MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3004-3004
Author(s):  
Funda Meric-Bernstam ◽  
John Hainsworth ◽  
Ron Bose ◽  
Howard A. Burris III ◽  
Claire Frances Friedman ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Targeted Therapies ◽  
Objective Response ◽  
Tumor Type ◽  
Loading Dose ◽  
Advanced Solid Tumors ◽  
Wild Type ◽  
Her2 Positive ◽  
Molecular Alterations ◽  
Kras Status

3004 Background: HER2 ( ERBB2) amplification and/or overexpression is observed in 2–3% of solid tumors, and is often associated with more aggressive disease. Thus far, HER2-targeted therapies are FDA-approved only for breast, gastric, and gastroesophageal cancers. MyPathway (NCT02091141) is a non-randomized, phase 2a multi-basket study assessing the activity of FDA-approved targeted therapies in non-indicated advanced solid tumors with relevant molecular alterations. We report results from the MyPathway HER2 basket, comprising a large, tissue-agnostic cohort of patients (pts) with HER2-altered tumors treated with P + H. Methods: Pts in this analysis were aged ≥18 years and had HER2-amplified and/or overexpressed tumors. Pts received P (840-mg IV loading dose, then 420-mg every 3 weeks [q3w]) + H (8-mg/kg IV loading dose, then 6-mg/kg q3w). The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Other endpoints included disease control rate (DCR, defined by objective response or stable disease >4 mos) and duration of response (DOR). Subgroup analyses were completed by tumor type and KRAS status. Results: Pts were fully enrolled from April 14, 2014 to June 15, 2020. By January 22, 2021, 260 pts were efficacy-evaluable. Confirmed ORR (cORR) was 23.1% (60/260, including 5 complete responses; 95% confidence interval [CI] 18.1–28.7), DCR was 44.2% (115/260, 95% CI 38.1–50.5), and median DOR was 7.9 mos (95% CI 6.2–9.3). In 199 pts with wild-type KRAS tumors, cORR was 25.6% (51/199, 95% CI 19.7–32.3), DCR was 48.7% (97/199, 95% CI 41.6–55.9), and median DOR was 8.3 mos (95% CI 6.2–10.8). In comparison, in 26 pts with KRAS-mutated tumors, cORR was 3.8% (1/26, responder had colorectal cancer; 95% CI 0.1–19.6), DCR was 3.8% (1/26, 95% CI 0.1–19.6), and DOR was 2.7 mos. KRAS status was unknown in 35/260 pts (cORR 22.9% [8/35, 95% CI 10.4–40.1]; median DOR 6.7 mos [95% CI 2.5–12.7]). Clinical outcomes by tumor type are shown in the Table. Conclusions: P+H was active in a wide variety of KRAS wild-type HER2-amplified/overexpressed tumor types, but had limited activity in KRAS-mutated tumors. Clinical trial information: NCT02091141. [Table: see text]

403 Early results from a phase 1 study to evaluate safety, pharmacokinetics, and efficacy of AMG 404, a programmed death-1 (PD-1) antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A428-A428
Author(s):  
Timothy Price ◽  
Sant Chawla ◽  
Gerald Falchook ◽  
Hans Prenen ◽  
Iwona Lugowska ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
Clear Cell ◽  
Phase 1 ◽  
Cell Cancer ◽  
Objective Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors

BackgroundEnhancement of antitumor immunity through inhibition of the checkpoint PD-1 receptor has been effective in the treatment of many malignancies. AMG 404 is a monoclonal antibody (mAb) targeting PD-1. This phase 1, open-label, multicenter first-in-human study (NCT03853109) will evaluate the safety, tolerability, pharmacokinetics, and efficacy of AMG 404 monotherapy in adult patients with advanced solid tumors.MethodsThe primary study endpoint is dose-limiting toxicity (DLT) and safety; key secondary endpoints include pharmacokinetic parameters, objective response rate (assessed Q8W), duration of response, and progression-free survival. Key inclusion criteria include histologically or cytologically proven metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation for which standard therapies have been exhausted or not available. Prior anti-PD-(L)1 or other checkpoint inhibitors were not allowed. Five dose-finding cohorts, including 2 expansion cohorts, ranged from 3–20 patients each. AMG 404 was given until disease progression, intolerance, or consent withdrawal.ResultsAs of the data cutoff date of May 4, 2020, 62 patients received at least 1 dose of AMG 404 and were included in the safety and efficacy analysis sets. Fifty percent were men, 72% had ECOG 1 performance status, median age was 62 years (range: 28–83), and 42% had ≥3 lines of prior anticancer therapy. Median AMG 404 exposure was ~3 months (maximum: ~12 months). No DLTs were observed. Treatment-related adverse events (TRAEs) were reported for 29 patients (47%): those reported for ≥2 patients were fatigue (n=7); hypothyroidism (n=6); increased blood thyroid stimulating hormone and nausea (n=4 each); increased aspartate aminotransferase, decreased appetite, and pyrexia (n=3 each); and increased alanine aminotransferase, arthralgia, diarrhea, and increased weight (n=2 each). AEs leading to withdrawal of AMG 404 were reported for 3 patients (5%); all were serious and considered to be not related to AMG 404. Sixteen (26%) patients died on study; no deaths were considered related to AMG 404. Preliminary pharmacokinetic results were consistent with those of other therapeutic anti-PD-1 mAbs. Three patients had a confirmed partial response (pancreatic cancer, clear cell cancer, and pleomorphic sarcoma); an additional 4 patients had one scan with a partial response and are pending a confirmatory scan (clear cell renal carcinoma, undifferentiated nasopharyngeal carcinoma, sarcomatoid carcinoma of unknown primary, and colon cancer).ConclusionsAMG 404 is tolerable at the tested doses with no DLTs reported. All observed TRAEs are consistent with other anti-PD-1 therapies. Encouraging anti-tumor activity has been observed in heavily pretreated patients. The study is continuing enrollment into additional cohorts.Trial RegistrationNCT03853109Ethics ApprovalThe study was approved by the Ethics Board of each institution involved in this study and can be produced upon request.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

Suboptimal clinician awareness of appropriate NTRK fusion testing and TRK inhibitor use in solid tumors.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 229-229
Author(s):  
Ryan P. Topping ◽  
Krista Marcello ◽  
Terrence Fagan ◽  
Timothy A. Quill ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Progressive Disease ◽  
Inhibitor Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Educational Activities ◽  
Time Period ◽  
Trk Inhibitors ◽  
Therapeutic Alternatives ◽  
Selection Of

229 Background: Since late 2018, 2 TRK inhibitors—larotrectinib and entrectinib—have been approved by the EMA and FDA for treating patients with advanced solid tumors harboring an NTRK fusion and progressive disease or no therapeutic alternatives. It is recommended that testing for NTRK fusions occur as early as possible after a diagnosis of advanced disease in patients with solid tumors to inform potential use of TRK inhibitors. Methods: Between April 2018 and April 2021, we conducted multiple live and online educational activities for oncology healthcare professionals (HCPs) on NTRK fusion testing and/or TRK inhibitor treatment for varied solid tumors. Each activity included polling questions designed to assess HCP knowledge and practice patterns. In this analysis, we assessed HCP responses to these questions to evaluate awareness of expert recommendations on NTRK fusion testing and the selection of TRK inhibitor therapy for appropriate patients. Results: In 6 live and online activities with data from April 2018 to April 2021, 29% of HCPs (n = 844) indicated that they ordered molecular profiling to test for NTRK fusions in all solid tumors in their current practice. Of note, low rates of testing were reported in TRK inhibitor/ NTRK testing-focused activities throughout this time period, with no significant increase over time. In assessing different patient cases across 8 activities where experts recommended TRK inhibitor therapy as optimal, many HCPs did not select a TRK inhibitor, with considerable variance by tumor type (Table). *For all cases, experts selected larotrectinib and/or entrectinib as optimal treatment. †HCP respondents. GBM, glioblastoma; GI, gastrointestinal; MSI-H, microsatellite instability-high; PD, progressive disease; PTC, papillary thyroid cancer.Conclusions: The rate of broad testing for NTRK fusions across patients with solid tumors remains low, and many HCPs lack awareness of when to consider a TRK inhibitor. Educational activities designed to address these deficiencies would be of clear benefit to HCPs treating patients with advanced solid tumors. A detailed analysis of HCP trends will be presented.[Table: see text]

scholarly journals 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
Elaine Shum ◽  
Matthew Reilley ◽  
Yana Najjar ◽  
Adil Daud ◽  
John Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Checkpoint Blockade ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

scholarly journals Rxdx-101, an Oral Pan-Trk, Ros1, and Alk Inhibitor, in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

2014 ◽  
Vol 25 ◽  
pp. iv148 ◽  
Author(s):  
F.G.M. De Braud ◽  
L. Pilla ◽  
M. Niger ◽  
S. Damian ◽  
B. Bardazza ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Molecular Alterations ◽  
Alk Inhibitor

Alka-372-001: First-in-human, phase I study of entrectinib – an oral pan-trk, ROS1, and ALK inhibitor – in patients with advanced solid tumors with relevant molecular alterations.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 2517-2517 ◽  
Author(s):  
Filippo G. De Braud ◽  
Monica Niger ◽  
Silvia Damian ◽  
Benedetta Bardazza ◽  
Antonia Martinetti ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Advanced Solid Tumors ◽  
Molecular Alterations ◽  
Alk Inhibitor

A phase 1b/2 study of ARRY-382, an oral inhibitor of colony stimulating factor 1 receptor (CSF1R), in combination with pembrolizumab (Pembro) for the treatment of patients (Pts) with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3110-TPS3110 ◽  
Author(s):  
Wael A. Harb ◽  
Melissa Lynne Johnson ◽  
Jonathan Wade Goldman ◽  
Amy M. Weise ◽  
Justin Anthony Call ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Solid Tumors ◽  
Response Rate ◽  
Objective Response ◽  
Human Study ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Part C ◽  
Phase 1B

TPS3110 Background: CSF1, which signals via CSF1R, regulates tumor-associated macrophages and myeloid-derived suppressor cells, both critical drivers of immune escape in the tumor microenvironment. ARRY-382 is a highly selective, oral inhibitor of the CSF1R intracellular tyrosine kinase. The first-in-human study of ARRY-382 monotherapy identified the maximum tolerated dose (MTD) of 400 mg QD, with biologic activity at doses ≥200 mg QD (Bendell JC et al. Mol Cancer Ther. 2013;12:A252). Preclinical data supports combining a PD-1 inhibitor with a CSF1R inhibitor (Zhu Y et al. Cancer Res. 2014;74:5057-69). This study is designed to evaluate ARRY-382 in combination with pembro, a potent and highly selective humanized monoclonal antibody that targets PD-1. Methods: This is an open-label, multicenter, phase 1b/2 study (NCT02880371) to determine the MTD and/or recommended phase 2 dose (RP2D) of ARRY-382 + pembro and to evaluate the activity of the combination in select indications. In phase 1b (Part A), the primary objective is to identify the MTD/RP2D. Up to 18 pts with select advanced solid tumors (Part A) will be enrolled in 2 successive cohorts evaluating ARRY-382 at doses of 200 mg QD and 400 mg QD, respectively, in combination with pembro 2 mg/kg Q3W. Once the MTD/RP2D has been determined in phase 1b, phase 2 will concurrently evaluate the combination in up to 20 pts with advanced unresectable/metastatic melanoma (Part B) and in up to 33 pts with PD-L1-positive (tumor proportion score ≥50) non-small cell lung cancer (NSCLC) (Part C). The primary objective of Part B is to assess the pharmacodynamics and antitumor activity of ARRY-382 + pembro in pts with advanced unresectable/metastatic melanoma, and the endpoints include effects of treatment on circulating growth factors and cytokines, markers of bone resorption, and objective response rate (ORR). The primary objective of Part C is to assess the efficacy of ARRY-382 + pembro in pts with PD-L1–positive NSCLC (Part C). The primary endpoint is ORR. Immune-related response rate and safety will be evaluated in all pts in the study. Clinical trial information: NCT02880371.

Sign in / Sign up

Export Citation Format

Share Document