Dr Sahin on the Design of the Northstar Response Assay in Advanced GI Cancer

Ilyas Sahin, assistant professor, Medicine, Department of Medicine, Division of Hematology & Oncology, University of Florida College of Medicine, discusses the design of the Northstar Response assay and the future of precision oncology in patients with advanced gastrointestinal (GI) cancer who are undergoing active treatment.

Other treatment response–monitoring assays, such as single nucleotide variant assessments, use variant allele frequencies to detect somatic variants in the blood. In contrast, the Northstar Response assay evaluates methylated circulating tumor DNA (ctDNA), which may provide more sensitive and specific results, Sahin says. Northstar Response can quantify an average of 90 methylated loci, 10 times more than can be quantified with the average tissue-informed assays. Although the Northstar Response assay measures treatment response, it may also be useful as a cancer screening tool, Sahin explains.

The Northstar Response assay does not need tissue biopsies, Sahin emphasizes. Instead, this assay consists of a series of blood tests that are conducted at baseline, at the time of imaging, and at 2 or more time points during treatment, approximately 30 days and 60 days after treatment initiation. Through analyzing the collected blood samples with the Northstar Response assay, oncologists can measure patients’ real-time treatment responses, Sahin notes.

As novel artificial intelligence platforms, including the Northstar Response assay, become increasingly prevalent and accurate, these types of tests may lead to new advances in precision oncology, Sahin says. Both oncologists and patients may benefit from these test results, leading to improved clinical outcomes in the future, Sahin concludes.

A prospective, observational study evaluating the clinical validity of the Northstar Response assay in patients with advanced GI cancer found that the assay consistently detected ctDNA in various advanced GI cancers. Interim findings from this study were subsequently presented at the 

. This study continues to enroll patients, and investigators plan to initiate a formal comparison between the detected responses and instances of clinical progression.

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Ilyas Sahin, MD, discusses the Northstar Response assay and the future of precision oncology in patients with advanced gastrointestinal cancer. 

Dr Sahin on the Utility of the Northstar Response Assay in GI Cancer

Ilyas Sahin, MD, assistant professor, medicine, Division of Hematology & Oncology, Department of Medicine, University of Florida College of Medicine, University of Florida Health, discusses the potential utility of Northstar Response, a novel blood test designed to quantify circulating tumor DNA (ctDNA) in patients with advanced gastrointestinal (GI) cancer currently receiving treatment for their disease.

NorthStar Response is a methylated ctDNA therapy monitoring assay, which could be a valuable tool for oncologists, especially in cases where patient safety is a concern due to treatment toxicity. This tool offers timely insights, potentially reducing wait times for accurate imaging results, and is particularly relevant for patients with mixed treatment responses or challenges regarding disease staging and imaging. In an ongoing study, investigators are examining treatment responses in patients with advanced GI cancer, Sahin begins. The primary objective of this investigation is to ascertain the efficacy of using the Northstar Response assay to accurately assess treatment outcomes. The study protocol involves conducting imaging assessments approximately 2 to 3 months after treatment initiation, he reports.

Moreover, Sahin foresees potential applications of the NorthStar Response tests in future studies, particularly in scenarios involving early-stage cancer post-surgery. In such cases, this test could serve as a tool in guiding decisions regarding additional chemotherapy or in promptly identifying cancer recurrences, he notes. Should these initial findings prove encouraging, subsequent studies will delve deeper into refining the understanding and use of this test, Sahin explains. This initial analysis is evaluating the accuracy of Northstar Response across diverse cancer types, with an emphasis on observing discernible trends, he adds.

Preliminary findings have shown a promising trend of decreased methylation scores in patients who experience partial or complete responses to their therapies, Sahin continues. However, one significant obstacle lies in the inherent heterogeneity of the patient population, encompassing various cancer types and treatment modalities. For instance, although patients with colorectal cancer may present with the highest methylation scores, those receiving immunotherapy for biliary tract cancer tend to exhibit the lowest scores, he adds.

Despite these challenges, investigators remain committed to refining this test, according to Sahin. Sahin and colleagues aim to enhance the overall accuracy and reliability of the Northstar Response assay.

Ilyas Sahin, MD, discusses the potential utility of Northstar Response assay in patients with advanced gastrointestinal cancer.

Dr Sahin on the Potential Use of Northstar Response in GI Cancer

Ilyas Sahin, MD, assistant professor, medicine, Division of Hematology & Oncology, University of Florida Health, discusses the clinical validation of NorthStar Response, a novel blood test designed to quantify circulating tumor DNA (ctDNA) in patients with advanced gastrointestinal (GI) cancer receiving active treatment.

NorthStar Response is a novel methylated ctDNA therapy response–monitoring assay. This tool holds the potential to be an asset for oncologists, particularly in cases where toxicity poses a concern for patients, Sahin begins. For instance, if a patient needs to change treatments because their current treatment is ineffective, the patient may wait prolonged periods for accurate imaging results, according to Sahin. NorthStar Response could mitigate these issues by offering timely insights, he explains. This tool would be especially relevant in patients exhibiting mixed treatment responses or in instances where disease staging and imaging may present challenges, Sahin states.

For patients under surveillance for recurrence, a positive NorthStar Response result could prompt early treatment interventions, potentially leading to improved clinical outcomes, he expands. Similarly, in post-surgery scenarios, the test could provide early treatment indications or guide decisions regarding the need for additional chemotherapy, Sahin notes. Investigators envision this tool as a valuable addition to oncologists’ arsenals, complementing existing diagnostic approaches, he elucidates.

The investigation of NorthStar Response in patients with advanced GI cancer plans to enroll100 patients, Sahin continues. At the 

, investigators presented interim findings from 44 patients, he says.

The primary objective of this assessment is to evaluate the effectiveness of this blood test in monitoring treatment responses across various types of advanced GI cancers and different lines of treatment, including chemotherapy, immunotherapy, and targeted therapies, Sahin explains. The aim is to assess whether this test proves effective in monitoring and gauging treatment responses in a diverse range of clinical scenarios, he concludes.

Ilyas Sahin, MD, discusses an assessment of the Northstar Response in patients with advanced gastrointestinal cancer undergoing active treatment.

Ilyas Sahin, MD, assistant professor, Division of Hematology & Oncology, University of Florida Health, discusses the investigation of milademetan (RAIN-32) in combination with imipridone ONC201 as a synergistic combination in solid tumors.

Various tumor types can harbor MDM2 amplifications, and researchers have developed inhibitors to block the MDM2-p53 interaction, such as milademetan, Sahin notes. Milademetan has been investigated in phase 1 and 2 trials, and it is currently under investigation in the phase 3 MANTRA trial (NCT04979442) in patients with dedifferentiated liposarcoma.

ONC201 is an orally active, small molecule DRD2 antagonist used in the treatment of patients with various tumor types, Sahin continues. The rationale for combining these 2 drugs is because MDM2-p53 inhibitors such as milademetan can increase levels of MDM2, which could lead to immune-mediated adverse effects independent of the p53 pathway, Sahin says. Additionally, MDM2 amplification is potentially predictive for hyper-progressive disease, Sahin explains. Adding ONC201 a MDM2-p53 inhibitor such as milademetan could inhibit MDM2 levels, Sahin adds.

Findings from a preclinical study of the combination of milademetan and ONC201 were presented at the 2023 AACR Annual Meeting, which identified an additional effect of ONC201 in significantly reducing detectable MDM2 levels in cell lines, suggesting synergy of the combination of ONC201 with milademetan. Additional research is underway, exploring this combination in mice, and the hope is to eventually progress to a first-in-human trial, Sahin says. If data continue to be positive, this strategy could represent a novel and translatable therapeutic approach for the treatment of patients with MDM2-overexpressing tumors, Sahin says. Investigators are also interested in testing this combination used in conjunction with immune checkpoint blockade since MDM2 amplification may have a role for immunotherapy resistance, Sahin concludes.

Ilyas Sahin, MD, discusses the investigation of milademetan in combination with imipridone ONC201 as a synergistic combination in solid tumors.

Dr Sahin on the Investigation of Milademetan and ONC201 in Solid Tumors

Ilyas Sahin, MD, assistant professor, Division of Hematology & Oncology, University of Florida Health, discusses the background and findings of the phase 2 IMbrave 151 trial (NCT04677504) in advanced biliary tract cancer.

The IMbrave 151 trial evaluated the efficacy and safety of bevacizumab (Avastin) plus atezolizumab (Tecentriq), cisplatin, and gemcitabine vs placebo plus atezolizumab, cisplatin, and gemcitabine as first-line treatment for patients with advanced biliary tract cancer. Findings presented at the 2023 Gastrointestinal Cancers Symposium showed that patients treated in the bevacizumab achieved a median progression-free survival (PFS) of 8.3 months (95% CI, 6.8-10.0) compared with 7.9 months (95% CI, 6.2-8.4) in the placebo arm (stratified HR, 0.76; 95% CI, 0.51-1.14).

Additionally, the 6-month PFS rates were 78.2% (95% CI, 68.8%-87.7%) in the bevacizumab arm and 63.1% (95% CI, 52.6%-73.6%) in the placebo arm. Study authors noted that higher PFS rates and longer duration of response in the bevacizumab arm suggested a clinical benefit in a subset of patients.

After the phase 3 TOPAZ-1 trial (NCT03875235) demonstrated the benefit of adding durvalumab (Imfinzi) to chemotherapy in the frontline treatment of patients with advanced biliary tract cancer, investigators aimed to take a deeper look at the potential role of immunotherapy in this space, Sahin starts.

Treatment with a VEGF inhibitor can cause changes in the tumor microenvironment and increase T-cell infiltration, Sahin adds, noting that this led investigators to hypothesize that the addition of bevacizumab could increase the efficacy of immunotherapy in patients with biliary tract cancer. He notes that IMbrave 151 was designed as a hypothesis-generating trial.

IMbrave 151 was the first phase 2 randomized trial testing the addition of a VEGF inhibitor to a PD-L1, Sahin continues. Although the primary end point was PFS, there was no statistical analysis in this study since it was meant to be hypothesis generating, Sahin says. Although data reported thus far were not promising, study authors will continue with additional follow-up and correlative studies to identify if some patients could derive a benefit from the addition of bevacizumab to atezolizumab and chemotherapy, Sahin concludes.

Ilyas Sahin, MD, discusses the background and findings of the phase 2 IMbrave 151 trial in advanced biliary tract cancer. 

Ilyas Sahin, MD

Articles

Dr Sahin on the Design of the Northstar Response Assay in Advanced GI Cancer

Dr Sahin on the Utility of the Northstar Response Assay in GI Cancer

Dr Sahin on the Potential Use of Northstar Response in GI Cancer

Dr Sahin on the Investigation of Milademetan and ONC201 in Solid Tumors

Dr. Sahin on the Background of the IMbrave 151 Trial in Biliary Tract Cancer