PMID- 36201194 OWN - NLM STAT- MEDLINE DCOM- 20221219 LR - 20231007 IS - 2374-2445 (Electronic) IS - 2374-2437 (Print) IS - 2374-2437 (Linking) VI - 8 IP - 12 DP - 2022 Dec 1 TI - Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status. PG - 1816-1820 LID - 10.1001/jamaoncol.2022.4432 [doi] AB - IMPORTANCE: Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments. OBJECTIVE: To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis. MAIN OUTCOMES AND MEASURES: Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD. RESULTS: A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs. CONCLUSIONS AND RELEVANCE: In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common. FAU - Abeykoon, Jithma P AU - Abeykoon JP AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Rech, Karen L AU - Rech KL AD - Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. FAU - Young, Jason R AU - Young JR AD - Department of Radiology, Mayo Clinic, Rochester, Minnesota. FAU - Ravindran, Aishwarya AU - Ravindran A AD - Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. FAU - Ruan, Gordon J AU - Ruan GJ AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Dasari, Surendra AU - Dasari S AD - Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. FAU - Morlote, Diana M AU - Morlote DM AD - Department of Pathology, University of Alabama at Birmingham. FAU - King, Rebecca L AU - King RL AD - Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. FAU - Rummage, Claire AU - Rummage C AD - Hematology/Oncology Clinical Pharmacist, University of Alabama at Birmingham. FAU - Zanwar, Saurabh AU - Zanwar S AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Acosta-Medina, Aldo M AU - Acosta-Medina AM AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Tobin, W Oliver AU - Tobin WO AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Shah, Mithun V AU - Shah MV AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Bennani, N Nora AU - Bennani NN AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Vassallo, Robert AU - Vassallo R AD - Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Ryu, Jay H AU - Ryu JH AD - Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Koster, Matthew J AU - Koster MJ AD - Division of Rheumatology, Mayo Clinic, Rochester, Minnesota. FAU - Davidge-Pitts, Caroline J AU - Davidge-Pitts CJ AD - Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota. FAU - Witzig, Thomas E AU - Witzig TE AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. FAU - Goyal, Gaurav AU - Goyal G AD - Division of Hematology-Oncology, University of Alabama at Birmingham. AD - Research Collaborator (limited tenure), Division of Hematology, Mayo Clinic, Rochester, Minnesota. FAU - Go, Ronald S AU - Go RS AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. CN - Mayo Clinic-University of Alabama at Birmingham Histiocytosis Working Group LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - JAMA Oncol JT - JAMA oncology JID - 101652861 RN - ER29L26N1X (cobimetinib) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - 0 (KRAS protein, human) SB - IM MH - Humans MH - Female MH - Adult MH - Middle Aged MH - Aged MH - Male MH - *Histiocytosis, Sinus/drug therapy/pathology MH - Proto-Oncogene Proteins p21(ras)/genetics MH - Retrospective Studies MH - Cohort Studies MH - *Neoplasms MH - Mitogen-Activated Protein Kinase Kinases PMC - PMC9539729 COIS- Conflict of Interest Disclosures: Dr Morlote reported receiving personal fees from Thermo Fisher outside the submitted work. Dr King reported receiving grants from Celgene/BMS (research funding unrelated to current study) outside the submitted work. Dr Tobin reported receiving grants from Mallinckrodt Inc outside the submitted work. Dr Bennani reported serving on an advisory board with no personal compensation for Daiichi Sankyo Inc, Kyowa Kirin, Vividion Therapeutics, Kymera, Secura Bio, and Affimed GmbH outside the submitted work. Dr Vassallo reported receiving grants from Pfizer, Bristol Myers Squibb, and Sun Pharma outside the submitted work. No other disclosures were reported. EDAT- 2022/10/07 06:00 MHDA- 2022/12/20 06:00 PMCR- 2023/10/06 CRDT- 2022/10/06 11:34 PHST- 2022/10/07 06:00 [pubmed] PHST- 2022/12/20 06:00 [medline] PHST- 2022/10/06 11:34 [entrez] PHST- 2023/10/06 00:00 [pmc-release] AID - 2797270 [pii] AID - cbr220022 [pii] AID - 10.1001/jamaoncol.2022.4432 [doi] PST - ppublish SO - JAMA Oncol. 2022 Dec 1;8(12):1816-1820. doi: 10.1001/jamaoncol.2022.4432.