Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers

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/m 2 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.

Development of a miniaturized 3D organoid culture platform for ultra-high-throughput screening

“…Dose‒response confirmatory screening provided further evidence for a panel of compounds that inhibit the KRAS G12D organoid growth, raising the possibility of KRAS G12D -dependent targets or pathways. Our results support the recent clinical trial of bortezomib in non-small cell lung cancer with two exceptional responders, both of whom had KRAS G12D mutant tumors ( Drilon et al., 2019 ). We also confirmed two proteasome inhibitors, carfilzomib and MLN9708, which potently inhibit the growth of KRAS G12D organoids.…”

Harnessing the vulnerabilities of p53 mutants in lung cancer – Focusing on the proteasome: a new trick for an old foe?

“…114 Another study in which patients were selected based on KRAS G12D mutation status also showed one exceptional responder with 66% tumor regression. 115 The authors later evaluated the p53 status of these patients based on preclinical in vivo studies showing increased response to proteasome inhibitors in a p53 null background compared to wild-type. Results were available in only 9 out of 22 patients due to tissue availability, and as a further caveat, p53 status was assessed by immunohistochemistry (IHC), which is at best, an imperfect correlate for p53 mutational status with a significant rate of both false positivity and negativity.…”

Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

“…In fact, the screens have been notable for little or no target overlap between their results, with the exception of proteosome-related genes [ 58 ]. Bortezomib, a proteosome inhibitor, was associated with modest anti-tumor activity and durable disease control in a small fraction of patients with KRAS G12D mutant lung tumors [ 63 , 64 ]. However, KRAS G12D mutation alone is not a robust predictor of response and further evaluation should only be performed after elucidation of co-mutations and histologic subtype that may predict therapy sensitivity [ 63 , 64 ].…”