Category: Hem/Onc Updates

TAGRISSO® after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

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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

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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

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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

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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.

FDA Grants Accelerated Approval to SCEMBLIX® for Newly Diagnosed Chronic Myeloid Leukemia

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SUMMARY: The FDA on October 29, 2024, granted accelerated approval to Asciminib (SCEMBLIX®), for adult patients with newly diagnosed Philadelphia Chromosome-positive Chronic Myeloid Leukemia (CML) in chronic phase. The American Cancer Society estimates that about 9,280 new CML cases will be diagnosed in the United States in 2024 and about 1,280 patients will die of the disease. Chronic Myeloid Leukemia constitutes about 15% of all new cases of leukemia and the average age at diagnosis of CML is around 64 years. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.

The Tyrosine Kinase Inhibitors (TKIs) approved for newly diagnosed chronic phase CML in the United States share the same therapeutic target, which is the ATP-binding site of BCR-ABL1 kinase. They include first-generation TKI Imatinib (GLEEVEC®) or second-generation TKIs Nilotinib (TASIGNA®), Dasatinib (SPRYCEL®), or Bosutinib (BOSULIF®). Imatinib is associated with lower patient response and a higher incidence of disease progression than those with second-generation TKIs, whereas treatment with second-generation TKIs can result in faster, deeper molecular responses than Imatinib in frontline therapy, but are associated with more adverse events, necessitating dose modifications and switching treatments. Further, close to 50% of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive. Therefore, resistance to one of the TKIs, will likely result in resistance to the others as well. Further, the “gatekeeper” T315I mutation, which has been reported in 20% of patients with mutations, confers resistance to all clinically available TKIs except Ponatinib (ICLUSIG®). There is therefore an unmet need for safe and effective frontline therapy for patients with newly diagnosed chronic phase CML

Asciminib (SCEMBLIX®) is a novel, first-in-class, potent and specific, oral BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Instead, it specifically targets the ABL1 myristoyl pocket, also known as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, with activity against native unmutated BCR-ABL1, and all clinically observed ATP-site mutants, including T315I. In a Phase I study, Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom Ponatinib had failed, and those with a T315I mutation.

Asciminib was previously approved by the FDA in the US for the treatment of adults with Philadelphia Chromosome positive chronic phase CML who have previously been treated with two or more TKIs. It is also approved in patients with Philadelphia Chromosome positive chronic phase CML with the T315I mutation.

The ASC4FIRST study is a pivotal Phase III, multi-center, open-label, randomized trial aimed at evaluating the efficacy and safety of Asciminib compared to investigator-selected Tyrosine Kinase Inhibitors (TKIs) in adult patients with newly diagnosed Philadelphia chromosome positive Chronic Myeloid Leukemia in chronic phase (CML-CP). A total of 405 patients were enrolled and were randomly assigned in a 1:1 ratio to receive either Asciminib 80 mg orally once daily (N=201) or investigator-selected TKIs which included Imatinib and second generation TKIs such as Bosutinib, Dasatinib or Nilotinib given at approved doses (N=204). Before randomization, investigators, after discussing with patients, selected a TKI (either Imatinib or one of the second-generation TKIs a patient would take, if randomly assigned to the comparator group-prerandomization selected TKI), considering treatment goals, disease and patient characteristics, and coexisting conditions. Randomization was stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk), and by TKI selected by investigators before randomization. The two Primary objectives of this study were to compare the efficacy of Asciminib with that of investigator-selected TKIs (all members of this class considered together as a group), and to compare the efficacy of Asciminib with that of Imatinib. Asciminib was not compared with second-generation TKIs as a primary objective. The Primary end point for both objectives was Major Molecular Response (defined as BCR/ABL1 transcript levels 0.1% or less on the International Scale at week 48 that did not meet any treatment failure criteria). The Secondary objective of this study was assessment of Major Molecular Response (MMR) at week 48 with Asciminib, as compared with investigator-selected TKIs among patients with second-generation TKIs as their prerandomization-selected TKI. The median follow-up was 16.3 months in the Asciminib group and 15.7 months in the investigator-selected TKI group.

At the 48-week mark, Asciminib demonstrated a significantly higher MMR rate compared to investigator-selected TKIs (67.7% versus 49.0%; P<0.001). Deep molecular response rates (BCR/ABL1 transcript levels 0.01% or less, were also superior in the Asciminib group compared to investigator-selected TKIs (38.8% versus 20.6%). Patients preselected for Imatinib who were randomized to Asciminib achieved an MMR rate of 69.3% compared to 40.2% in the Imatinib group (P<0.001). Among those preselected for second-generation TKIs, the MMR rate was 66.0% for Asciminib versus 57.8% for the second-generation TKI group.

Asciminib exhibited a favorable safety profile with fewer Grade 3 or higher Adverse Events and lower rates of treatment discontinuation due to Adverse Events. Grade 3 or higher Adverse Events for Asciminib was 38%, for Imatinib was 44.4% and for second-generation TKIs was 54.9%. Discontinuation due to Adverse Events for Asciminib was 4.5%, for Imatinib was 11.1% and for Second-generation TKIs was 9.8%.

It was concluded that Asciminib is the only agent to demonstrate superiority over investigator selected standard-of-care TKIs in achieving higher MMR rates at 48 weeks in newly diagnosed chronic phase CML patients, alongside a better safety and tolerability profile. These findings indicate that Asciminib could significantly improve the treatment landscape for this group of patients, offering hope for better disease control and quality of life, thereby addressing key unmet needs in CML management.

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. Hochhaus A, Wang J, Kim DD, et al. for the ASC4FIRST Investigators. N Engl J Med 2024;391:885-898.

Adjuvant TAFINLAR® plus MEKINIST® in Stage III Melanoma – 10 Year Follow up

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SUMMARY: The American Cancer Society estimates that for 2024, about 100,640 new cases of melanoma of the skin will be diagnosed in the United States and 8,290 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early-stage melanoma.

Patients with resected Stage IIB/C disease comprise a significant group of patients at significant risk of recurrence. Patients with Stage IIB disease have primary tumors that are more than 2 mm, and 4 mm or less in thickness, with ulceration (T3b), or more than 4 mm in thickness without ulceration (T4a). Patients with Stage IIC disease have primary tumors more than 4 mm in thickness with ulceration (T4b). Although Stage II melanoma is less advanced than Stage III, the 5-year risk of recurrence in patients with Stage IIB or Stage IIC disease without adjuvant therapy is approximately 35% and 50% respectively. The 5-year Melanoma-Specific Survival (MSS) rates for patients with Stage IIB/IIC disease are similar to those for Stage IIIA, Stage IIIB and Stage IIIC disease.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib) is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with Stage III melanoma, with BRAF V600E or V600K mutations, after complete surgical resection.

COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected Stage III melanoma, and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had Stage IIIA disease, 41% had Stage IIIB disease, and 40% had Stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant Metastasis-Free Survival, Freedom from relapse, and Safety.

The authors had previously reported the results for RFS and Distant Metastasis-Free Survival at 5 years of follow up. Overall survival was not analyzed as the data was not mature. The minimum duration of follow up was 59 months. The RFS at 5 years was 52% with TAFINLAR® plus MEKINIST® and 36% with placebo (HR for relapse or death=0.51). The Distant Metastasis-Free Survival at 5 years was 65% with TAFINLAR® plus MEKINIST® and 54% with placebo (HR for distant metastasis or death=0.55). As has been reported in previous studies, majority of relapses occurred within the first 3 years after surgery.

The researchers herein reported the final results of the COMBI-AD trial after a long-term follow-up of more than 8 years. The RFS continued to favor TAFINLAR® plus MEKINIST® over placebo. The median RFS was 93.1 months with TAFINLAR® plus MEKINIST® and 16.6 months with placebo (HR for relapse or death= 0.52). The estimated RFS at 10 years was 48% with TAFINLAR® plus MEKINIST® and 32% with placebo. A relapse with distant metastasis occurred in 28% of patients in the combination-therapy group and in 37% of patients in the placebo group (HR for distant metastasis or death=0.56). The estimated Distant Metastasis-Free Survival at 10 years was 63% and 48%, respectively. The estimated Overall Survival at 8 years was 71% with TAFINLAR® plus MEKINIST® and 65% with placebo (HR for death=0.80; P=0.06). However, this benefit was not statistically significant. A consistent survival benefit was seen across several prespecified subgroups, including those with BRAF V600E mutated tumors (HR for death=0.75). There was no new safety signals noted.

It was concluded that after nearly 10 years of follow-up, 12 months of adjuvant therapy with a combination of TAFINLAR® plus MEKINIST® resulted in longer Relapse Free and Distant metastasis-free Survival, compared to placebo, among patients with resected Stage III melanoma, with 25% reduction in the risk of death among those with BRAF V600E mutations.

Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. Long GV, Hauschild A, Santinami M, et al. N Engl J Med 2024;391:1709-1720.

Late Breaking Abstract – ESMO 2024: Addition of XTANDI® to XOFIGO® Significantly Improved Survival in Metastatic Castrate Resistant Prostate cancer

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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. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).

For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter, and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral hydroxyapatite, in areas where there is increased bone turnover such as bone metastases. Ra-223 induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike its historical counterpart Ra-226 which was first isolated by Madame Curie, Ra-223 has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure. Ra-223 in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved Overall Survival in patients with CRPC with bone metastases (mCRPC).

Enzalutamide is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens.

The PEACE-3 trial is a pivotal double-blind, randomized Phase III study exploring whether combining Enzalutamide with Ra-223 dichloride provides enhanced efficacy over Enzalutamide monotherapy in mCRPC with bone metastases. As a cooperative effort led by EORTC, CTI, CUOG, LACOG, and UNICANCER, the trial enrolled 426 mCRPC patients (N=426) from 12 countries between 2015 and 2023. Participants were required to have bone metastases, be asymptomatic or mildly symptomatic, and be naïve to prior treatments with Enzalutamide, Ra-223, or other specific anti-androgen therapies (Apalutamide or Darolutamide). Patients were randomized in a 1:1 to receive either Enzalutamide monotherapy (Standard of Care) at 160 mg taken orally once daily, or a combination of Enzalutamide 160 mg daily plus Ra-223 administered at 55 kBq/kg IV every four weeks, for six cycles. Patients were stratified by factors including country, baseline pain scores, prior use of Docetaxel, previous treatment with Abiraterone, and use of bone-protecting agents (which became mandatory after an early protocol amendment). The decision to require bone-protecting agents was driven by fracture rate concerns seen in the ERA-223 study, which had paired Ra-223 with Abiraterone and showed increased fracture risks without these bone-protecting agents. The median age of patients was 70 years and both treatment groups were well balanced. About 30% had received Docetaxel, with fewer than 5% previously treated with Abiraterone. About 42-44% of patients had ten or more bone lesions, and about 37% had elevated alkaline phosphatase levels, an indicator of high bone turnover. The Primary endpoint was radiological Progression-Free Survival (rPFS). Secondary endpoints include Overall Survival (OS), Time to subsequent systemic anti-neoplastic therapy, Time to pain progression, and Time to first symptomatic skeletal event. The median follow-up duration was 42.2 months.

The combination of Enzalutamide and Ra-223 showed a statistically significant improvement in rPFS. Patients in the combination arm had a median rPFS of 19.4 months, compared to 16.4 months for enzalutamide alone (HR=0.69; P=0.0009). Interim results demonstrated a 31% reduction in mortality risk in the combination arm, with median OS extending from 35 months with Enzalutamide alone to 42.3 months with the combination (HR=0.69; P=0.0031). Although nonproportional hazards were observed, necessitating a continued final OS analysis, these interim findings strongly suggest the potential survival benefit with this combination therapy.

Patients on the combination therapy had a significantly longer period before needing subsequent systemic treatments, with a 43% lower risk of starting a new therapy compared to those on Enzalutamide alone (HR=0.57; P< 0.0001). At the two-year mark, 51% of patients in the Enzalutamide-only group required additional treatments, compared to 30% in the combination group. There were no significant differences between the groups in time to pain progression or the onset of Symptomatic Skeletal Events (SSEs), which include fractures and spinal cord compression.

The combination of Enzalutamide plus Ra-223 was well tolerated, although it led to a slight increase in Grade 3 or higher adverse events (28%) compared to 19% in the Enzalutamide monotherapy group. Approximately 30% of patients in both groups experienced hypertension, though severe cases were more frequent in the combination arm. Other common side effects included fatigue and cytopenias. The safety protocol of the study was adjusted to include mandatory bone-protecting agents such as Denosumab or Zoledronate and baseline DEXA scans, contributing to fewer symptomatic skeletal events. Over 80% of patients received these agents during the trial, likely mitigating the risk of fractures and other bone-related adverse effects seen in similar trials.

It was concluded from the PEACE-3 trial that adding 6 cycles of Ra223 to Enzalutamide as first-line therapy for mCRPC patients, significantly improved radiological Progression-Free Survival. A preplanned interim analysis showed a statistically significant Overall Survival benefit favoring the Enzalutamide plus Ra-223 combination, although further analysis will address long-term survival and Quality of Life outcomes.

A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Gillessen S, Choudhury A, Saad F, et al. Annals of Oncology, Volume 35, S1254. September 2024.

SARCLISA® with VRd Regimen for Transplant Ineligible Newly Diagnosed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024, and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails. Additionally, Isatuximab infusions are less cumbersome.

The FDA in September 2024, approved Isatuximab with Bortezomib, Lenalidomide, and Dexamethasone for adults with newly diagnosed multiple myeloma who are not eligible for Autologous Stem Cell Transplant (ASCT). This approval was based on the IMROZ trial (NCT03319667), which was an international, multicenter, open-label, Phase 3, randomized, controlled trial, designed to evaluate the efficacy and safety of Isatuximab in combination with the established regimen of Bortezomib, Lenalidomide, and Dexamethasone (VRd) compared to VRd alone. This study aimed to address a critical gap in treatment options for patients with newly diagnosed multiple myeloma who are ineligible for ASCT, a situation often faced by older patients or those with significant comorbidities. A total of 446 patients, aged 18 to 80 years, with symptomatic, previously untreated multiple myeloma were randomly assigned in a 3:2 ratio to receive either the Isatuximab-VRd regimen (N=263) or the standard VRd regimen alone (N=181). The Induction phase of the treatment consisted of 4 cycles, with each cycle lasting 6 weeks. Patients in the Isatuximab-VRd Group received Isatuximab 10 mg/kg IV weekly during Cycle 1, then every 2 weeks for subsequent cycles. Patients received subcutaneous Bortezomib (1.3 mg/m²) on specified days, along with oral Lenalidomide (25 mg daily for 14 days) and Dexamethasone (20 mg on specified days). The VRd group received the same VRd regimen without Isatuximab. Following the induction phase, both groups continued treatment with a regimen consisting of Lenalidomide and Dexamethasone. For the Isatuximab-VRd group, Isatuximab was given every 2 weeks, transitioning to monthly administration starting at Cycle 18. The median patient age was 72 years and treatment groups were well balanced. The Primary endpoint of the trial was Progression-Free Survival (PFS), assessed by an Independent Review Committee in accordance with International Myeloma Working Group criteria. Secondary endpoints included Complete Response (CR) or better, Minimal Residual Disease (MRD) negativity in patients achieving a Complete Response, assessed at a sensitivity level of 10⁻⁵ using Next-Generation Sequencing, Overall Survival (OS) and Quality of Life measures.

The results from the interim analysis at a median follow-up of 59.7 months demonstrated a significant improvement in PFS for the Isatuximab-VRd group compared to the VRd group. The 60-month PFS was estimated at 63.2% in the Isatuximab-VRd group versus 45.2% in the VRd group (HR=0.60; P<0.001), indicating a 40% reduction in the risk of disease progression or death for the Isatuximab group. Approximately 75% of patients in the Isatuximab-VRd group achieved a Complete Response or better compared to 64.1% in the VRd group (P=0.01). Higher rates of MRD negativity (55.5% vs. 40.9%; P=0.003) were also observed in the Isatuximab group. The safety profile of the Isatuximab-VRd combination mirrored that of established regimens, with no new safety signals identified. Incidences of serious adverse events were comparable between the two groups, though a slight increase in infections and neutropenia was noted with the addition of Isatuximab.

In conclusion, the results from the IMROZ trial clearly indicate that the addition of Isatuximab to the VRd regimen provides significant benefits in terms of Progression-Free Survival and Response Rates in patients with newly diagnosed multiple myeloma who are ineligible for transplantation, addressing an important unmet need. Further follow-up and analyses will continue to elucidate the long-term benefits and safety of this promising therapeutic strategy.

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Facon T, Dimopoulos M-A, Leleu XP, et al. for the IMROZ Study Group. N Engl J Med 2024;391:1597-1609.

IMFINZI® after Chemoradiotherapy in Limited-Stage Small Cell Lung Cancer

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SUMMARY: 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.

Superior Outcomes with First Line OPDIVO® versus ADCETRIS® in Advanced Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 8570 new cases of Hodgkin Lymphoma will be diagnosed and about 910 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In the ECHELON-1 study, frontline treatment with Brentuximab Vedotin (BV) in combination with Doxorubicin, Vinblastine and Dacarbazine (AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival, after a median follow up of 6 years. However, frontline BV adds toxicity, and 7-20% of patients still develop Relapsed/Refractory Hodgkin Lymphoma.

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

SWOG S1826 was an open-label, randomized Phase III trial conducted to compare the combination of Nivolumab plus AVD to Brentuximab Vedotin plus AVD, in patients with advanced-stage classical Hodgkin Lymphoma (cHL). In this study, 976 newly diagnosed Stage III or IV cHL patients (N=976) were randomly assigned 1:1 to receive either 6 cycles of Nivolumab at 240 mg IV on days 1 and 15 (N=489) or Brentuximab Vedotin 1.2 mg/kg IV on days 1 and 15 (N=487). Both treatment groups also received AVD IV (Doxorubicin, Vinblastine, Dacarbazine ) on days 1 and 15, and treatment was repeated every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte-Colony Stimulating Factor (G-CSF) Pegfilgrastim SC on days 2 and 16, or Filgrastim SC on days 6-10 and 21-25 was optional in the Nivolumab group (N-AVD) but was required in the Brentuximab Vedotin group (BV-AVD). Approximately 54% in the N-AVD group received G-CSF compared to 95% in the BV-AVD group. After completion of cycle 6, patients could receive radiation therapy at the discretion of the treating physician, to metabolically active residual lesions noted on the end of treatment PET. Less than 1% of patients had received radiotherapy. Patients were stratified by age, International Prognostic Score (IPS) and intent to use radiation therapy. The median age was 27 years, 76% were Caucasian, 55% were men, 64% had Stage IV disease and 32% had IPS of 4-7. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Event-Free Survival (EFS), Patient-Reported Outcomes (PROs), and Safety.

At the planned 2nd interim analysis, upon recommendation from the SWOG Data and Safety Monitoring Committee, the primary results were reported. With a median follow up of 12.1 months, PFS was superior in the N-AVD group compared to the BV-AVD group (HR=0.48; P=0.001). The 1 year PFS was 94% in the N-AVD group compared with 86% among patients treated with BV-AVD.

The researchers repeated the analysis after an additional one year of follow up, to assess the durability of PFS benefit. At a median follow-up of 2.1 years, the 2-year PFS was 92% with N-AVD compared to 83% with BV-AVD (HR=0.45). The PFS benefit was consistent across prespecified treatment subgroups, including subgroups according to age, disease stage and IPS score. The 2-year EFS was 90% with N-AVD versus 81% with BV-AVD (HR for death=0.50). More importantly, N-AVD was associated with favorable side-effect profile with a lower frequency of neurotoxicities. Further, there was a dramatic reduction in the use of radiation in adolescent patients.

The rate of Grade 3 or more hematologic AEs were 48.4% after N-AVD, compared to 30.5% after BV-AVD. There was however no increase in infectious complications even though there was a higher rate of neutropenia in the N-AVD group. It should be noted that the frequency of neutropenia with BV-AVD was ameliorated by the required use of G-CSF, as compared with the optional use of G-CSF with N-AVD. Hypo/Hyperthyroidism was more frequent after N-AVD whereas peripheral neuropathy was more common after BV-AVD.

The researchers concluded that in this largest Hodgkin Lymphoma study in National Clinical Trials Network (NCTN) history, Nivolumab in combination with AVD significantly improved Progression Free Survival with fewer toxicities, compared to Brentuximab Vedotin in combination with AVD, in patients with advanced stage Hodgkin Lymphoma. Nivolumab in combination with AVD may be the new standard therapy for this group of patients. Follow-up is ongoing to confirm the durability of PFS benefit, and to assess Overall Survival and Patient Reported Outcomes.

Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma. Herrera AF, LeBlanc M, Castellino SM, et al. N Engl J Med 2024;391:1379-1389.