Survival Outcomes and Treatment Patterns in Patients With NFE2L2 and/or KEAP1 Mutation-Positive Advanced Squamous Cell NSCLC Using a Real-World Clinico-Genomic Database.

BACKGROUND: NFE2L2 and/or KEAP1 mutations are associated with worse prognosis in all non-small cell lung cancer (NSCLC). We determined real-world survival outcomes and treatment patterns among patients with advanced squamous cell NSCLC by NFE2L2 and KEAP1 mutation status. PATIENTS AND METHODS: A retrospective study (January 2011-December 2018) was conducted using a de-identified US-based clinico-genomic database. Adult patients with advanced squamous cell NSCLC with ≥ 2 in-network visits and comprehensive genomic profiling during the study period were included. Outcomes included real-world progression free survival (rwPFS) by line of therapy and overall survival (OS). The real-world effectiveness of anti-PD-1/PD-L1 first-line therapy was also evaluated in patients with a NFE2L2 and/or KEAP1 mutation. RESULTS: Of 703 patients included (median age: 70.0 years), 31.6% had a NFE2L2 and/or KEAP1 mutation. The most common first- and second-line treatments regardless of mutation status were platinum-based chemotherapies and anti-PD-1/PD-L1 therapies. The most common third-line treatment was anti-PD-1/PD-L1 therapy in patients with a NFE2L2 and/or KEAP1 mutation and single-agent chemotherapy in patients with wild-type disease. Patients with a NFE2L2 and/or KEAP1 mutation versus wild-type disease had significantly shorter rwPFS (4.54 vs. 6.25 months; P = .003) following first- but not second- or third-line therapy and shorter median OS (13.59 vs. 17.37 months; P  =  .4105). No survival differences were observed in patients with a NFE2L2 and/or KEAP1 mutation receiving first-line anti-PD-1/PD-L1 therapies versus other therapies. CONCLUSIONS: Patients with advanced squamous cell NSCLC with a NFE2L2 and/or KEAP1 mutation have poor real-world survival, highlighting the need for a genotype-directed therapeutic strategy in this population.

Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes.

INTRODUCTION: EGFR exon 20 insertion mutation-positive non-small cell lung cancer (NSCLC) is rare, has a poor prognosis, and outcomes are not fully established. We describe and evaluate outcomes from real-world and clinical evidence in these patients. METHODS: A systematic literature review (SLR) identified interventional and real-world evidence (RWE) studies reporting clinical outcomes for EGFR exon 20 insertion mutation-positive NSCLC. Meta-analyses were conducted by line of therapy to synthesize pooled survival and response outcomes across RWE. Published evidence from interventional studies was summarized individually. RESULTS: The SLR identified 23 RWE and 19 original interventional studies. In the meta-analysis of RWE, pooled response and survival outcomes were low for first-line EGFR-tyrosine kinase inhibitors (TKIs) and immuno-oncology (IO) agents. First-line chemotherapy resulted in a pooled ORR 25.7%, pooled PFS 5.6 months, and pooled OS 18.3 months. Pooled outcomes were further reduced in second or later lines (≥2 L): pooled ORR was 5.0%, 3.3%, and 13.9%; pooled PFS was 2.1 months, 2.3 months, and 4.4 months; and pooled OS was 14.1 months, 8.8 months, and 17.1 months (not a pooled result) for EGFR-TKIs, IO agents, and chemotherapy, respectively. Interventional studies reported outcomes for TKIs (mobocertinib, poziotinib, osimertinib, afatinib, CLN-081, DZD9008), a monoclonal antibody (amivantamab), and a heat shock protein 90 inhibitor (luminespib). While there is limited RWE for the recently approved agents mobocertinib and amivantamab, which specifically target exon 20 insertion mutations, interventional evidence supports their potential as effective treatment options. CONCLUSIONS: Conventional treatments used in patients with EGFR exon 20 insertion mutation-positive NSCLC have limited efficacy, though chemotherapy appeared to be associated with better response and survival outcomes than non-exon 20 targeting EGFR-TKIs and IO agents. This supports the need to identify EGFR exon 20 insertion mutations as the availability of new targeted treatments may offer additional therapeutic options to these patients.

EGFR Testing Patterns and Detection of EGFR Exon 20 Insertions in the United States.

INTRODUCTION: EGFR exon 20 insertions (EGFRex20ins) are a diverse set of mutations in NSCLC that are refractory to tyrosine kinase inhibitors. We describe real-world EGFRex20ins detection patterns in patients with advanced NSCLC in the United States. METHODS: Data from 2011 to 2020 were extracted from the Flatiron Health electronic health record-derived deidentified database. RESULTS: Among 67,281 patients with advanced NSCLC and at least two clinic visits, 66.8% were tested for EGFR mutations, of whom 13.9% tested positive. Of these, 4.9% had EGFRex20ins. The median time from NSCLC diagnosis to the first positive EGFRex20ins test result was 23 days, including 9 days of laboratory testing time. The EGFRex20ins were reported in 0.6% to 1.0% of all patients with advanced NSCLC and account for 3.9% to 5.3% of all EGFR mutations. During the study period, reverse transcription-polymerase chain reaction testing rates decreased whereas next-generation sequencing rates increased both in overall and among patients with tumors positive for EGFRex20ins. Tissue was the most common sample type used for EGFR and EGFRexon20ins detection (81.1% and 84.9%, respectively), whereas blood sampling for EGFRexon20ins detection increased from 0% (2011) to 37.2% (2020). For 23.7% of patients with EGFRex20ins, treatment was initiated before receiving the first positive EGFRex20ins test result, with therapies including immuno-oncology agents as the most common treatment type from 2017 to 2020. CONCLUSIONS: EGFR testing and detection of EGFRex20ins in patients with NSCLC have increased slightly over time with the increasing use of next-generation sequencing. The current late-stage development of EGFRex20ins-targeted therapy is driving a need for more efficient testing.

Co-ordinated control of the Aurora B abscission checkpoint by PKCε complex assembly, midbody recruitment and retention.

A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody. This localisation is demonstrated to be an autonomous property of the inactive PKCε D532N mutant, consistent with activity-dependent dissociation. The C1A and C1B domains are necessary for this localisation, while the C2 domain and inter-C1 domain (IC1D) are necessary for retention at the midbody. Furthermore, it is shown that while the IC1D mutant retains 14-3-3 complex proficiency, it does not support Aurora B phosphorylation, nor rescues division failure observed with knockdown of endogenous PKCε. It is concluded that the concerted action of multiple independent events facilitates PKCε phosphorylation of Aurora B at the midbody to control exit from the abscission checkpoint.

Regulation of the cytokinesis cleavage furrow by PKCε.

Cytokinesis is the final act of the cell cycle where the replicated DNA and cellular contents are finally split into two daughter cells. This process is very tightly controlled as DNA segregation errors and cytokinesis failure is commonly associated with aneuploidy and aggressive tumours. Protein kinase Cε (PKCε) is a lipid-activated serine/threonine kinase that is part of the PKC superfamily. PKCε plays a complex role in the regulation of migration, adhesion and cytokinesis and in the present article we discuss the interplay between these processes. Integrin-mediated interaction with the actin cytoskeleton is a known regulator of cell adhesion and migration and there is emerging evidence that this pathway may also be essential for cytokinesis. We discuss evidence that a known actin-binding region in PKCε is involved in PKCε-mediated regulation of cytokinesis, providing a link between integrin-mediated stabilization of the cytokinesis furrow and PKCε recruitment.