A phase 2 study of MK-2206 in patients with incurable adenoid cystic carcinoma (Alliance A091104) Journal Article
| Authors: | Ho, A. L.; Foster, N. R.; Deraje Vasudeva, S.; Katabi, N.; Antonescu, C. R.; Frenette, G. P.; Pfister, D. G.; Erlichman, C.; Schwartz, G. K. |
| Article Title: | A phase 2 study of MK-2206 in patients with incurable adenoid cystic carcinoma (Alliance A091104) |
| Abstract: | Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB-NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK-2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772). Methods: Patients with progressive, incurable ACC were enrolled and received MK-2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression-free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK-2206 on MYB expression was conducted in a subset of patients. Results: Sixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression-free survival was 9.7 months (95% CI, 3.8–11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8–29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment-related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB-NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK-2206 in four of five patients. Conclusions: MK-2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed. © 2023 American Cancer Society. |
| Keywords: | immunohistochemistry; protein kinase b; adult; cancer survival; clinical article; controlled study; human tissue; middle aged; human cell; overall survival; genetics; clinical trial; constipation; fatigue; diarrhea; drug safety; hypophosphatemia; systemic therapy; bone metastasis; cancer patient; cancer radiotherapy; follow up; anorexia; progression free survival; pain; phase 2 clinical trial; neoplasm recurrence, local; anemia; mucosa inflammation; nausea; vomiting; dehydration; tumor regression; pathology; biopsy; coughing; drug dose escalation; dyspnea; hyperglycemia; lymphocytopenia; pruritus; rash; allergic rhinitis; confusion; liver metastasis; lung metastasis; gene rearrangement; tumor recurrence; proto-oncogene proteins c-akt; xerostomia; recurrent disease; salivary gland tumor; salivary gland neoplasms; headache; adenoid cystic carcinoma; akt; dyspepsia; dry eye; dry skin; fused heterocyclic rings; alopecia; protein c myb; carcinoma, adenoid cystic; lymphocyte count; dysgeusia; hypocalcemia; lymphatic system disease; cheilitis; exploratory research; protein myb; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; heterocyclic compounds, 3-ring; humans; human; male; female; article; myb; myb-nfib; mk-2206 |
| Journal Title: | Cancer |
| Volume: | 130 |
| Issue: | 5 |
| ISSN: | 0008-543X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-03-01 |
| Start Page: | 702 |
| End Page: | 712 |
| Language: | English |
| DOI: | 10.1002/cncr.35103 |
| PUBMED: | 37947157 |
| PROVIDER: | scopus |
| PMCID: | PMC10922149 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK authors: Alan L. Ho -- Source: Scopus |
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