{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:52:55Z","timestamp":1787010775207,"version":"build-2736575974"},"reference-count":16,"publisher":"Cold Spring Harbor Laboratory","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>\n                    <jats:italic>KRAS<\/jats:italic>\n                    G12D-mutant\/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-\u03baB 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\n                    <jats:italic>KRAS<\/jats:italic>\n                    G12D-mutant NSCLC, prompting the initiation of this single-center phase 2 trial. Patients with advanced\n                    <jats:italic>KRAS<\/jats:italic>\n                    G12D-mutant NSCLC were eligible. Bortezomib was administered at 1.3 mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    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\n                    <jats:italic>KRAS<\/jats:italic>\n                    G12D-mutant lung adenocarcinomas were treated. Patients had a median pack year smoking history of 4 (range 0\u201345). A partial response (PR) was observed in one patient (\u221266% from baseline) and stable disease in five patients on the first stage of this study (overall response rate of 6%, 95% CI: 0.2\u201330.2), and further patients were not accrued. The median progression-free survival was 1 mo (95% CI: 1\u20136). The median overall survival was 13 mo (95% CI: 6\u2013NA). The most common treatment-related adverse events were fatigue (38%) and diarrhea (26%).\n                    <jats:italic>TP53<\/jats:italic>\n                    status did not predict response on exploratory testing. Of note, the patient with a PR had a unique subtype of lung adenocarcinoma\u2014invasive mucinous adenocarcinomas (IMA)\u2014and had rapid clinical improvement and substantial disease regression, which was also previously observed in two other patients with advanced\n                    <jats:italic>KRAS<\/jats:italic>\n                    G12D-mutant lung cancer with IMAs who received bortezomib on separate clinical trials. Exceptional responses to bortezomib can be achieved in\n                    <jats:italic>KRAS<\/jats:italic>\n                    G12D-mutant NSCLCs.\n                    <jats:italic>KRAS<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1101\/mcs.a003665","type":"journal-article","created":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T14:45:19Z","timestamp":1554129919000},"page":"a003665","source":"Crossref","is-referenced-by-count":32,"title":["Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with\n                    <i>KRAS<\/i>\n                    G12D-mutant lung cancers"],"prefix":"10.1101","volume":"5","author":[{"given":"Alexander","family":"Drilon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Schoenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn C.","family":"Arbour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Litvak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Montecalvo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena 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