Arcus Biosciences Presents Updated Data for Etrumadenant in Third-Line Metastatic Colorectal Cancer and New Data on its HIF-2α Program at the AACR 2021 Annual Meeting

On April 10, 2021 Arcus Biosciences, Inc. (NYSE:RCUS), an oncology-focused biopharmaceutical company working to create best-in-class cancer therapies, today presented progression-free survival (PFS) and overall survival (OS) data in patients with advanced metastatic colorectal cancer (mCRC) from the ARC-3 study at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Arcus Biosciences, APR 10, 2021, View Source [SID1234577866]). ARC-3 was a Phase 1/1b, multicenter, open-label, dose-escalation and dose-expansion study that evaluated the safety, tolerability, PK and early clinical activity of etrumadenant, the first dual adenosine A2a/A2b receptor antagonist in the clinic, in subjects with mCRC.

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Additionally, Arcus presented details of its Hypoxia-Inducible Factor 2α (HIF-2α) research program, including the design of a novel series of HIF-2α inhibitors, which has resulted in the identification of molecules such as AB521, with excellent potency, selectivity, biological activity and pharmacokinetic properties suitable for further development.

ARC-3: Updated Results of Etrumadenant (AB928) + mFOLFOX-6 in Patients with Metastatic Colorectal Cancer

Initial results from ARC-3 demonstrated that etrumadenant + modified FOLFOX-6 (mFOLFOX-6) in patients with mCRC was well tolerated and associated with a substantial disease control rate (DCR) across all lines of therapy, including in patients with microsatellite stable disease and RAS/BRAF-mutated mCRC1,2.

Updated data from the 3L+ cohort (median of 3 and a range of 2 to 7 prior lines), in which 87% of the patients had received prior FOLFOX, demonstrated the following:

Safety Results (n=23 safety-evaluable 3L+ patients as of the DCO of Feb. 26, 2021)
Etrumadenant + mFOLFOX-6 was well tolerated, and etrumadenant, at the evaluated doses of 75mg and 150mg once daily (QD), did not appear to add significant toxicity to that expected for mFOLFOX-6.
No grade 3 or above neuropathy events were observed in this heavily pretreated population.
The most common treatment emergent adverse events (TEAEs) for the etrumadement- mFOLFOX-3 combination were fatigue (70%), thrombocytopenia (57%), diarrhea (52%) and nausea (52%).
Efficacy Results (n=22 efficacy-evaluable 3L+ patients as of the DCO of Feb. 26, 2021)
Median progression-free survival (PFS) of 4.2 months. Reported data for current standard-of-care (SOC) therapies have shown a median PFS of 2.0 and 1.9 months for trifluridine-tipiracil and regorafenib, respectively3,4.
Median overall survival (OS) of 13.6 months. Reported data for trifluridine-tipiracil and regorafenib have shown a median OS of 7.1 and 6.4 months, respectively3,4.
Objective response rate (ORR) of 9.1% and an encouraging 8-week DCR of 86%. Reported data for trifluridine-tipiracil and regorafenib have shown ORRs of 1.6% and 1%, respectively 3,4.
Patients with higher tumor mutation burden and intra-tumoral expression of CD73 demonstrated improved outcomes compared to patients with lower levels of these biomarkers, consistent with previous findings1, which may be reflective of an etrumadenant-mediated effect.
"Based on these very encouraging early results, we have advanced etrumadenant into ARC-9, a randomized Phase 2 platform study to evaluate this first-in-class molecule in combination with zimberelimab, our anti-PD-1 antibody, and FOLFOX +/- bevacizumab in second- and third-line mCRC," said Bill Grossman, M.D., Ph.D., Chief Medical Officer of Arcus. "The results presented today, combined with our recent promising early data evaluating AB680, our small-molecule CD73 inhibitor, in pancreatic cancer, support an expanding rationale for targeting the ATP-adenosine axis to meet critical unmet needs in gastrointestinal cancers."

"Few options exist today to treat third-line colorectal cancer, and these therapies are associated with significant toxicity and limited efficacy. While this was an early-stage study, etrumadenant’s efficacy in this difficult-to-treat patient population was impressive, particularly the doubling of progression-free and overall survival that was observed relative to what has been reported for current standard-of-care therapies," said Michael Cecchini, MD, Assistant Professor of Medicine (Medical Oncology), Yale Cancer Center and Smilow Cancer Hospital. "Importantly, etrumadenant also added very little toxicity, enabling patients to remain on treatment for extended periods of time. I look forward to working with Arcus to advance etrumadenant, and Arcus’s other ATP-adenosine axis-targeting agents, into later-stage studies for gastrointestinal cancers in order to broaden access to these innovative potential therapies."

Preliminary data from ARC-9, a global follow-on study to ARC-3, are expected to be presented in the first half of 2022. For additional information on this trial, please visit NCT04660812, at www.clinicaltrials.gov.

Discovery and Characterization of AB521, a Novel, Potent, and Selective HIF-2 α Inhibitor

Preclinical and clinical evidence indicate that HIF-2α inhibition is a validated approach for the treatment of clear cell renal cell carcinoma (ccRCC) and tumors associated with mutant/deficient Von Hippel-Lindau (VHL). Arcus has developed a broad research program to identify drug candidates against this target. Despite the inherent difficulties in identifying drug-like inhibitors of HIF-2α, Arcus scientists have generated highly optimized inhibitors, including AB521, which exhibit high potency, selectivity and biological activity, as well as a favorable pharmacokinetic profile in preclinical species, that we expect will facilitate achieving optimal plasma levels of drug in the clinic.

We expect to initiate clinical development for our lead HIF-2α inhibitor in the second half of 2021 and plan to combine this molecule with other product candidates from our pipeline, including our first-in-class adenosine axis-targeting agents.

Additional information about these presentations may be found on the Arcus website at Arcus Publications.

About Etrumadenant

Etrumadenant (AB928), the first dual A2a/A2b adenosine receptor antagonist in the clinic, is designed to maximally inhibit the adenosine-driven impairment of tumor-infiltrating lymphocytes (mainly CD8+ T cells and NK cells) and myeloid cells (dendritic cells, macrophages), mediated by A2aR and A2bR, respectively. A2bR is also upregulated by certain cancer cells, such as in prostate cancer and KRAS- mutated cancers. As a result, etrumadenant may uniquely block adenosine’s immunosuppressive and cancer cell-intrinsic effects. Developed specifically for the oncology setting, etrumadenant achieves high penetration of tumor tissue, robust potency in the presence of high adenosine concentrations, and minimal shift in potency from non-specific protein binding. Etrumadenant has demonstrated a favorable safety profile with a variety of combination regimens and exhibits pharmacokinetics / pharmacodynamics consistent with once-daily dosing. AB928 is currently being evaluated in several Phase 1b/2 studies across multiple indications.

Biodesix Releases New Data at AACR on Proteomic Profiling to Help Guide Physician Treatment Strategies for NSCLC Patients

On April 10, 2021 Biodesix, Inc. (Nasdaq: BDSX), a leading data-driven diagnostic solutions company with a focus in lung disease, reported that three abstracts from multiple clinical studies will be showcased at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held virtually April 10-15, 2021 and May 17-21, 2021 (Press release, Biodesix, APR 10, 2021, View Source [SID1234577865]). Findings from these studies address the utility of physicians using blood-based proteomic testing as an approach to interpret each patient’s immune response to cancer, which can help guide treatment decisions.

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Abstract #520: Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer

An abstract authored by Young Kwang Chae, MD, MPH, MBA of Northwestern University Feinberg School of Medicine, with lead author Dr. Myungwood Nam, reports data from a study on the Primary Immune Response (PIR) test. PIR is a serum-based proteomic classifier that, in this case, was used to study the correlation between immunotherapy and the development of immune-related adverse events (irAEs) in patients with non-small cell lung cancer (NSCLC). Following a baseline PIR test, patients were categorized as sensitive or not sensitive to immunotherapy treatment, then monitored for irAEs after the start of immunotherapy. The study found that patients who had been categorized as sensitive were more likely to tolerate immunotherapy without developing irAEs. The abstract concludes that the PIR test may be able to predict the development of irAEs, and identify patients who should be monitored more closely during treatment with immunotherapy. The data will be available for viewing at 4:30 p.m. ET on April 10 and poster sessions will be available at 8:30 a.m. ET on April 10.

Abstract #673: The role of mass spectrometry-based serum proteomics signatures in predicting clinical outcomes in cancer patients treated with immune check point inhibitors (ICI)

A second abstract, also authored by Dr. Chae, presents an analysis of a recent study using PIR to predict patient responses to ICI therapy. The study found the PIR test was able to reliably stratify patients into groups based on their expected prognosis. This information can be used by physicians to help guide their frontline ICI treatment decisions for patients with NSCLC who are identified as not sensitive to immunotherapy treatment and may benefit from more aggressive treatment. This data will become available at 4:30 p.m. ET on April 10 and poster sessions will be available at 8:30 a.m. ET on April 10.

Abstract #662: Longitudinal blood-based proteomic testing in advanced non-small cell lung cancer

An abstract authored by Eric Schaefer, MD, of Highlands Oncology Group, demonstrates that the VeriStrat blood-based immune profiling test is capable of monitoring changes in disease state and patient immune response for patients with advanced NSCLC. The INSIGHT observational study (NCT03289780) found that the VeriStrat test was able to group patients according to their disease state and then monitor changes in disease state in response to treatment at 6- and 12-month follow-ups. This result suggests that longitudinal immune profile testing may be a viable option in monitoring such changes, and that the resulting data can be used to help guide treatment strategy. The data will become available for viewing at 4:30 p.m. ET on April 10.

"Our aim is to help patients access the most targeted treatment possible by providing physicians with timely, actionable data, that will assist their treatment decisions," said Scott Hutton, CEO of Biodesix. "By continuing to invest in and increase our understanding of patient immune response, we can equip physicians with critical information to help them determine the best treatment strategy for patients with NSCLC."

Xencor Presents Data from Multiple Preclinical XmAb® Bispecific Antibody and Cytokine Programs at the AACR Annual Meeting 2021

On April 10, 2021 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported the presentation of new data from multiple preclinical XmAb bispecific antibody programs and its preclinical IL-12-Fc cytokine program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held virtually April 10-15, 2021 (Press release, Xencor, APR 10, 2021, View Source [SID1234577864]).

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"Xencor’s XmAb bispecific Fc domains enable the rapid design and simplified development of Fc-containing protein structures and are being used to create new platforms, a wide range of multi-specific antibodies and engineered cytokines. At AACR (Free AACR Whitepaper), we are presenting emerging preclinical data from early-stage programs that highlight the potential of our CD28 platform and XmAb 2+1 bispecific antibody format, as well as our more advanced IL-12 cytokine, which builds off our prior work with IL-15 and IL-2," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "In 2021, we anticipate submitting an IND for XmAb819, our lead XmAb 2+1 CD3 bispecific antibody targeting ENPP3, and initiating a Phase 1 study in early 2022. We are also advancing through preclinical development our wholly owned lead CD28 candidate, a B7-H3 x CD28 bispecific antibody designed to be evaluated for the treatment of patients with a range of solid tumors."

Poster presentations will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

XmAb Engineered Cytokine Platform

Abstract 1743, "IL12 heterodimeric Fc-fusions engineered for reduced potency exhibit strong anti-tumor activity and improved therapeutic index compared to native IL12 agents"
IL-12 is a potent proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. As a potent immune stimulating protein, IL-12 can have a significant effect on shrinking tumors; however, prior clinical studies have demonstrated it to have a narrow therapeutic window, limiting potential response rates.

Xencor’s IL-12-Fc cytokine program builds on the Company’s prior work with IL-15-Fc cytokines in oncology, where reduced potency led to improved pharmacokinetics, pharmacodynamics and tolerability in preclinical studies. IL-12-Fc fusions were engineered with reduced potency in order to improve potential tolerability, slow receptor-mediated clearance and prolong the molecules’ half-lives, compared to native IL-12. The potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity in vivo concurrent with activation and proliferation of CD8+ T cells and increased levels of interferon gamma in serum. In non-human primates, the engineered cytokines had an improved pharmacokinetic profile and therapeutic window compared to a native cytokine-Fc fusion, with superior exposure, a more gradual dose response and similar levels of cytokine production in serum.

XmAb CD28 Bispecific Antibody Platform

T cells in the tumor microenvironment require both T cell receptor (TCR) and co-stimulatory receptor engagement to achieve full activation. CD28 is a key immune co-stimulatory receptor on T cells; however, the ligands that activate T cells through CD28 are usually not expressed on tumor cells. Targeted CD28 bispecific antibodies, a new class of T cell engager, may provide conditional co-stimulation of T cells, for example, to T cells recognizing neoantigens or in concert with CD3 T-cell engaging bispecific antibodies.

Abstract: 1880, "PDL1-targeted CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors"
Xencor engineered PD-L1 x CD28 bispecific antibodies to provide conditional co-stimulation of T cells, activating them when bound to tumor cells. PD-L1, which is expressed on many types of tumors, suppresses anti-tumor responses by the immune system and has been shown to directly inhibit CD28 co-stimulation. A PD-L1 x CD28 bispecific antibody, therefore, may promote CD28 co-stimulation and simultaneously block CD28’s suppression by PD-L1.

In vitro, the combination of the PD-L1 x CD28 and a CD3 T cell engager enhanced T cell activation and proliferation compared to the CD3 bispecific alone, as designed. PD-L1 x CD28 also enhanced the interaction between T cells and antigen presenting cells and exhibited strong CD28-dependent anti-tumor activity in mice. PD-L1 x CD28 was well tolerated in non-human primates and exhibited favorable pharmacokinetics.

XmAb 2+1 Bispecific Antibody Format

Xencor’s XmAb 2+1 bispecific antibodies are a type of CD3 T cell engager, with two tumor binding domains and one CD3 binding domain. The affinities for tumor binding are tuned, allowing for selective killing of high antigen-expressing tumor cells, potentially sparing low antigen-expressing normal cells. The XmAb 2+1 format may be especially beneficial when developing bispecific antibodies that target solid tumors, where tumor-associated antigens are often expressed on a range of normal tissues, including critical organs.

Abstract: 1860, "Bispecific claudin-6 x CD3 antibodies in a 2+1 format demonstrate selectivity and activity on human ovarian cancer cells"
Claudin-6 (CLDN6) is a tumor-associated antigen overexpressed in ovarian cancer and other solid tumors, and its differential expression in cancerous tissue makes CLDN6 an intriguing target for CD3 bispecific antibodies. Many members of the claudin family, which are small transmembrane proteins, have high sequence identity, which complicates selectivity among claudins. CLDN6 x CD3 bispecific antibodies were engineered in the XmAb 2+1 format, and the tumor binding domain was further engineered for improved selectivity of CLDN6 over similar claudin family members, such as CLDN9. In preclinical models, CLDN6 x CD3 bound more preferentially to tumor cells compared to cell lines with normal tissue CLDN9 expression levels. Lead candidates demonstrated reversal of tumor growth in human-cell engrafted mouse models of ovarian cancer. Further data from non-human primate studies demonstrated the candidates were well-tolerated with favorable pharmacokinetic profiles.

Abstract: 1831, "Affinity tuned XmAb 2+1 GPC3 x CD3 bispecific antibodies demonstrate selective activity in liver cancer models"
GPC3 is an antigen associated with hepatocellular carcinoma, squamous cell carcinoma of the lung and other cancers. Under certain conditions, GPC3 can trigger Wnt signaling and promote tumor proliferation. Despite a favorable expression profile, unfavorable tolerability has been reported from multiple clinical studies evaluating CAR-T therapy and T cell engaging bispecific antibodies that target GPC3. GPC3 x CD3 bispecific antibodies in the XmAb 2+1 format selectively recruited T cells to kill high GPC3-expressing cancer cells and avoided cytotoxicity to a low GP3C-expressing cell line. A comparison of GPC3 x CD3 bispecific antibodies with the XmAb 2+1 format and first-generation T cell engagers demonstrated similar anti-tumor activity and immune cell proliferation in vitro.

Freenome Presents Data Revealing Signatures of Immune Checkpoint Inhibitor Treatment Response Found to Be Common Across Kidney, Melanoma, and Lung Cancers

On April 10, 2021 Freenome, a privately held biotechnology company that has pioneered a comprehensive multiomics platform for early cancer detection using a routine blood draw, reported results of an analysis revealing the potential to use its platform for patient stratification and monitoring (Press release, Freenome, APR 10, 2021, View Source [SID1234577863]). Plasma samples from patients with kidney (n=21), melanoma (n=14) or non-small cell lung cancer (n=91) revealed signatures of immune checkpoint inhibition treatment response found to be common across all three cancer types. Whole-genome cell-free DNA (cfDNA) sequencing identified 13 transcription factors and 269 genes that reveal a potential pathway of treatment resistance and a possible epithelial mesenchymal transition signature in responders. A subsequent longitudinal analysis on a subset of lung cancer patients also identified markers for treatment response.

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"These results show the promise of our multiomics platform, which combines signatures from both tumor- and non-tumor-derived sources," commented Mike Nolan, Chief Business Officer of Freenome. "A blood-based test that can predict and monitor treatment response would help address the clear need for improved biomarkers for cancer patients undergoing immune checkpoint inhibitor treatment, where responses are highly variable."

"This work further demonstrates the many applications of our multiomics platform, and highlights our commitment to understanding the full potential of cfDNA," commented C. Jimmy Lin, M.D., Ph.D., M.H.S., Chief Scientific Officer at Freenome. "Inferring nucleosome positioning through cfDNA is yet another way we can provide more insight to answer research questions and, ultimately, apply this to clinical questions that are integral to patient care."

Data were presented in a poster presentation at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The poster is available online at View Source

Synthekine Presents Data at AACR Annual Meeting 2021 Demonstrating Selective IL-2 Partial Agonist, STK-012, Promotes Anti-Tumor Response without Related Toxicities

On April 10, 2021 Synthekine Inc., an engineered cytokine therapeutics company, reported preclinical data presented at the American Association of Cancer Research Annual Meeting 2021 demonstrating its alpha/beta selective IL-2 partial agonist, STK-012, induced potent anti-tumor activity while avoiding the toxicities that have hindered the development of IL-2 therapeutics, including vascular leak syndrome (VLS) (Press release, Synthekine, APR 10, 2021, View Source [SID1234577862]). Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001).

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"IL-2 offers a wealth of therapeutic promises and challenges. While wild-type IL-2 is a potent T-cell stimulator and has shown single agent activity in late-stage cancers, its broad and non-specific activation leads to critical, dose-limiting toxicities," said Martin Oft, M.D., chief development officer at Synthekine. "We believe that the efficacy of IL-2 is driven by the proliferation and activation of antigen activated T cells, while the toxicity of IL-2 is driven by its broad and non-specific proliferation, extravasation, and activation of all lymphocytes, including NK cells and naïve T cells. We have designed our alpha/beta IL-2 to selectively bias towards antigen activated T-cells and avoid NK cells and naïve T cells, a new approach designed to improve on both the efficacy and the toxicity of wild-type IL-2. STK-012 demonstrates improved therapeutic index compared to wild-type IL-2 and a non-alpha comparator. We look forward to advancing this program to an IND filing in 2021."

Efficacy of STK-012 was evaluated in multiple mouse models using a mouse surrogate of STK-012 (alpha/beta IL-2). In these studies, the alpha/beta IL-2 achieved superior efficacy in control of tumor growth and rate of complete responses compared to both wild-type IL-2 and a non-alpha IL-2. Synthekine’s alpha/beta IL-2 was significantly more effective than these comparators at increasing intratumoral CD8+ T-cells, including the ratio of CD8 T cells to Tregs. Importantly, studies showed the alpha/beta IL-2 did not induce lethality or VLS at therapeutic or supratherapeutic doses. Both wild-type and non-alpha IL-2 showed vascular toxicity, including VLS and lethality in mice. This finding was also supported by data from non-human primates, with the comparators resulting in significantly more infiltration of inflammatory cells in the lung relative to STK-012.

Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001). New analyses further demonstrate STK-009 upregulates markers for expansion and activation of SYNCAR-001 cells in a CAR refractory lymphoma model and confers a gene signature indicative of long-term memory T cell development.