The FDA on November 8, 2024, approved AUCATZYL®, a CD19-directed genetically modified autologous T cell immunotherapy, for adults with Relapsed or Refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL). AUCATZYL® is a product of Autolus Inc.
Author: RR
SCEMBLIX® (Asciminib)
The FDA on October 29, 2024, granted accelerated approval to SCEMBLIX® (Asciminib) for adult patients with newly diagnosed Philadelphia chromosome-positive Chronic Myeloid Leukemia (Ph+ CML) in Chronic Phase (CP). SCEMBLIX® is a product of Novartis AG.
VYLOY® (Zolbetuximab-clzb)
The FDA on October 18, 2024, approved VYLOY®, a Claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with Fluoropyrimidine- and Platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic Human Epidermal growth factor Receptor 2 (HER2)-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. VYLOY® is a product of Astellas Pharma US, Inc.
ITOVEBI® (Inavolisib)
The FDA on October 10, 2024, approved ITOVEBI® with Palbociclib and Fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, Human Epidermal growth-factor Receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. ITOVEBI® is a product of Genentech, Inc.
FDA Approves IMFINZI® after Chemoradiotherapy in Limited-Stage Small Cell Lung Cancer
SUMMARY: The FDA on December 4, 2024, approved Durvalumab (IMFINZI®) for adults with Limited Stage-Small Cell Lung Cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. The American Cancer Society estimates that for 2024 about 234,580 new cases of lung cancer will be diagnosed and about 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive. Limited Stage-Small Cell Lung Cancer – LS-SCLC (Stage I-III) accounts for approximately 30% of SCLC diagnoses and the disease is confined to one hemithorax. These patients are often treated with a combination of Carboplatin or Cisplatin with Etoposide and radiotherapy. Despite initial response, LS-SCLC typically recurs and progresses rapidly, and only 15-30% of patients are alive, five years after diagnosis.
Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic, and more recently immunotherapy with checkpoint inhibitors has demonstrated clinical activity in SCLC. Durvalumab (IMFINZI®) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. Tremelimumab (IMJUDO®) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses.
The rationale for the ADRIATIC trial was supported by findings from the pivotal Phase III PACIFIC and CASPIAN trial. In the PACIFIC trial, Durvalumab after concurrent chemoradiotherapy for Stage III Non-Small Cell Lung Cancer, improved both Overall Survival (OS) and Progression Free Survival (PFS), whereas in the CASPIAN trial, Durvalumab with Platinum and Etoposide chemotherapy significantly improved OS, compared to chemotherapy alone, in newly diagnosed patients with extensive-stage SCLC.
The ADRIATIC trial is a Phase III, randomized, double-blind, placebo-controlled, multicenter, global study that assessed the efficacy and safety of Durvalumab as consolidation therapy in patients with Limited-Stage Small Cell Lung Cancer (LS-SCLC) who had not progressed after concurrent platinum-based chemoradiotherapy. This trial randomized 730 patients with Stage I to III LS-SCLC, including those with inoperable Stage I/II disease. Eligible patients had a WHO Performance Status of 0 or 1 and had not experienced disease progression after completing concurrent chemoradiotherapy. Chemotherapy consisted of a combination of Platinum plus Etoposide for up to 4 cycles, and the radiation therapy could either be once daily up to 66 Gy, or twice a day up to 45 Gy. Prophylactic Cranial Irradiation (PCI) was allowed before randomization. Patients were randomized within 6 weeks after completing concurrent chemoradiotherapy to experimental arms Durvalumab monotherapy 1500 mg IV every 4 weeks with or without Tremelimumab 75 mg IV every 4 weeks for up to 4 cycles each, followed by Durvalumab every four weeks for up to 24 months or Placebo every 4 weeks. There was a protocol amendment in November 2020, and patients were randomly assigned in a 1:1 ratio to the Durvalumab group or placebo group only. Baseline characteristics and prior treatment were well balanced between groups. The median age was 62 years and 87% of patients had Stage III disease at diagnosis. This analysis compared the outcomes in patients assigned to receive Durvalumab monotherapy (N=264) with patients who received placebo (N=266). The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) for Durvalumab monotherapy versus placebo. Key Secondary endpoints included OS and PFS for Durvalumab plus Tremelimumab versus placebo, Safety, and Quality of Life measures. The median duration of follow-up for OS and PFS in censored patients at this first planned interim analysis was 37.2 and 27.6 months, respectively.
Durvalumab demonstrated a statistically significant improvement in OS compared to placebo (HR=0.73; P=0.01), translating to a 27% reduction in the risk of death. The estimated median OS with Durvalumab was 55.9 months, compared to 33.4 months with placebo. The 24-month OS rate was 68% with Durvalumab versus 58.5% with placebo, and the 36-month OS rate was 56.5% versus 47.6%, respectively. The median PFS was 16.6 months with Durvalumab versus 9.2 months with placebo, representing a 24% reduction in the risk of disease progression or death (HR=0.76; P=0.02). The 18-month PFS rate was 48.8% with Durvalumab versus 36.1% with placebo, and the 24-month PFS rate was 46.2% with Durvalumab versus 34.2% with placebo. Treatment benefit was generally consistent across predefined patient subgroups for both OS and PFS. Grade 3/4 Adverse Events (AEs) were similar in both treatment groups at 24.3%, but treatment discontinuation due to AEs was slightly higher in the Durvalumab arm (16.3% versus 10.6% in the placebo arm). Any grade pneumonitis was reported in 38.0% of patients in the Durvalumab arm compared to 30.2% in the placebo arm.
The results of the ADRIATIC trial represent a significant advancement in the treatment of Limited Stage-Small Cell Lung Cancer (LS-SCLC). Durvalumab consolidation therapy demonstrated a statistically significant and clinically meaningful improvement in both OS and PFS compared to placebo. These findings support Durvalumab as a new standard of care for patients with LS-SCLC following concurrent chemoradiotherapy, potentially changing the treatment landscape for this aggressive disease.
Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. Cheng Y, Spigel DR, Cho BC, et al. for the ADRIATIC Investigators. N Engl J Med 2024;391:1313-1327.
Stockholm3 Blood Test Identifies Aggressive Prostate Cancer
SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.
PSA (Prostate Specific Antigen) is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on PSA levels remains controversial, and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. PSA test CANNOT distinguish between aggressive and benign cancer. As a result, many men have to undergo unnecessary follow-ups with a biopsy of the prostate. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. PSA test is also difficult to interpret, and PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer.
Stockholm3 is a blood test that combines 5 protein biomarkers, 101 genetic markers, and clinical data with an advanced algorithm, in order to detect almost 100% of aggressive prostate cancers at an early stage. The Stockholm3 test provides an answer that can be negative or positive. A negative answer represents low or normal risk of developing prostate cancer, whereas referral to an urologist is recommended if the test is positive. The Stockholm3 test has been validated in over 75, 000 men and has been used in health systems in Sweden, Norway, Finland, Germany, Switzerland, UK and Turkey, and results have been published in international peer-reviewed journals. Evidence suggests that Stockholm3 is more effective at predicting risk than PSA testing alone, for men aged 45-74 with PSA of at least 1.5ng/ml. Several studies have shown that the application of this test can reduce the number of biopsies by 32%, without compromising the diagnostic capacity of intermediate grade prostate cancers (Gleason 7 or higher), in comparison with the use of the PSA value 3 ng/ mL as cut-off value for biopsy recommendation. However, none of the validation studies included ethnically diverse population.
SEPTA is a prospective trial conducted to validate Stockholm3 in an ethnically diverse population, for prostate cancer risk stratification, and determine whether it could achieve noninferior sensitivity and superior specificity in this diverse population. This trial included men who were referred for prostate biopsy at North American sites from 2019 to 2023. Study participants had no previous diagnosis of prostate cancer. This study also used bio-banked specimens from 2008 to 2020. The cohort comprised 912 enrolled men and 1,217 with bio-banked blood. The median age was 63 years, 46% were White, 24% Black, 16% Asian and 14% were Hispanic.
This trial had 2 prespecified Primary goals: 1) Demonstrate noninferiority of the test in detecting Clinically Significant Prostate Cancer (defined as Gleason Grade group 2 or more), compared to PSA testing. 2) Prove superior specificity of the test versus PSA testing, thereby reducing the number of biopsies in men with benign or Gleason Grade group 1 biopsies. A Secondary goal was to evaluate Stockholm3 and PSA across ethnic subgroups. The study assessed Stockholm3 performance using prespecified thresholds and compared it to PSA across different ethnic subgroups. Statistical analysis plans were established before data analysis.
It was noted that the median PSA and Stockholm3 values among the participants were 6.1 ng/mL and 17, respectively. A total of 16% underwent MRI-targeted biopsies, and 20% had a prior benign biopsy. On biopsy, 29% were diagnosed with Clinically Significant Prostate Cancer, 14% with Gleason Grade group 1 cancer, and 57% with benign findings. The detection rate for Clinically Significant Prostate Cancer varied across ethnic groups: African American/Black (37%), White/Caucasian (28%), Hispanic/Latino (29%), and Asian (21%).
Overall, Stockholm3 value 15 or higher demonstrated noninferiority to a PSA value of 4 ng/mL or higher and nearly three times superior specificity. These results were consistent across ethnic subgroups. The researchers noted that using a Stockholm3 value of 15 or higher would have reduced benign and Gleason Grade group 1 biopsies by 45% overall and between 42-52% across ethnic subgroups, compared to PSA of 4 ng/ml or higher.
The study concluded that in an ethnically diverse population, Stockholm3 could significantly reduce unnecessary biopsies and diagnoses of low-grade tumors, while maintaining similar sensitivity to PSA, for detecting Clinically Significant Prostate Cancer. The results suggest that
Stockholm3 could improve risk stratification and reduce harms associated with prostate cancer screening in diverse populations.
Stockholm3 in a Multiethnic Cohort for Prostate Cancer Detection (SEPTA): A Prospective Multicentered Trial. Vigneswaran HT, Eklund M, Discacciati A, et al. on behalf of the SEPTA STHLM3 Study Group. J Clin Oncol. 2024;42:3806-3816. DOI:10.1200/JCO.24.00152.
TAGRISSO® after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC
SUMMARY: The FDA on September 25, 2024, approved Osimertinib (TAGRISSO®) for adult patients with locally advanced, unresectable (Stage III) Non-Small Cell Lung Cancer (NSCLC) whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).
EGFR (Epidermal Growth Factor Receptor) mutations are found in up to one third of patients with unresectable Stage III NSCLC. There are currently no approved targeted treatments for patients with unresectable Stage III EGFR-mutated NSCLC. The current standard of care, which includes consolidation therapy with Durvalumab, may not offer clear benefits to this subset of patients with EGFR mutations.
Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (TKI), presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Osimertinib is also approved by the FDA as adjuvant treatment for resected Stage IB–IIIA EGFR-mutated NSCLC. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.
LAURA was a global, randomized, double-blind, placebo-controlled, multicenter Phase III trial conducted to assess the efficacy and safety of Osimertinib in patients with unresectable Stage III NSCLC harboring EGFR mutations (EGFR exon 19 deletion or exon 21 L858R mutation). The trial enrolled patients who had not experienced disease progression during or after definitive platinum-based chemoradiotherapy (CRT). A total of 216 patients who had undergone CRT were randomly assigned 2:1 to receive Osimertinib 80 mg orally once daily (N=143) or placebo once per day (N=73). Treatment was continued until Blinded Independent Central Review (BICR)–assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Upon disease progression, patients in the placebo arm were permitted to receive Osimertinib, allowing for crossover therapy. Stratification factors included method of CRT (concurrent versus sequential) and disease Stage (IIIA versus IIIB/C). Both treatment groups were well balanced. The median patient age was 63 years, approximately 60% of participants were female, 83% were Asian, 69% had never smoked and 85% had Stage IIIA and B disease. Majority of patients received concurrent CRT rather than sequential CRT. The Primary end point was Progression Free Survival (PFS) as assessed by BICR. Key Secondary end points included Overall Survival (OS), survival without progression of CNS disease (CNS Progression Free Survival), Objective Response Rate (ORR), Duration of Response, Quality of Life, and Safety.
Treatment with Osimertinib resulted in significant PFS improvement compared to placebo. The median PFS was 39.1 months in the Osimertinib group versus 5.6 months in the placebo group, representing an 84% reduction in the risk of disease progression or death (HR=0.16; P<0.001). Additionally, a higher percentage of patients in the Osimertinib group remained alive and progression-free at 12 months compared to the placebo group (74% versus 22% respectively). Subgroup analyses were conducted to evaluate the consistency of treatment effects across various demographic and clinical factors. The benefits of Osimertinib were observed across all prespecified subgroups, indicating a consistent treatment effect, regardless of patient characteristics. The incidence of new lesions was lower with Osimertinib compared to placebo (22% versus 68%), and this included new brain lesions (8% versus 29%) and new lung lesions (6% versus 29%) respectively. The Objective Response Rate was higher with Osimertinib than with placebo (57% versus 33%). The median Duration of Response was longer with Osimertinib (36.9 months) than with placebo (6.5 months). Interim OS data showed a favorable trend for Osimertinib, although maturity was limited at the time of analysis. Further follow-up will be conducted to assess OS as a secondary endpoint. The adverse event profile of Osimertinib was generally consistent with previous studies. Grade 3 or higher adverse events occurred more frequently in the Osimertinib group, with radiation pneumonitis being the most common. However, no new safety concerns emerged during the trial.
In summary, treatment with Osimertinib resulted in significantly longer Progression Free Survival than placebo in patients with unresectable Stage III EGFR-mutated NSCLC following definitive CRT, and should be considered the new standard of care for this group of patients. Overall, the LAURA study represents a major breakthrough in the treatment of EGFR-mutated Stage III NSCLC, addressing an unmet need for targeted therapies in this setting. Further follow-up will provide additional insights into the long-term efficacy and safety of Osimertinib in this patient population.
Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. Lu S, Kato T, Dong X, et al. for the LAURA Trial Investigators. N Engl J Med. 2024;391:585-597.
FDA Grants Accelerated Approval to ZIIHERA®for Metastatic HER2-Positive Biliary Tract Cancer
SUMMARY: The FDA on November 20, 2024, granted accelerated approval to Zanidatamab-hrii (ZIIHERA®), a bispecific HER2-directed antibody, for previously treated, unresectable or metastatic HER2-positive (IHC 3+) Biliary Tract Cancer (BTC), as detected by an FDA-approved test. The FDA simultaneously also approved VENTANA PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody as a companion diagnostic device to aid in identifying patients with BTC who may be eligible for treatment with Zanidatamab.
Biliary Tract Cancer (Cholangiocarcinoma) is a rare and highly aggressive heterogenous cancer and is the second most common type of primary liver cancer after Hepatocellular carcinoma. It comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. It is estimated that approximately 211,000 patients are diagnosed with Biliary Tract Cancer and 174,000 patients will die of the disease each year globally. Biliary Tract Cancer is most frequently diagnosed in patients between 50 to 70 years old, and 75% of patients are diagnosed at an advanced stage. BTCs consist of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and Ampulla of Vater cancer. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. Patients diagnosed with Biliary Tract Cancer have a very poor prognosis, and the 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an urgent unmet need for new effective therapies. Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment.
BTCs are heterogenous and thus their pathogenesis and genomic drivers may vary. HER2 overexpression or gene amplification is one of the genomic drivers and HER2 overexpression rates vary depending on the anatomic origin of the Biliary Tract Cancer. Extrahepatic cholangiocarcinoma has a higher rate of HER2 overexpression (about 16-18%), compared to intrahepatic cholangiocarcinoma (about 5%), and about 10-16% for gallbladder cancers, making HER2 a potential therapeutic target in a vast majority of these patients.
Zanidatamab is a novel HER2-targeted, humanized, immunoglobulin G1 (IgG1), bispecific monoclonal antibody, that targets two distinct non-overlapping extracellular domains of HER2, ECD2 and ECD4 (biparatopic binding). This results in dual HER2 signal blockade, HER2 clustering, receptor internalization, and downregulation. This inhibits HER2 activation, HER2-mediated signaling and HER2-mediated tumor cell growth. The specific binding of Zanidatamab to tumor cells and HER2 aggregation also activates various immune-mediated responses, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP) against tumor cells that overexpress HER2. Zanidatamab binds to HER2-expressing tumor cells with greater antibody saturation than Trastuzumab or Pertuzumab.
The present FDA approval was based on data from HERIZON-BTC-01 (NCT04466891), a pivotal Phase 2b, open-label, multicenter, single-arm trial, that evaluated the efficacy and safety of Zanidatamab in patients with HER2-positive BTC. This study included 87 patients with unresectable or metastatic HER2-positive BTC, and all patients received at least one prior Gemcitabine-containing regimen in the advanced disease setting. The median age was 64 years, 54% were women, 66% were Asian, 52% had gallbladder cancer, 30% had intrahepatic cholangiocarcinoma and 18% had extrahepatic cholangiocarcinoma. Patients received Zanidatamab at 20 mg/kg IV every two weeks in 28-day cycles.
Patients were assigned to one of two cohorts based on immunohistochemistry (IHC) status.
Cohort 1 (HER2-positive): Patients with IHC 3+ or IHC 2+ disease (N=80 total, including 62 with IHC 3+).
Cohort 2 (HER2-negative): Patients with IHC 0 or 1+ disease (N=7).
The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) as determined by an Independent Central Review.
Among the 62 patients with IHC3+ status per central assessment, the ORR was 52% and the median DOR was 14.9 months. The median Overall Survival was 18.1 months for IHC 3+ patients and 5.2 months for IHC 2+ patients. Common treatment related adverse events included diarrhea, infusion related reactions, nausea, vomiting, fatigue, and elevated liver enzymes. Treatment discontinuation rate was 2.3%.
In conclusion, the approval of Zanidatamab represents a significant advancement in the management of HER2-positive BTC and a critical unmet need. A Phase 3 trial is planned to evaluate Zanidatamab in the first-line setting for metastatic BTC.
Zanidatamab in previously-treated HER2-positive (HER2+) biliary tract cancer (BTC): Overall survival (OS) and longer follow-up from the phase 2b HERIZON-BTC-01 study. Pant S, Fan J, Oh D-Y, et al. J Clin Oncol. 2024;42(suppl 16):4091. doi:10.1200/JCO.2024.42.16_suppl.4091.
FDA Approves REVUFORJ® for Acute Leukemia with KMT2A Translocation
SUMMARY: The FDA on November 15, 2024, approved Revumenib (REVUFORJ®), a menin inhibitor, for Relapsed or Refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older. The American Cancer Society estimates that in 2024, 20,800 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,220 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium. Over 50% of AML cases lack targetable mutations, relying instead on toxic chemotherapy.
Rearrangements of KMT2A gene previously known as MLL are found in 80% of infant Acute Lymphoblastic Leukemia (ALL) and in 5-15% of acute leukemia cases in children and adults, including myeloid, lymphoid, or mixed phenotypes. NPM1 mutations are the most common genetic alteration in adult Acute Myeloid Leukemia (AML), occurring in up to 30% of cases. Acute leukemias with KMT2A rearrangements have a poor prognosis, with a 5-year overall survival rate of less than 25%. There are no targeted therapies currently approved specifically for acute leukemia with KMT2A gene rearrangements or NPM1 mutations. Both KMT2A gene rearrangements and NPM1 mutations cause blood cells to regress to a stem-cell-like state, leading to the formation of leukemia cells. For leukemias driven by KMT2A gene rearrangements and NPM1 mutations, menin is a critical oncogenic cofactor. Menin interacts with the protein MLL1 (produced by KMT2A), forming a menin–MLL1 complex. This complex binds to chromatin and activates aberrant gene pathways, specifically HOX genes and their cofactor MEIS1, critical for leukemia development.
Revumenib is a potent, oral, small molecule menin inhibitor. It blocks the menin–MLL1 interaction, preventing the formation of the menin–MLL1 complex. By disrupting this complex, Revumenib stops the aberrant activation of HOX and MEIS1 gene expression and allows leukemia cells to either die or differentiate back into normal blood cells. Unlike other targeted therapies that block dysfunctional proteins, Revumenib prevents aberrant gene expression at its source. Its ability to target a common mechanism in AML makes it broadly applicable. Preclinical Studies demonstrated that menin inhibition reverses leukemia progression by downregulating HOX and MEIS1 transcription disrupting oncogenic complexes formed by either option for patients with KMT2A gene arrangements or NPM1-mutated AML. Revumenib showed dramatic antileukemic activity, making this agent promising.
AUGMENT-101 is a single-arm cohort of an open-label, multicenter trial which included 104 adult and pediatric patients (at least 30 days old) with Relapsed or Refractory (R/R) acute leukemia with a KMT2A translocation. Eligible patients had a corrected QT interval of less than 450 milliseconds and those with an11q23 partial tandem duplication were excluded. Revumenib was administered at a dose that was approximately equivalent to 160 mg in adults orally twice daily. Treatment was continued until progressive disease, unacceptable toxicity, failure to achieve a morphological leukemia-free state by 4 cycles of treatment, or Hematopoietic Stem Cell Transplantation (HSCT). The median patient age was 37 years, 83% of patients had AML, 15% had Acute Lymphoblastic Leukemia, and 2% had mixed phenotype acute leukemia. Approximately 59% had relapsed/refractory disease, 21% had primary refractory disease, 20% of patients had untreated relapsed disease and 44% of patients underwent prior HSCT. The main efficacy outcome measures were Complete Remission (CR) plus CR with partial hematologic recovery (CRh), the duration of CR plus CRh, and conversion from transfusion dependence to independence.
The CR plus CRh rate was 21.2%, and the median CR plus CRh duration was 6.4 months. Of the 22 patients achieving CR or CRh, the median time to CR or CRh was 1.9 months. Among the 83 patients dependent on RBC and/or platelet transfusions at baseline, 14% became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 21 patients independent of both RBC and platelet transfusions at baseline, 48% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions noted in this study were hemorrhage, nausea, increased phosphate, musculoskeletal pain, neutropenia, infection, elevated liver enzymes, differentiation syndrome, QT prolongation and fatigue.
It was concluded that Revumenib is the first menin inhibitor and its efficacy represents a substantial improvement over previously available therapies, and represents a major breakthrough for patients with Relapsed or Refractory acute leukemia with a KMT2A translocation.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation
Early Detection of Pancreatic Cancer with an Exosome-Based Liquid Biopsy
SUMMARY: The American Cancer Society estimates that in 2024, about 66,440 people will be diagnosed with pancreatic cancer and 51,750 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes.
Several multi-cancer early detection tests are being developed that involve blood-based circulating cell-free tumor DNA (cfDNA) in the plasma, to track hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD) , as well as detection of abnormal methylation patterns, followed by machine learning approaches, to differentiate between cancer and non-cancer for detecting clinically significant, late-stage (III and IV) cancers. Early detection of cancer, however, is the key to improving survival. This is particularly relevant for certain cancer types. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers, and a leading cause of all cancer-related deaths in the United States and is typically detected when the disease is advanced. However, when detected at Stage I, survival rates can be as high as 80%. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is NOT recommended by the FDA for screening, as it may be elevated in several benign conditions. Currently, there are no general screening strategies to detect asymptomatic, early-stage PDAC and there is therefore a significant unmet need in this patient group.
Exosomes are 30-150 nm-sized Extracellular Vesicles (EVs) secreted by multiple different cell types and released by tumors into the bloodstream. They mediate intercellular signaling by shuttling mRNAs and microRNAs between distant cells and tissues and therefore carry functional protein biomarkers representing the tumor proteome. MicroRNAs play a role in regulating gene expression and have been implicated in various cancer types due to their stability and specific expression patterns associated with tumor presence. Exosomes retain the cytoplasmic content of the cell from which they were shed, essentially replicating the biology of their tissue of origin. Exosomes represent one potential approach for more sensitive detection of cancer-related biomarkers from blood.
The researchers developed an exosome-based liquid biopsy signature as a diagnostic tool to detect pancreatic cancer through the analysis of circulating biomarkers in blood samples. This signature utilizes two primary types of biomarkers – Eight microRNAs unique to exosomes shed from pancreatic cancer cells, combined with five cell-free DNA (cfDNA) markers such as mutations or alterations in DNA methylation patterns found in the blood of patients with pancreatic cancer.
In previous work, researchers had tested an exosome-based liquid biopsy signature on a cohort of 95 individuals from either the United States or Japan. This initial study reported an impressive 98% detection rate for pancreatic cancer. Building on this success, the latest research aimed to validate this liquid biopsy approach in larger, more diverse populations across multiple institutions and countries.
The most recent study involved a comprehensive, multi-cohort evaluation to assess the performance of the exosome-based liquid biopsy signature. The study enrolled participants from four countries, each contributing both pancreatic cancer patients and healthy donors:
• Japan: 150 individuals with pancreatic cancer and 102 healthy donors
• United States: 139 individuals with pancreatic cancer and 193 healthy donors
• South Korea: 184 individuals with pancreatic cancer and 86 healthy donors
• China: 50 individuals with pancreatic cancer and 80 healthy donors
The research methodology involved training the liquid biopsy signature using data from the Japanese cohort. Machine learning algorithms were likely used to train and validate the diagnostic model, optimizing its sensitivity and specificity. After training the signature on the Japanese cohort, the researchers validated its performance using data from cohorts in the United States, South Korea, and China. Each of these cohorts included a mix of pancreatic cancer patients and healthy controls, allowing for an assessment of the signature’s performance across diverse populations.
The performance of the liquid biopsy signature across different cohorts was as follows:
• United States Cohort: The test detected 93% of pancreatic cancers.
• South Korean Cohort: The test detected 91% of pancreatic cancers.
• Chinese Cohort: The test detected 88% of pancreatic cancers.
These validation results demonstrated the signatures robustness and effectiveness in detecting pancreatic cancer across different ethnic and geographic backgrounds, although there was a noted decrease in detection rates with different cohorts.
To enhance the diagnostic accuracy, the researchers combined their exosome-based signature with the traditional pancreatic cancer marker CA 19-9, a carbohydrate antigen often elevated in pancreatic cancer but is less sensitive for detecting early-stage disease. The combination of the exosome-based signature with CA 19-9 improved the detection rate of early-stage pancreatic cancers (Stage I and II) to 97% in the U.S. cohort. This suggests that the combination approach offers a more comprehensive evaluation than CA 19-9 alone.
In conclusion, the exosome-based liquid biopsy signature represents a significant advancement in the early detection of pancreatic cancer. By leveraging the unique properties of exosomal microRNAs and cfDNA, the researchers have developed a diagnostic tool with high sensitivity and specificity. The successful validation in multiple cohorts underscores its potential utility in clinical practice. This assay may be helpful for early detection of pancreatic cancer in certain groups with a high risk for pancreatic cancer such as a family history of pancreatic cancer, germline BRCA mutations, new-onset diabetes, chronic pancreatitis or pancreas precancer lesion such as intraductal papillary mucinous neoplasm. However, addressing the limitations and further optimizing the technology will be crucial for its widespread adoption and effectiveness in diverse populations.
An exosome-based liquid biopsy for non-invasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter and prospective study. Xu C, Xu Y, Han H, et al. AACR Annual Meeting 2024. Abstract 3899. Presented April 8, 2024.