Tag: General Medical Oncology & Hematology

Cardiovascular Adverse Events Associated with Bispecific T-cell Engager Therapy

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SUMMARY: Bispecific T-cell engager (BTE) therapies are a novel class of targeted immunotherapies with activity against hematologic malignancies. These bispecific antibodies have 2 binding domains, one targeting and binding to CD3 on the T-cell receptor, whereas the other is a modifiable domain designed to bind to specific tumor-associated antigens, which can be CD19, CD20, B-Cell Maturation Antigen (BCMA) or GPRC5D. Blinatumomab (BLINCYTO®) targets the CD19 on B-cells and is approved for the treatment of advanced Acute Lymphoblastic Leukemia (ALL); Mosunetuzumab (LUNSUMIO®), Glofitamab (COLUMVI®), and Epcoritamab (EPKINLY®), target CD20 on B cells and have also been approved for the treatment of Non-Hodgkin lymphoma; Teclistamab (TECVAYLI®), targets BCMA expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma; Talquetamab (TALVEY®) targets GPRC5D expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma.

Adverse events of BTEs include Cytokine Release Syndrome (CRS), hematological toxicities, and neurotoxicity. Serious CardioVascular Adverse Events (CVAEs) have been reported with certain BTEs. However, this has not been clearly defined. Given that CVAEs have not been observed in a previous pharmacovigilance analysis focused on CAR-T therapy, it appears that the pathophysiology of CVAEs associated with novel T-cell modulatory therapies (BTEs) may be different.

The present study was conducted to examine the CardioVascular Adverse Events (CVAEs) associated with Bispecific T-cell Engager therapies (BTEs). The five BTE products considered for analysis were Blinatumomab, Teclistamab, Mosunetuzumab, Glofitamab, and Epcoritamab. Leveraging the vast repository of the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), researchers embarked on a meticulous analysis, investigating the frequency and association of CVAE reporting with BTE, the prognostic implications of CVAEs in patients receiving BTEs, as well as the extent these adverse events overlap with CRS, spanning from October 2014 to March 2023. The primary objective was to delineate the frequency and fatality rates of CVAEs associated with BTEs, encompassing a spectrum of conditions including bleeding, hypotension or shock, thromboembolic disease, heart failure, and conduction abnormalities, myocarditis, pericarditis, sudden death, and vasculitis.

Utilizing multivariable logistic regression models, adjusted for age, sex, and disease status, the researchers calculated adjusted Reporting Odds Ratios (RORs). These RORs served as a metric to gauge the likelihood of reporting a given adverse event with BTEs compared to reporting the same event with all other drugs in the FAERS database.

Their study examined 3,668 cases of reported adverse events, 73.9% of which involved Blinatumomab and 11.2% involved Teclistamab as the primary suspected drug. Mosunetuzumab, Glofitamab and Epcoritamab accounted for a smaller proportion of events. (7.4%, 5.2% and 2.3%, respectively). The median age of patients was 52.0 years, with individuals from 52 countries represented in this analysis, with 43.2% of cases coming from the U.S. The indication for BTE therapy was leukemia/lymphoma in 88.7% of cases, multiple myeloma in 11.2% of cases, and both in 0.1% of cases.

The results of the study unveiled several significant findings:
1) Of the 3668 BTE-related cases reported to FAERS, 20.4% involved CVAEs.
2) BTEs were associated with disproportionately higher rates of fatal CVAEs, an association mainly driven by Teclistamab. Teclistamab was also associated with a disproportionate risk of myocarditis and shock, whereas Blinatumomab was associated with a disproportionate risk of Disseminated Intravascular Coagulation and hypotension.
3) Majority of these fatal CVAEs (96.7%) occurred in individuals without previously documented cardiovascular comorbidities.
4) CVAEs were more likely to be fatal compared with non-CVAEs (31.1% versus 17.4%).
5) CVAEs were not necessarily a consequence of Cytokine Release Syndrome (CRS), as approximately 85% of CVAE reports did not involve concurrent CRS.
6) In general, CVAEs tended to occur sooner following BTE therapy compared with non-CVAEs (median time to onset 6 days versus17 days; p<0.001).
7) No significant associations with CVAEs were observed with the other three BTE products (Glofitamab, Mosunetuzumab, and Epcoritamab).
8) Compared with CVAEs, neurotoxicity and CRS commonly associated with BTEs were associated with lower mortality. The elevated risk of death following CVAEs was especially noted for myocarditis, heart failure, bleeding, and DIC, with which mortality rates were 2-3 times higher than other AEs.

The researchers concluded that in this first postmarketing pharmacovigilance analysis of BTEs, CVAEs were involved in approximately 1 in 5 Adverse Event reports, and carried a significantly high mortality rate. The researchers cautioned that clinicians must be cognizant of the potential of CVAEs when treating patients with BTEs, and consider either stopping or switching therapies when CVAEs are suspected.

Cardiovascular toxicities associated with bispecific T-cell engager therapy. Sayed A, Munir M, Ghazi SM, et al. J Immunother Cancer. 2024 Feb 21;12(2):e008518. doi: 10.1136/jitc-2023-008518.

FDA Approves ENHERTU® for Unresectable or Metastatic HER2-Positive Solid Tumors

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SUMMARY: The FDA on April 5, 2024, granted accelerated approval to ENHERTU® (fam-Trastuzumab Deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment, and have no satisfactory alternative treatment options. This tumor agnostic indication was approved based on Objective Response Rate and Duration of Response.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor growth-promoting protein and is involved in normal cell growth. It is expressed on the surface of various tissue cells throughout the body. In some cancers, HER2 expression is amplified or the cells have activating mutations. HER2 gene amplification can result in HER2 protein overexpression which is often associated with aggressive disease and poor prognosis. Approximately 15-20% of invasive breast cancers as well as advanced Gastric and GastroEsophageal (GE) junction cancers overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody. Additionally, HER2 directed therapies have been used to treat lung and colorectal cancers. HER2 is an emerging biomarker in other solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers with HER2 positive expression rates varying from 1-28%. There are currently no approved HER2 directed therapies for these cancers following progression on standard of care therapies. There is an unmet need for effective therapies for these HER2 expressing tumor types.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

The FDA approval was based on the efficacy of ENHERTU® in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of Interstitial Lung Disease /pneumonitis requiring treatment with steroids or Interstitial Lung Disease /pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status more than 1. Treatment was administered until disease progression or unacceptable toxicity. The major efficacy outcome measure in all three trials was confirmed Objective Response Rate (ORR), and an additional efficacy outcome was Duration of Response (DOR). All outcomes were assessed by Independent Central Review based on RECIST criteria.

DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label, ongoing Phase II trial evaluating the efficacy and safety of ENHERTU® 5.4 mg/kg IV for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. DESTINY-PanTumor02 enrolled 267 patients (N=267) at multiple sites in Asia, Europe and North America. Patients had received a median of two prior cancer therapies. In this study, the ORR was 51.4% and median DOR was 19.4 months.

DESTINY-Lung01 is a global, open-label, two-cohort, Phase II trial evaluating the efficacy and safety of ENHERTU® 6.4 mg/kg IV and 5.4 mg/kg IV in patients with HER2 mutant (cohort 2, N=91) or HER2 overexpressing (cohort 1 and 1a, N=90) (defined as IHC 3+ or IHC 2+) unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC), who had progressed after one or more systemic therapies. In this study, the ORR was 52.9% and the median DOR was 6.9 months.

DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter Phase II trial evaluating the efficacy and safety of two doses, 5.4 mg/kg IV or 6.4 mg/kg IV of ENHERTU® in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types, previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (N=80) were randomized 1:1 to receive either 5.4 mg/kg IV or 6.4 mg/kg IV of ENHERTU®. In the second stage, additional patients (N=42) were enrolled in the 5.4 mg/kg IV arm. In DESTINY-CRC02, ORR was 46.9%, and DOR was 5.5 months.

The most common adverse reactions were cytopenias, nausea, vomiting, fatigue, liver function abnormalities and upper respiratory tract infection. The recommended dose of ENHERTU® for this indication is 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity.

The forementioned trials validate HER2 as an actionable biomarker across a broad range of tumor types, and ENHERTU® has the potential to benefit patients with HER2 expressing advanced disease, who may face a poor prognosis and currently have limited treatment options.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2.

April 2024: Current Tumor-Agnostic Therapies

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The FDA on April 5, 2024, granted accelerated approval to Fam-trastuzumab deruxtecan-nxki (ENHERTU®) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

This is the 6th Tumor-Agnostic therapeutic target for which an agent has received regulatory agency approval.

A current summary of the Tumor-Agnostic therapeutic targets, and agents approved, is provided below. Please review the drug Prescribing Information for the respective therapeutic agents, as NOT all products are approved for First Line therapy.

MMRd/MSI-H: Pembrolizumab (KEYTRUDA®) and Dostarlimab (JEMPERLI®)
TMB-H: Pembrolizumab (KEYTRUDA®)
NTRK fusions: Larotrectinib (VITRAKVI) and Entrectinib (ROZLYTREK®)
BRAF V600E: Dabrafenib (TAFINLAR®) plus Trametinib (MEKINIST®)
RET Fusions: Selpercatinib (RETEVMO®)
HER2 Overexpression: Fam-trastuzumab deruxtecan (ENHERTU®)

The National Cancer Institute describes Tumor-Agnostic therapy as a type of targeted treatment that uses drugs or other substances to treat cancer based on the cancer’s genetic and molecular features, without regard to the cancer type or where the cancer started in the body. Tissue-Agnostic therapy uses the same drug to treat all cancer types that have the genetic mutation or biomarker, that is targeted by the drug.

Metformin May Reduce the Risk of Cancers, Especially GI Malignancies

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SUMMARY: The American Cancer Society estimates that in 2024, 2,001,140 new cancer cases will be diagnosed, and 611,720 cancer deaths are projected to occur in the United States. The Center for Disease Control and Prevention recommends healthy eating habits, limiting alcohol consumption and skin protection for cancer prevention, screening tests for breast, cervical, colorectal and lung cancer for early detection, as well as HPV and Hepatitis B vaccination to lower the risk of cervical and liver cancer respectively.

Metformin is one of the most commonly prescribed agents for Type 2 diabetes worldwide. Metformin is a synthetic guanidine derived compound. Numerous epidemiological studies have shown that Type 2 diabetes patients receiving Metformin had a decreased risk of the occurrence of various types of cancers, compared to those taking other antidiabetic agents. Numerous meta-analyses have also confirmed that Metformin reduces cancer incidence by 30-50%. These findings in addition to the safety and cost-effectiveness of Metformin have generated a lot of interest in the research community. Metformin exhibited promising anticancer effects in preclinical studies by inducing cell cycle arrest at different stages of cell division depending on the cancer type, promoting cell death, suppressing cancer cell migration, invasion and metastasis, as well as deregulating cancer metabolism. Further Metformin enhanced sensitivity to radiotherapy, chemotherapy, and immunotherapy.

There has been renewed interest in the anticancer mechanisms of Metformin and it has been reported to mimic significant metabolic effects of caloric restriction at both cellular and systemic levels. It has been postulated that Metformin induces a direct effect on cancer cells, independent of blood glucose and insulin levels, and indirect effect thru systemic metabolic changes depending on blood glucose and insulin levels. The primary site at which Metformin exerts its anticancer activity is the mitochondria. Metformin inhibits mitochondrial complex I and triggers energy depletion, which activates AMPK (Adenosine Monophosphate-activated Protein Kinase ) and inhibits mTOR, limiting cancer growth. Additionally, metformin also exerts anticancer effects that are independent of AMPK but rather dependent on Rag GTPases or REDD1.

To date, there has been no comprehensive review of the literature assessing the relationship between Metformin and cancer risk. The researchers therefore conducted a comprehensive systematic review of literature and meta-analysis, to investigate the association between Metformin or any of its analogs use, and cancer risk, and specific cancer type when possible. From an initial pool of more than 6,000 articles, identified in PubMed/MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from inception through March 7, 2023, 166 studies with cancer incidence information were included in the meta-analysis. Majority of these studies took place in populations with Type 2 diabetes. This analysis was then stratified by cancer type and study type. The authors decided not to provide a summary analysis for specific cancer types because of the heterogeneity between studies due to different study designs, as this analysis included many case-control studies, some prospective cohort studies and some retrospective cohort studies.

This analysis showed a reduced risk for overall cancer in case-control studies (RR=0.55) and in prospective cohort studies (RR = 0.65). Metformin use was associated with reduced risk of gastrointestinal cancer (RR = 0.79), urologic cancer (RR = 0.88) and hematologic malignancies (RR = 0.87). The most striking association was observed for gastrointestinal cancer risk, which showed a risk reduction of 21%.

It was concluded that Metformin may be associated with a decreased risk of many cancer types, and there appears a striking association between Metformin and reduced risk for gastrointestinal cancers. The researchers added that additional studies in populations without diabetes are needed to better understand the utility of Metformin in cancer prevention.

Association of metformin use and cancer incidence: a systematic review and meta-analysis. O’Connor L, Bailey-Whyte M, Bhattacharya M, et al. JNCI:Journal of the National Cancer Institute, djae021, https://doi.org/10.1093/jnci/djae021. 30 January 2024.

Late Breaking Abstract: ASH – 2023: Pomalidomide Reduces Epistaxis and Improves Quality of Life in Hereditary Hemorrhagic Telangiectasia

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SUMMARY: Hereditary Hemorrhagic Telangiectasia (HHT) is an Autosomal Dominant inherited disorder caused by mutations in regulators of angiogenesis. Also known as Osler-Weber-Rendu syndrome, HHT is the second most common inherited bleeding disorder after Von Willebrand Disease, with an estimated prevalence of 1 in 5000. HHT presents with a triad of recurrent epistaxis with iron deficiency anemia, mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs) and in more severe cases, patients may experience life-threatening hemorrhage, stroke, or high-output heart failure, requiring hospitalizations, with a negative impact on Quality of Life (QOL). HHT is caused by disruptions in angiogenesis signaling, resulting in impaired vascular development. Three genes in the Transforming Growth Factor-beta (TGF-β) signaling pathway have been implicated and they include Endoglin (ENG), activin A receptor ligand type I (ACVRL1 or ALK-1), and SMAD family member 4 (MADH4 or SMAD4).

Small non-randomized studies suggested that systemic antiangiogenic agent Bevacizumab or immunomodulatory drugs with antiangiogenic properties such as Thalidomide, Lenalidomide, and Pomalidomide may be effective in treating HHT. There are presently no FDA approved therapies for HHT.

PATH-HHT is a randomized, placebo-controlled, multicenter clinical trial, conducted in the US to determine the safety and efficacy of Pomalidomide, for bleeding in HHT. In this study, 144 patients (N=144) diagnosed with HHT were randomly assigned in a 2:1 ratio to receive either Pomalidomide 4 mg orally daily or a matching placebo, for a duration of six months. Pomalidomide, instead of another immunomodulatory drug, was chosen due to its favorable safety profile. Eligibility criteria included a confirmed HHT diagnosis per Curaçao Diagnostic Criteria, documented anemia, and an Epistaxis Severity Score (ESS) of 3 or more over the prior 3 months. Epistaxis Severity Score (ESS) was developed to self- describe epistaxis severity from 0-10, with 10 representing the most severe epistaxis. Mild is ESS of 1-4, moderate is ESS of 4-7 and Severe is ESS of 7-10. The mean age was 59 years and 48% were female. Among the 134 patients who agreed to genetic testing, ENG mutations were detected in 37%, ACVRL1 in 51%, and SMAD4 in 1%. Patients had a mean ESS of 5 at baseline, and mean daily epistaxis duration of 16 minutes. In the preceding 6 months, 84% of patients had required iron infusions and 19% required blood transfusions. More than a third of the patients also had GI bleeding, and 40% had pulmonary AVMs. The Primary endpoint of the study was the change in Epistaxis Severity Score (ESS), from baseline to the end of the six-month treatment period. Secondary endpoints included changes in the average daily self-reported duration of epistaxis from the 4 weeks preceding the baseline visit to weeks 20-24 of treatment, the amount of parenteral iron infused or blood transfused, and change in Quality-of-Life (QOL) measurements, including an HHT-specific QOL score.

The results of this study showed that treatment with Pomalidomide led to a significant reduction in epistaxis severity compared to placebo. The mean ESS decreased by -1.84 in the Pomalidomide group versus -0.89 in the placebo group at 24 weeks (P=0.003). This benefit was seen as early as week 12. Additionally, patients treated with Pomalidomide reported greater improvements in Quality of Life (QOL) related to HHT. The HHT-specific QOL score (ranges from 0-16 with higher scores indicating more limitations) also decreased more in the Pomalidomide group versus the placebo group at 24 weeks (P=0.015). Adverse events were more common in the Pomalidomide group and included mild to moderate neutropenia (45% versus 10%), constipation/diarrhea (60% versus 37%), and rash (36% versus 10%).

It was concluded from this largest HHT study that treatment with Pomalidomide demonstrated a significant and highly clinically relevant reduction in epistaxis, as well as an improvement in the HHT-specific QOL score. Pomalidomide holds promise as a therapeutic option for patients with HHT, addressing an unmet medical need, in managing this challenging genetic disorder. Additional studies may identify biomarkers predicting responses to Pomalidomide.

PATH-HHT, a Double-Blind, Randomized, Placebo-Controlled Trial in Hereditary Hemorrhagic Telangiectasia Demonstrates That Pomalidomide Reduces Epistaxis and Improves Quality of Life. Al-Samkari H, Kasthuri RS, Iyer V, et al. Blood (2023) 142 (Supplement 2): LBA-3. https://doi.org/10.1182/blood-2023-191983.

ROZLYTREK® (Entrectinib)

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The FDA on October 20, 2023, granted accelerated approval to ROZLYTREK® for pediatric patients older than 1 month with solid tumors that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. In August 2019, FDA granted accelerated approval to ROZLYTREK® for pediatric patients 12 years of age and older for this indication. ROZLYTREK® is a product of Genentech Inc.

TEMODAR® (Temozolomide)

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The FDA on September 14, 2023, approved updated labeling for TEMODAR® under Project Renewal, an Oncology Center of Excellence (OCE) initiative aimed at updating labeling information for older oncology drugs to ensure information is clinically meaningful and scientifically up-to-date. This is the second drug to receive a labeling update under this pilot program. The first drug that received approval under Project Renewal was XELODA® (Capecitabine). TEMODAR® is a product of Merck & Co., Inc..

HEPZATO® KIT (Melphalan for Injection/Hepatic Delivery System)

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The FDA on August 14, 2023, approved HEPZATO® KIT as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. HEPZATO® is a product of Delcath Systems, Inc.

Single Blood Test for Multi-Cancer Early Detection

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SUMMARY: The American Cancer Society estimates that in 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Although cancer mortality rates continue to decline with advances in treatment, improving early detection can reduce disease and treatment-related morbidity, improve treatment outcomes, quality of life and reduce financial burden both for the patient as well as the society as a whole. Currently the USPSTF (Unites States Preventive Services Task Force) and ACS (American Cancer Society) recommend screening for breast, cervical, colorectal, and lung cancers. Neither the ACS nor USPSTF have specific recommendations for prostate cancer screening. These cancers collectively account for only 42% of annual cancer incidence in people aged 50-79 years. It has been estimated that detection of cancer at an earlier stage could reduce cancer-related deaths by 15% or more within 5 years. Some of the available screening tests reduce cancer-specific mortality, but are associated with high false-positive rates, overdiagnosis, and overtreatment.

Galleri is a Multi-Cancer Early Detection (MCED) test developed for the early detection of multiple asymptomatic cancers that lack recommended screening tests, using a blood sample. DNA (cell free DNA) is shed into the blood stream both by tumor cells as well as healthy cells. The Galleri test uses Next Generation Sequencing (NGS) and machine-learning algorithms to isolate cell-free DNA and analyze more than 100,000 DNA regions and over a million specific DNA sites, to screen for a signal shared by cancers. The test looks for cell-free DNA and identifies whether it comes from healthy or cancer cells. DNA from cancer cells has specific methylation patterns that identify it as a cancer signal. Methylation patterns also contain information about the tissue type or organ associated with the cancer signal. So, once a cancer signal is detected, the Galleri test predicts the Cancer Signal Origin, or the tissue or organ where the cancer signal originated, to help guide diagnostic evaluation. The Galleri test is recommended for use in adults with an elevated risk for cancer, such as those aged 50 or older, and should be used in addition to routine cancer screening tests. Galleri is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.

A validation study (Circulating Cell-free Genome Atlas study-CCGA) was conducted to evaluate the accuracy of the Galleri test. This study included 2,823 people with a known diagnosis of cancer and 1,254 healthy people. The overall Sensitivity for cancer signal detection was 51.5% and the Specificity was 99.5%. The sensitivity of the test increased with advanced cancer stages. Cancer signals were detected across over 50 cancer types and the overall accuracy of predicting Cancer Signal Origin in those who tested true positive was 88.7% (Ann Oncol. 2021;32:1167-1177).

PATHFINDER was a pilot, prospective cohort study conducted to investigate the feasibility of MCED testing for cancer screening. This study included 6,621 participants from oncology and primary care outpatient clinics at seven U.S. health networks who underwent MCED blood testing. Participants were 50 years or older, with no signs or symptoms of cancer, and majority were women (63.5%) and White (91.7%). Approximately 56% of participants had additional risk factors such as smoking, germline cancer predisposition, or personal history of treated cancer. The Primary outcome was time to diagnosis, and extent of diagnostic testing required to confirm the presence or absence of cancer.

MCED testing detected a cancer signal in 1.4% of the total patient sample of whom 38% had cancer confirmed (true positives), while 62% had no cancer (false positives). In patients in whom no cancer signal was detected, 95.5% were true negatives, 1.3% was false negatives, and 3.2% did not have cancer-status assessment at the end of the study. The tests accuracy in predicting the primary cancer location (Cancer Signal Origin) among the true positives was high at 97%. The median time to achieving a diagnostic resolution was 79 days, 57 days in true-positive patients and 162 days in false-positive ones. Fewer procedures were done in participants with false-positive results compared to true-positive results (30% versus 82% respectively) and few participants had surgery (one with a false-positive result and three with a true-positive result).

Among participants whose testing was true-positive and who had a confirmed new cancer diagnosis, nearly half (48%) were detected at an early stage (Stage I-II) when the potential for curative treatment is increased. Further, 74% of the MCED-detected cancers were cancer types that do not currently have USPSTF screening recommendations. These included cancers of the bile duct, pancreas, small intestine, and spindle cell neoplasm, which are all associated with high mortality rates and may be amenable to surgical resection at early stages.

In the 12 months study period, 121 cancers were diagnosed, of whom 29% had a cancer signal detected by MCED, while 31% were detected thru screening and 40% were detected clinically. The overall Positive Predictive Value of MCED was 38%, Negative Predictive Value was 98.6%, and specificity was 99.1%. The cancer yield rate was 0.53% (number needed to screen to find one MCED-detected cancer was 189).

The researchers concluded that this study demonstrates the feasibility of screening for multiple cancers using a blood test and lays the foundation for large, controlled trials necessary to establish clinical utility and cost-effectiveness. Multi Cancer Early Detection test was also able to accurately predict tumor origin, and the diagnosis of cancer was established in less than 2 months in the true-positive patients.

Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Schrag D, Beer TM, McDonnell CH, et al. The Lancet 2023;402:1251-1260.