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.

Recently, the ADAURA study demonstrated statistically significant improved disease-free survival (DFS) with adjuvant osimertinib in patients with resected stage IB-IIIA non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A consistent improvement in disease-free survival (DFS) was shown, regardless of whether or not patients received adjuvant chemotherapy. Given benefit seen with and without adjuvant chemotherapy, some clinicians may be tempted to forgo chemotherapy and only offer osimertinib post surgical resection. Would this approach be appropriate? Here we carefully dissect data from the ADAURA trial and review how this may fit into the existing evidence on the treatment of early stage NSCLC by discussing five themes, the study design of ADAURA, attempts on adjuvant tyrosine kinase inhibitors, prior studies to support adjuvant chemotherapy, how adjuvant chemotherapy was administered in ADAURA and consideration of toxicities.

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.

Non-small cell lung cancer (NSCLC) patients demonstrating sensitizing oncogenic driver mutations have derived clinical benefit from targeted therapy. EGFR mutations constitutively activate the signaling pathway, leading to prosurvival and antiapoptotic signals. Classic sensitizing EGFR mutations, such as exon 19 deletions and exon 21 L858R point mutations, respond well to tyrosine kinase inhibitors (TKIs). On the other hand, EGFR exon 20 in-frame insertions are observed in 4-12% of EGFR-mutated NSCLC and are resistant to targeted therapy with TKIs. In May 2021, the Federal Drug Administration (FDA) provided accelerated approval to amivantamab (Rybrevant) in adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations after treatment with platinum-based chemotherapy. Here, we discuss properties of amivantamab, clinical trial results, and management of patients with EGFR exon 20 insertion mutated NSCLC.

Small cell lung cancer (SCLC) is characterized by rapid progression and poor prognosis. Although the phase II CITYSCAPE-02 trial found objective response rate (ORR) and progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients improved when tiragolumab was added to atezolizumab and chemotherapy, the phase III SKYSCRAPER-02 failed to find PFS or OS benefit in patients with SCLC. Atezolizumab was the first immunotherapy to show survival benefit in extensive SCLC based on the phase III IMpower133 study. Given that immunotherapy has become the standard of care for SCLC patients, further research is needed into ways to augment the immune system to better treat these patients.

In this report, we present a 29-year-old African American female who was brought to a local emergency department after being found unresponsive by her mother. The etiology of her stroke and severe hemolysis remained unknown, despite her mother reporting the patient's history of co-inheritance of sickle cell trait and beta-thalassemia trait, and extensive workup during her prolonged hospitalization. She was diagnosed with sickle cell disease (Sβ+ type) two years after discharge when she was referred to a sickle cell specialist for persistent anemia. Here, we also briefly review the challenges to diagnose rarer subtypes of sickle cell disease (SCD), in this case Sβ+ type, as well as the pathophysiology and current management of stroke in SCD.

KRASG12C is one of the most common oncogenes in non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Historically, KRAS mutations have been difficult to target due to lack of binding sites and exceptionally high affinity for guanosine triphosphate/guanosine diphosphate (GTP/GDP). Recently, KRASG12C selective inhibitors have shown promising results in Phase I/II studies. Here we discuss the mechanism of action, pharmacokinetic and pharmacodynamic properties, efficacy, and tolerability of adagrasib (MRTX849).

Mesenchymal-epithelial transition (MET) receptor tyrosine kinase is overexpressed, amplified, or mutated in 1-20% of NSCLC. MET dysregulation is associated with a poor prognosis. Recently, development of targeted therapies against MET exon 14 mutations has demonstrated efficacy and tolerability in early trials. Here we focus on tepotinib and capmatinib in regards to molecular characteristics, early preclinical and clinical data, and the emerging role in future studies and clinical practice.

Molecular testing is performed upon diagnosis of non-small cell lung cancer (NSCLC) because of the large success of targeted therapies for oncogenic mutations. Epidermal growth factor receptor (EGFR) mutations are the most commonly identified mutation in NSCLC, and EGFR exon 20 insertion mutations (exon20ins) are the third most common mutation in EGFR following EGFR exon 19 deletions and exon 21 L858R mutations. EGFR exon20ins have regularly demonstrated resistance to classical EGFR inhibition. Two treatments-mobocertinib and amivantamab-have recently been the first drugs to be approved by the US Food and Drug Administration (FDA) for treatment of lung cancers with these mutations following platinum-based therapy. Research surrounding these two drugs demonstrates strong efficacy, but with an intense array of side effects. Another targetable driver mutation is the human epidermal growth factor receptor 2 (HER2) exon20ins, representing approximately 2-3% of NSCLC patients. This mutation has been heavily studied in vitro as well as clinically, and trastuzumab deruxtecan was just recently granted accelerated FDA approval based on the high efficacy demonstrated in the Destiny-Lung01 study. However, similar to their EGFR counterparts, HER2 inhibitors also have evidence of toxicity in clinical studies. In this paper, we discuss the limited response of EGFR and HER2 exon20ins to a wide range of standard treatment regimens, such as platinum-based chemotherapy and classic EGFR tyrosine kinase inhibitors, as well as immunotherapy. We also review recently approved and upcoming targeted therapeutic options, considering what research is presently being done regarding efficacy and the reduction of side effects, as well as the agents risks and benefits for incorporation into an approved treatment regimen.

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.