Category: Meeting Updates

FDA Approves RYBREVANT® plus Chemotherapy for EGFR-Mutated NSCLC

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SUMMARY: The FDA on September 19, 2024 approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for adult patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. 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 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of 5 months.

Amivantamab (RYBREVANT®) is a fully-human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, and is approved for the treatment of patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

The efficacy of Amivantamab was assessed in the Phase 3 MARIPOSA-2 trial, a multicenter, open-label study involving 657 patients. These participants, all with EGFR-mutant NSCLC, who had progressed on Osimertinib treatment, were randomly assigned in a 1:2:2 ratio to receive either Amivantamab with Carboplatin and Pemetrexed (referred to as Amivantamab plus chemotherapy-N=131), Carboplatin and Pemetrexed alone (chemotherapy alone-N=263), or Amivantamab combined with other regimens (N=263). Eligible patients had documented presence of EGFR exon 19 deletion or exon 21 L858R mutation and experienced disease progression after receiving Osimertinib as their most recent line of therapy. Patients received Amivantamab 1400 mg IV (1750 mg for body weight 80 kg or greater) weekly for the first 4 weeks, then 1750 mg (2100 mg for body weight 80 kg or greater) every 3 weeks starting at cycle 3 (week 7). The first Amivantamab infusion was split over 2 days, with 350 mg IV on cycle 1, day 1 and the remainder on cycle 1, day 2. Chemotherapy consisted of Carboplatin AUC 5 IV, starting on day 1 every 3 weeks for the first 4 cycles along with Pemetrexed 500 mg/m2 IV every 3 weeks until disease progression. The median age was 62 years, 48% of patients were Asian and approximately 70% of patients had Osimertinib as first line treatment and 30% had Osimertinib as second line treatment. Randomization was stratified by Osimertinib line of therapy (first or second), and race (Asian or non-Asian). All three treatment groups were well balanced. The Primary endpoint of the study was Progression-Free Survival (PFS), assessed by Blinded Independent Central Review (BICR). Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Time to Treatment Discontinuation (TTD), Time to Subsequent Therapy (TTST), Progression-Free Survival after first subsequent therapy (PFS2) and Time to Symptomatic Progression (TTSP).

At a median follow-up of 8.7 months, the PFS was significantly longer for Amivantamab plus chemotherapy versus chemotherapy alone. The median PFS was 6.3 months in the Amivantamab plus chemotherapy group and 4.2 months in the chemotherapy alone group (HR for disease progression or death=0.48; P<0.0001), indicating a a 52% reduction in the risk of progression or death. The ORR was significantly higher in the Amivantamab plus chemotherapy group at 53%, compared to 29% in the chemotherapy alone group (P<0.0001).

In the prespecified second interim analysis, a numerical improvement in OS was noted for the Amivantamab plus chemotherapy group with a median OS of 17.7 months compared to 15.3 months for the chemotherapy alone group (HR=0.73; P=0.039). However, this did not meet the prespecified significance level.

With regards to Post-Progression Endpoints, the median TTD was significantly longer in the Amivantamab plus chemotherapy group versus chemotherapy alone group (10.4 months versus 4.5 months; HR=0.42; P<0.0001). The Median TTST was also prolonged in the Amivantamab plus chemotherapy group versus chemotherapy alone group (12.2 months compared to 6.6 months HR=0.51; P< 0.0001). The median PFS2 was significantly longer in the Amivantamab plus chemotherapy group compared to the chemotherapy alone group (16.0 months versus 11.6 months (HR= 0.64; P=0.002). Common adverse reactions observed in patients receiving Amivantamab plus chemotherapy included rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection.

In conclusion, the results from the MARIPOSA-2 trial provide compelling evidence for the use of Amivantamab in combination with Carboplatin and Pemetrexed in the treatment of advanced EGFR-mutant NSCLC post-Osimertinib progression. While the PFS outcomes were significantly improved, the OS benefits, promising as they may be, require further follow-up for conclusive results. The final Overall Survival analysis will be eagerly awaited, as it will further illuminate the long-term efficacy of this treatment approach.

Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Popat S, Reckamp KL, Califano R, et al. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. LBA54.

Ivonescimab may be Superior to Pembrolizumab as First-Line Treatment in NSCLC

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SUMMARY: 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.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby unleashing the T cells. Five year results from the Phase III KEYNOTE-042 study which included eligible patients with locally advanced/metastatic NSCLC without EGFR/ALK alterations and with PD-L1 Tumor Proportion Score (TPS) 1% or more favored Pembrolizumab over chemotherapy, regardless of PD-L1 TPS.

Ivonescimab (AK112) is a novel bispecific antibody designed to target both PD-1 and Vascular Endothelial Growth Factor (VEGF). Its dual targeting mechanism is intended to enhance the therapeutic efficacy against advanced NSCLC, and has shown promising results in early-phase trials. Dual inhibition of PD-1 and VEGF by Ivonescimab might provide synergistic effects, enhancing therapeutic efficacy beyond what is achieved with PD-L1 inhibition alone.

The HARMONi-2 (AK112-303) is a randomized Phase III study designed to evaluate the efficacy and safety of Ivonescimab compared to Pembrolizumab, a well-established PD-1 inhibitor, in patients with advanced NSCLC. In this study, 398 eligible patients (N=398) from 55 centers in China with untreated locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) NSCLC were randomly assigned in a 1:1 ratio to receive either Ivonescimab 20 mg/kg administered IV every 3 weeks or Pembrolizumab 200 mg administered IV every 3 weeks. Patients were required to have PD-L1 positive tumors (TPS 1% or more), and patients with known EGFR mutations, ALK rearrangements, or prior systemic therapy were excluded. Randomization was stratified by histology (squamous versus non-squamous), clinical stage (IIIB/IIIC versus IV), and PD-L1 expression levels (TPS 1-49% versus TPS 50% or more).
The Primary endpoint was Progression-Free Survival (PFS), assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), Investigator-assessed PFS, Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate (DCR), and Safety.

The interim analysis of this study was conducted after a median follow-up of 8.7 months, from November 2022 to August 2023. The median PFS was significantly longer with Ivonescimab compared to Pembrolizumab. Patients receiving Ivonescimab had a median PFS of 11.14 months versus 5.82 months with Pembrolizumab. The Hazard Ratio (HR) was 0.51 (P<0.0001), indicating a 49% reduction in the risk of disease progression or death. The PFS benefit of Ivonescimab was consistent across various subgroups including histology, PD-L1 expression and metastatic sites. Ivonescimab demonstrated superior outcomes in ORR and DCR compared to Pembrolizumab with an ORR for Ivonescimab of 50%, compared to 38.5% for Pembrolizumab. The DCR was 89.9% with Ivonescimab and 70.5% with Pembrolizumab.

Both treatments showed similar safety profiles with no new safety signals for Ivonescimab. Treatment-Related Serious Adverse Events (TRSAEs) occurred in 20.8% of Ivonescimab-treated patients and 16.1% of Pembrolizumab-treated patients. Grade 3 or more immune-related Adverse Events (irAEs) were comparable: 7.1% with Ivonescimab and 8.0% with Pembrolizumab. Specifically, in patients with squamous cell carcinoma, TRSAEs were 18.9% with Ivonescimab and 18.7% with Pembrolizumab. Ivonescimab was associated with slightly higher rates of proteinuria and hypertension but overall demonstrated a manageable safety profile. Overall survival data and long-term safety data are awaited to confirm the clinical benefits of Ivonescimab.

In conclusion, the HARMONi-2 trial provided compelling evidence that Ivonescimab offers a statistically significant and clinically meaningful improvement in PFS compared to Pembrolizumab, in PD-L1 positive advanced NSCLC patients, with manageable safety profile. If subsequent data continue to support these findings, Ivonescimab may be a valuable alternative to existing therapies. One limitation is that the trial was conducted exclusively in China, which might affect the generalizability of the results to other populations.

Phase 3 study of ivonescimab (AK112) vs pembrolizumab as first-line treatment for PD-L1–positive advanced NSCLC: Primary analysis of HARMONi-2. Zhou C, Chen J, Wu L, et al. 2024 World Conference on Lung Cancer. Abstract PL02.04. Presented September 8, 2024. San Diego, CA.

Avoiding Regional Nodal Irradiation after Neoadjuvant Chemotherapy in Some Breast Cancer Patients

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Neoadjuvant or preoperative therapy is often a component of combined-modality treatment, and facilitates the rapid assessment of new cancer therapies. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pathological Complete Response (pCR) following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS).

When patients with early stage breast cancer present with pathologically positive axillary nodes, neoadjuvant chemotherapy is often recommended to eradicate cancer cells. These patients are often treated with adjuvant regional nodal irradiation including the chest wall after mastectomy and with whole breast irradiation after breast conserving surgery.

However, there is no established protocol for treatment when chemotherapy converts node-positive disease to node-negative disease. There is an ongoing debate whether these individuals should be treated as lymph node-positive disease (as it was at the time of diagnosis) and treated with radiation treatment, or as node-negative disease (presentation after neoadjuvant chemotherapy and following surgery). Radiation Therapy can be associated with fatigue, radiation dermatitis, lymphedema, and can have an impact on breast reconstruction. The following study was conducted to evaluate whether radiation treatment can be safely omitted in this patient population

The NRG Oncology/NSABP B-51/RTOG 1304 was conducted to evaluate the impact of Regional Nodal Irradiation (RNI) on patient outcomes following neoadjuvant chemotherapy. In this Phase III clinical trial, 1,641 enrolled patients had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven node positive by FNA/core needle bx), and had completed 8 weeks or more of neoadjuvant chemotherapy and anti-HER2 therapy if HER2-positive), and were ypN0 after mastectomy or breast conserving surgery and sentinel node biopsy (2 or more nodes), axillary lymph node dissection, or both. These patients were then randomly assigned 1:1 to either the “no RNI” group (observation after mastectomy, or whole breast irradiation after breast-conserving surgery) or the “RNI” group (chest wall irradiation plus RNI after mastectomy, or whole breast irradiation plus RNI after breast-conserving surgery). Both treatment groups were well balanced. The median age was 52 years, majority of the patients (60%) were cT2, 23% were triple-negative, 21% HR+/HER2-negative, 56% were HER2-positive and 78% had breast pathologic Complete Response. The Primary endpoint was Invasive Breast Cancer Recurrence-Free Interval (IBC-RFI). Secondary endpoints reported here included Loco-Regional Recurrence-Free interval (LRRFI), Distant Recurrence-Free Interval (DRFI), Disease-Free Survival (DFS), and Overall Survival (OS). The median follow up was 59.5 months and 1,556 patients were available for primary event analysis.

In the evaluable patients (N=1556), similar outcomes were noted whether the patients received adjuvant Regional Nodal Irradiation (RNI) or not. Approximately 92% of patients in the “no RNI” group and 92.7% of those in the “RNI” group were free of Invasive Breast Cancer Recurrences five years after surgery. Distant Recurrence and Overall Survival rates were also similar between the treatment groups, with 93.4% of patients in each treatment group free from Distant Recurrence five years after surgery, and 94% of those in the “no RNI” group and 93.6% of those in the “RNI” group alive after five years. There were no study-related deaths and no unexpected toxicities.

It was concluded from this study that certain breast cancer patients who respond well to neoadjuvant chemotherapy and achieve negative lymph nodes after surgery may safely omit adjuvant lymph node radiation without compromising outcomes. If confirmed by further research and endorsed by medical guidelines, these findings could spare many breast cancer patients from unnecessary radiation therapy, thereby reducing treatment-related side effects and improving quality of life. This study underscores the importance of individualized treatment approaches in oncology, highlighting the need to reassess treatment strategies based on evolving evidence.

Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Mamounas E, Bandos H, White J, et al: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. 2023 San Antonio Breast Cancer Symposium. Abstract GS02-07. Presented December 7, 2023.

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.

Lung Cancer Risk with Vaping and Cigarette Smoking

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SUMMARY: According to the American Cancer Society, tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Smokeless tobacco products are a major source of cancer causing nitrosamines, and increase the risk of developing cancer of the oropharynx, esophagus, and pancreas. Cigarette smoke contains more than 7,000 chemicals, many of which are toxic and some linked to cancer.

The use of e-cigarettes (electronic cigarettes) often referred to as “vaping” was introduced to the U.S. market in 2007 after e-cigarettes were first developed in China. When a smoker inhales through the mouth piece of an e-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well as other chemicals and these e-liquids are powerful neurotoxins. With the rapid growth of the e-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world’s leading lung organizations were compelled to release a POSITION statement on e-cigarettes, specifically focusing on their potential adverse effects on human health, and calling on government organizations to ban or restrict the use of e-cigarettes, until their impact on health is better understood. With epidemiological data demonstrating that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction, the Forum of International Respiratory Societies (FIRS), an organization composed of the world’s leading international respiratory societies including American Thoracic Society (ATS) and the American College of Chest Physicians (ACCP) made several important recommendations (not included here).

The health risks associated with vaping might be compounded by the presence of harmful substances in e-cigarette aerosols, such as diacetyl, diethylene glycol, aldehydes, cadmium, benzene, and heavy metals like nickel, tin, and lead. These components are known to be toxic and carcinogenic, raising concerns about their contribution to lung cancer risk.

Recent concerns have emerged about the potential health risks associated with vaping, particularly in relation to lung cancer. Although nicotine exposure from electronic delivery systems (vaping) has been linked to elevated risks of lung conditions, the impact on lung cancer risk has remained relatively unexplored. To address this gap, the researchers in this publication conducted a comprehensive case-control study at The Ohio State University in Columbus, Ohio, examining the association between vaping, cigarette smoking, and lung cancer risk. The researchers in this study analyzed medical records from the James Cancer Hospital and Solove Research Institute, encompassing data from 4,975 patients diagnosed with pathologically confirmed lung cancer between 2013 and 2021. This patient cohort was meticulously matched to 27,294 control individuals without cancer on a 5:1 ratio based on age, gender, race, and year of ascertainment. The researchers utilized descriptive statistics and performed logistic regression analyses to evaluate the associations between vaping, smoking, and lung cancer risk. This analysis aimed to determine how these factors individually and synergistically contributed to the likelihood of developing lung cancer.

The results of this analysis demonstrated that the demographic profile of the lung cancer cases showed a predominance of males (55%), with a majority being White (88%). The mean age at diagnosis was 62 years. There was a significantly higher risk of lung cancer among individuals who both vaped and smoked compared to those who only smoked. Specifically, the adjusted Odds Ratio (OR) for those who reported both vaping and smoking was 21.1 (95% CI = 17.1, 26.1), while for smoking alone, it was 6.3 (95% CI = 5.8, 6.8). Further stratification by gender and histologic cell type demonstrated that the risk associated with combined vaping and smoking was consistently over 3X higher compared to smoking alone (P<0.001). This elevated risk persisted even after adjusting for comorbidities, Chronic Obstructive Pulmonary Disease (COPD), and cardiovascular disease.

The researchers added that these findings underscore a markedly higher risk of lung cancer associated with the combination of vaping and smoking compared to smoking alone. This synergistic effect is reminiscent of the risks associated with known carcinogens such as radon or asbestos. The results suggest that the addition of vaping to smoking significantly accelerates the risk of developing lung cancer.

The limitations of this study are that this analysis did not include a vaping-only group, as nearly 97% of those who vaped also reported smoking. Additionally, there was no detailed temporal data on the duration and frequency of vaping versus smoking. However, the consistent significant increase in lung cancer risk observed with combined vaping and smoking indicates a potentially substantial interaction effect.

In conclusion, this case-control study provides compelling evidence suggesting that vaping combined with smoking may significantly elevate lung cancer risk. While these preliminary findings highlight the potential dangers of e-cigarettes, further research is necessary to confirm these results and explore the long-term implications of vaping on lung cancer risk. Physicians should reconsider harm-reduction messages related to vaping, as it may NOT be safer than smoking. Further studies are needed to quantify the exact risks associated with vaping and smoking, as well as to understand the long-term effects.

Vaping, smoking and lung cancer: A case-control study. Bittoni MA, Carbone D, Harris R. Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract 2213.

Late Breaking Abstract – ASCO 2024: Docetaxel may be Preferable Taxane for Black Women to Mitigate Taxane-Induced Peripheral Neuropathy

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SUMMARY: Taxane-induced peripheral neuropathy (TIPN) is a notable side effect associated with taxane chemotherapy agents, particularly Paclitaxel, and has significant implications for patient quality of life and treatment outcomes. Notably, Black women with early-stage breast cancer exhibit a disproportionately higher incidence of TIPN compared to their White counterparts. This disparity is critical, as TIPN can lead to increased dose reductions, which in turn may adversely affect treatment efficacy and long-term cure rates.

Historically, retrospective analyses, such as those from the ECOG-ACRIN-E5103 trial, revealed that Black patients experience more severe TIPN and subsequent dose reductions when treated with weekly Paclitaxel. This pattern was less pronounced in patients treated with every 3 week Docetaxel. Additionally, genetic studies identified specific germline variants associated with a heightened risk of severe TIPN in individuals of African ancestry. These findings prompted the need for a prospective trial to validate these genetic markers and to evaluate the comparative tolerability of Paclitaxel versus Docetaxel specifically in Black women.

The EAZ171 study was designed with several key objectives. It aimed to prospectively validate whether specific germline genetic variants are associated with a higher risk of TIPN in Black women. The focus was on genetic variants in the SBF2 and FCAMR genes. The Secondary objective of this study was to compare the incidence of TIPN and the frequency of dose reductions between two taxanes—weekly Paclitaxel and every 3 week Docetaxel, in a cohort of Black women with early-stage breast cancer.

This study included 249 Black women who self-identified as such and were scheduled to receive either Paclitaxel 80 mg/m² IV weekly for 12 doses (N=121) or Docetaxel 75 mg/m² IV every 3 weeks for 4-6 cycles (N=128). The study utilized a pragmatic design where the choice of taxane was based on physician discretion and patient-specific disease characteristics, rather than a randomized design. Patients could also receive Cyclophosphamide, Doxorubicin, Trastuzumab, and/or Pertuzumab per institution routine care, per treating physician discretion. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Participants were genotyped to identify genetic variants associated with neuropathy risk. Those with FCAMR homozygous wild type or SBF2 mutations were categorized as high risk, while those with variant alleles in FCAMR and wild type SBF2 were categorized as low risk. The incidence of Grade 2-4 TIPN was evaluated using physician-reported CTCAE v.5, while patient-reported outcomes were assessed through PRO-CTCAE, FACT/GOG-NTx, and EORTC CIPN20 questionnaires.

The key findings were:

Genetic Predictors: Germline variations did not significantly influence the risk of TIPN for either treatment group. The anticipated differences in TIPN based on genetic risk did not reach statistical significance.

TIPN Incidence: Grade 2-4 TIPN was notably higher in the Paclitaxel group compared to the Docetaxel group. Physician-reported TIPN was 45% in the Paclitaxel arm versus 29% in the Docetaxel arm (P=0.02). Similarly, patient-reported TIPN symptoms were 40% with Paclitaxel versus 24% with Docetaxel (P=0.03).

Dose Reductions: Patients receiving Paclitaxel experienced more frequent dose reductions due to TIPN (28% vs. 9%, p<0.001) and for any cause (39% vs. 25%, p=0.02) compared to those receiving Docetaxel.

Patient-Reported Outcomes: The trends in worsening neuropathy scores over time were similar between the two arms, but significant differences were not observed at the one-year mark.

In summary, the EAZ171 study provided crucial insights into the management of TIPN in Black women with early-stage breast cancer. Despite the lack of significant impact from genetic markers, the clear advantage of Docetaxel over Paclitaxel in terms of lower incidence of severe TIPN and fewer dose reductions underscores its potential as a preferable taxane for this patient population. This trial results advocate for considering Docetaxel in treatment regimens for Black women to mitigate TIPN-related complications and possibly enhance treatment outcomes. The findings emphasize the need for tailored treatment strategies to improve health equity and therapeutic efficacy in breast cancer care.

ECOG-ACRIN EAZ171: Prospective validation trial of germline variants and taxane type in association with taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer. Ballinger TJ, Zhao F, Sparano JA, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA503). DOI: 10.1200/JCO.2024.42.17_suppl.LBA503

Late Breaking Abstract – ASCO 2024: Switching to VERZENIO® Post-CDK4/6 inhibitor Progression May Improve Outcomes in HR-positive/HER2-negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation and associated with increased expression of CDK4. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

Abemaciclib (VERZENIO®) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. Abemaciclib is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only Abemaciclib causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that Abemaciclib may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors.

For the patient group with advanced or metastatic HR-positive, HER2-negative breast cancer, Abemaciclib has FDA approval in combination with an Aromatase Inhibitor as initial endocrine-based therapy, in combination with Fulvestrant, with disease progression following endocrine therapy, and as monotherapy with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Abemaciclib has activity in the Central Nervous System, and is included in the ASCO guidelines among the active agents in ER-positive/HER2-amplified breast cancer with brain metastasis. Abemaciclib has been shown to be an effective therapy after treatment with Palbociclib, another CDK4/6 inhibitor.

postMONARCH is a global, randomized, double-blind, placebo-controlled Phase III trial conducted to evaluate the efficacy and safety of Abemaciclib in combination with Fulvestrant compared to a placebo plus Fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer, who experienced disease progression on a prior CDK4/6 inhibitor plus endocrine therapy. In this study, 368 patients (N=368) were randomized in a 1:1 ratio to receive either Abemaciclib plus Fulvestrant (N=182) or placebo plus Fulvestrant (N=186). The eligibility criteria included disease progression on a CDK4/6 inhibitor plus Aromatase Inhibitor as initial therapy for advanced disease, or relapse on or after CDK4/6 inhibitor plus endocrine therapy as adjuvant therapy for early breast cancer. No prior treatment for advanced disease aside from the initial regimen was allowed. The majority (99%) had progressed on a CDK4/6 inhibitor plus endocrine therapy as initial therapy for advanced disease. Prior CDK4/6 inhibitor treatments included Palbociclib (59%), Ribociclib (33%), and Abemaciclib (8%). Approximately 99% of patients had progressed on CDK4/6 inhibitor plus endocrine therapy as initial treatement for advanced breast cancer. The two treatment groups were well balanced. The median age was 59 years and stratification factors included duration of prior CDK4/6 inhibition, visceral metastases, and geographic region. Approximately 60% of patients had visceral metastasis and Imaging studies were performed every 8 weeks for the first 12 months and then every 12 weeks. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary endpoints encompassed PFS assessed by Blinded Independent Central Review (BICR), Overall Survival (OS), Objective Response Rate (ORR), and Safety. The study analysis was event-driven, with the primary outcome targeting 258 events, and with an interim analysis planned at 70% of events.

At the interim analysis, with 70% of the planned events, Abemaciclib plus Fulvestrant demonstrated a statistically significant improvement in investigator-assessed PFS compared to placebo plus Fulvestrant (HR=0.66; P=0.01). Upon completion of the primary analysis with 258 events, the HR for PFS was 0.73 reflecting a 27% reduction in the risk of disease progression or death. The 6-month PFS rates were 50% for the Abemaciclib group versus 37% for the placebo group. The benefit of Abemaciclib was more pronounced with BICR-assessed PFS, showing a HR of 0.55 representing a 45% reduction in the risk of disease progression or death. In patients with measurable disease, the ORR was 17% for the Abemaciclib group compared to 7% for the placebo group (P=0.0145 by investigator assessment and P=0.0008 by BICR). OS data remained immature with a 20.9% event rate at the time of analysis.

Subgroup Analyses suggested that patients with prior CDK4/6 inhibitor use for more than 12 months had a median PFS of 7.0 months versus 5.4 months in the placebo group (HR=0.70; 95% CI = 0.52–0.94). For those with treatment durations up to 12 months, the median PFS was 5.5 months versus 3.0 months (HR=0.80; 95% CI = 0.50–1.29). The benefit was greater in patients without visceral metastases (HR=0.53; 95% CI = 0.34–0.83), though there was still a benefit observed in those with visceral metastases (HR=0.87; 95% CI = 0.64–1.17). Benefit was observed regardless of presence of ESR1 mutations or PI3K pathway alterations.

The safety profile of Abemaciclib plus Fulvestrant was consistent with known profiles. Grade 3 neutropenia occurred in 25% of patients receiving the combination therapy. Adverse events led to discontinuation in 6% of patients on the Abemaciclib arm, compared with none in the placebo group. The most common Grade 3 or higher adverse events included neutropenia, anemia, and leukopenia.

In summary, the postMONARCH trial supports the use of Abemaciclib plus Fulvestrant as an effective treatment for patients with HR-positive/HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy, offering a viable option and underscoring the value of continued CDK4/6 inhibition beyond progression in the evolving landscape of breast cancer treatment.

This combination offers significant improvement in PFS, especially in patients with longer durations of prior CDK4/6 inhibition and those without visceral metastases and may be a preferred strategy in the second-line setting for patients who have progressed on initial CDK4/6-based therapies, particularly when biomarker-specific therapies are not available.

Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial. Kalinsky K, Bianchini G, Hamilton EP, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA1001). DOI 10.1200/JCO.2024.42.17_suppl.LBA1001

Late Breaking Abstract – ASCO 2024: Integrating Carboplatin in Early Stage Triple Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival (OS) of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Neoadjuvant chemotherapy is the preferred treatment approach in this group of patients and can potentially increase the likelihood of tumor resectability and breast conservation. Further, a pathological Complete Response (pCR) after neoadjuvant chemotherapy can result in a longer Event-Free Survival and Overall Survival. Pathological Complete Response is therefore used as an end point for clinical testing of neoadjuvant treatment in patients with early TNBC.

Conventionally, TNBC has been treated with cytotoxic chemotherapy regimens incorporating anthracyclines and taxanes, which remain foundational despite ongoing exploration of novel agents. The role of immune checkpoint inhibitors such as Pembrolizumab (KEYTRUDA®) has expanded into neoadjuvant settings, in addition to its consistent Progression Free Survival (PFS) and Overall Survival (OS) benefits in advanced TNBC. Recent studies have investigated the addition of platinum agents due to their ability to induce DNA damage and apoptosis in tumors with defective DNA repair mechanisms, such as those seen in BRCA-mutated breast cancer. Triple-Negative Breast Cancers that do not harbor BRCA1/2 mutations show defects in the DNA repair mechanism, similar to BRCA1/2 mutant TNBC, and are called BRCAness. Platinum agents have shown promise in increasing the pCR rate when combined with standard taxane and anthracycline regimens in neoadjuvant settings, potentially enhancing outcomes for patients who otherwise face high recurrence risks. The importance of achieving pCR has been underscored by studies like the CTNeoBC pooled analysis, which demonstrated significantly improved survival outcomes in TNBC patients who achieved pCR, compared to those with residual disease. This has prompted the exploration of combination therapies aimed at maximizing response rates and minimizing residual disease burden.

PEARLY is a randomized, multicenter, open-label, Phase III trial in which anthracyclines followed by taxane was compared with anthracyclines followed by taxane plus Carboplatin as (neo)adjuvant therapy in patients with TNBC. Patients with Stage II or III TNBC who need adjuvant or neoadjuvant chemotherapy were included. Any prior systemic therapy for breast cancer was not allowed. In this study, 868 patients (N=868) were randomized 1:1 to either standard arm treatment, which consisted of Doxorubicin 60 mg/m2 IV along with Cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles followed by taxane treatment (Paclitaxel 80 mg/m2 IV weekly for 12 doses or Docetaxel 75mg/m2 IV every 3 weeks for 4 cycles), or experimental group in which Carboplatin AUC5 IV every 3 weeks for 4 cycles was added during taxane treatment. Patients were stratified based on the nodal status (N0 versus N+), treatment setting (neoadjuvant versus adjuvant), and BRCA mutation status (positive versus negative). Patients with bilateral, metastatic, and inflammatory breast cancer were excluded. The Primary objective was to evaluate 5-year Event Free Survival (EFS) rate in the enrolled patients. Secondary objectives included Overall Survival (OS), Distant Recurrence-Free Survival (DRFS), pathologic Complete Response (pCR), and tolerability.

At a median follow up of 51.1 months, Carboplatin significantly improved the 5-year EFS compared to the control arm (HR 0.68; P=0.017). The 5-year EFS rates were increased from 74.4% to 81.9% with the addition of Carboplatin, demonstrating a 7.5% absolute difference in EFS rates. Subgroup analysis showed consistent benefits across various patient subgroups. Secondary endpoints such as OS and DRFS showed favorable trends in the Carboplatin group, although OS data were not mature at the time of reporting. Grade 3 or more treatment-related Adverse Event rates were 74.6% in the Carboplatin group and 56.7% in the control group, but were generally manageable.

In conclusion, the PEARLY trial demonstrated that the addition of Carboplatin to standard anthracycline followed by taxane therapy significantly improved Event-Free Survival in early-stage Triple-Negative Breast Cancer. These findings suggest that Carboplatin has a role in enhancing treatment outcomes in TNBC, particularly by reducing the risk of recurrence. Further research and longer-term follow-up are necessary to fully validate these results and refine treatment strategies for this challenging subtype of breast cancer.

A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo) adjuvant therapy in patients with early triple-negative breast cancer: Korean Cancer Study Group BR 15-1 PEARLY trial. Sohn J, Kim GM, Jung KH, et al. Journal of Clinical Oncology. Volume 42, Number 17_suppl. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA502

Late Breaking Abstract – ASCO 2024: ADCETRIS® Combination Improves Overall Survival in Relapsed and Refractory Diffuse Large B-Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and more than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases. The incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL can develop spontaneously or as a result of Richters transformation of low grade diseases such as Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Follicular Lymphoma, or Marginal Zone Lymphoma.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless of molecular subtype, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL. Approximately 30-40% of patients experience disease progression or relapse during the first 2 years, and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor. There is a critical unmet need for this patient group.

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. Preclinical data and early phase studies provided the rationale for combining Brentuximab vedotin, Lenalidomide and Rituximab for the treatment of Relapsed/Refractory DLBCL.

ECHELON-3 is an ongoing, global, randomized, double-blind, multicenter Phase III study, designed to evaluate the efficacy and safety of Brentuximab vedotin in combination with Lenalidomide and Rituximab, compared to Lenalidomide and Rituximab plus placebo, in adult patients with Relapsed/Refractory DLBCL, regardless of CD30 expression, who have received two or more prior lines of therapy and were ineligible for or had previously failed Hematopoietic Stem Cell Transplant (HSCT) or Chimeric Antigen Receptor (CAR) T-cell therapy.

In this global study, 230 patients were randomized 1:1 to receive either Brentuximab vedotin plus Lenalidomide and Rituximab (BV+R2) – N=112, with Brentuximab vedotin administered at 1.2 mg/kg IV every 3 weeks, Lenalidomide at 20 mg orally daily, and Rituximab at 375 mg/m² IV every 3 weeks, or Placebo plus Lenalidomide and Rituximab (placebo+R2) – N=118. Placebo for Brentuximab vedotin with Lenalidomide and Rituximab was administered in the same manner. Treatment continued until disease progression or unacceptable toxicity. The median age was 71 years, 56% were male, median prior lines of therapy was 3, 29% had prior CAR T-cell therapy, approximately 15% of patients had prior bispecific antibody exposure, and 68% were CD30 negative with CD30 tumor expression of less than 1%. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR) and Complete Response (CR) Rate.

At the interim analysis, with a median follow-up of 16.4 months, BV+R2 regimen demonstrated a median OS of 13.8 months compared to 8.5 months with placebo+R2, representing a 37% reduction in the risk of death (HR=0.63; P=0.0085). The median PFS was 4.2 months in the BV+R2 arm versus 2.6 months in the placebo+R2 arm (HR=0.53; P<0.0001). The ORR was 64.3% with BV+R2 compared to 41.5% with placebo+R2 (P=0.0006). The CR rate was 40.2% with BV+R2 versus 18.6% with placebo+R2. The efficacy benefits of BV+R2 were consistent across key subgroups, including patients with CD30-positive and CD30-negative disease, highlighting the broad applicability of the regimen.

Grade 3 or higher adverse events were more frequent in the BV+R2 arm compared to placebo+R2 (88% versus 77%), and the most common Grade 3 or higher adverse events included neutropenia, anemia and diarrhea. Peripheral Neuropathy was higher with BV+R2 compared to placebo+R2, although generally manageable.

In conclusion, the ECHELON-3 study demonstrated that the addition of Brentuximab vedotin to Lenalidomide and Rituximab significantly improved Overall Survival, Progression-Free Survival, and Response Rates in patients with Relapsed/Refractory DLBCL, compared to Lenalidomide and Rituximab alone. This regimen offers a promising new treatment option for patients who have exhausted standard therapies, or are ineligible for intensive treatments like CAR-T cell therapy or HSCT. The results underscore the potential of targeted therapies in reshaping the management of DLBCL, providing renewed hope for improved outcomes in this challenging disease setting. As the study continues to follow patients for long-term outcomes, ongoing research will further elucidate the durability of responses and additional safety data, thereby informing future clinical practice guidelines and optimizing patient care strategies.

Brentuximab vedotin in combination with lenalidomide and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: Results from the phase 3 ECHELON-3 study. Kim JA, Hahn U, Kim W-S, et al. Journal of Clinical Oncology. Volume 42, Number 17_suppl. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA7005

Late Breaking Abstract – ASCO 2024: Sustained Improvement in Relapse Free Survival with Personalized mRNA Cancer Vaccine plus KEYTRUDA® in Resected High Risk Melanoma

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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.

Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk resected melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab (KEYTRUDA®) was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab (OPDIVO®) versus 41.2% for ipilimumab (YERVOY®). Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

Pembrolizumab is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

mRNA-4157 (V940) is a novel messenger RiboNucleic Acid (mRNA)-based individualized neoantigen therapy consisting of a single synthetic mRNA coding for up to 34 neoantigens, that is designed and produced based on the unique mutational signature of the DNA sequence of the patients tumor. Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) was designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patients tumor. Early clinical studies demonstrated that combining mRNA-4157 (V940) with Pembrolizumab may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.

KEYNOTE-942 is an ongoing randomized, open-label, Phase IIb trial, designed to evaluate the efficacy and safety of mRNA-4157, an individualized neoantigen therapy, in combination with Pembrolizumab, in patients with completely resected high-risk Stage III/IV cutaneous melanoma. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157 in combination with Pembrolizumab (N=107) or Pembrolizumab alone (N=50). The vaccine was administered 1 mg every three weeks for a total of nine doses, and Pembrolizumab was given at 200 mg IV every three weeks for up to 18 cycles (approximately one year). All patients had tumor sample (Formalin Fixed Paraffin Embedded-FFPE) available for Next Generation Sequencing and patients were stratified by disease stage. mRNA-4157 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patients had Stage IIIC disease. Approximately 64% of patients were PD-L1 positive and 74% had high Tumor Mutational Burden-TMB (10 or more mutations/Mb) in the combination treatment group, whereas 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. HLA genotyping was performed to explore associations between specific HLA alleles and treatment response. Additionally, subgroup analyses were conducted based on TMB, PD-L1 expression, and circulating tumor DNA (ctDNA) status.

The Primary endpoint was Relapse Free Survival (RFS), defined as the time from first dose of Pembrolizumab until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause. Secondary endpoints included Distant Metastasis-Free Survival and Safety. Exploratory endpoints included distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint.

At a median follow up of 23 months for the mRNA-4157/V940 plus Pembrolizumab group, and 24 months for Pembrolizumab alone group, the Relapse Free Survival at 18 months was 78.6% for the immunotherapy combination versus 62.2% for Pembrolizumab alone (HR=0.56; P=0.0266), and this equated to a 44% reduction in the risk of recurrence or death with 2 years of follow-up. mRNA-4157/V940 and Pembrolizumab combination treatment demonstrated an improvement in RFS, irrespective of PD-L1 status and TMB status.

In the recent data presented at ASCO 2024, with an additional year of planned follow-up, at a median of approximately 34.9 months, the combination of mRNA-4157 and Pembrolizumab demonstrated a significant clinically meaningful and durable improvement in RFS, the Primary endpoint of the study, compared to Pembrolizumab alone. The risk of recurrence or death was reduced by 49% (HR=0.51; P=0.019), compared to Pembrolizumab monotherapy. The 2.5-year RFS rate for the combination group was 74.8% compared to 55.6% in the Pembrolizumab alone group. The RFS improvement was observed across subgroups irrespective of TMB and PD-L1 levels.

The combination therapy also showed a meaningful improvement in Distant Metastasis-Free Survival, which was a key Secondary endpoint, compared to Pembrolizumab alone (HR=0.38; P=0.015). This represented a 62% reduction in the risk of developing distant metastases or death compared to Pembrolizumab alone.

While not formally tested as a Primary endpoint, Overall Survival trended favorably with the combination therapy, with a 2.5-Year OS Rate of 96.0% for combination versus 90.2% for Pembrolizumab alone (HR=0.425).

The safety profile of mRNA-4157 in combination with Pembrolizumab was consistent with previous analyses and the common adverse events were fatigue (60.6%), injection site pain (56.7%), and chills (49.0%). Grade 3 or higher adverse events occurred in 25% of patients receiving combination therapy and 18% in the Pembrolizumab alone group. Immune-related adverse events were reported by approximately 37.5% of patients in the combination group and 36% in the Pembrolizumab alone group, with no new safety signals identified.

The KEYNOTE-942 trial demonstrated that mRNA-4157 in combination with Pembrolizumab significantly improved Recurrence-Free Survival and Distant Metastasis-Free Survival in patients with resected high-risk Stage III/IV melanoma, compared to Pembrolizumab alone. These findings suggest a potential benefit across various patient subgroups based on TMB, PD-L1 expression, and ctDNA status. The safety profile was manageable and consistent with expectations for both treatments. Based on these positive results, further investigation in the Phase III INTerpath-001 trial is underway to validate these findings and potentially transform the adjuvant treatment landscape for melanoma patients.

Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial.Weber JS, Khattak MA, Carlino MS, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA9512). DOI 10.1200/JCO.2024.42.17_suppl.LBA9512