) (KCSG HN14-18).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4051-4051
Author(s):  
Min Hee Hong ◽  
Yun-Gyoo Lee ◽  
Hyo Song Kim ◽  
Keon Uk Park ◽  
Hoon-Gu Kim ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Clinical Investigation ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Open Label ◽  
Platinum Based Chemotherapy

4051 Background: Afatinib, an irreversible pan-ErbB kinase inhibitor showed anti-tumor activity against esophageal cancer in phase I trial. In this multicenter, open-label, single arm phase II study, we aimed to evaluate the activity and safety of afatinib in R/M ESCC. Methods: Patients (pts) who had ECOG PS 0-2 and had progressed on platinum-based chemotherapy for R/M ESCC were enrolled. Pts were treated with afatinib 40mg/day until disease progression, unacceptable toxicity, or patient’s refusal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. The estimated sample size was 49, using a two-stage minimax design to evaluate incremental response rate from 5 to 15%. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profile. Additionally, we try to identify biomarker to predict efficacy of afatinib with target capture sequencing and gene expression profile as exploratory endpoints. Results: In a total of 49 enrolled pts (median age 60; range 44 -84), ORR and DCR were 14.3 % and 73.3%, respectively. With a median follow-up of 6.6 months, median PFS and OS was 3.4 months (95% CI 2.2-4.6) and 6.6 months (95% CI 5.2-8.0). Median treatment duration and duration of response were 2.8 months (range, 0.4-15.3) and 7.1 months (range, 2.5-13.9), respectively. Dose reduction and interruption occurred in 19 (38.8%) and 15 (30.6 %) pts. Treatment-related adverse events (TRAE) occurred in 33 pts (67.3%) with most common TRAEs being diarrhea (n=22, 44.9%) and acneiform rash (n=12, 24.5%). G3-4 TRAEs were rare, occurring in 7 pts (14.3 %). Conclusions: Afatinib demonstrated modest efficacy with manageable toxicity in platinum-resistant R/M ESCC patients. Given the modest response rate, identification of predictive biomarkers is essential for further clinical investigation of afatinib in R/M ESCC. Those biomarkers are being analyzed and will be presented in the conference (NCT02353936). Clinical trial information: NCT02353936. [Table: see text]

Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9065-9065 ◽  
Author(s):  
Joseph W. Kim ◽  
Navid Hafez ◽  
Hatem Hussein Soliman ◽  
Siqing Fu ◽  
Shumei Kato ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Platinum Based Chemotherapy

9065 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We therefore tested the anti-tumor activity of cediranib and olaparib combination in patients (pts) with advanced solid tumors. Here, we report the data from the SCLC cohort. Methods: This multi-institutional, two-stage, phase 2 study enrolled pts with metastatic SCLC previously treated with a minimum of one prior line of platinum-based chemotherapy in advanced setting. Patients were treated with cediranib 30mg po daily plus olaparib 200mg po BID until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses. Results: Baseline characteristics of the 25 pts enrolled are summarized below. The overall ORR rate was 28% (95% CI: 0.104,0.456). Median duration of response was 3.8 months (mos). Six of 8 pts had an objective response lasting longer than 3 mos up to 10.3 months. Disease control rate (# of pts with CR, PR or SD / # evaluable pts) was 88% (95% CI: 0.75,1.01). Median progression free survival was 4.1 mos (95% CI: 2.3, 6.2). Median OS was 5.5 mos (95% CI: 3.4, NA). Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 14 of 25 (56%). G3/4 AEs occurring in > 10% of pts were hypertension (21%), fatigue (17%) and weight loss (13%). Conclusions: The cediranib/olaparib combination resulted in promising clinical activity with ORR of 28% in biomarker-unselected pts with platinum-pretreated SCLC. The regimen required prompt initiation of antihypertensives, but AEs were overall manageable. Analyses of mutation status in homologous recombination DNA repair genes are going and will be correlated with clinical activity. Clinical trial information: NCT02498613. [Table: see text]

Biomarker analysis from a randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 7-7
Author(s):  
Rana R. McKay ◽  
Marc R Radke ◽  
Yu Shyr ◽  
Shilin Zhao ◽  
Mary-Ellen Taplin ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Randomized Phase Ii ◽  
Biomarker Analysis ◽  
Gene Status ◽  
Brca1 Brca2 ◽  
Homozygous Deletions ◽  
Endothelial Growth Factor

7 Background: We previously reported that cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, combined with olaparib, a poly (ADP-ribose) polymerase inhibitor, prolonged radiographic progression-free survival (rPFS) compared with olaparib alone in patients with mCRPC. Herein, we present updated clinical data in the overall population and in subgroups by homologous recombination (HR) gene status. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily (C+O) or olaparib 300 mg by mouth twice daily (O). Patients were required to undergo a baseline metastasis biopsy. Next generation sequencing of HR genes was performed on available samples using BROCA-HR assay. HR deficiency (HRD) was defined by presence of homozygous deletions or deleterious mutations in HR genes including BRCA1, BRCA2, ATM, and others. The primary endpoint was rPFS and secondary endpoint was overall survival (OS). Results: Eighty-four patients were included in the analysis of whom 26 patients (31.0%) had HRD mCRPC. The most common HR gene alterations included BRCA2 (n=17, 20%), CDK12 (n=9, 11%), and ATM (n=7, 8%). Consistent with our prior report, in the overall cohort, C+O compared to O resulted in a significant improvement in rPFS (Table). The benefit in rPFS was most pronounced in patients with HRD mCRPC; however, there was no difference between arms in HR proficient (HRP) cancers. Independent of arm allocation, rPFS and OS were numerically longer in patients with HRD mCRPC compared to HRP mCRPC (rPFS: 8.8 versus 4.3 months, p=0.14; OS: 18.6 vs. 12.3 months, p=0.24). Conclusions: C+O improved rPFS in patients with mCPRC compared with O alone. The biomarker analyses revealed that the rPFS benefit of C+O over O is likely driven by patients with HRD mCRPC. Our data warrant validation and support further investigation of the combination of C+O in patients with HRD mCRPC. Clinical trial information: NCT02893917. [Table: see text]

Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors

2009 ◽  
Vol 27 (30) ◽  
pp. 5094-5101 ◽  
Author(s):  
Neeltje Steeghs ◽  
Ferry A.L.M. Eskens ◽  
Hans Gelderblom ◽  
Jaap Verweij ◽  
Johan W.R. Nortier ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Systemic Exposure ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Dose Escalation Study ◽  
Phase Ii Studies ◽  
Nonhematologic Toxicity ◽  
Biomarker Analysis

PurposeDanusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.Patients and MethodsPatients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m2in the 6-hour IVS, and from 250 mg/m2in the 3-hour IVS, were studied.ResultsFifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m2for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m2or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.ConclusionDose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m2infused over 6 hours on days 1, 8, and 15 every 28 days.

Early predictors of benefit to dual anti-PD1/HER2 inhibition: Biomarker analysis from phase 2 trial of pembrolizumab/trastuzumab in HER2-positive metastatic esophagogastric (mEG) cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4058-4058
Author(s):  
Steven Brad Maron ◽  
Walid Khaled Chatila ◽  
Henry S. Walch ◽  
Ryan Ptashkin ◽  
Shalom Sabwa ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Ct Scans ◽  
Her2 Positive ◽  
Phase 2 Trial ◽  
Biomarker Analysis ◽  
Pre Treatment ◽  
Pet Scans

4058 Background: Pembrolizumab and trastuzumab (P&T) and chemotherapy demonstrated 27 month mOS, 13 month mPFS, and 91% response rate in first-line HER2-positive mEG cancer irrespective of PD-L1 status (Janjigian Lancet Oncology 2020). Biomarkers including 89Zr-trastuzumab PET, blood, and tumor analysis were correlated with progression-free survival. Methods: Twenty-five patients received P&T once 3 weeks prior to addition of chemotherapy to P&T. Pre-treatment tumor biopsies, 89Zr-trastuzumab PET scans, serial plasma ctDNA (Guardant360, Redwood City, CA) and CT scans were performed. Tumor-matched DNA alterations were identified by correlating ctDNA and tissue-NGS variant calls. Pre-, on-, and post-treatment biopsies were analyzed using WES and IHC (HER2, PD-L1). Biomarkers were correlated with mPFS and 6-month PFS, the primary endpoint. Results: Of patients with tumor-matched mutations ctDNA at baseline, 12 of 16 had a decline in their maxVAF by week 3, corresponding to a mPFS of 14.7 (11.0-NR) vs 5.9 (95% CI 4.1-NR) months (p=0.009) and a mOS of 29.7 (95% CI 27.2-NR) vs 7.71 (95% CI 6.6-NR) months (p=0.006). 9 of 12 (75%) patients with decline in ctDNA at 3 weeks post-P&T achieved the 6-month PFS primary endpoint while the 4 patients with no decline in ctDNA all progressed in under 6-months. Similarly, 7 of 9 (78%) patients who had a decline in CT-measurements in all disease sites achieved the 6 month PFS primary endpoint, versus 10 of 16 (62.5%) of patients who did not respond in all sites (p=0.66), suggesting that ctDNA is superior to CT as an early predictive biomarker of response. Lack of ERBB2 amplification (amp) by NGS in ctDNA and/or tumor was associated with lack of response to P&T alone prior to addition of chemotherapy. Interestingly, no lesions from patients lacking ERBB2 ctDNA amp (n=3) responded to induction P&T by CT, while lesions from 3/9 patients lacking ERBB2 tissue amp responded to P&T by 3-week CT, suggesting intrapatient HER2 heterogeneity. Eight patients also underwent 89Zr-Trastuzumab PET scans prior to P&T and up to 5 lesions per disease site were measured on serial CT scans. All 15 lesions with intense uptake (SUVmax>10) responded to P&T, but only 9/24 lesions with SUVmax<10. All 4 patients who had at least 1 intense lesion achieved a post-P&T CT response and later 6+ month PFS. All 3 of 3 evaluable patients with intense uptake had baseline ctDNA ERBB2 amp. Conclusions: Patients with a decline in tumor-matched maxVAF after one dose of P&T were more likely to achieve durable PFS. Pre-treatment ctDNA ERBB2 amp and/or intense 89Zr-trastuzumab PET avidity are non-invasive predictive biomarkers of response to HER2-directed therapy. Evaluation of tumor immune environment digital spatial profiling is underway. Clinical trial information: NCT02954536.

Sign in / Sign up

Export Citation Format

Share Document