Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with ...differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone.
ASTRA (ClinicalTrials.gov identifier: NCT01843062) is an international, phase III, randomized, placebo-controlled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland T4 disease; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes any size) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29-31, recombinant human thyroid-stimulating hormone (0.9 mg)-stimulated RAI (
I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population.
Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 67%; placebo, n = 78 33%). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 40%; placebo n = 30 38%; odds ratio 1.07 95% CI, 0.61 to 1.87;
= .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 7%). No treatment-related deaths were reported.
Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype-tailored drug selection and maintaining drug dosing to optimize RAI efficacy.
Abstract
Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor ...approved for HER2+ metastatic breast and gastric cancer. Clinically, T-DXd has demonstrated antitumor activity in both HER2+ and HER2-low cancers. PARP performs a key role as a mediator in the resolution of topoisomerase1 cleavage complexes (TOP1cc) through recruitment of tyrosyl-DNA phosphodiesterase 1 (TDP1). We hypothesized that combination of T-DXd with the PARP1/2 inhibitor olaparib, will halt the resolution of TOP1cc and enhance the activity of T-DXd. Methods: To test the hypothesis, we evaluated the antiproliferative ability of the combination of T-DXd with olaparib in a panel of 27 breast cancer cell lines in an in vitro 7-day viability assay. The combination was also evaluated in vivo in two non-HRD models, a HER2+ (KPL4) and HER2-low (JIMT1) cell line xenograft at 3mg/kg and 10mg/kg Q3W for T-DXd, as well as 100mg/kg BID of olaparib. To evaluate the specificity of the combination activity in tumor cells (vs normal tissue), we further evaluated the combination in a human 2D in vitro bone marrow progenitor assay. Results: We found that the combination had enhanced in vitro cell killing activity over single agents in 8/27 of the models tested. The benefit was present in both Homologous Repair Deficient (HRD) as well as wild-type models, suggesting it does not depend on HRD (as defined by mutations in DNA damage repair genes). In vivo, the combination was more active than monotherapy of either compound in both KPL4 (28d TGI of 76% with T-DXd, olaparib 17% TGI, and T-DXd + olaparib 94.4% TGI; p=0.009) and JIMT1 (28d TGI of 80.8% with T-DXd, olaparib 52%, and T-DXd + Olaparib 88.1%; p=0.03). In the in vitro human bone marrow assay, the combination demonstrated modest enhancement over monotherapy activity (average Loewe Synergy Score of 2.5). To explore the ability to optimize therapeutic index, we tested alternative doses and schedules of the combination in vivo. Specifically, we tested whether lower doses of T-DXd or delayed administration of olaparib would provide greater activity. We found that combination of 3mg/kg of T-DXd with olaparib provided greater activity in KPL4 xenograft model than 3mg/kg T-DXd alone (69% TGI for combination vs. 35% TGI for monotherapy on d28), but this was no greater than high dose 10mg/kg monotherapy T-DXd (76% TGI on d28; p=0.19). Interestingly, 7-day delay of olaparib in combination with 10mg/kg T-DXd provided greater activity (91% TGI on d28) than monotherapy T-DXd or olaparib alone (76% TGI and 17% TGI on d28, respectively). Conclusions: These results suggest that T-DXd combined with olaparib is a potentially active combination in breast cancer, with preclinical activity demonstrated in HRD and non-HRD models.
Citation Format: Theresa Proia, Yann Wallez, Azadeh Cheraghchi Bashi, Zena Wilson, Suzanne Randle, Mark Anderton, Danielle Carroll, Zeshaan Rasheed, J. Elizabeth Pease, Elisabetta Leo, Jerome Mettetal. Activity and tolerability of combination of trastuzumab deruxtecan with olaparib in preclinical HER2+ and HER2-low breast cancer models abstract. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-18.
Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian ...species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has a modification at the fusion protein (F) cleavage site to reduce the efficiency of F protein cleavage and an insertion of a 198-nucleotide sequence into the HN-L intergenic region, resulting in reduced viral gene expression and replication in avian cells but not in mammalian cells. In mammalian cells, except for viral polymerase (L) gene expression, viral gene expression is not negatively impacted or increased by the HN-L intergenic insertion. Furthermore, the virus can be engineered to express a foreign gene while still retaining the ability to grow to high titers in cell culture. The recombinant NDV selectively replicates in and kills tumor cells and is able to drive potent tumor growth inhibition following intratumoral or intravenous administration in a mouse tumor model. The candidate is well positioned for clinical development as an oncolytic virus.
Avian paramyxovirus type 1, NDV, has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step toward moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide without impacting viral production in cell culture. The selective tumor replication of this recombinant NDV, both in vitro and in vivo, along with efficient tumor cell killing makes it an attractive oncolytic virus candidate that may provide clinical benefit to patients.
Abstract
About 15% of breast cancers are HER2 over-expressing (HER2 IHC 3+ or IHC 2+/ISH+)), but another 45% have low levels of HER2 (HER2 IHC 2+/ISH- or IHC 1+), and these patients are not currently ...approved for treatment with trastuzumab. Recently, a new HER2 ADC, DS-8201 showed anti-tumor activity, not only in patients with HER2 over-expressing breast cancer but also in HER2 low expressing tumors in whom to date, there are no effective anti-HER2 therapies indicated. FDA-approved HER2 in vitro diagnostic tests have recognized several limitations including effects of pre-analytical variable (fixation affects antibody sensitivity), limited dynamic range of chromogen-based IHC, and subjectivity in interpretation of the HER2 score. Additionally, the cut-off values (percentage of cells to be positive) defining HER2 positive have been changing over time. Therefore, more accurate, sensitive, precise and objective assays to better identify patients who may benefit from anti-Her2 treatment therapies (e.g DS-8201) are needed. To address this gap, we evaluated upcoming technologies targeted MS and QRT-PCR and aim to compare expression with current diagnostic HER2 tests in FFPE samples
Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified proteins from formalin-fixed, paraffin-embedded tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by IHC (n=107). HER2 protein concentration measured by SRM-MS was compared between patients in different HER2 IHC classifications using an ANOVA, adjusting for multiple comparisons.
HER2 concentration (measured by SRM-MS) was progressively increased according to HER2 IHC grouping (i.e. lowest concentration in HER2 0 samples, highest in HER2 3+ samples). HER2 levels were significantly elevated in 2+ vs. 0 (2.2-fold increase, p < 0.05) samples, and trended higher in 2+ vs. 1+ (1.6-fold increase, p = 0.07) and in 1+ vs. 0 (1.4-fold increase, p = 0.17) samples. About 73% of samples scored as IHC0 had detectable Her2 by SRM-MS (from 168 to 623 amol/µg). Among HER2 IHC 0 samples, ~15% (7/47) had HER2 concentrations above the median levels for the 1+ group. Similarly, 19% (3/16) 1+ samples had HER2 levels above the median for the 2+ group. About 20% of samples co-expressed either ERBB1 and/or ERBB3. Simultaneously from FFPE sections we quantified protein level of payload response and resistance markers (MDR, MRP1, Topo1 and SLFN11).
We used an objective multiplex non-antibody-based method to quantify multiple targets from FFPE tissue. SRM-MS revealed a range of HER2 expression over 100 orders of magnitude and identify markers of payload response or resistance in the same assay. The differences seen in payload markers expression could affect therapeutic efficacy and may suggest differing responses to Her2-targeted ADC, depending on tumor biology. Multiplexed quantitative MS could be used to accurately predict which patients will derive the most benefit from Her2-ADC therapy based on the specific biology of their tumor. These studies are ongoing.
Citation Format: Fabiola Cecchi, Mark Gustavson, Danielle Carroll, Sriram Sridhar, Steven Coats, Anuja Bhalkikar, Sheeno Thyparambil, Wei-Li Liao, Todd Hembrough. Quantitative mass spectrometry of HER2 protein levels reveals high variability within HER2 IHC grades abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5128.
449
Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for treatment of HER2-positive GC/gastroesophageal junction adenocarcinoma (GEJA) after chemotherapy ...(Japan) and for advanced/metastatic GC/GEJA after a trastuzumab-containing regimen (US/Israel/Singapore). Conventional HER2 immunohistochemistry (IHC) scoring identifies potential responders to trastuzumab but may not be suitable for next-generation ADCs capable of bystander killing, such as T-DXd Modi NEJM 2022. Use of computational pathology–based tools enables precise and accurate quantification of HER2 expression and spatial analysis, which enables design of better scores to reflect the T-DXd mechanism of action. Methods: Quantitative continuous scoring (QCS) was performed to quantify HER2 expression and distribution per cell in digitized images of HER2-stained (IHC, Ventana 4B5) GC. A QCS-derived signature was identified, called the continuous spatial proximity score (cSPS), which considers spatial location of tumor cells in addition to HER2 expression level and can be used as a surrogate for potential bystander activity. We retrospectively stratified patients in DESTINY-Gastric01 (DG-01; NCT03329690; T-DXd arm: n=123
a
; standard of care SOC arm: n=59
a
) using cSPS to give a binary QCS biomarker positive (BM+) or negative (BM−) status. QCS cSPS signature was independently validated on the DESTINY-Gastric02 cohort (DG-02; NCT04014075; n=71
a
). Results: In the DG-01 cohort, enrolled per HER2-positive status by IHC using ASCO/CAP GC scoring guidelines, median progression-free survival (mPFS) was 5.5
a
mo with T-DXd and 2.8
a
mo with SOC. QCS-derived cSPS scores showed significant survival benefit for BM+ vs BM− in the DG-01 T-DXd arm ( P<0.0001; HR=0.37 0.24-0.58) and longer mPFS for BM+ (8.3 mo) vs BM− (3.9 mo). Within the SOC arm, this signature showed the inverse prognosis ( P=0.034; HR=2.17 1.06-4.44; mPFS, 2.8 mo for BM+ vs 4.9 mo for BM−), strongly suggesting the signature is predictive of T-DXd response. This signature was validated in the DG-02 cohort (mPFS, 5.5 mo on enrollment by IHC status, 10.1 mo for BM+ vs 3.7 mo for BM−; HR=0.24 0.13-0.45; P<0.0001). Conclusions: We established QCS, a novel scoring method for tissue biomarkers. Our validated data and results support possible future use of this quantitative approach against manual scoring for identification of patients with GC who may benefit from T-DXd therapy. Clinical trial information: NCT03329690 , NCT04014075 . Table: see text
Abstract
Background AZD9833 is a next-generation oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown anti-tumor efficacy in a range of pre-clinical xenograft models of ...breast cancer. The first-in-human study, assessing AZD9833 as a monotherapy and in combination with palbociclib (SERENA-1; NCT03616587), established a dose-dependent safety profile with clinical benefit and target engagement in pre- and post-menopausal women at all dose levels. Here, we describe the design of SERENA-2, a Phase 2 randomized, open-label trial of three different doses of AZD9833 versus fulvestrant. Methods SERENA-2 is a global comparative study of three different doses of AZD9833 versus fulvestrant in post-menopausal women with advanced ER+, HER2− breast cancer with disease recurrence or progression after ≥1 endocrine therapy. The study will evaluate the efficacy and safety of AZD9833 monotherapy once daily at three dose levels, versus fulvestrant monotherapy administered according to its label. Eligible patients will have received no prior fulvestrant or other oral SERD, and no more than one endocrine therapy and one chemotherapy in the advanced setting. Prior treatment with CDK4/6 inhibitors is permitted. Patients will be randomized 1:1:1:1 to one of four treatment groups: AZD9833 75 mg, 150 mg, 300 mg, or fulvestrant. The primary objective of the study is to determine the clinical efficacy of AZD9833 as assessed by progression-free survival, compared with fulvestrant. Secondary objectives include objective response rate, duration of response, percentage change in tumor size at 16 weeks, clinical benefit rate at 24 weeks, and overall survival. Pharmacokinetics, pharmacodynamic biomarker changes from baseline, and effects of AZD9833 and fulvestrant on patients’ health-related quality of life will also be assessed. Exploratory endpoints include predictive markers of response and/or acquired resistance to AZD9833 and fulvestrant, including circulating tumor DNA mutation profiling and dynamics, circulating tumor cell enumeration, and analysis of tumor samples. Patient enrollment commenced in Q2 2020, with a target enrollment of 288 patients across approximately 100 sites in up to 17 countries. Efficacy analyses will compare each dose of AZD9833 with fulvestrant. Sample size was calculated to provide 80% power for the primary endpoint. The primary analysis will use a Cox proportional hazards model stratified by prior use of CDK4/6 inhibitors and presence of lung and/or liver metastases to compare progression-free survival in each dose of AZD9833 versus fulvestrant. Another randomized, open-label, parallel-group, pre-surgical study investigating the biological effects of AZD9833 in ER+, HER2− primary breast cancer (SERENA-3) is also ongoing. For more information please contact Dr Mafalda Oliveira at: moliveira@vhio.net.
Citation Format: Mafalda Oliveira, Maxine Bennett, Ali Khalil, Richard Mather, Rhiannon Maudsley, Sam McGuinness, Christopher J Morrow, Andy Sykes, Li Zhang, Teresa Klinowska, Justin PO Lindemann, Danielle Carroll. A randomized, open-label, parallel-group, multicenter phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2) abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-02.
Abstract
MEDI5395 is a genetically modified attenuated Newcastle disease virus (NDV). A reverse genetic system has overcome environmental and regulatory concerns by uncoupling oncolytic potency from ...avian pathogenicity. MEDI5395 has the intrinsic ability to infect and kill tumor cells and has been inserted with a GM-CSF transgene to potentiate a stronger adaptive immune response. Described here is an extensive in vitro and in vivo pharmacology package that reveals the broad oncolytic activity and immune-modulatory properties of MEDI5395 in a variety of pre-clinical models.
In vitro, MEDI5395 lytic activity in human tumor cells is associated with elevated levels of tumor selective viral replication and expression of the GM-CSF transgene. MEDI5395 infection of immune cells indicated preferential uptake of virus and subsequent self-limiting replication in myeloid cells. Infected myeloid cells expressed cell surface activation markers (e.g. PD-L1) after 24 hours and were effective carriers of virus and mediated the transfer of infectious NDV particles to tumor cells resulting in death through oncolysis. Further mechanistic studies, indicated NDV-killed tumor cells released antigens that were capable of cross-presentation by dendritic cells driving activation of tumor antigen-specific autologous T cells.
In murine models, IV delivery of NDV leads to long lasting tumor selective replication and transgene expression. MEDI5395 administration results in significant anti-tumor activity, observed in patient-derived xenograft models, and in murine syngeneic cancer models. Together, the results suggest that MEDI5395 may act to positively transform the tumor microenvironment. This, coupled to its tumor-selective oncolytic capacity, further underscore NDV as a promising multimodal cancer therapeutic platform and why FTIH studies are planned to start in 2019.
Citation Format: James A. Harper, Shannon Burke, Andrew Leinster, Nicola Rath, Xing Cheng, Hong Jin, Robert W. Wilkinson, Danielle Carroll. MEDI5395: A recombinant oncolytic virus with oncolytic and immune modulatory properties abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1456.
Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER
breast cancer, but it has administration and pharmacokinetic limitations. ...Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER
HER2
primary breast cancer awaiting curative intent surgery.
Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.
Forty-six women received treatment (AZD9496
= 22; fulvestrant
= 24); 35 paired biopsies were evaluable (AZD9496
= 15; fulvestrant
= 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (
= 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%,
= 0.97; Ki-67: -75.4%,
= 0.98). No new safety findings were identified.
This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
Abstract
Background
T-DXd (Enhertu®) is an FDA-approved antibody-drug conjugate (ADC) targeting HER2. T-DXd has shown anti-tumor activity, not only in patients with HER2-overexpressing (IHC3+/2+ ...ISH+) breast cancer (BC) but also in patients with BC with low HER2 expression (IHC1+/2+ ISH−). Current HER2 protein expression assessment is based on manual pathologist scoring that classifies tumors by the percentage of tumor cells with highest intensity and completeness of staining. A critical need exists for more objective and quantitative methods to assess HER2 expression, specifically to better identify patients with low-level expression if T-DXd proves to be efficacious in this patient population.
Methods
We used deep learning (DL)-based image analysis (IA) to generate a novel HER2 Quantitative Continuous Score (QCS). Data analytic techniques determined optimal HER2 QCS for the J101 trial (NCT02564900) of 151 patients with varying HER2 expression levels (1+, 2+, 3+). HER2 QCS consists of DL models to detect membrane, cytoplasm, and nuclei of all tumor cells. QCS was extensively trained using pathologists’ annotations, and the performance was validated on unseen data to ensure its generalization and robustness. QCS was blindly applied to J101 data. The optical density (OD; level of brown stain intensity) was computed on detected membrane to derive features that could be linked to survival prediction. QCS features were selected to maximize ORR in positive group, minimize ORR in negative group maintaining while high prevalence in the positive group.
Results
Analytical validation showed high correlation between QCS from automatically detected membranes and QCS from those annotated by pathologists (R=0.993). This is in the same range as correlation between three pathologists (R=0.995). HER2 QCS was largely consistent with pathologist HER2 scoring as well but showed broad quantitative overlap between IHC and ISH categories. HER2 QCS showed a direct linear relationship between ORR and increased HER2 expression across the entire assay range. In the HER2-low population (n = 65), for whom HER2-targeting therapies are not currently approved, 42% of patients responded to T-DXd, with a median PFS (mPFS) of 11 mo. Using HER2 QCS, we were able to further stratify this population into a subgroup of QCS-high patients (above a staining intensity cut-off determined by IA), with response and mPFS increased to 53% (95% CI: 36%-68%) and 14.5 mo (95% CI: 10.9 mo-NR) respectively, while the QCS-low group only showed ORR of 24% (95% CI: 9%-45%) and mPFS of 8.6 mo (95% CI: 4.2 mo-NR). Generally, best-performing QCS cutoffs were driven by most tumor cells expressing a minimal amount of HER2, in contrast to current clinical guidelines that are driven by a minority of cells expressing higher levels of HER2. We also examined spatial heterogeneity by characterizing cells as either bearing membrane stain above a determined OD threshold (positive cell) or lying within certain distances from a positive cell. We observed similar efficacy with best performing-cutoffs, again, being found when a minimal level of HER2 expression (OD) was examined.
Conclusions
Taken together, these data establish a first proof-of-concept demonstrating that use of HER2 QCS can potentially enhance prediction of patient outcome with T-DXd by increasing sensitivity and specificity of response, especially in the HER2-low population. The ability to identify patients in the HER2-low group who could benefit from T-DXd is critical for its use in a patient population with a high unmet need that would otherwise not be treated with anti-HER2 therapy. Further clinical verification and validation is ongoing.
Citation Format: Mark Gustavson, Susanne Haneder, Andreas Spitzmueller, Ansh Kapil, Katrin Schneider, Fabiola Cecchi, Sriram Sridhar, Guenter Schmidt, Sotirios Lakis, Regina Teichert, Anatoliy Shumilov, Ana Hidalgo-Sastre, Magdalena Wienken, Hadassah Sade, J. Carl Barrett, Danielle Carroll. Novel approach to HER2 quantification: Digital pathology coupled with AI-based image and data analysis delivers objective and quantitative HER2 expression analysis for enrichment of responders to trastuzumab deruxtecan (T-DXd; DS-8201), specifically in HER2-low patients abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-01.
Abstract
Objectives: PI3Kγ inhibition re-polarizes macrophages to an immuno-stimulatory phenotype, thereby activating a T-cell mediated tumor immune response. AZD3458 is a highly selective PI3Kγ ...inhibitor. Administration of AZD3458 in combination with checkpoint inhibitors such as α-PD-(L)1 antibodies had greater anti-tumor effects (TGI 26-86%) than checkpoint inhibitor alone in 4T1, LLC, CT-26 and MC-38 syngeneic mouse models. In these, AZD3458 remodeled the tumor microenvironment (TME), reducing immunosuppressive markers (e.g in 4T1 model there was a 20% decrease in total macrophages and 50% decrease in markers of immune suppression like CD206 by flow cytometry) and promoting cytotoxic T-cell activation (e.g. in CT-26 model there was a 2-fold increase in gzmB mRNA). We developed a predictive quantitative systems pharmacology (QSP) model, to quantitatively simulate TME effects and delineate mechanistic principles underlying AZD3458 and α-PD-(L)1 synergistic effects.
Methods: The QSP model captures mechanistic, molecular and cellular interactions between PI3Kγ inhibition and checkpoint inhibitors, together with the pharmacokinetics acting on the respective targets. Features such as PI3Kγ inhibition-dependent tumor-associated macrophages, protein expression of immunosuppressive markers, reduction of MDSC activation and promotion of cytotoxic T-cell activation were included in the model. These immuno-changes were then linked to tumor cell death, resulting in macroscopic dynamic effects on tumor size. Some model parameters were taken from the literature and internal studies; some were estimated using NLME modeling of tumor size data.
Results: The model adequately described individual and population tumor size patterns. Inter-animal variability was described using a random effect on a parameter related to the ability of T cells to infiltrate the tumor in response to systemic antigen. Additionally, the model incorporated in one quantitative framework data from 4 syngeneic tumors capturing respective changes in TME conditions. Simulations for the various treatments supported the mechanistic interpretation of the observed AZD3458 and α-PD-(L)1 synergistic effects. The model was further used to simulate treatment scenarios, to infer optimal dosing and scheduling for the combination and given underlying TME conditions.
Conclusions: This study provides quantitative mechanistic insights into the links between PI3Kγ inhibition and anti-tumor immune responses, supporting our understanding of how AZD3458 may alleviate brakes in a myeloid immuno-suppressive TME and revert resistance to immunotherapy. This mechanistic understanding is critical when proceeding with dose escalation in an early clinical trial setting, as it allows to contextualize any potential compound-induced immuno-modulation in patients, for given doses and schedules.
Citation Format: Pablo Morentin Gutierrez, Yuri Kosinsky, Kirill Peskov, Ivan Azarov, Lulu Chu, Veronika Voronova, Martin Johnson, Yingxue Chen, Larissa Carnevalli, Danielle Carroll, Michele Moschetta, Teresa Klinowska, Gabriel Helmlinger. Mechanistic insights and dose optimization for AZD3458, a novel selective PI3Kg immuno-modulator, using a quantitative systems approach abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 104.
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