On April 10, 2021 Guardant Health, Inc. (Nasdaq: GH), along with leading academic institutions and pharmaceutical companies, reported new data at the AACR (Free AACR Whitepaper) Virtual Annual Meeting I, April 10-15, 2021, highlighting the use of the company’s proprietary blood tests to advance precision oncology (Press release, Guardant Health, APR 10, 2021, View Source [SID1234577868]).

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Key findings demonstrate the value of Guardant360, Guardant360 CDx, and GuardantOMNI liquid biopsy tests to detect clinically actionable mutations, inform treatment for patients as their cancer progresses, and reveal tumor evolution and resistance in response to interventional therapies, including immunotherapies.

"At this year’s AACR (Free AACR Whitepaper), we highlight the growing clinical utility of our liquid biopsy tests, from revealing critical genomic and molecular insights that contribute to vitally important drug development efforts, to further informing treatment decisions as patients with advanced disease progress," said Helmy Eltoukhy, Guardant Health CEO. "As we exit the pandemic, the ability to effectively treat advanced cancers that may have remained undetected during the past year will be critical, and there is no room for error or further delays in finding the right treatment or clinical trial. Now more than ever, our liquid biopsies are needed to accelerate the accessibility of effective treatment options for patients most in need of precise clinical therapies."

Guardant360 CDx validated for use with Amgen’s investigational KRASG12C inhibitor, sotorasib

Data from the phase 2 CodeBreaK 100 trial evaluating investigational sotorasib in patients with advanced non-small cell lung cancer (NSCLC) showed the objective response rate was comparable in patients selected using Guardant360 CDx liquid biopsy or tissue biopsy, with high concordance demonstrated between the two assays.

"The study results highlight that the Guardant360 blood-based companion diagnostic test was effective at selecting patients with KRAS G12C who may benefit from treatment with sotorasib, said Darryl Sleep, senior vice president, global medical and chief medical officer, Amgen. "KRAS G12C can only be detected with a biomarker test and with one in eight patients with NSCLC harboring the KRAS G12C mutation, there is a critical need to improve access to high quality diagnostics and more routine screening."

Title

Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC

Abstract No.

CT181

Session

Phase II Clinical Trials

Date / Time

e-Poster Presentation: April 10, 2021, 8:30 AM – 11:59 PM EDT

Guardant360 CDx delivers results at low inputs, which can potentially increase patient samples for clinical decision-making and clinical studies

Study shows Guardant360 CDx provides comprehensive tumor profiling results with robust analytical performance at demonstrated low inputs (5ng cutoff). These data suggest that Guardant360 CDx has the potential to guide therapy decisions for about 34% more patients compared to some liquid biopsies that use 2 blood collection tubes (BCT) for minimal 30ng of cell-free DNA (cfDNA). The data also show that the ability to process samples below 15ng input from a single BCT increases the yield of EGFR driver mutations by >25%. Furthermore, because retrospective studies are often performed with as little as 2mL of plasma, the study shows that the Guardant360 CDx is expected to return valid results on over 88% of such samples, which may be outside the performance specifications for other assays.

Title

The liquid biopsy Guardant360 CDx has robust performance at low inputs allowing for high rate of returning patient results

Abstract No.

572

Session

Liquid Biopsies: Circulating DNA

Date / Time

April 10, 2021, 8:30 AM – 11:59 PM EDT

Studies show Guardant360 provides early indication of treatment response and resistance mechanisms in the management of advanced cancer

Data presented are consistent with prior studies, across various treatments and indications,1-10 showing Guardant360 provides early indication of treatment response and clinical outcomes by measuring molecular response or changes to circulating tumor DNA from baseline at different time-points. In addition, data presented show that Guardant360 can also reveal tumor evolution and resistance in response to interventional therapies, including immunotherapies.

Title

Reversion patterns in homologous recombination repair genes in metastatic cancer patients profiled by cell-free DNA

Abstract No.

25

Session

Biomarkers

Date / Time

MINISYMPOSIUM PRESENTATION
April 10, 2021, 2:20 PM – 2:30 PM EDT

Title

Comparison of molecular response calculations for prediction of patient outcome

Abstract No.

401

Session

Biomarkers Predictive of Therapeutic Benefit

Date / Time

Poster presentation: April 10, 2021, 8:30 AM – 11:59 PM EDT

Other abstracts and poster presentations

Title

Confirmation of Target Inhibition and Anti-Tumor Activity of the SHP2 Inhibitor RMC-4630 via Longitudinal Analysis of ctDNA in RAS-Addicted Tumors in a Phase 1 Clinical Study

Title

A single institution experience with Guardant360 liquid biopsy for therapeutic decision in advanced solid tumors

Title

NTRK1 fusion detection from clinical cfDNA NGS using a de novo fusion caller

Title

Detection of somatic copy number alterations from on-target and off-target sequencing data

On April 10, 2021 Bayer reported Results from the randomized, double-blind, placebo-controlled Phase III trial CHRONOS-3 show a significant improvement in progression-free survival (PFS) with the investigational combination of Aliqopa (copanlisib) and rituximab given intravenously in patients with relapsed indolent non-Hodgkin’s Lymphoma (iNHL) compared to the combination of rituximab and placebo (Press release, Bayer, APR 10, 2021, View Source [SID1234577867]). After a median follow-up of 19.2 months, patients treated with this combination had a median PFS of 21.5 months (95% CI 17.9, 33.0) versus 13.8 months in patients treated with rituximab and placebo (95% CI 10.2, 17.5), (HR=0.52, p=0.000002). No new safety signals were identified for Aliqopa in the combination arm of the study.1 The data will be presented in a Clinical Trials Plenary Session on April 10 at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 and simultaneously published in The Lancet Oncology.

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CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled trial with the objective to evaluate whether Aliqopa in combination with rituximab is superior to placebo plus rituximab in extending PFS in patients with relapsed iNHL following at least one prior rituximab-containing therapy. Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included.2

In 2017, Aliqopa was approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies based on the results of a single-arm, multicenter, Phase II clinical trial (CHRONOS-1).3 Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial.

"In clinical practice, we have seen an overall improvement in the prognosis of iNHL patients, yet relapsed disease is still a prominent treatment challenge," said Matthew J. Matasar, M.D., Medical Oncologist, Regional Care Network Medical Site Director, Memorial Sloan Kettering Cancer Center (MSK) Bergen. "The results reported with the combination of copanlisib and rituximab suggest a potential advancement for patients with these diverse types of cancers."

"Bayer is committed to putting patients’ needs first and delivering innovative treatment options that address areas of high unmet need, and clinical research is the first step in that process," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer. "These data highlight the potential of Aliqopa and rituximab as a new strategy for treating these patients and we look forward to advancing regulatory discussions."

Bayer is in discussions with health authorities worldwide regarding the data from CHRONOS-3.

Additional CHRONOS-3 Data Being Presented at AACR (Free AACR Whitepaper)
In addition to the primary endpoint of PFS, data on the secondary endpoints of ORR and complete response rate (CRR) will also be presented. Best ORR for the combination of Aliqopa and rituximab was 80.8% (95% CI 76, 85) versus 47.7% (95% CI 40, 56) for rituximab and placebo (p<0.0001), with 33.9% and 14.6% of patients achieving CR, respectively. Of the relapsed iNHL patients included in the trial, 60% had FL, 20.7% marginal zone lymphoma (MZL), 10.9% small lymphocytic lymphoma (SLL) and 8.3% lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). Analysis of the subtypes will be presented at AACR (Free AACR Whitepaper) and published in The Lancet Oncology.1

All-grade treatment-emergent adverse events (TEAEs) observed with the Aliqopa and rituximab combination that occurred in more than 20% of the patients included hyperglycemia (69.4%), hypertension (49.2%), diarrhea (33.6%), neutropenia (20.8%), nausea (22.5%) and pyrexia (20.5%). Discontinuation due to all-grade TEAEs in CHRONOS-3 for Aliqopa and rituximab was 32% versus 8% for rituximab and placebo.1

Aliqopa is an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant activity against alpha and delta isoforms the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.4 Aliqopa is approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with relapsed FL who have received at least two prior systemic therapies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Accelerated approval was granted for this indication based on an ORR of 59% (n=61/104; 95% CI 49, 68), including 14% (15/104) of CRs from the open-label, single-arm multicenter, Phase II clinical trial (CHRONOS-1), in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin’s Lymphoma who had relapsed disease following at least two prior treatments. In the updated two-year follow-up analysis conducted on data until 16 weeks after the last patients eligible for full analysis started treatment, Aliqopa ORR was 59% (n=61; 95% CI 49, 68), including 20% CR (n=21).5 Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on ORR was assessed by an Independent Review Committee.

Disclosure: This study was sponsored by Bayer AG. Dr. Matasar has received honoraria from Bayer AG and subsidiaries of Bayer AG for advising and related activities. Bayer AG also provides research funding for Dr. Matasar through Memorial Sloan Kettering Cancer Center (MSK). In addition, Dr. Matasar has received honoraria from Roche/Genentech for advising and related activities, and the company also provides research funding for him through MSK.

About Aliqopa (copanlisib) Injection3
Aliqopa (copanlisib) is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Aliqopa is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Aliqopa has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Aliqopa inhibits several key cell-signaling pathways, including B-cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

IMPORTANT SAFETY INFORMATION FOR ALIQOPA (copanlisib)

Infections: Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection.

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

Hypertension: Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension.

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis.

Neutropenia: Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia.

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.

For important risk and use information about Aliqopa, please see the full Prescribing Information.

About CHRONOS-3
CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Aliqopa in combination with rituximab versus placebo in combination with rituximab in patients with relapsed indolent NHL who have received at least one or more lines of prior rituximab-containing therapy. Histological subtypes included in the trial were follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and marginal zone lymphoma (MZL). Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included (NCT02367040). The study enrolled 458 participants.2

About non-Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma (NHL) comprises a highly heterogeneous group of chronic diseases with poor prognosis. NHL is the most common hematologic malignancy and the eleventh most common cancer worldwide, with nearly 510,000 new cases diagnosed in 2018. It accounted for nearly 249,000 deaths worldwide in 2018.6,7

Indolent NHL consists of multiple subtypes, including follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). While the disease is typically slowly growing, it can become more aggressive over time. Despite treatment advances, there remains a need for improved treatment options for the relapsed or refractory stage of the disease. After response to initial therapy, response rates and duration of response decline with subsequent lines of therapy, underscoring the need for patients whose disease has already progressed.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

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.

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."

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.