ABSTRACT
KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-κB pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed on prior clinical trials of bortezomib, both of whom had KRAS G12D-mutant NSCLC, prompting the initiation of this single-center phase 2 trial. Patients with advanced KRAS G12D-mutant NSCLC were eligible. Bortezomib was administered at 1.3 mg/m2 subcutaneously (days 1, 4, 8, 11; 21-d cycle) until progression or unacceptable toxicity. The primary objective was best objective response (RECIST v1.1). Sixteen patients with KRAS G12D-mutant lung adenocarcinomas were treated. Patients had a median pack year smoking history of 4 (range 0-45). A partial response (PR) was observed in one patient (-66% from baseline) and stable disease in five patients on the first stage of this study (overall response rate of 6%, 95% CI: 0.2-30.2), and further patients were not accrued. The median progression-free survival was 1 mo (95% CI: 1-6). The median overall survival was 13 mo (95% CI: 6-NA). The most common treatment-related adverse events were fatigue (38%) and diarrhea (26%). TP53 status did not predict response on exploratory testing. Of note, the patient with a PR had a unique subtype of lung adenocarcinoma-invasive mucinous adenocarcinomas (IMA)-and had rapid clinical improvement and substantial disease regression, which was also previously observed in two other patients with advanced KRAS G12D-mutant lung cancer with IMAs who received bortezomib on separate clinical trials. Exceptional responses to bortezomib can be achieved in KRAS G12D-mutant NSCLCs. KRAS G12D mutation alone, however, is not a robust predictor of response. Further evaluation should only be performed after further elucidation of other factors such as co-occurring alterations and histologic subtype such as IMA that may predict sensitivity to therapy.
Subject(s)
Adenocarcinoma, Mucinous/drug therapy , Antineoplastic Agents/administration & dosage , Bortezomib/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Proto-Oncogene Proteins p21(ras)/genetics , Adenocarcinoma, Mucinous/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Bortezomib/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Female , Humans , Injections, Subcutaneous , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Prospective Studies , Treatment OutcomeABSTRACT
Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non-small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1-2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093-9. ©2018 AACR.
Subject(s)
Antibodies, Monoclonal/adverse effects , Carcinoma, Non-Small-Cell Lung/therapy , Immunotherapy/adverse effects , Aged , Aged, 80 and over , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Immunological , Female , Humans , Immunotherapy/methods , Male , Middle Aged , Programmed Cell Death 1 Receptor/immunology , Retreatment , Retrospective StudiesABSTRACT
BACKGROUND: This article discusses and describes the experiences of five Hispanic bilingual (English and Spanish) research assistants (RAs) who were undergraduate and graduate nursing students and who were part of a research team. METHOD: A capacity-building framework was used, which has six guiding principles: a whole-system approach; accommodating diversity; reducing barriers to participation; enabling collaboration; mentoring; and facilitating networking. In addition, mentorship and peer learning were essential components of building research capacity. RESULTS: Reflections of the five RAs highlighting how these principles were applied are described. The experiences of the five Hispanic RAs and the outcomes of the projects are also described. CONCLUSION: These experiences demonstrate the importance of involving undergraduate and graduate nursing students in research, which can build research capacity and increase the number of Hispanic nurses in the workforce.
