On May 28, 2021 ECOG-ACRIN Cancer Research Group reported that New research results for patients with breast and HPV-associated throat cancers are the highlights among 23 presentations at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, occurring virtually June 4-8 (Press release, ECOG-ACRIN, MAY 28, 2021, View Source [SID1234583289]). The National Cancer Institute (NCI), part of the National Institutes of Health, funded these studies.

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Breast Cancer
Platinum chemotherapy fails in phase III trial for triple-negative breast cancer, basal-like subtype

Abstract 605: About 80% of triple-negative breast cancers (TNBC) are a subtype called ‘basal-like.’ Typically, patients with TNBC receive chemotherapy before surgery to shrink the tumor(s). The presence of residual cancer in the breast after chemotherapy signals a higher likelihood that the cancer will return after surgery. A previous clinical trial demonstrated that additional capecitabine chemotherapy after surgery helps decrease the chance of recurrence. Yet, although capecitabine helps, researchers do not know whether treatment with different chemotherapy drugs could have the same or better results than capecitabine. Other research showed that basal-like TNBCs are more sensitive to platinum chemotherapies that damage DNA.

This abstract presents data from study EA1131, a randomized phase III clinical trial conducted to assess whether platinum chemotherapy would be as effective or more effective than capecitabine (NCT02445391). The study was for patients in a very high-risk group: those who had basal-like triple-negative breast cancer that was still present after initial chemotherapy. Patients were randomly assigned to one of two treatment groups after receiving standard chemotherapy and surgery. The first group received capecitabine chemotherapy after surgery. The second group received a platinum chemotherapy—either cisplatin or carbonation, after surgery.

After a recent interim analysis, the EA1131 trial was stopped early by the ECOG-ACRIN Data and Safety Monitoring Committee. The interim analysis showed it was unlikely that platinum chemotherapy would be any better than standard capecitabine chemotherapy at preventing recurrence in patients with residual basal-like triple-negative breast cancers following neoadjuvant chemotherapy.

On June 6, the study will be presented at the ASCO (Free ASCO Whitepaper) Annual Meeting and published in the Journal of Clinical Oncology.

First author Ingrid A. Mayer, MD (Vanderbilt-Ingram Cancer Center): "While platinum chemotherapy has been routinely adopted by many to treat basal-like triple-negative breast cancer still present after initial chemotherapy, the results of the randomized phase III trial EA1131 show that it should no longer be used in this setting. The group of men and women in the trial who received platinum chemotherapy had more serious side effects than those who received the standard chemotherapy drug capecitabine."

Breast Cancer
First racially diverse study of severe joint pain, a common side effect in postmenopausal women with HR-positive early breast cancer taking aromatase inhibitors

Abstract 12003: E1Z11 is the first clinical trial in a racially diverse group of postmenopausal women with early breast cancer to study severe pain in the bones, muscles, ligaments, tendons, and nerves caused by aromatase inhibitor (AI) treatment (NCT01824836). Previous similar studies mainly included white women, whereas E1Z11 set individual accrual goals for self-reported Black, Asian, and white participants. Total enrollment was 1,046, including Black (201), Asian (205), and white (640) participants. Women were eligible for the study if they had early (stage I to III) hormone receptor-positive breast cancer, were postmenopausal, had completed planned local therapy, and had not received prior AI therapy as first-line treatment.

AIs stop estrogen production and are widely prescribed in postmenopausal women, typically for five or more years after surgery/chemotherapy, to prevent a breast cancer recurrence. Yet their effectiveness is compromised because 40-50% of women stop treatment early due to the severe pain caused by AI-associated musculoskeletal symptoms (AIMSS). The syndrome was not recognized during the FDA registration trials for this class of drugs, which includes anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara).

The E1Z11 study collected data from women during their first year of AI therapy. More Black and Asian women developed severe musculoskeletal pain during this time than white women (48%, 50%, and 38%, respectively). Rates of AI discontinuation within one year were similar across the three cohorts (10%, 12%, and 13%, respectively).

Participants also completed extensive questionnaires about their symptoms, quality of life, and anxiety about recurrence. The surveys occurred every three months during the first year of AI treatment. Survey completion rates were high across all cohorts at every time point: 98% at baseline, 93% at three months, 89% at six months, 88% at nine months, and 90% at 12 months. The choice for patients to complete questionnaires on paper or online contributed to the extraordinarily high survey completion rates.

E1Z11 participants also contributed blood samples to build a biobank to examine germline genetic variants in DNA for this and future research. Genotyping success rates were high across all cohorts (>95%). This analysis was not able to demonstrate associations between AIMSS symptom development and ten germline DNA variants thought to be predictors. However, one gene (rs2296972/HTR2A) warrants further study.

First author Vered Stearns, MD (Johns Hopkins University): "More Black and Asian postmenopausal women than white women with early breast cancer developed severe musculoskeletal pain within the first year of aromatase inhibitor (AI) therapy. However, the rates of early discontinuation of AI therapy were similar across the three groups. The E1Z11 biospecimens bank and patient-reported outcomes data are a treasure trove for future discovery across the three racial cohorts. For example, there will be data from this trial on the tolerability of AIs from the patient’s perspective, yielding important insights on how to support women from minoritized groups to gain maximum benefit from treatment."

HPV Throat Cancer
Outstanding 3-year progression-free survival outcomes from a less intense treatment

Abstract 6010: The phase II E3311 trial offers new information about using less treatment in patients with HPV-associated oropharynx cancer and a medium risk of recurrence (NCT01898494). While surgeons and patients widely favor the organ-preservation approach of transoral robotic surgery, there remain serious concerns about both short- and long-term toxicities associated with chemotherapy. First, this trial found a better way to assess each patient’s individual risk (presented at ASCO (Free ASCO Whitepaper) 2020). The new method uses tumor testing along with patient characteristics to measure the level of risk: low, intermediate (medium), or high. Physicians may safely consider offering patients less therapy if their risk of recurrence is low. High-risk patients may receive standard chemotherapy and radiation after surgery. But what about patients with intermediate, or medium risk? The E3311 phase II study proved that medium-risk patients could safely forego chemotherapy altogether and receive transoral surgery (TOS) followed by a lower dose of radiation than is standard and still have good outcomes.

This analysis reports three-year progression-free survival (PFS) data. The three-year PFS estimate for the two medium-risk groups is 94.9% for a 50 Gy dose of radiation and 93.5% for a 60 Gy dose. It also reports on an exploratory comparison of quality of life between the two medium-risk groups. Patient reports (FACT HN) completed at baseline (before TOS) and six months post-radiation therapy revealed that 63% vs. 49% of patients in the 50 or 60 Gy arms, respectively, had stable/improved quality of life.

First author Robert L. Ferris, MD, PhD (UPMC Hillman Cancer Center): "Primary transoral surgery followed by reduced-dose radiation therapy is safe in patients with intermediate-risk HPV-positive oropharyngeal cancer, with favorable quality of life and functional outcomes. With three years of follow-up, this group continued to have better outcomes than the group on usual high-dose radiation plus chemotherapy. Our patient stratification identified low and intermediate-risk patients well, preserving patients’ throat function and sparing them unnecessary short- and long-term toxicities. These data support ECOG-ACRIN’s plans for a phase III confirmatory trial."

Breast Cancer
Inflammation biomarker may predict distant recurrence in HER2-negative breast cancer

First author Joseph A. Sparano, MD, is the recipient of the 2021 ASCO (Free ASCO Whitepaper) Gianni Bonadonna Breast Cancer Award and Lecture. Learn more about Dr. Sparano in this ASCO (Free ASCO Whitepaper) Daily News tribute article.

Abstract 520: Systemic inflammation may contribute to the progression or recurrence of early breast cancer. This analysis mined a bank of biospecimens collected before treatment from women with stage II-III HER2-negative breast cancer in a previous randomized phase III trial, E5103 (Miller KM. J Clin Oncol. 2018 Sep 1). Here, researchers utilized serum samples (PMC6118403) to test the hypothesis that higher levels of inflammatory cytokines and chemokines (proteins in immune cells that participate in the body’s immune response) might be associated with cancer coming back in a part of the body away from the breast (distant recurrence). The only biomarker associated with a significantly increased distant recurrence risk when adjusted for multiple testing was the pro-inflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Komen Foundation and the Breast Cancer Research Foundation also funded this study, along with the National Cancer Institute.

First author Joseph A. Sparano, MD (Montefiore Medical Center/Albert Einstein College of Medicine): "We found an association between higher levels of the cytokine IL-6 at diagnosis and a significantly higher risk of distant recurrence in patients with high-risk stage II-III, HER2-negative breast cancer, despite optimal adjuvant systemic therapy. This discovery provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway."

On May 28, 2021 HCW Biologics reported that it has filed to raise up to $50 million in an IPO (Press release, HCW Biologics, MAY 28, 2021, View Source [SID1234583286]). The money will set HCW up to take two immunotherapy treatments into the clinic in solid tumors and an autoimmune disorder.

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Florida-based HCW licensed rights to use its most advanced candidate, HCW9201, to Wugen, which is using the molecule in the generation of memorylike NK cell products in two phase 2 clinical trials in patients with relapsed or refractory acute myeloid leukemia. With Wugen initiating those studies with Washington University, HCW is working to get its next two drug candidates into the clinic.

The most advanced of the two wholly owned assets is HCW9218, a bifunctional fusion protein that HCW plans to take into a phase 1b/2 pancreatic cancer clinical trial by the end of the year. HCW9218 is designed to optimize the efficacy and minimize the side effects of chemotherapy by activating IL-15R signaling and trapping three TGF-β isoforms.

In its IPO paperwork, HCW said the "approach is unique from most other existing or investigational therapies," although it still expects to face competition from T-cell engagers, CAR-Ts and other drugs "that target specific tumor-associated antigens using immune cells or other cytotoxic modalities."

HCW is running IND-enabling studies of HCW9218 while carrying out earlier-stage work on its next candidate, HCW9302. The second asset is an IL2-based immunotherapeutic protein designed to treat autoimmune disorders such as alopecia areata by driving the expansion of regulatory T cells. HCW is aiming to take HCW9302 into clinical development in the first half of next year.

The biotech raised the money to reach this point across series A, B and C rounds from 2018 to 2020. HCW CEO Hing Wong and his spouse bought stock in the financing rounds, culminating in the pair holding a 51% stake in the company. Medmira Capital and DeepWork HCW Partners are the two other biggest stockholders.

On May 28, 2021 Ryvu Therapeutics (WSE: RVU), a clinical stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported that its Clinical Trial Application (CTA) to commence a single-agent, open-label Phase I/II trial, investigating the safety and efficacy of RVU120 (SEL120) in patients with relapsed/refractory metastatic or advanced solid tumors in Poland, has been fully approved by the Polish Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, and the respective Central Ethics Committee (Press release, Ryvu Therapeutics, MAY 28, 2021, View Source [SID1234583282]).

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Following the above-mentioned approvals, Ryvu Therapeutics will be able to initiate a clinical study and start enrolling patients in Poland.

The study is designed in two phases. Phase I part has the key objectives of assessing safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of RVU120 (SEL120) during dose escalating cohorts, and determination of the recommended phase II dose (RP2D), and the phase II part, subsequently will include specific tumor indications, enrolled at distinct study groups, such as Triple Negative Breast Cancer (TNBC).

"With approvals from Polish Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products and Central Ethics Committee, we are making another important step in the clinical development of our flagship RVU120 (SEL120) program. We are very excited to develop RVU120 (SEL120) as a potential treatment in both hematological and solid malignancies," comments Setareh Shamsili, MD, PhD, Chief Medical Officer, and EVP at Ryvu Therapeutics.

"We are delighted that the new Phase I/II RVU120 (SEL120) study in patients with solid tumors will be conducted in Poland. Clinical Trial Applications in other European countries will be submitted over the coming months," adds Setareh Shamsili.

About RVU120 (SEL120)

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 inhibitor, which has demonstrated efficacy in a number of solid tumor types in in vitro and in vivo models as well as in onco-hematological malignancies. The first-in-human (FIH) phase I study with RVU120(SEL120), in relapsed or refractory AML or high-risk myelodysplastic syndromes (HRMDS), is currently enrolling patients in 5 investigational sites in USA (View Source).

Current translational data suggest that RVU120 (SEL120) is particularly effective in undifferentiated AML STAT5-positive cancers. Administration of RVU120 (SEL120) in orthotopic AML patient derived xenograft models reduced tumor burden to the level undetectable in the peripheral blood, decreased splenomegaly and resulted in partial bone marrow recovery at well tolerated doses, providing therefore a strong rationale for the clinical development of RVU120 (SEL120) as an effective treatment for AML and potentially other hematological malignancies.

On March 25, 2020, the U.S. Food and Drug Administration (FDA) granted an orphan drug designation (ODD) to RVU120 (SEL120), for the treatment of patients with acute myeloid leukemia (AML).

On April, 2021 U.S. Food and Drug Administration, FDA, placed a partial clinical hold on the first in human Phase Ib, dose escalation clinical trial of RVU120 in patients with relapsed/refractory (R/R) AML and high-risk MDS. Patients who are currently taking RVU120 may continue treatment. Ryvu continues to work closely with the FDA to resolve the partial clinical hold with the objective of resuming enrollment in the study. RVU120 (SEL120) was discovered with the Ryvu Therapeutics discovery engine platform and has received support from The Leukemia & Lymphoma Society Therapy Acceleration Program (TAP), a strategic initiative to partner directly with innovative biotechnology companies and leading research institutions to accelerate the development of promising new therapies for blood cancers. More information about TAP program is available at: View Source

On May 28, 2021 Fluxion Biosciences reported the publication of a paper on ERASE-Seq liquid biopsy with molecular amplification pools (MAPs) (Press release, Fluxion Biosciences, MAY 28, 2021, View Source [SID1234583281]). The paper, "Sensitivity, specificity, and accuracy of a liquid biopsy approach utilizing molecular amplification pools", published in Nature Scientific Reports on May 24, is co-authored by researchers at Fluxion and the Hospices Civils de Lyon Cancer Institute. Data showed the ERASE-Seq/MAPs approach to have a 98.8% concordance to the benchmark droplet digital PCR (ddPCR) approaches.

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Liquid biopsies offer the potential to improve treatment of cancer by providing affordable, non-invasive detection of actionable cancer mutations from a blood sample. However, the relative abundance of cancer DNA in blood is extremely low, limiting test sensitivity. Recent studies demonstrate good concordance between liquid biopsies when the cancer DNA exceeds 1% allele fraction (AF), but concordance falls off below 1% AF, where many variants are detected.

In this large-scale study, Fluxion’s ERASE-Seq approach was compared directly to benchmark ddPCR tests for EGFR variants that represent treatable biomarkers or indicate the onset of drug resistance mutations. Patient blood samples were drawn and split between the tests, allowing a direct, blinded head-to-head comparison for both sensitivity and specificity. ERASE-Seq demonstrated excellent concordance in the allele fraction of 0.05%-1%, where other sequencing-based liquid biopsies have reduced performance.

"Although ERASE-Seq is a sequencing-based test, it provides levels of sensitivity normally only associated with droplet digital PCR (ddPCR), an analytical technique that is considered the gold standard for sensitivity. ERASE-Seq can test for thousands of variants in a single sample, where ddPCR is limited to only a few variants per test, which means ERASE-Seq can assay many more actionable markers in one test. This is one of the largest liquid biopsy concordance studies ever conducted, and we’re excited to see that ERASE-Seq performs at this level," Fluxion CEO Jeff Jensen explains.

Fluxion offers Spotlight liquid biopsy panels utilizing the ERASE-Seq variant caller, with panels available for pan-cancer, myeloid, TP53, and others. Additionally, ERASE-Seq is easily incorporated with custom-designed panels based on user-selected genomic targets.

On May 28, 2021 QIAGEN N.V. (NYSE: QGEN; Frankfurt Prime Standard: QIA) reported the launch of an expanded scope of companion diagnostic (CDx) claims for the therascreen KRAS RGQ PCR Kit (therascreen KRAS Kit) after it received U.S. regulatory approval as a companion diagnostic to aid in the identification of non-small cell lung cancer (NSCLC) patients that may be eligible for treatment with LUMAKRASTM (sotorasib), a newly approved therapy developed and marketed by Amgen Inc. (AMGN) (Press release, Qiagen, MAY 28, 2021, View Source [SID1234583280]).

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The therascreen KRAS Kit is the first companion diagnostic test to obtain premarket approval from the U.S. Food and Drug Administration (FDA) for use to identify the KRAS G12C mutation in samples of NSCLC tumour tissue. KRAS is one of the most frequently occurring mutation in this form of cancer, and is estimated to be present in up to 13% of cases of the disease. Until now KRAS G12C has not been actionable, and in fact had only previously been linked with resistance to therapies. The real-time qualitative PCR kit is used with the Rotor-Gene Q MDx instrument, a member of the modular QIAsymphony family of automation solutions, and builds upon QIAGEN’s nine years of experience in KRAS CDx test development and commercialization.

"We are pleased to announce this significant expansion in the scope of FDA-approved CDx claims for the therascreen KRAS Kit" said Jean-Pascal Viola, Senior Vice President and Head of QIAGEN’s Molecular Diagnostics Business Area. "This new approval further expands our market-leading therascreen portfolio of companion diagnostic tests, and illustrates our determination to support the delivery of the latest innovations in precision healthcare to patients with NSCLC, for whom every new treatment option is extremely welcome."

"With advances in precision medicine, biomarker testing is critical for patients with non-small cell lung cancer because it informs treatment options during the course of their disease. It is important that patients and their healthcare providers know that KRAS G12C is now an actionable mutation and start testing for it," said Darryl Sleep, M.D., chief medical officer and senior vice president of Global Medical at Amgen. "With the approval of QIAGEN’s companion diagnostic for LUMAKRAS, patients and clinicians will have more options and flexibility for biomarker testing."

Up to 13% of NSCLC-patients may have KRAS G12C positive tumours and hence be potentially eligible for treatment with LUMAKRASTM. To accelerate identification of these patients, following the FDA approval of this test QIAGEN is making testing of NSCLC tumour tissue samples with the therascreen KRAS Kit available immediately at leading laboratories across the U.S, through QIAGEN’s Day-One Lab Readiness program for Precision Medicine.

QIAGEN’s therascreen KRAS Kit was used to support the CodeBreaK 100 clinical trial of sotorasib and the expansion of the Kit’s CDx claims to include identification of the KRAS G12C mutation in NSCLC samples has been co-approved with LUMAKRAS by the FDA. The Amgen drug is a new inhibitor of the G12C-mutated form of the KRAS (Kirsten rat sarcoma) protein, and is the first-in-class drug approved for treatment of this form of cancer. Further details about the Kit are available at www.qiagen.com/KRAS.

QIAGEN’s Day-One Lab Readiness program builds on the FDA’s modernized regulatory approach to benefit patients by accelerating the launch of advanced diagnostics. An updated list of U.S. laboratories offering testing of NSCLC samples for the KRAS G12C mutation using the therascreen KRAS test is available at www.qiagen.com/KRAS-lab-finder.

QIAGEN is a pioneer in Precision Medicine and the global leader in collaborations with pharmaceutical and biotechnology companies to co-develop companion diagnostics, which detect clinically relevant genetic abnormalities to provide insights that guide clinical decision-making in diseases such as cancer. QIAGEN has an unmatched depth and breadth of technologies from next-generation sequencing (NGS) to polymerase chain reaction (PCR) for companion diagnostic development. QIAGEN now has ten PCR based companion diagnostic indications that are FDA approved, including therascreen EGFR for non-small cell lung cancer, therascreen KRAS for colorectal cancer, therascreen FGFR for urothelial cancer, therascreen PIK3CA for breast cancer based on tissue or plasma samples and the therascreen BRAF kit for colorectal cancer.

Currently, QIAGEN is working under master collaboration agreements with more than 25 companies to develop and commercialize companion diagnostic tests for their drug candidates – a deep pipeline of potential future products to advance Precision Medicine for the benefit of patients. The therascreen KRAS Kit co-approval with LUMAKRASTM marks the tenth FDA approval of a therapy partnered with a QIAGEN companion diagnostic assay.