Checkmate 77T: Perioperative chemoimmunotherapy outperforms in early-stage NSCLC.

Approximately 1 in 4 patients with NSCLC present with resectable disease. Although surgery is potentially curative, 30%-50% of patients relapse. Studies have shown that neoadjuvant, adjuvant, and perioperative chemoimmunotherapy improve outcomes. The Checkmate 77T trial explored if perioperative platinum-based chemotherapy plus nivolumab, surgical resection, then adjuvant nivolumab further improved outcomes including EFS.1.

Assessing Health-Related Quality of Life in Mycosis Fungoides and Sézary Syndrome: Unmet Needs.

Mycosis fungoides (MF) and Sézary syndrome (SS) can impair multiple dimensions of health-related quality of life (HRQoL). Currently, there is no standardized assessment tool for measuring HRQoL in patients with MF/SS. Here, we describe the existing literature on multiple dimensions of HRQoL in MF/SS with a special focus on the gaps in the current knowledge and identify future directions necessary to assess the HRQoL of patients with this disease.

Detangling the Threads of Hairy Cell Leukemia, Beyond the Morphology and Into the Molecular.

Hairy cell leukemia (HCL) makes up 2% of leukemias in the United States and encompasses great molecular heterogeneity. The standard treatment paradigm involves purine nucleoside analogues in the upfront setting with high complete response rate to initial therapy but frequent relapses. There is an increasing role for BRAF inhibitors, with or without rituximab, in refractory and even in untreated patients. The response to purine analogues in HCL variant cases, otherwise classified as splenic lymphoma with prominent nucleolus in the 5th WHO edition classification, is less robust. Several antibodies, small molecular inhibitors, and combination regimens have been explored in HCL but data is frequently limited by case reports or small case series. Here we review available treatment options including their efficacy and safety profiles. We also explore investigational agents and potential future targets. The goal is to present a comprehensive therapeutic review of this rare disease entity and outline the ever increasing and novel therapeutic management options which interrupt key pathways in the pathogenesis of this malignancy.

Baseline immunoglobulin G and immune function in non-Hodgkin lymphoma: a retrospective analysis.

Introduction: Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in treatment-naïve patients is associated with poorer survival in high grade B-cell non-Hodgkin's lymphomas, though it is not known how this applies across all B-cell lymphoid malignancies. Methods: We conducted a retrospective study of immunoglobulin levels and clinical outcomes including survival, hospitalization, and infection rates in patients diagnosed with B-cell non-Hodgkin lymphomas of all grades at our institution. Results: Two-hundred twenty-three adults (aged = 18 years) with available pre-treatment IgG levels were selected, with hypogammaglobulinemia defined as IgG< 500 mg/mL. For this analysis, we grouped DLBCL (n=90), Primary CNS (n=5), and Burkitt lymphoma (n=1) together as high-grade, while CLL (n=52), mantle cell (n=20), marginal zone (n=25), follicular (n=21), and Waldenstrom macroglobulinemia (n=5) were low-grade. The incidence of hypogammaglobulinemia in our cohort of both high and low-grade lymphoma patients was 13.5% (n=30). Across all NHL subtypes, individuals with baseline IgG< 500 mg/dL showed an increased rate of hospitalization (4.453, CI: 1.955-10.54, p= 0.0005) and higher mortality (3.325, CI: 1.258, 8.491, p= 0.013), yet no association in number of infections when compared with those with IgG=500 mg/dL. There was a higher hospitalization rate (3.237, CI: 1.77-6.051, p=0.0017) in those with high-grade lymphoma with hypogammaglobulinemia when compared with low-grade. There was no statistically significant difference in individuals who were alive after three years in those with baseline IgG<500 mg/dL. Discussion: Our study is the first to analyze incidence of hypogammaglobulinemia at the time of diagnosis of NHL as a potential biomarker of interest for future outcomes including hospitalization and infection.

Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC.

Kristen Rat Sarcoma viral oncogene (KRAS) mutations are one of the most common oncogenic drivers found in 12-14% of non-small cell lung cancer (NSCLC) and 4% of colorectal cancer tumors. Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations. In preclinical studies, divarasib was 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib. While sotorasib met its primary endpoint in the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed. Adagrasib has demonstrated clinical benefit in the phase I/II KRYSTAL-1 study setting, however, 44.8% of patients reported grade 3 or higher toxicities. Divarasib has been studied in a phase I dose expansion cohort with promising efficacy [objective response (ORR) 53.4% and PFS 13.1 months]. Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.

MARIPOSA: Can Amivantamab and Lazertinib Replace Osimertinib in the Front-Line Setting?

Osimertinib is the current first-line treatment for EGFR-mutated NSCLC, however, patients frequently relapse due to acquired resistance mutations. Amivantamab is a bispecific antibody against EGFR and MET alterations. Lazertinib is a tyrosine kinase inhibitor active against EGFR mutations including common resistance mutations. The MARIPOSA trial was designed to study if the combination of amivantamab plus lazertinib in untreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients would provide improved progression-free survival. Here, we discuss the rationale for the study and the early results of MARIPOSA.

Taletrectinib for the treatment of ROS-1 positive non-small cell lung cancer: a drug evaluation of phase I and II data.

INTRODUCTION: While crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC), unmet needs remain. These unmet needs include treatment options for patients with resistance mutations and efficacious options even in the presence of brain metastasis while simultaneously avoiding unwanted neurological side effects. AREAS COVERED: Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address central nervous system penetration while conferring fewer neurological adverse events. All of these features are demonstrated and supported by data from the phase I and the regional phase II TRUST-I clinical trial. Here, we describe the preclinical and clinical characteristics of taletrectinib and evaluate the data from phase I and II studies and review the rationale and design of TRUST-II, a global phase II study of taletrectinib, which is enrolling patients in North America, Europe, and Asia. EXPERT OPINION: Taltrectinib has the potential to improve PFS based on its greater potency against ROS1+ tumors and high CNS penetration. By selectively inhibiting ROS1 wild-type and its resistant mutations over TRKB, taltrectinib has a better safety profile with minimal CNS-related AEs compared to other ROS1+ inhibitors.