On June 3, 2024 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported its research collaborators from Washington University’s Siteman Cancer Center will lead an oral presentation today at the 2024 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting highlighting the potential role of liquid biopsy in addressing racial inequities in enrollment in clinical trials and in the use of targeted therapies for advanced breast cancer (Press release, Guardant Health, JUN 3, 2024, View Source [SID1234644057]).

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The Rapid Oral Abstract Session (#1017), titled "Racial differences in genomic profiles and targeted treatment use in ER+ HER2- metastatic breast cancer," will be held between 11:30 am and 1:00 pm CT in Hall D1.

The retrospective study, led by first author Emily Podany, MD, and senior author Andrew Davis, MD, both from Washington University, focused on patients with hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer with PIK3CA mutations, which had an equal incidence in Black and White patients. The 1,327 patients in the study, who were treated at Washington University in St. Louis, Massachusetts General Hospital, and Northwestern University, had the Guardant360 liquid biopsy test as part of clinical care and these results were combined with annotated clinical data. Results indicated that Black patients were significantly less likely than White patients to receive PIK3CA targeted therapy or to be enrolled in a clinical trial for biomarkers that required targetable mutations identified via circulating tumor DNA (ctDNA). There were no differences in the use of therapies that did not require a targetable mutation identified via ctDNA.

"These data show clinical inequities in the use of targeted therapies and enrollment in clinical trials, which must be the focus of future interventions," said Podany. "We must now identify ways to ensure all patients equitably receive the recommended precision medicine treatments based on the results of ctDNA testing."

"These data highlight the importance of using ctDNA to identify targetable mutations," noted Davis. "And they reinforce the urgent need to ensure equitable implementation of precision medicine therapies for patients of all races."

The study is part of an ongoing collaboration between Guardant Health and the multicenter Precision Medicine Academic Consortium (PMAC) aimed at advancing the use of liquid biopsy in patients with metastatic breast cancer.

"This landmark study highlights the importance of equitable access to precision medicine," said Craig Eagle, MD, chief medical officer of Guardant Health. "The results confirm the potential role liquid biopsy can have in helping researchers and clinicians equitably match patients with appropriate trials and clinically effective therapies."

Currently, PMAC is working with Guardant Health to validate genomic findings from this and prior projects using the GuardantINFORM clinical-genomic dataset of over 400,000 patients with advanced cancer. The collaboration will continue to pursue future research focused on increasing equitable utilization of targeted therapies.

"The current study demonstrates the importance of studying real-world annotated molecular data related to the use of ctDNA testing and targeted therapies in advanced cancer," said Massimo Cristofanilli, MD, co-founder of PMAC. "It provides valuable insights that can help us understand the complex relation among biological, ethnic and social diversity and offers potential tools to overcome inequity in care."

The full abstract for the study and a list of all abstracts being presented at the meeting can be found at the ASCO (Free ASCO Whitepaper) website.

For more information and updates from the meeting, follow Guardant Health on LinkedIn and X (Twitter) or visit ASCO (Free ASCO Whitepaper) booth #28115.

On June 3, 2024 Zephyr AI, a high-growth healthcare technology company committed to developing AI-Enabled Composite Biomarkers to expand the horizon of precision medicine in cancer drug development, reported a poster at the Annual Meeting for the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Press release, Zephyr AI, JUN 3, 2024, View Source [SID1234644055]). Entitled "Evaluation of a novel signature for PARP inhibitor sensitivity prediction using real-world data," the presentation demonstrates the game-changing patient insights that AI can derive from complex and diverse data sets that can be used to predict a patient’s sensitivity to a class of medicines called poly ADP ribose polymerase (PARP) inhibitors.

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PARP inhibitors are currently authorized for use in the treatment of cancers that exhibit homologous recombination repair deficiencies (HRD+) or mutations in the breast cancer gene (BRCA) 1 or 2. These biomarkers are predominantly present in patients diagnosed with breast, ovarian, prostate, and pancreatic cancer and can predispose patients to PARP inhibitor sensitivity. However, recent data, across this class of medicines have revealed that their benefit-risk profile in late-line ovarian cancer patients using these biomarkers is insufficient to support their continued prescription. As such, these drug labels have recently been withdrawn creating a critical unmet need in late-line ovarian cancer patients to access this class of agent with the appropriate biomarker in place.

The Zephyr AI team has developed a novel, next-generation biomarker that could be used to identify late-line patients whose tumors harbor latent sensitivities to the PARP inhibitor olaparib, distinct from HRD+ and BRCA mutations. The team resolved this novel composite biomarker by using its custom machine learning (ML) foundation model developed over the last several years. This novel AI-enabled composite biomarker was validated using a real world cohort of ovarian cancer patients that had received olaparib in diverse drug combinations, typically, as a late-line therapy.

"Zephyr’s ML technology has the ability to precipitate a stepchange in patient enrichment approaches for new drugs emerging in oncology, an area where historically many drugs have failed or we have needed to refine our knowledge slowly and empirically," said Jeff Sherman Co-Founder, Interim CEO, and Chief Technology Officer at Zephyr.

Zephyr validated its drug response predictions for this cohort using clinico-genomics and patient outcomes data. This analysis revealed that for patients predicted to be sensitive based on the Zephyr model a statistically significant improvement in real-world progression free survival from 24 months to more than 60 months (rw-PFS hazard ratio of 2.04 with a p-value less than 0.001) and a rw-overall survival improvement from 23 months to more than 60 months (rw-OS hazard ratio of 3.37 with a p-value less than 0.005) was observed. This profile was in contrast to analysis using the conventional HRD+ biomarker in the same cohort, where there was no statistically significant improvement in either of the clinically relevant, real-world end points reported.

"It is exciting to be able to share one of the applications of our ML foundation model that the team at Zephyr has been building. We anticipate that the assembly of enormous and complex multi-model data sets into a neural network that forms the basis of our foundation model will enable a new, composite approach to biomarkers broadly. This model will reveal novel insights across many mechanisms of action as we increase the breadth of training data provided to these models," said Rachael Brake, PhD, Zephyr AI’s Chief Scientific Officer. "We believe that by looking beyond HRD+ and ‘BRCAness,’ we can uncover novel and latent drivers of PARP inhibitor sensitivity. This coincides with many next-generation PARP inhibitors entering clinical development and we are excited to partner with these drug development teams to increase the reach and probability of success of this important class of medicine."

On June 3, 2024 OS Therapies, Inc. (NYSE-A: OSTX), a clinical-stage oncology-focused immunotherapy company developing cancer vaccines and antibody drug conjugate (ADC) therapeutic candidates, reported a positive clinical update for AOST-2121 (NCT04974008), its ongoing Phase 2b clinical trial of its immunotherapy OST-HER2 (OST31-154) in patients with resected, recurrent osteosarcoma (Press release, OS Therapies, JUN 3, 2024, View Source [SID1234644054]).

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OST-HER2, a biologic therapeutic candidate, is a Lm (Listeria monocytogenes) vector-based off-the-shelf immunotherapeutic vaccine designed to prevent metastasis, delay recurrence, and increase overall survival in patients with Osteosarcoma. The AOST-2121 study is designed to demonstrate efficacy in patients who have already had recurrent disease and are highly likely to recur again. A total of 18 OST-HER2 doses are administered once every three weeks, for a total 51 weeks. Radiographic evaluation of recurrence is evaluated throughout treatment.

The proposed OST-HER2 mechanism of action is based on innate and adaptive immune stimulating responses activated by the Lm vector. This treatment generates T cells that can eliminate or slow potential micrometastases that can grow into recurrent osteosarcoma. T cell responses home-in on HER2 expressed by the tumor and then kill the cell, releasing additional tumor targets. There are currently no approved adjuvant treatments for recurrent osteosarcoma in the United States.

AOST-2121 has achieved full enrollment of 41 patients treated with OST-HER2 at 21 clinical trial sites across the United States. A few patients remain in the active treatment stage with the remainder in follow-up for overall survival. The primary endpoints for the AOST-2121 study are Event Free Survival (‘EFS’, defined as absence of recurrence of primary tumor or metastasis) at 12 months and Overall Survival at 36 months, with interim Overall Survival endpoints at 12 months and 24 months. Topline EFS data, interim 1-year OS data, as well as additional secondary data analyses are expected to be reported in the fourth quarter of 2024. No novel therapeutic interventions have improved the clinical outcomes for patients with resected, recurrent osteosarcoma in over 40 years.

The clinical updates reported today include:

1-year EFS rate of 32.5% vs. 20% EFS rate for unsuccessful investigational therapeutic comparator1
1-year overall survival rate of 90.4%
18-month overall survival rate of 90.4%
Treatment has been well tolerated and there have been no grade 3, 4 or 5 treatment-related adverse events reported for the 41 patients.
"OST-HER2’s strong safety profile supports its potential to become a practical adjuvant therapy to delay or prevent subsequent recurrences and improve overall survival in the very difficult challenge of recurrent osteosarcoma. Promoting innate and adaptive immune surveillance against lurking micrometastases could become a potentially powerful tool for oncologists as they seek to improve the quality of life and prolong survival of patients who have suffered from Osteosarcoma," said Dr. Robert Petit, Chief Medical & Scientific Officer of OS Therapies. "OST-HER2 has the potential to significantly improve the standard of care in this difficult to treat patient population. In light of today’s encouraging clinical trial update, we are hopeful that final data coming in the fourth quarter of this year, combined with supplemental data that will follow in 2025, positions OST-HER2 to become available to help clinicians better protect people with difficult cancers like osteosarcoma."

"With historical 1-year EFS estimated in the low-to-mid teens with the current standard of care, and the most recent investigational therapeutic comparator yielding 1-year EFS of 20%, we believe that the 32.5% EFS data observed to date in this trial compares favorably and positions OS Therapies to deliver final Phase 2b co-primary endpoint data by the end of 2024," said Paul Romness, President & CEO of OS Therapies. "With OST-HER2’s strong safety profile and consistent overall survival at the 1-year and 18 month timepoints, and given the dearth of therapeutic options for the resected, recurrent osteosarcoma patient population, we are hopeful that OS Therapies will be gain approval for the first new osteosarcoma treatment, a novel immunotherapy, in over 40 years."

The FDA has granted Rare Pediatric Disease Designation (RPDD), Orphan Drug Designation (ODD), and Fast Track Designation (FTD) for OST-HER2 in Osteosarcoma.

References

Lagmay JP, Krailo MD, Dang H, et al: Outcome of patients with recurrent osteosarcoma enrolled in seven Phase II trials through Children’s Cancer Group, Pediatric Oncology Group, and Children’s Oncology Group: learning from the past to move forward. J Clin Oncol. 2016;34:3031-8.
About Osteosarcoma

Osteosarcoma is a solid tumor of the bone that predominantly occurs in adolescents and young adults (AYA). Standard treatment includes surgery and chemotherapy. For patients with metastatic osteosarcoma or have recurrence after chemotherapy, the prognosis is poor.

On June 3, 2024 InvoX Pharma Limited ("invoX"), a research-driven global biopharmaceutical company with an advancing pipeline of innovative products, reported updated findings from its ongoing phase 1 study of FS222, an investigational CD137/PD-L1 bispecific antibody, in patients with advanced solid tumours (Press release, InvoX Pharma, JUN 3, 2024, View Source [SID1234644053]). These data demonstrated encouraging anti-tumour activity in multiple tumour types with a manageable safety profile. These preliminary findings were presented today at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago as an oral presentation during the Development Therapeutics – Immunology Session.

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FS222 is a novel tetravalent bispecific antibody, using invoX’s proprietary Fcab platform technology, that drives PD-L1 dependent CD137 agonism. The data presented today are from 100 subjects in the ongoing first-in-human (FIH) dose-escalation phase 1 clinical trial of FS222 (NCT04740424) in patients with advanced solid tumours. The study is designed to evaluate safety and identify the maximum tolerated dose, with secondary objectives related to anti-tumour activity, pharmacokinetics, and pharmacodynamics.

As a monotherapy dosed once every 4 weeks, FS222 increased T cell proliferation and intratumoural CD8+ T cell infiltration across a wide range of doses. The rate of treatment-related adverse events (TRAEs) was generally dose dependent. Overall, TRAEs were consistent with the intended dual mechanism of action of CD137 agonism and PD-L1-blockade and were generally manageable and reversible. Grade ≥ 3 TRAEs occurred in 36/100 subjects, with the most common including increases in aspartate aminotransferase and alanine aminotransferase, thrombocytopenia, neutropenia and febrile neutropenia.

In the study, FS222 demonstrated encouraging anti-tumour activity in multiple tumour types. Responses (as defined by RECIST1.1 criteria) were observed in cutaneous melanoma (n=9), ovarian cancer (n=2), non-small cell lung cancer (NSCLC) (n=2), and one each for mucosal melanoma, triple negative breast cancer (TNBC), mesothelioma and MSS colorectal cancer. The rate of disease control (defined as the rate of complete responses, partial responses and stable disease combined) was 45.0% for all patients in the study.

In 19 patients with metastatic/advanced cutaneous melanoma previously treated with a PD-1 antibody the overall response rate (defined as the rate of complete responses and partial responses combined) was 47.4% and the disease control rate was 68.4%.

Elena Garralda, MD, MSc, Director of Early Drug Development at Vall d’Hebron University Hospital, said: "While there have been great advances in immuno-oncology research, existing treatments continue to face challenges with response rates and duration of response, especially in treatment-resistant cancer. The opportunity to target multiple complementary immune mechanisms with a single agent is very exciting and has significant potential to address an unmet need for patients. These results for FS222 are really encouraging and should be studied further, as they show a promising anti-tumour effect with a manageable safety profile."

Ben Toogood, Chief Executive Officer at invoX, said: "We are encouraged by these results and are impressed by the preliminary anti-tumour activity observed with FS222, especially in melanoma patients previously treated with a PD-1 antibody. There is an urgent need for innovative immuno-oncology treatments for patients with treatment-resistant cancers. We see significant potential for FS222 in this area and will continue to investigate FS222 further, with the aim of providing benefit to patients in the future."

Ben added: "These data also provide important validation of our antibody platform. We are excited about the potential to utilise our proprietary CD137-agonist domain from our Fcab platform in additional bispecific antibodies targeting multiple tumour types and patient populations."

Enrollment in this phase 1 study of FS222 is ongoing and the study is exploring additional FS222 dose optimization.

On June 3, 2024 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported the presentation of alisertib for the treatment of patients with advanced osimertinib-resistant epidermal growth factor receptor-mutated (EGFR-mutated) non-small cell lung cancer (NCT04085315) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting currently being held in Chicago (Press release, Puma Biotechnology, JUN 3, 2024, View Source [SID1234644052]). The poster (Abstract #8572, Poster Bd #436), entitled, "A Phase I/Ib study of the aurora kinase A inhibitor alisertib in combination with osimertinib in advanced osimertinib-resistant EGFR-mutated lung cancer," was presented by Turja Chakrabarti, MD., University of California, San Francisco, at the Lung Cancer – Non-Small Cell Metastatic Poster Session, on June 3 at 1:30 p.m. CDT. A copy of the poster is available on the Puma website.

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This open-label, single-center Phase I/Ib study enrolled 21 evaluable patients with stage IV EGFR-mutated NSCLC (EGFR driver mutation: 76.1% exon 19 deletion; 14.3% L858R; 9.5 % L861Q) who had progressed on osimertinib monotherapy. 47.6% of patients had previously received only first-line osimertinib monotherapy, while 52.3% had received two or greater prior lines of therapy. In the Phase I portion of the trial, 10 patients were treated in a 3+3 dose escalation phase with alisertib using an intermittent dosing strategy of 30 mg (n = 6) or 40 mg (n = 4) twice daily (BID) in combination with osimertinib 80 mg daily. Alisertib was added to osimertinib treatment at the time of disease progression on osimertinib. Intermittent alisertib 30 mg BID was identified as the MTD and RP2D in combination with osimertinib 80 mg daily.

In the Phase Ib expansion portion of the trial, 11 additional patients were treated at the 30 mg alisertib BID intermittent dosing schedule in combination with osimertinib 80 mg daily with alisertib being added to osimertinib treatment at the time of disease progression on osimertinib.

The most common treatment-related adverse events (AEs) (any grade) included neutropenia (42.9%), anemia (42.9%), diarrhea (38.1%), and lymphopenia (33.3%). Grade 3 or higher AEs neutropenia (4.8%), anemia (4.8%), diarrhea (14.3%), and lymphopenia (4.8%).

For the 21 evaluable patients, the investigator assessed overall response rate was 9.5% (95% CI: 0 to 22%) and disease control rate was 81% (95% CI: 69% to 93%). The median PFS for all patients was 5.5 months, while the median OS was 23.5 months. For patients with TP53 mutations (n=9), the overall response rate was 0%, and the disease control rate was 66.7%. For patients who were tp53 wild type (n=8), the overall response rate was 25%, and the disease control rate was 87.5%. For patients with TP53 mutations, the progression free survival was 3.7 months, and for patients who were tp53 wild type, the progression free survival was 8.0 months (hazard ratio:0.42, p = 0.05).

Dr. Collin M. Blakely, the lead principal investigator of the study and senior author of the presentation, from the University of California in San Francisco, said, "We are pleased with the initial results of the clinical trial and very interested in the cohort of patients who are tp53 wild type as tp53 is known to be involved in the aurora kinase pathway. We are modifying the protocol to limit further enrollment in the trial to patients who are tp53 wild type and we look forward to further studying this combination in this biomarker directed cohort of patients."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the promising efficacy signals in the cohort of patients who are tp53 wild type. As tp53 is well known to be involved in the aurora kinase pathway, we are pleased to see the activity of alisertib when given in combination with osimertinib in this population of patients. We look forward to continuing to enroll this trial in this cohort of patients."