Single-agent Antitumor Activity Research Articles

Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone acetate (abi)–pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-921.

TPS262 Background: Docetaxel is an established treatment for pts with mCRPC. Pembro, a PD-1 inhibitor, showed single-agent antitumor activity in mCRPC. In the phase 1b/2 KEYNOTE-365 study (NCT02861573), docetaxel + pembro and prednisone showed activity in pts treated with abi or enza for mCRPC, warranting further evaluation. Methods: KEYNOTE-921 (NCT03834506) is a phase 3 trial to evaluate efficacy and safety of pembro + docetaxel and prednisone in chemotherapy-naive pts who progressed with enza or abi therapy for mCRPC. An estimated 1000 pts will be randomly assigned 1:1 to receive docetaxel 75 mg/m2 IV every 3 weeks (Q3W) + prednisone/prednisolone orally 5 mg twice daily (BID) and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID + placebo IV Q3W. Treatment will be stratified by previous next-generation hormone agent (abi or enza) and metastases location (bone only, liver, other). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who progressed with androgen deprivation therapy (or postbilateral orchiectomy) ≤6 months of screening, have ECOG PS 0 or 1, and have adequate organ function are eligible. Pts must have experienced either progression after ≥8 weeks (≥14 weeks for bone progression) or intolerance after ≥4 weeks of abi or enza (but not both) in a chemotherapy-naive mCRPC state. Pts will be required to provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment will continue with docetaxel and prednisone for up to 10 cycles and with pembro for up to 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are rPFS by BICR and OS. Secondary end points are time to initiation of subsequent anticancer therapy or death, PSA response rate, time to PSA progression, ORR and DOR per PCWG3-modified RECIST v1.1 assessed by BICR, and safety. Accrual began May 2, 2019. Clinical trial information: NCT03834506.

HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer.

There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.

Abstract P5-04-19: Sulindac sulfide as a non-immune suppressive gamma secretase modifier to target triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is defined as pathologically negative for estrogen receptor (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 amplification (HER2-). TNBCs are a heterogeneous group of clinically aggressive cancers with high risk of recurrence and metastasis, and current treatment options remain limited. Immunotherapy with checkpoint inhibitors shows promise. However, recent data show that crosstalk between cancer stem cells (CSC) and the immune microenvironment leads to immunotherapy resistance, while myeloid-derived suppressor cells (MDSC) promote CSC survival via Notch signaling. Strong evidence supports the involvement of Notch, a prominent CSC pathway, in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, Including Gamma Secretase Inhibitors (GSIs) are quite effective in preclinical models of TNBC. However the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and adverse immunological effects. We identified Sulindac Sulfide (SS), the active metabolite of FDA-approved NSAID Sulindac, as a potential candidate to replace GSIs. We confirmed that SS has Gamma Secretase Modifier (GSM) activity, in addition to cyclo-oxygenase (COX) inhibition. SS inhibits Notch1 cleavage in TNBC cells, but not in murine T-cells. SS significantly inhibited mammospheres growth in all human and murine TNBC models we tested: 1) human MDA-MB-231 cells; 2) murine TNBC model C0321, from targeted conditional knockout of Lunatic Fringe (LFng-/-); and 3) Two TNBC patient-derived xenograft models, 2K1 and 4IC. In C0321 tumors in mice, we found that SS had remarkable single-agent anti-tumor activity and virtually eliminated Notch1 expression in tumors without intestinal toxicity. SS caused an increase in intra-tumoral CD11c+ dendritic cells and CD8 cells. SS did not affect the numbers of tumor infiltrating macrophages or myeloid-derived suppressor cells (MDSC). However, SS blocked the immunosuppressive function of bone marrow-derived MDSC. RNA-Sequencing of SS-treated tumors revealed significant reduction of CXCL14, EGR1, HOXC6, MAGI2, NCAM1, APOE, CLU (a Wnt target), DTX4 (an E3-ligase positive regulator of Notch activation), and TGFB3 genes and upregulation of CCL17, EPCAM, FABP4, C4A, LTF, ZBTB16, INADL, and FGFR2 genes. Importantly, SS enhanced the antitumor effect of a-PDL1 immunotherapy in our 0321 TNBC mouse model. Our data support further investigation of SS for the treatment of TNBC, with standard of care or with immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be significantly easier and more cost-effective than developing unproven investigational agents. Citation Format: Fokhrul Hossain, Deniz A Ucar, Samarpan Majumder, Margarite Matossian, Giulia Monticone, Keli Xu, Yong Ran, Lisa Minter, Yaguang Xi, Matthew Burow, Todd Golde, Barbara Osborne, Lucio Miele. Sulindac sulfide as a non-immune suppressive gamma secretase modifier to target triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-19.

Abstract PD7-07: Final analysis of phase 1 study of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer

Abstract Background: The majority of patients (pts) with advanced ER+ breast cancer (BC) will experience progression of disease after endocrine therapy (ET) due to acquired resistance, including development of ESR1 mutations (mut). Response to conventional ET agents, including aromatase inhibitors and fulvestrant, in late lines of therapy is poor with overall response rates (ORR) less than 10% and median progression free survival (mPFS) of 2-3 months. Elacestrant is a novel, nonsteroidal, oral SERD with marked antitumor activity documented in multiple in vivo pt derived xenograft models of BC, including those derived from heavily pretreated pts and those with ESR1 mut. Methods: RAD1901-005 is a multi-part phase 1 study of elacestrant with the primary objective to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Secondary objectives are safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Part A was dose escalation with 3+3 design (capsule; doses 200, 400 and 600 mg QD); Part B was safety expansion (capsule); Part C was expansion (tablet); Part D expansion (tablet) was added by amendment to study later line pts including prior CDK4/6 inhibitor (i) use (NCT02338349). Key eligibility criteria: advanced or metastatic (m) ER+, HER2- BC; postmenopausal status. For Parts A-C: ≤2 prior chemotherapy regimens (CT) for mBC and >6 mo ET with progression (PD). For Part D: ≤1 prior CT for mBC, ≥2 prior lines of ET including PD on fulvestrant, and CDK4/6i. We present updated and final results from the trial (all parts). Results: From April 2015 to March 2018, 57 pts were enrolled: Part A: 13, B: 20, C: 14, D: 10 (of 36 planned; enrollment was terminated due to change in regulatory strategy). MTD/RP2D was 400 mg QD. For all pts treated at 400 mg (n=50): stage IV 100%; visceral disease 70%; median prior lines of tx 3 (Part D: 4), including median of 1 prior line of CT and 3 prior lines of ET; prior CDK4/6i 52% (Part D: 100%); prior fulvestrant 50% (Part D: 100%); prior mTORi 26%. At baseline, 51% of pts had detectable ESR1 mut, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q. Among pts treated with 400 mg tablet (n=24), treatment-emergent adverse events in ≥20% were nausea, hypertriglyceridemia, hypophosphatemia, vomiting, dyspepsia, constipation, hypokalemia, fatigue, back pain, myalgia, headache, and urinary tract infection; the majority were grade 1 and 2. There were no treatment-related deaths. 13% of pts discontinued due to AEs. Antitumor activity is summarized in Table 1. There were 6 confirmed partial responses; median duration of response was 24.9 wk; median time to response was 8.2 wk. One pt with ESR1 mut with best response of SD remains on treatment at 3 yr. Conclusion: Elacestrant at the RP2D of 400 mg QD has an acceptable safety profile and demonstrated significant single-agent anti-tumor activity in heavily pretreated (mostly 4th line or greater) ER+, HER2- mBC pts. Activity was seen following prior fulvestrant, prior CDK4/6i, and in pts with ESR1 mut. The ORR of 19.4% and mPFS of 4.5 mo compare favorably with those reported for fulvestrant and AIs given in earlier treatment settings. Elacestrant monotherapy vs. standard of care ET monotherapy is currently being studied in ER+, HER2- mBC with 1 or 2 lines of prior tx including prior CDK4/6i, in the phase 3 “EMERALD” study (NCT03778931). Table 1. Efficacy OutcomesParts A-CPart DOverallORR, % (RECIST-evaluable pts) (n/N)27.3% (6/22)0% (0/9)19.4% (6/31)Clinical Benefit Rate, % (PR+SD ≥24 wk) (n/N)47.4% (18/38)22.2% (2/9)42.6% (20/47)mPFS (95% CI), mo, N=50 (ITT population)5.4 (3.7, 11.2)1.9 (1.8, 8.6)4.5 (1.9, 7.4) Citation Format: Virginia Kaklamani, Aditya Bardia, Sharon Wilks, Amy Weise, Donald Richards, Wael Harb, Cynthia Osborne, Robert Wesolowski, Meghan Karuturi, Paul Conkling, Rebecca Bagley, JungAh Jung, Teeru Bihani, Maureen Conlan, Peter Kabos. Final analysis of phase 1 study of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-07.

CXCR4 inhibition modulates the tumor microenvironment and retards the growth of B16-OVA melanoma and Renca tumors.

To determine whether blockade of the chemokine receptor CXCR4 might alter the tumor microenvironment and inhibit tumor growth, we tested the efficacy of the CXCR4 antagonist X4-136 as a single agent and in combination with various immune checkpoint inhibitors in the syngeneic murine melanoma model B16-OVA. We also tested its activity alone and in combination with axitinib in the renal cancer model Renca. We found that X4-136 exhibited potent single agent antitumor activity in the B16-OVA model that was additive to that of an anti-PDL1 antibody. The antitumor activities were associated with a reduction in the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells and an increase in the number of tumor-specific CD8/perforin cells in the tumor-microenvironment. Apart from these immune effects, X4-136 alone and in combination with checkpoint inhibitors inhibited the Akt/FOXO-3a cell survival pathway in vitro and in vivo, suggesting that it might have antitumor activity independent of its effects on immune cell trafficking. Similar effects on tumor growth and cytotoxic T lymphocytes infiltration were observed in the Renca model. These studies show that the effects of CXCR4 blockade on immune cell trafficking might serve as a useful adjunct to immune checkpoint inhibitors and other therapies in the treatment of cancer.

A Non-Genotoxic Anti-CD117 Antibody Drug Conjugate (ADC) Designed for Patient Conditioning Prior to Stem Cell Transplant and HSC-Based Gene Therapy Has a Broad Therapeutic Window across Species

Current approaches to conditioning prior to transplant and gene therapy employ non-specific genotoxic agents that are associated with severe acute and long-term toxicities. Consequently, many transplant eligible patients either refuse transplant or receive reduced intensity regimens, which still have adverse toxicities with increased risk of relapse and graft failure. Importantly, patients with non-malignant disease may choose to forgo a potentially curative transplant due to risks of conditioning-associated toxicities, potentially limiting access of these patients to transplant and emerging HSC-based gene therapy. Thus, safe and effective targeted conditioning agents would have broad application to transplant in both malignant and non-malignant settings as well as gene therapy. We developed a CD117 antibody conjugated to amanitin (anti-CD117-AM) to specifically deplete hematopoietic stem and progenitor cells (HSPCs) as a novel approach to patient preparation for allogeneic and autologous transplant. ADCs have significant single agent anti-tumor activity in the clinic, however, achieving suitable tolerability at efficacious doses has presented a clinical challenge. We engineered the properties of the anti-CD117-AM to provide a broad therapeutic window across pre-clinical models. Through modification of the linker moiety, the maximum tolerated dose (MTD) of the ADC in C57Bl6 mice was improved 17-fold compared to previous versions. The engineered anti-CD117-AM maintained potent cytotoxicity on primary human CD34+ cells and a CD117+ AML cell line ( 95% of human HSPCs (Fig. 1A). Single doses of the anti-CD117-AM demonstrated robust tumor control in xenograft models of AML, despite its purposefully shortened half-life as a targeted agent for transplant indications (Fig. 1B). The tolerability of the engineered anti-CD117-AM was assessed in cynomolgus NHPs. The ADC was well-tolerated with an MTD at ≥ 2 mg/kg (Fig. 1C). A single dose of the ADC was able to drive marked depletion of HSPCs and downstream progeny. The pharmacokinetics of the ADC exhibited linear clearance supporting tolerability well above target saturation. In summary, optimization of the chemical linker between antibody and payload yielded a well-tolerated ADC with wide safety margins that could eliminate HSPCs and confer survival benefit in AML xenograft models. ADC-mediated conditioning through selective depletion of CD117+ cells may provide an improved approach to patient preparation for transplant in malignant and non-malignant disease including gene therapy, broadening patient access to potentially curative treatments.

The Role of CHK1 Varies with the Status of Oestrogen-receptor and Progesterone-receptor in the Targeted Therapy for Breast Cancer.

Objective: The therapeutic effects of the checkpoint kinase 1 (CHK1)-targeted inhibition in tumor therapy have been confirmed, but how to choose an effective application method in breast cancer with heterogeneous molecular characteristics has remained unclear.Methods: We evaluated the status of CHK1 in breast cancer using the cancer genome atlas database. Chemosensitivity and single-agent antitumor activity of CHK1 inhibition were measured by drug sensitivity assay, cell proliferation assay, cell cycle and apoptosis analysis in breast cancer with different ER/PR status. And based on the conjoint transcriptome atlas analyses, the corresponding mechanism were explored.Results: In ER-/PR-/HER2- breast cancer, CHK1 inhibition enhanced adriamycin (ADR) chemosensitivity which was mediated by the mitotic checkpoint complex (MCC)-anaphase-promoting complex/cyclosome (APC/C)-cyclin B1 axis, Msh homeobox 2 (MSX2) and Bcl-2-like protein 11 (BIM). However, in ER+/PR+/HER2- breast cancer, because of the significant suppression for centromere protein F (CENPF)-mediated transcriptional activation of CHK1 induced by ADR itself, CHK1 inhibition fails to sensitize ADR toxicity. Interestingly, CHK1 inhibition showed the single-agent antitumor activity in ER+/PR+/HER2- breast cancer which was mediated by the cyclin dependent kinase inhibitor 1A (p21), kinesin family member 11 (Eg5) and cell surface death receptor (Fas).Conclusions: CHK1's variable role determines the application of CHK1 inhibition in breast cancer with ER/PR heterogeneity.

Phase I dose-escalation and expansion study of PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors.

ObjectiveFluzoparib (SHR3162) is a novel, potent poly(ADP-ribose) polymerases (PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models. We conducted a phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial in patients with advanced solid cancer.MethodsThis was a 3+3 phase I D-Esc trial with a 3-level D-Ex at 5 hospitals in China. Eligible patients for D-Esc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer (OC). Fluzoparib was administered orally once or twice daily (bid) at 11 dose levels from 10 to 400 mg/d. Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity.ResultsSeventy-nine patients were enrolled from March, 2015 to January, 2018 [OC (47, 59.5%); breast cancer (BC) (16, 20.3%); colorectal cancer (8, 10.1%), other tumors (8, 10.1%)]; 48 patients were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg bid, with a half-life of 9.14 h. Grade 3/4 adverse events included anemia (7.6%) and neutropenia (5.1%). The objective response rate (ORR) was 30% (3/10) in patients with platinum-sensitive OC and 7.7% (1/13) in patients with BC. Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival (mPFS) was 7.2 [95% confidence interval (95% CI), 1.8−9.3] months in OC, 9.3 (95% CI, 7.2−9.3) months in platinum-sensitive OC, and 3.5 (range, 2.0−28.0) months in BC. In patients with germline BC susceptibility gene mutation (gBRCAMut) (11/43 OC; 2/16 BC), mPFS was 8.9 months for OC (range, 1.0−23.2; 95% CI, 1.0−16.8) and 14 and 28 months for BC (those two patients both also had somaticBRCAMut). ConclusionsThe MTD of fluzoparib was 150 mg bid in advanced solid malignancies. Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCAMut and platinum-sensitive OC.

Abstract B011: Synergistic activity of tazemetostat in combination with androgen signaling inhibitors in preclinical models of prostate cancer demonstrates potential for clinical expansion

Abstract Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. Current available treatments include chemical castration and therapies targeting androgen receptor (AR) signaling pathways. Although initial responses are observed, 30% of patients have primary resistance to both forms of treatment and the majority of patients progress from androgen-dependent PCa (ADPC) to castration-resistant PCa (CRPC). Studies on mechanisms of resistance suggest that AR signaling remains a key driver in PCa even after treatment with AR-targeted therapies. Co-treatment with therapies that modulate alternative signaling pathways involved in oncogenesis in PCa including epigenetic modifiers, have been proposed as a modality to overcome resistance. Enhancer of Zeste Homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 and is one of the most highly upregulated genes in CRPC compared to localized PCa. Several reports suggest that EZH2 plays an oncogenic role both in ADPC and CRPC.Tazemetostat is a potent, selective, orally bioavailable, investigative first-in-class small molecule inhibitor of EZH2. Phase 2 clinical trials have demonstrated objective clinical responses in patients with B-cell lymphomas and molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors. Given the implication of EZH2 in PCa, we explored the combination potential of tazemetostat with current second-line therapies, the androgen signaling inhibitors (ASIs) abiraterone and enzalutamide. Tazemetostat displayed both time- and dose-dependent antiproliferative activity in PCa cell lines dependent on AR signaling or those of the neuroendocrine subtype with IC50 values at or below 1 μM in 14-day assays. Synergistic activity was observed in vitro in a subset of cell lines when tazemetostast was combined with ASIs in a 7-day co-treatment model and this activity was further enhanced when cells were pretreated with tazemetostat prior to the cotreatment. To further validate these findings, we conducted in vivo studies in PCa cell line-derived xenograft models. Tazemetostat and enzalutamide showed single agent antitumor activity in a subcutaneous LNCaP xenograft mouse model. Co-administration of enzalutamide and tazemetostat markedly reduced tumor growth rate compared to either of the single agent(s). Similar results were observed with the combination of tazemetostat and abiraterone. Interestingly in the 22Rv1-derived in vivo xenograft model, a cell line that expresses AR-V7, a splice variant implicated in resistance to ASIs in CRPC, modest tumor growth inhibition was observed with tazemetostat and no significant antitumor activity was observed when given in combination with abiraterone or enzalutamide. A significant decrease in intratumoral H3K27me3 levels were observed in all treatment groups containing tazemetostat in both in vivo models, indicating an on-target activity of EZH2 inhibition. Current efforts are underway to investigate the mechanism of action and cellular inhibitory pathways for these combinations. In summary, our preclinical data demonstrates the importance of EZH2 inhibition in CRPC and provides a rationale for combination of tazemetostat with abiraterone and enzalutamide in the clinic. Citation Format: Vinny Motwani, Dorothy Brach, Chloe Pantano, Vania Estanek, Jeffrey A. Keats, Daniel T. Dransfield, Alejandra Raimondi. Synergistic activity of tazemetostat in combination with androgen signaling inhibitors in preclinical models of prostate cancer demonstrates potential for clinical expansion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B011. doi:10.1158/1535-7163.TARG-19-B011

Abstract B100: AO-176, a highly differentiated humanized anti-CD47 antibody, exhibits single-agent and combination antitumor efficacy with chemotherapy and targeted antibodies

Abstract Purpose of study: To determine whether AO-176, a highly differentiated, humanized antibody targeting CD47, shows efficacy alone or in combination with a variety of approved anti-cancer drugs in solid tumors. Methods: We investigated AO-176 as a single agent and in combination with chemotherapies and targeted antibodies, utilizing standard in vitro phagocytosis assays, tumor cell killing assays, and in vivo xenograft models. Results: AO-176 is a highly-differentiated anti-CD47 antibody that not only blocks the CD47/SIRPα interaction to stimulate phagocytosis of tumor cells, but also exerts direct killing activity on tumor cells (non-ADCC), induces immunogenic cell death, and exhibits preferential binding to tumor cells compared to normal cells. In addition, tumor-specific CD47 binding by AO-176 increases in the acidic tumor microenvironment. As a single agent, AO-176 induced cell killing (14-52% Annexin V positivity, EC50 = 1-30 μg/ml) and phagocytosis (10-34%, EC50 = 0.8-3.3 μg/ml) in ovarian, gastric, non-small cell lung, head and neck, colorectal, thyroid, pancreatic and endometrial solid tumor cell lines. When combined with tumor-targeted antibodies (i.e. cetuximab against head and neck and colorectal cancer cell lines, or the checkpoint inhibitor avelumab against ovarian cancer cell lines), AO-176 significantly enhanced phagocytosis of the tumor cells in vitro. In combination with the chemotherapeutics paclitaxel and cisplatin, AO-176 also potentiated direct tumor killing of gastric cancer cells in vitro. In vivo, AO-176 showed potent single-agent anti-tumor activity against ovarian and gastric tumor xenografts. These data add to the previous pre-clinical anti-tumor activity of AO-176 reported in breast cancer, multiple myeloma, and non-Hodgkin’s lymphoma xenografts. When cisplatin or paclitaxel was added to the AO-176 treatment regimen against xenografted ovarian tumors in vivo, significant combination anti-tumor activity was observed. We then sought to extend our promising in-vitro findings from combining AO-176 with a checkpoint inhibitor to in-vivo models. As AO-176 is human CD47-specific, we utilized an in-house murine reactive anti-CD47 blocking antibody and combined it with a murine-reactive anti-PDL1 antibody to treat MC38 murine tumors established in syngeneic mice. Combination of the two antibodies significantly improved anti-tumor efficacy compared to either single agent. Conclusions: AO-176 has demonstrated broad in vitro phagocytosis/killing as well as in vivo efficacy that supports its development, both as a single agent and in combination with other anti-cancer drugs. With a highly differentiated mechanism of action and binding profile, AO-176 may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Citation Format: Casey Wilson, Myriam Bouchlaka, Robyn Puro, Ben Capoccia, Ronald Hiebsch, Prabir Chakraborty, Michael Donio, Vicki Sung, Daniel Pereira. AO-176, a highly differentiated humanized anti-CD47 antibody, exhibits single-agent and combination antitumor efficacy with chemotherapy and targeted antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B100. doi:10.1158/1535-7163.TARG-19-B100

The Ribosomal Biogenesis Inhibitor CX-5461 Is an Anti-Cancer Therapeutic That Increases Platelet Count in Mice and in Humans

Background: The ribosomal biogenesis inhibitor CX-5461 is a first-in-class selective inhibitor of ribosomal RNA gene transcription with single-agent antitumor activity against advanced hematologic cancers and synergistic activity when combined with front-line and emerging agents (Devlin et al. 2015, Sornkom et al. 2018, Maclachlan et al. 2018). It has predictable pharmacokinetics and a safety profile allowing prolonged dosing (Khot et al, Cancer Discov 2019). Unexpectedly, CX-5461 treatment increases platelet count by ~50% in tumour diseased mice; an effect that was maintained for up to 6 months of treatment. Aims: We investigated mechanisms that may contribute to increased platelet counts following CX-5461 treatment in a liver carcinoma mouse model or disease-free mice and evaluated blood test data from patients with haematological malignancies treated with CX-5461. Methods: We evaluated blood cell numbers in blood from vehicle- or CX-5461 treated mice with liver carcinoma, and blood cell numbers, bone marrow megakaryocytes, platelet receptors, immature platelets, platelet function, thrombopoietin (TPO) and inflammatory cytokine levels in disease-free C57BL/6 KaLwRij mice treated with 35 mg/kg CX-5461 or vehicle (n=15). Human platelet receptors and function were assessed in CX-5461-treated platelet-rich plasma by flow cytometry, platelet spreading assays and light transmission aggregometry. We evaluated temporal platelet count, and the platelet activation marker soluble glycoprotein (GP) VI in patient plasma samples who had received a single dose of 25-250 mg/m2 CX-5461 (n=16) with 1-way ANOVA. Results: In a model of liver carcinoma, mice with disease displayed significantly elevated (2.3-fold) platelet counts after 3 months treatment with biweekly injections of 35 mg/kg CX-5461 compared with vehicle-treated diseased mice (p = 0.0013). Disease-free mice treated for 7 or 14 days (3 or 6 x 35 mg/kg doses) with CX-5461 showed ~60% increase in platelet count; in comparison white and red cells were mildly suppressed. The CX-5461-mediated platelet increase at d7 (p<0.0005) was reversible within 1 week. At d14 (p<0.01, 1.7-fold increase in platelet count) a significant increase in megakaryocytes (p<0.05) and immature platelets (p<0.01) was observed. CX-5461 treatment had no effect on plasma TPO, platelet lifespan or platelet GPVI or GPIbα levels. Integrin αIIb was significantly elevated. Inflammatory cytokines interleukin (IL)-6 (p<0.05) and TNFα (p<0.01) increased at d7 in plasma. After pre-treatment for 30 min with CX-5461 ex vivo, human platelet function (aggregation and platelet spreading on collagen and fibrinogen) and receptor levels were normal. In 8/16 patients receiving CX-5461, increases of up to 34% in platelet counts were measured at day 15 of CX-5461 treatment, with no change in sGPVI. Conclusions: CX-5461 treatment of mice for two weeks increased platelet counts, megakaryocyte number and immature platelet fraction by an unknown mechanism however IL-6 has been reported by others to enhance megakaryopoeisis. Brief CX-5461 treatment in a group of patients with advanced haematological malignancy resulted in small increases in platelet count with retained platelet activation and treatment ex-vivo demonstrated platelet function to be unaffected. Future work will explore the link between CX-5461 treatment and megakaryopoiesis and thrombopoiesis, including the potential for CX-5461 to ameliorate drug-induced thrombocytopenia. Disclosures Harrison: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hannan:Pimera: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase IIa, Open-Label, Multicenter Study of Single-Agent Tafasitamab (MOR208), an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma: Long-Term Follow-up, Final Analysis

A Phase IIa, Open-Label, Multicenter Study of Single-Agent Tafasitamab (MOR208), an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma: Long-Term Follow-up, Final Analysis

Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma

Introduction: Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human study (ADCT-402-101), Lonca demonstrated single agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK), a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. BTK plays a crucial role in B-cell-receptor signaling, resulting in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. In vitro data show synergy between the two compounds, providing the rationale for studying them in combination. Study Design and Methods: This is a Phase 1b (ADCT-402-103; NCT03684694), open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with ibrutinib in patients with R/R DLBCL or MCL. The key inclusion and exclusion criteria for this study are reported in Table 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of this combination. Patients will receive Lonca once every 3 weeks for a total of 2 doses, and ibrutinib daily for up to 1 year. Patients with a partial response or stable disease at the second disease evaluation may receive 2 additional doses of lonca. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design. The dose of ibrutinib will be fixed. Part 2 will consist of up to 2 expansion cohorts, one for each of the DLBCL and MCL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of ibrutinib. The trial opened in February 2019 and recruitment is ongoing. Study sponsored by ADC Therapeutics SA, with the support of Pharmacyclics LLC, an AbbVie company, which supplies ibrutinib (http://clinicaltrials.gov/show/NCT03684694). Disclosures Ungar: ADC Therapeutics: Employment, Other: Stock options;equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Interim Futility Analysis of a Phase 2 Study of Loncastuximab Tesirine, a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Interim Futility Analysis of a Phase 2 Study of Loncastuximab Tesirine, a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma

Introduction: Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody (Ab) conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human ADCT-402-101 clinical study, Lonca demonstrated single-agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Durvalumab is a human monoclonal Ab of the immunoglobulin G-1 kappa subclass that blocks the interaction of programmed death-ligand 1 (PD-L1) with PD-1 on T-cells and with CD80 (B7.1) on other immune cells. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. Preclinical data, as well as early results from clinical trials combining ADCs and checkpoint inhibitors, show potentially increased effectiveness of these therapeutics when used in combination and provide the rationale for the current trial. Study Design and Methods: This is a Phase 1b, open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with durvalumab in patients with R/R DLBCL, MCL, or FL (NCT03685344). The key inclusion and exclusion criteria for the ADCT-402-104 study are reported in Table 1, and the dosing schema is presented in Figure 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of Lonca combined with durvalumab. Patients will receive Lonca once every 3 weeks for 2 doses in total, and durvalumab every 4 weeks for up to 1 year. Patients with only partial response or stable disease at the second disease evaluation may receive 2 additional doses of Lonca given once every 3 weeks. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design with a fixed dose of durvalumab. Part 2 will consist of up to 3 expansion cohorts, one for each of the DLBCL, MCL, and FL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of durvalumab. The trial opened in February 2019 and recruitment is ongoing. Study sponsored by ADC Therapeutics SA with the support of MedImmune Limited, a wholly-owned subsidiary of AstraZeneca Pharmaceuticals PLC, which supplies durvalumab (http://clinicaltrials.gov/show/NCT03685344). Disclosures Moskowitz: ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options.

First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983.

HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of Fc\u03b3R-binding functionality

BackgroundGlucocorticoid-induced TNFR-related protein (TNFRSF18, GITR, CD357), expressed by T cells, and its ligand (TNFSF18, GITRL), expressed by myeloid populations, provide co-stimulatory signals that boost T cell activity. Due to the important role that GITR plays in regulating immune functions, agonistic stimulation of GITR is a promising therapeutic concept. Multiple strategies to induce GITR signaling have been investigated. The limited clinical efficacy of antibody-based GITR agonists results from structural and functional characteristics of antibodies that are unsuitable for stimulating the well-defined trimeric members of the TNFRSF.MethodsTo overcome limitations of antibody-based TNFRSF agonists, we have developed HERA-GITRL, a fully human hexavalent TNF receptor agonist (HERA) targeting GITR and mimicking the natural signaling concept. HERA-GITRL is composed of a trivalent but single-chain GITRL-receptor-binding-domain (scGITRL-RBD) unit fused to an IgG1 derived silenced Fc-domain serving as dimerization scaffold. A specific mouse surrogate, mmHERA-GITRL, was also generated to examine in vivo activity in respective mouse tumor models.ResultsFor functional characterization of HERA-GITRL in vitro, human immune cells were isolated from healthy-donor blood and stimulated with anti-CD3 antibody in the presence of HERA-GITRL. Consistently, HERA-GITRL increased the activity of T cells, including proliferation and differentiation, even in the presence of regulatory T cells.In line with these findings, mmHERA-GITRL enhanced antigen-specific clonal expansion of both CD4+ (OT-II) and CD8+ (OT-I) T cells in vivo while having no effect on non-specific T cells. In addition, mmHERA-GITRL showed single-agent anti-tumor activity in two subcutaneous syngeneic colon cancer models (CT26wt and MC38-CEA). Importantly, this activity is independent of its FcγR-binding functionality, as both mmHERA-GITRL with a functional Fc- and a silenced Fc-domain showed similar tumor growth inhibition.Finally, in a direct in vitro comparison to a bivalent clinical benchmark anti-GITR antibody and a trivalent GITRL, only the hexavalent HERA-GITRL showed full biological activity independent of additional crosslinking.ConclusionIn this manuscript, we describe the development of HERA-GITRL, a true GITR agonist with a clearly defined mechanism of action. By clustering six receptor chains in a spatially well-defined manner, HERA-GITRL induces potent agonistic activity without being dependent on additional FcγR-mediated crosslinking.

Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress.

DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and CDKN2A/B deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G1 cells leading to G1 arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis. In vivo xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need. SIGNIFICANCE: ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.

Abstract 2060: Combination of CD20 targeted engineered toxin body, MT-3724, with chemotherapy or IMiDs for the treatment of non Hodgkin's lymphoma

Abstract MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1 (SLTA) ribosome inactivating protein. Engineered Toxin Bodies (ETBs) are unique as they can induce internalization after binding to non- or poorly-internalizing receptors with subsequent enzymatic and permanent ribosome destruction through SLTA, representing a novel mechanism of direct cell-kill in oncology. MT-3724 has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory (R/R) Non-Hodgkin’s lymphoma NHL patients in a Phase I clinical study. Specifically, in R/R diffuse large B cell lymphoma (DLBCL) patients who had low pre-existing serum levels of rituximab, an objective response rate (ORR) of 30% (3 of 10) and disease control rate of 70% (7 of 10) has been observed thus far (NCT02361346). Given the unique ribosomal inhibition mechanism of action for MT-3724, we hypothesized that combination of MT-3724 with agents possessing a differentiated mechanism of action could result in additive or synergistic cellular cytotoxicity in CD20 positive NHL cell lines. Preclinical studies were conducted to assess MT-3724 in combination with cytotoxic chemotherapeutic agents (doxorubicin, gemcitabine, bendamustine, and vincristine) or an immunomodulatory (IMiD) agent (lenalidomide) on selected NHL cell lines. The combination of MT-3724 with all agents demonstrated additive or synergistic cytotoxicity of NHL cell lines. The single agent clinical activity of MT-3724 in heavily pre-treated R/R NHL patients along with this preclinical combinatorial effect of MT-3724 with chemotherapy and IMiDs used in the treatment of R/R NHL have lead the opening of a Phase 2a study of MT-3724 in combination with Gemcitabine and oxaliplatin (GEMOX, NCT03488251) and another planned Phase 2a study of MT-3724 in combination with lenalidomide (NCT03645395). MT-3724 has demonstrated good tolerability and early signs of clinical activity as monotherapy in patients with R/R NHL along with additive and/or synergistic effects in combination with chemotherapy and IMiDs preclinically. Additional clinical studies to evaluate MT-3724 as single agent and in combination with GEMOX or lenalidomide are underway. Citation Format: Jack P. Higgins, Aimee Iberg, Caleigh Howard, Erin Willert. Combination of CD20 targeted engineered toxin body, MT-3724, with chemotherapy or IMiDs for the treatment of non Hodgkin's lymphoma [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 2060.

Abstract 1210: Targeting the IDO1-Kynurenine-AhR pathway for cancer immunotherapy

Abstract The aryl hydrocarbon receptor (AhR) is a ligand-controlled transcription factor that is primarily known to be a sensor of xenobiotics and tumor-promoting activities of halogenated hydrocarbons and polycyclic aromatic hydrocarbons. Several endogenous ligands such as metabolites produced by commensal microorganisms on skin and in gut and metabolites of L-Tryptophan - produced under control of the Tryptophan dioxygenases IDO1 and TDO2 such as L-Kynurenine and Kynurenic acid are known to modulate the transcriptional activity of AhR. The activity of AhR is predominant in many different immune and epithelial cells, thereby balancing immune responses towards various signals. Activation of the IDO1-Kyn-AhR pathway and accumulation of nuclear AhR protein is frequently seen in different tumor types and possibly linked to the observed diminished anti-tumor immune response. AhR agonizing ligands produced by cancer cells and/or lymphocytes recruited to the TME reduce the anti-tumor immune response through increasing the numbers and function of regulatory T cells while reducing that of cytotoxic CD8+ T cells. In order to reduce AhR-mediated immune-suppression in cancer patients, Phenex Pharmaceuticals initiated a program to identify small molecule AhR antagonists to block activated downstream signaling of AhR. To this end, we have identified novel AhR antagonists, which showed strong antagonistic activity against agonist-activated human AhR in a cell based CYP1A1 promoter-driven luciferase reporter assay in HepG2 cells. The compound series display good oral bioavailability and low clearance in mice. Our AhR antagonist molecules show single agent anti-tumor activity and increase the efficacy of Gemcitabine and anti-PD-L1 checkpoint inhibition in different syngeneic mouse tumor models. Overall, AhR antagonist treatment increased CD8+ T cell and M1 macrophage numbers, and decreased IL22 levels, which might be of functional relevance in the tumor context. Future research is directed to determine PK-PD markers suitable for clinical development and identification of human malignancies likely of responding to AhR antagonist treatment. Citation Format: Sheena Pinto, Christoph Steeneck, Michael Albers, Simon Anderhub, Manfred Birkel, Larisa Buselic-Wölfel, Gisela Eisenhardt, Claus Kremoser, Thomas Hoffmann, Ulrich Deuschle. Targeting the IDO1-Kynurenine-AhR pathway for cancer immunotherapy [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 1210.