Abstract P045: LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO and PVSRIPO in combination with anti-PD-1/L1 checkpoint inhibitors in patients with advanced solid tumors

3510 Background: Pyrotinib is a potent, irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the erythroblastic leukemia viral oncogene homolog (erbB) receptors, which has previously demonstrated promising antitumor activity in patients (pts) with breast cancers. We studied the safety and efficacy of pyrotinib in pts with non-small cell lung cancer (NSCLC) and other solid tumors with activating human epidermal growth factor receptor 2 ( HER2, ERBB2) alterations. Methods: This is an open-label, multicenter phase 1 dose expansion basket trial of pyrotinib given 400mg oral daily at 28-day cycles. Expansion cohorts included pts with HER2-mutant NSCLC and advanced solid tumors with HER2 mutation or amplification. HER2 testing was conducted using next generation sequencing or fluorescence in situ hybridization. Primary endpoints included toxicities as evaluated by NCI CTCAE v5.0, and overall response rate (ORR) as evaluated by RECIST v1.1. Secondary objectives included progression-free survival (PFS). Results: A total of 62 pts were enrolled. The median age was 67 (range 40 – 86 years), 61% were female and the median lines of prior systemic therapy was 3 (range 1-11). There were no treatment related deaths. The most common adverse events were diarrhea (96.8%), nausea (82.3%) and vomiting (41.9%). The only ≥ grade 3 treatment related toxicity was diarrhea (24.2%). Prophylactic anti-diarrhea treatment was introduced to facilitate continuation of pyrotinib. At the Jan 13, 2020 cut-off, 24 pts with HER2-mutant NSCLC (20, i.e. 65% of which were the A775_G776insYVMA mutation) and 18 pts with HER2-mutant or amplified solid tumors completed end of Cycle 2 imaging scan and were evaluable for tumor responses. The ORR was 19% (8/42, 95% CI 7-31%); confirmed responses include a complete response (CR) and 3 partial responses (PRs) in HER2-mutant NSCLC, and 4 PRs in HER2-amplified cholangiocarcinoma, ovarian, endometrial and salivary gland carcinomas. There were 7 stable disease ≥ 6 months. Median progression-free survival was 5.4 months (95% CI 4.4-7.3). Conclusions: Pyrotinib demonstrated a manageable safety profile and encouraging efficacy in pts with heavily pre-treated HER2-mutant NSCLC. Furthermore, it is the first TKI to produce durable responses in pts with HER2-amplified biliary tract, ovarian, endometrial and salivary gland cancers. These results warrant further clinical development of pyrotinib. Clinical trial information: NCT02500199 .

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A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3101 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3101-3101

Author(s):

Ying Cheng ◽

Ying Liu ◽

Jinhua Xu ◽

Jing Zhu ◽

Ying Wang ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Solid Tumors ◽

Renal Cancer ◽

Phase I Study ◽

Angiogenesis Inhibitor ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

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Abstract PR09: Phase 1 clinical safety and efficacy of ASN007, a novel oral ERK1/2 inhibitor, in patients with RAS, RAF or MEK mutant advanced solid tumors

10.1158/1535-7163.targ-19-pr09 ◽

2019 ◽

Author(s):

Anthony W. Tolcher ◽

Ryan J. Sullivan ◽

Drew W. Rasco ◽

Zeynep Eroglu ◽

Nehal Lakhani ◽

...

Keyword(s):

Solid Tumors ◽

Phase 1 ◽

Advanced Solid Tumors ◽

Clinical Safety ◽

Safety And Efficacy

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A pilot study of safety and efficacy of pandimex with or without paclitaxel in the treatment of advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.3188 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 3188-3188 ◽

Cited By ~ 2

Author(s):

X. Ouyang ◽

Z. Yu ◽

Z. Chen ◽

F. Xie ◽

W. Fang ◽

...

Keyword(s):

Pilot Study ◽

Solid Tumors ◽

Advanced Solid Tumors ◽

Safety And Efficacy

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High baseline lymphocyte count is a predictive biomarker of prolonged time to progression in patients with advanced solid tumors receiving checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14532 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14532-e14532

Author(s):

Mariangela Maltese ◽

Stefano Panni ◽

Silvia Lazzarelli ◽

Matteo Brighenti ◽

Federica Negri ◽

...

Keyword(s):

Solid Tumors ◽

Lymphocyte Count ◽

Checkpoint Inhibitors ◽

Absolute Lymphocyte Count ◽

Predictive Biomarker ◽

Rank Test ◽

Advanced Solid Tumors ◽

Time To Progression ◽

Neutrophil Lymphocyte Ratio ◽

Kaplan Meier

e14532 Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or > 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC < 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR < 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.

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Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2554 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2554-2554 ◽

Cited By ~ 1

Author(s):

Jermaine Coward ◽

Vinod Ganju ◽

Ramin Behzadigohar ◽

Kenneth Kwong ◽

June Xu ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Human Study ◽

Safety Data ◽

Advanced Solid Tumors ◽

Duration Of Treatment ◽

Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

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Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15068 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15068-e15068

Author(s):

Vaibhav G. Patel ◽

Qian Qin ◽

Bo Wang ◽

Mahalya Gogerly-Moragoda ◽

George Mellgard ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Model Systems ◽

Beta Blockade ◽

Clinical Activity ◽

Tumor Type ◽

Advanced Solid Tumors ◽

Adrenergic Signaling

e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.

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