On June 3, 2024 Kite, a Gilead Company (Nasdaq: GILD), reported data from a pilot study in collaboration with Dana-Farber Cancer Institute that demonstrate Yescarta (axicabtagene ciloleucel) is well-tolerated in patients living with relapsed or refractory (R/R) primary or secondary central nervous system lymphoma (PCNSL and SCNSL) (Press release, Kite Pharma, JUN 3, 2024, View Source [SID1234644058]). The findings, which also suggest a trend in efficacy, were presented today in an oral session (Abstract #2006) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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Central nervous system lymphoma (CNSL) is an aggressive and rare form of non-Hodgkin lymphoma that has either originated in (primary) or spread to (secondary) the brain, eye, spinal cord or cerebrospinal fluid. The prognosis of PCNSL has historically been poor with a five-year survival rate of only 30%. More than half of the patients experience a relapse after front-line treatment, with a median survival of approximately two months. R/R CNSL is considered an area of unmet clinical need with no standard of care treatment options.

"Patients with central nervous system involvement of large B-cell lymphoma were excluded from the studies that led to the FDA approval of axi-cel in relapsed/refractory large B-cell lymphoma," said Lakshmi Nayak, MD, Associate Professor of Neurology, Harvard Medical School and Director of the Center for CNS Lymphoma, Dana-Farber Cancer Institute. "We conducted this pilot study to evaluate the safety of axi-cel in CNSL patients and to see if there would be a preliminary signal of efficacy. Not only did we see a high response rate with axi-cel in this heavily pre-treated population, but importantly they were durable. While we need more data to evaluate axi-cel in a larger study, these results are promising and represent a potential breakthrough in the treatment of this particularly rare and aggressive brain cancer for which there are limited options when it recurs."

In this pilot study of 18 patients with CNSL, at a median follow-up of 24.2 months, no treatment-limiting toxicities and no apparent additional risk of adverse events were reported. Immune effector cell-associated neurologic syndrome (ICANS) was observed among 44% of patients (27.8% Grade >3).

The objective response rate was 94.4% and the complete response rate was 66.7%. The median time to best response was three months. The median duration of response was 13.4 months and 9 patients had progressed. At a median follow-up of 24 months, the median progression-free survival was 14.3 months (95% CI: 6.3-NR) and median overall survival was 26.4 months (95% CI: 11.2-NR).

Ninety percent of patients developed grade 1 or 2 cytokine release syndrome; two patients developed Ommaya-related meningitis requiring explant with subsequent recovery. One patient developed grade 3 electrographic focal status epilepticus that resolved with anti-epileptic agents. Seven patients have died, all from disease progression.

"We are very encouraged by the data presented today that indicate the potential to extend the benefits of Yescarta to people with relapsed/refractory primary and secondary central nervous system lymphoma, whose prognoses are typically very poor," said Ibrahim Elhoussieny, MD, Vice President, Medical Affairs, Kite. "These early data support that CAR T-cell therapy may potentially offer a treatment option to these patients."

The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

About Central Nervous System Lymphoma

Central nervous system lymphoma (CNSL) is an aggressive and rare form of non-Hodgkin lymphoma that has either originated in (primary) or spread (secondary) to the brain, eye, spinal cord or cerebral spinal fluid. The prognosis of PCNSL has historically been poor with a five-year survival rate of only 30%. More than half of the patients experience a relapse, after which the average survival is approximately two months. R/R CNSL is considered an area of unmet clinical need with no standard of care treatment options.

There is an estimated annual incidence of 1,500 cases of primary CNSL in the United States. Primary CNS comprises 3% of all primary brain tumors and 1% of all cases of non-Hodgkin lymphoma. CNSL is most likely to be seen in the elderly and people with a compromised immune system.

About the Study

The pilot study enrolled 18 patients (13 PCNSL, 4 SCNSL, 1 concurrent systemic and ocular lymphoma), of whom the first six patients were observed for treatment-limiting toxicities (TLTs). The primary endpoint was safety, measured by rate of TLTs and grade 3+ adverse events (AEs). Secondary endpoints included objective response rate, complete response rate, duration of response, progression-free survival and overall survival (OS).

About Yescarta

Please see full US Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including YESCARTA.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 CRS in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days).

CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 CRS in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include, cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Patients treated with YESCARTA may develop secondary malignancies. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including YESCARTA. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes.

Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

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.