Author: RR

Unfulfilled Potential: The Gap in Genetic Testing for Breast Cancer Patients

RR

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.

The availability of multigene panel testing and next-generation sequencing is changing the landscape of cancer prevention and treatment. The necessity for genetic testing in breast cancer has gained support due to its critical role in treatment management and family risk assessment. Clinical guidelines have evolved to expand eligibility for genetic testing, yet many patients who could benefit from these tests either do not receive them or face delays in testing. This is concerning, as genetic testing informs treatment decisions, surveillance for second cancers, and risk management for relatives. This present study aimed to explore the receipt of genetic testing and communication with relatives about results in women diagnosed with early-stage breast cancer, examining patterns from initial diagnosis through survivorship, a time that is often overlooked for its importance in continued care. Specifically, it aimed to assess how these factors influence survivorship and familial risk communication over time.

The study utilized a cohort of women aged 20-79 years diagnosed with early-stage breast cancer in 2014-2015, sourced from the Georgia and Los Angeles County SEER registries. A total of 1,412 women were surveyed approximately 7 months after diagnosis and again 6 years later. The surveys collected data on genetic counseling, testing, and communication about test results. Participants were categorized based on clinical guidelines into three groups:
• Indications at Baseline: Women who had indications for genetic testing at the time of initial diagnosis.
• Indications at Follow-up Only (FUPs): Women who had indications for testing only during follow-up.
• No Indications: Women who did not have indications for genetic testing at any point.

The findings revealed that nearly half (47.4%) of the women had indications for genetic testing at some point- 28.0% at baseline and an additional 19.4% during follow-up. Among those who had an indication at baseline, 71.9% reported having undergone genetic testing. This rate was significantly higher compared to those with an indication only at follow-up (53.3%) and those with no indication (35.0%). Statistical analysis showed significant differences in testing rates between these groups (P<0.001). Importantly, racial and ethnic differences did not significantly affect the receipt of testing when controlling for age and clinical indications (P=0.239). The results for genetic counseling were similar.

Only a small fraction (3.4%) of the women pursued Direct-to-Consumer genetic testing (DTCt) for cancer.

Women who tested positive for a Pathogenic Variant (N = 62) were significantly more likely to discuss their results with most or all of their first-degree relatives compared to those with a Variant of Unknown Significance (N = 49) or a negative result (N = 419). Specifically, 62.7% of women with Pathogenic Variants communicated results to their relatives, compared to those with a Variant of Unknown Significance (38.8%) or a negative result (38.0%), (P<0.001).

In conclusion, this study underscores a significant gap in the uptake of genetic counseling and testing among women who are eligible for it based on clinical guidelines. While the proportion of women with indications for genetic testing increased over time, many women did not receive it. This gap was consistent across racial and ethnic groups, suggesting that the issue is widespread rather than confined to specific subpopulations. The study emphasizes that positive genetic results lead to increased family communication about cancer risk, whereas the uptake of DTCt remains low, reaffirming its limited role in replacing clinical-grade genetic testing in this population.

Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer. Katz SJ, Abrahamse P, Furgal A, et al. J Clin Oncol. 2024;doi:10.1200/JCO.24.00122.

Immune Checkpoint Inhibitor Therapy and Cardiovascular Adverse Events

RR

SUMMARY: Immune checkpoint inhibitors (ICIs) have dramatically transformed the management and prognosis of various malignancies. By enhancing the immune systems ability to identify and destroy cancer cells, ICIs have provided significant improvements in treatment outcomes across a range of tumor types. However, the introduction of these therapies has also been accompanied by a spectrum of immune-related Adverse Events (irAEs), including those affecting the cardiovascular system. These CardioVascular Adverse Events (CVAEs) present a serious concern due to their potential impact on patient health and treatment outcomes.

The cardiovascular manifestations associated with ICIs encompass a range of conditions such as myocarditis, pericarditis, acute coronary syndrome, heart failure, arrhythmias, conduction abnormalities, and cardiac arrest. Although the incidence of these events is relatively low (less than 1% of patients), their severity can be profound. Myocarditis, in particular, is a critical concern due to its association with a high mortality rate, which can be as high as 60%. This underscores the need for vigilant monitoring and management strategies to mitigate these risks.

The objective of the systematic review and meta-analysis was to elucidate the incidence and outcomes of CVAEs associated with ICIs and to assess the effectiveness of various management strategies for myocarditis. This analysis sought to update the clinical understanding of these adverse effects and provide recommendations based on the most recent data.

The researchers review process involved searching several databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, up to April 4, 2023, and with the gathered data, two separate analyses were performed:
1. Phase 1 to 4 Trials Analysis: Focused on trials involving adults with malignant neoplasms treated with FDA- or EMA-approved ICIs. This analysis aimed to gather data on the incidence of CVAEs associated with these therapies.
2. Case Reports and Retrospective Studies Analysis: Concentrated on clinical manifestations and treatment outcomes for patients who developed CVAEs due to ICIs.

Data were meticulously extracted by two independent investigators, with stringent criteria applied to ensure the relevance and quality of the studies included. For instance, studies with dose escalation, small sample sizes, or non-English publications were excluded. The Primary outcome measure was the incidence of CVAEs.

Incidence of Cardiovascular Adverse Events
The meta-analysis of clinical trials included data from 83,315 participants across 589 trials. The therapies investigated included several ICIs such as Pembrolizumab (KEYTRUDA&reg:), Nivolumab (OPDIVO®), Cemiplimab (LIBTAYO®), Atezolizumab (TECENTRIQ®), Durvalumab (IMFINZI®), Avelumab (BAVENCIO®), and Ipilimumab (YERVOY®). The overall incidence of CVAEs in patients treated with anti-PD-1 or anti-PD-L1 therapies was found to be 0.8%. Notably, Cemiplimab was associated with a higher risk of high-grade cardiovascular adverse events compared to other ICIs (2.91% for Cemiplimab versus 0.69% overall).

The incidence of myocarditis specifically was reported as 0.24% for any grade and 0.2% for high-grade myocarditis. While dual ICI therapy was linked to a higher incidence of myocarditis compared to other regimens, the overall incidence of CVAEs did not significantly differ between dual ICI therapy, ICI plus chemotherapy, or ICI plus Tyrosine Kinase Inhibitors.

Management and Outcomes of Myocarditis
In the analysis of myocarditis cases, which included 223 patients (64.5% men), the majority had received PD-1 or PD-L1 inhibitors. A substantial proportion of these patients had cardiovascular risk factors: 41.1% had hypertension, 16.3% had diabetes, and 46.5% had other risk factors. Among 220 evaluable patients, the mortality rate for myocarditis was alarmingly high at 37.7%.

Management strategies for myocarditis varied, with treatments including high-dose Corticosteroids, Methylprednisolone, IV immunoglobulin, Plasma exchange, Mycophenolate mofetil, Infliximab, and Antithymocyte globulin. Outcomes of these treatments showed mixed results. For instance, high-dose Corticosteroids were associated with a 63.5% improvement rate but also a 26% cardiac mortality rate. Abatacept showed promise with an improvement rate of 91.7% among those who received it. Prospective data suggested that systematic screening for respiratory muscle involvement, active ventilation, prompt use of Abatacept, and the addition of Ruxolitinib might reduce mortality rates. However, the review emphasized that the current management strategies are largely empirical, and there is no definitive evidence on the most effective approach.

Recommendations and Conclusions
The review highlighted a critical need for standardized diagnostic and therapeutic approaches due to the variability in management strategies and the lack of prospective clinical trials. The findings underscore the importance of early recognition, cessation of ICI therapy, and prompt initiation of corticosteroid therapy for optimal management of myocarditis. The review also suggests that further research, including prospective clinical trials and the establishment of international registries, is necessary to enhance the understanding and management of ICI-induced CVAEs.

In summary, while cardiovascular adverse events related to ICIs are rare, their potential severity, particularly myocarditis, warrants heightened awareness and proactive management by clinicians. Early identification and intervention are crucial to improving patient outcomes and reducing mortality associated with these adverse effects.

Immune Checkpoint Inhibitor–Induced Cardiotoxicity. A Systematic Review and Meta-Analysis. Nielsen DL, Juhl CB, Nielsen OH, et al. JAMA Oncol. 2024;doi:10.1001/jamaoncol.2024.3065.

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

RR

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.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

RR

SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC were diagnosed in the United States in 2023 and about 52,550 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies however have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

Sotorasib (LUMAKRAS&reg;) is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

CodeBreaK 300 trial is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively. Overall survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960-mg dose appeared to yield more clinically significant benefits than the 240-mg dose, across all efficacy endpoints, without additional toxic effects. Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that both doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher incidence of Response Rate than standard treatment. Ongoing analysis and longer follow up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

TAGRISSO® after Chemoradiotherapy in Stage III EGFR Mutated Non-Small Cell Lung Cancer

RR

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. 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

Enfortumab Vedotin plus Pembrolizumab: A Breakthrough in Locally Advanced or Metastatic Urothelial Carcinoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic urothelial carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is a first-in-class Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, MonoMethyl Auristatin E (MMAE), which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

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. 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. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-302 is a landmark Phase III, global, open-label, randomized trial comparing the efficacy and safety of Enfortumab vedotin and Pembrolizumab with the efficacy and safety of platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma. A total of 886 eligible patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of Enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 and Pembrolizumab 200 mg IV on day 1 of every 3-week cycle (N=442) or chemotherapy consisting of Gemcitabine and either Cisplatin or Carboplatin (N=444), determined on the basis of eligibility to receive cisplatin, for a maximum of 6 cycles. The maximum number of Pembrolizumab cycles allowed was 35 and there was no maximum number of cycles set for Enfortumab vedotin. The treatment groups were well balanced. The median age was 69 yrs and randomization was stratified according to eligibility to receive Cisplatin (eligible or ineligible), PD-L1 expression status (High-CPS 10 or more versus Low-CPS less than 10), and liver metastases (present or absent). The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included Overall Response Rate (ORR) as assessed by BICR, Duration of Response, and Safety. As of the data cutoff date, the median duration of follow-up for survival was 17.2 months.

The PFS was significantly longer in the Enfortumab vedotin plus Pembrolizumab group compared to the chemotherapy group (median duration 12.5 months versus 6.3 months; HR=0.45; P<0.001), representing a 55% reduction in the risk of disease progression or death. Enfortumab vedotin plus Pembrolizumab also substantially improved median OS, and the median OS was 31.5 months compared to 16.1 months with chemotherapy (HR=0.47; P<0.001) representing a 53% reduction in the risk of death. These PFS and OS benefits were consistent between the intention-to-treat population and all the prespecified subgroups, including those defined according to Cisplatin eligibility status and PD-L1 expression status. The Overall Response Rate (ORR) in the Enfortumab vedotin plus Pembrolizumab group was 67.7%, significantly higher than the 44.4% ORR observed with chemotherapy alone (P<0.001), with a Complete Response rate of 29.1% versus 12.5% respectively. The median Duration of Response was Not Reached in the Enfortumab vedotin plus Pembrolizumab group and was 7.0 months in the chemotherapy group.

Treatment-related adverse events of Grade 3 or higher occurred in 55.9% of the patients in the Enfortumab vedotin plus Pembrolizumab group, and was 69.5% in the chemotherapy group. The most common treatment-related adverse events of any grade in the Enfortumab vedotin plus Pembrolizumab group were peripheral sensory neuropathy, pruritus and alopecia, whereas the most common such events in the chemotherapy group were anemia, neutropenia and nausea.

It was concluded that treatment with Enfortumab vedotin plus Pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, emerging as a potential new standard of care, irrespective of Cisplatin eligibility. The results from this study mark a significant paradigm shift in the management of locally advanced or metastatic urothelial carcinoma, offering new hope for patients and clinicians alike.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. Powles T, Valderrama BP, Gupta S, et al. for the EV-302 Trial Investigators. N Engl J Med 2024;390:875-888.

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.

Cannabis Use Increases the Risk of Head and Neck Cancer

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SUMMARY: The American Cancer Society estimates that about 58,450 new cases of oral cavity and pharynx cancer will be diagnosed in the US in 2024 and about 12,230 patients will die of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.

Cannabis refers to all products derived from the plant Cannabis sativa, and is the most commonly used illicit substance worldwide. The cannabis plant contains about 540 chemical substances and has similar carcinogens as tobacco. Marijuana refers to the dried leaves, flowers, stems, and seeds from the plant Cannabis sativa that contain substantial amounts of TetraHydroCannabinol (THC), which is primarily responsible for the effects of marijuana on a persons mental state. Individuals with head and neck cancer have used cannabis to help alleviate pain and improve well-being. In 2022, 30.7% of 12th graders reported using marijuana in the previous year and 6.3% reported using marijuana daily. In addition, many young people also use vaping devices to consume cannabis products.

As cannabis use grows, understanding its carcinogenic potential becomes increasingly important, particularly given its rising popularity and industry expansion. Cannabis smoke may be more proinflammatory than tobacco smoke due to its unfiltered nature and higher combustion temperature. This increased inflammation could lead to cancer development. Cannabis smoke also enhances the expression of Epidermal Growth Factor Receptor (EGFR), which is associated with many head and neck squamous cell carcinomas, including Laryngeal cancer. It remained unclear if cannabis use is associated with increased risk of head and neck cancer.

The researchers conducted a large-scale, retrospective cohort study over a 20 year period from April 19, 2004, to April 19, 2024, to investigate whether there is an association between cannabis use and an increased risk of head and neck cancers. Given the growing prevalence of cannabis use and its potential health effects, understanding this relationship is crucial for public health. In this study, clinical records of 116,076 U.S. adults with and without cannabis-related disorders who had outpatient hospital clinic visits and no prior history of head and neck cancers were extracted from a database covering 64 healthcare organizations across the United States. The mean age of 46.4 years, 44.5% were women and 60% white. Cannabis-related disorder was defined as excessive cannabis use leading to psychosocial symptoms, including impaired occupational or social functioning. The control cohort consisted of 3,985,286 individuals with a mean age of 60.8 years (54.5% women, 74.6% white), with no cannabis-related disorder. Participants were matched for age, race, tobacco use, and alcohol-related disorders. Relative risks (RRs) for head and neck cancers and subtypes were calculated, with stratified analysis for those younger and older than 60 years.

It was noted that Individuals with cannabis-related disorder had a significantly higher risk of developing any type of head and neck cancer, compared to those without such disorders. Specifically, the risk for any head and neck cancer was 3.49 times greater in the cannabis-related disorder group. A site-specific analysis yielded that among those with cannabis-related disorder, Laryngeal cancer risk was 8.39 times higher, Oropharyngeal cancer risk was 4.9 times higher, Salivary gland cancer risk was 2.7 times higher, Nasopharyngeal cancer risk was 2.6 times higher and Oral cancer risk was 2.51 times higher. Risks were consistent across different age groups. Elevated risks persisted when cancer diagnoses were considered at least one year or five years after the initial cannabis use, indicating a sustained risk over time.

One of the study limitations was that the study did not capture information on the frequency, quantity, or type of cannabis use, which are crucial for understanding the dose-response relationship.

In conclusion, this study confirms a significant association between cannabis-related disorder and an increased risk of head and neck cancers, particularly Laryngeal and Oropharyngeal cancers. Future studies should focus on understanding the mechanisms behind this association and investigate the impact of cannabis use dose and duration on cancer risk. More comprehensive data collection and analysis are necessary to solidify these findings and inform public health recommendations.

Cannabis Use and Head and Neck Cancer. Gallagher TJ, Chung RS, Lin ME, et al. JAMA Otolaryngol Head Neck Surg. Published online August 8, 2024. doi:10.1001/jamaoto.2024.2419.

FDA Approves LYMPHIR® for Relapsed and Refractory Cutaneous T-Cell Lymphoma

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SUMMARY: The FDA on August 7, 2024 approved LYMPHIR® (Denileukin diftitox-cxdl), a novel immunotherapy for the treatment of relaped/refractory Cutaneous T-Cell Lymphoma (CTCL) after at least one prior systemic therapy.

Primary Cutaneous T Cell Lymphoma is a type of Non Hodgkin Lymphoma and includes a spectrum of diseases that primarily involve the skin, but may ultimately involve lymph nodes, blood and visceral organs such as spleen, liver and lungs. CTCL initially presents as red, scaly, itchy patches on the skin and is often misdiagnosed as eczema. Approximately 3,000 new cases are reported in the United States every year, with an estimated 30,000 – 40,000 individuals living with the disease. The incidence is higher in blacks than Caucasians or Asians. It is more common in men, and is typically first diagnosed in patients between the ages of 50 and 60 years of age. Mycosis Fungoides/Sezary Syndrome is the most common type of CTCL. There is currently no curative therapy for advanced CTCL other than Allogeneic Stem Cell Transplantation. Patients often receive several skin-directed therapies as well as systemic therapies to achieve effective disease control, but the disease eventually becomes refractory. There is therefore an unmet clinical need for novel therapies.

Denileukin diftitox is a recombinant fusion protein composed of Interleukin-2 (IL-2) receptor binding domain and diphtheria toxin fragments. It selectively targets IL-2 receptor-expressing cells, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis, leading to apoptosis. Its unique mechanism of action targets both malignant T-cells and immunosuppressive regulatory T-cells (Tregs). Transiently eliminating Tregs has the potential of unleashing potent immune responses by the immune system of the patient against their tumors. This agent was approved and marketed as ONTAK® in the US from 1999-2014 for the treatment of relapsed/refractory CTCL. However, the product was withdrawn from the market in 2014 because of manufacturing issues related to its bacterial expression. Manufacturing improvements to decrease the presence of misfolded and aggregated proteins resulted in a new and more purified bioactive formulation LYMPHIR®, that has 1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK®. It is considered a new drug by the FDA, requiring a new registrational clinical trial.

The efficacy and safety of LYMPHIR® was assessed in a multicenter, open-label, Phase III Pivotal Study 302 of CTCL patients, who had previously received at least one systemic treatment. This analysis included 69 patients (N=69) with Stage I-III CTCL who had CD25 expression on at least 20% of biopsied malignant cells per immunohistochemistry and had received a median four prior therapies. The median age was 64 years, 65% were men, 73% were White and 19% were African American, 66 patients had Mycosis fungoides and 3 had Sezary syndrome. Approximately 30% had Stage I disease, 48% had Stage II disease and 22% had Stage III disease. Patients received LYMPHIR® 9 mcg/kg/day for 5 days, every 21 days for up to 8 cycles. The Primary efficacy outcome measure was Objective Response Rate (ORR), as assessed by an Independent Review Committee (IRC).

The Objective Response Rate was 36.2%, with 8.7% achieving a Complete Response. The median time to response was 1.41 months, with 70% of responders seeing results after 1-2 cycles of treatment. Duration of response was at least 6 months for 52% of the patients and 84% (54/64) of skin evaluable patients had a decrease in skin tumor burden, and 12.5% (8/64) saw complete clearing of skin disease. Pruritis was evaluated as an exploratory endpoint with 31.7% of patients demonstrating clinically significant pruritus improvement. Importantly, no cumulative toxicity was observed in patients receiving LYMPHIR®.

The safety profile of LYMPHIR® was consistent with the known safety profile for Denileukin diftitox. Across three studies of 119 CTCL patients receiving 9 μg dose of Denileukin diftitox, the most common (20% or more) adverse reactions including laboratory abnormalities were, infusion reactions, increased transaminases, decreased albumin, nausea, edema, anemia, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, blurred vision and Capillary Leak Syndrome (CLS). Infusion reactions, CLS, and visual impairment were mostly Grade 1/2 and effectively managed.

In conclusion, LYMPHIR® represents a significant advancement in treating Cutaneous T-Cell Lymphoma, especially for patients who have not responded well to previous treatments. As the first systemic option in years targeting the IL-2 receptor on malignant T-cells and Tregs, LYMPHIR® provides new hope for managing the long-term challenges of CTCL, such as severe skin symptoms and secondary infections. This development moves us closer to addressing the needs of CTCL patients who struggle with ongoing disease despite prior therapies.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761312s000lbl.pdf