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First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma with Combined BRAF and MEK Inhibition

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First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma with Combined BRAF and MEK Inhibition 1166 Molecular Insights in Patient Care First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK Inhibition Victor T.G. Lin, MD, PhDa; Lisle M. Nabell, MDa,b; Sharon A. Spencer, MDb,c; William R. Carroll, MDb,d; Shuko Harada, MDb,e; and Eddy S. Yang, MD, PhDb,c Abstract Salivary duct carcinoma (SDC) is a rare and aggressive malignancy for which limited data exist to guide treatment decisions. With the ad- vent of advanced molecular testing and tumor genomic profiling, clinicians now have the ability to identify potential therapeutic targets in difficult-to-treat cancers such as SDC. This report presents a male patient with widely metastatic SDC found on targeted next-generation sequencing to have a BRAF p.V600E mutation. He experienced a prolonged and robust response to first-line systemic chemotherapy with dabrafenib and trametinib. During his response interval, new data emerged to justify subsequent treatment with both an immune check- point inhibitor and androgen blockade after his disease progressed. To our knowledge, this is the first report of frontlineBRAF -directed therapy eliciting a response in metastatic SDC. J Natl Compr Canc Netw 2018;16(10):1166–1170 doi: 10.6004/jnccn.2018.7056 1 Salivary gland cancers are a heterogeneous collection mingham (UAB) Molecular Tumor Board (MTB). To of malignancies defined primarily by different histolo- our knowledge, this is the first reported use of combined gies, which include adenoid cystic carcinoma (ACC), BRAF and MEK inhibition for the treatment of meta- mucoepidermoid carcinoma, and salivary duct carcino- static BRAF-mutated SDC in the frontline setting. ma (SDC). In particular, SDC is a neoplasm known for both its poor prognosis and its rarity. Because of these characteristics, data are currently insufficient to confi- Case Report dently recommend a standard of care for these tumors. A 54-year-old white male presented initially with 6 Recently, clinical oncologists have had increas- weeks of swelling in the left cheek and neck that failed ing access to tumor genomic profiling, which allows to improve with clindamycin. CT imaging showed mul- for identification of mutations, gene fusions, and copy tiple intraparotid nodules and cervical lymphadenopa- number variants that may predict response to specific thy. Ultrasound-guided core biopsies were positive for targeted therapies. This approach has been of particu- indeterminate carcinoma. Staging by PET/CT showed lar interest in so-called difficult-to-treat cancers, which involvement of the left cervical nodes with no definite include rare malignancies such as SDC, that have a distant metastases. He was subsequently referred to UAB, very limited evidence base to guide treatment decisions. where he underwent direct laryngoscopy with biopsy, fol- This report presents a patient with a widely metastat- lowed by a left modified radical neck dissection and left ic SDC harboring a BRAF p.V600E mutation that was total parotidectomy. Pathology from his surgical resection treated with a precision oncology approach developed revealed a high-grade, locally advanced (pT4aN2b,cM0) in conjunction with the University of Alabama at Bir- SDC with multiple high-risk features, including a posi- aDivision of Hematology and Oncology, Department of Medicine, The authors have disclosed that they have no financial interests, University of Alabama at Birmingham; bUniversity of Alabama at arrangements, affiliations, or commercial interests with the manufacturers Birmingham Comprehensive Cancer Center; and Departments of cRadiation of any products discussed in this article or their competitors. d e Oncology, Otolaryngology, and Pathology, University of Alabama at Correspondence: Eddy S. Yang, MD, PhD, Department of Radiation Birmingham, Birmingham, Alabama. Oncology, University of Alabama at Birmingham, 1700 6th Avenue S, Submitted February 22, 2018; accepted for publication June 29, 2018. HSROC Suite 2232N, Birmingham, AL 35249. Email: [email protected] © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 16 Number 10 | October 2018 Molecular Insights in Patient Care 1167 BRAF V600E Salivary Duct Carcinoma tive margin of resection, extracapsular extension, and ity for phase I clinical trials and limited alternatives tumor involvement of 31 of 40 resected lymph nodes. in the setting of mostly stable disease. Restaging PET/ He was enrolled in a clinical trial comparing adjuvant CT performed after 13 total months of treatment re- chemoradiation versus radiation therapy (RT) alone vealed multiple new bony metastases (Figure 2D), at (RTOG 1008), and was randomly assigned to treat- which point dabrafenib and trametinib were re-esca- ment with RT alone. lated to full doses without any of the prior toxicities. Three months after completing adjuvant RT, he Shortly thereafter, he underwent a surgical biopsy of was found to have widespread osseous metastases with a posterior sacral metastasis, which was submitted to involvement of the intrathoracic lymph nodes. After HER2 amplification was ruled out by immunohisto- PierianDx for repeat targeted NGS (gene list shown chemistry and in situ hybridization, tumor tissue was in supplemental eAppendix 2) and did not find any sent to Genomics and Pathology Services at Washing- new actionable mutations. With clinical evidence of ton University in St. Louis for targeted next-genera- progression, including a rising alkaline phosphatase tion sequencing (NGS; gene list shown in supplemen- that had previously normalized with treatment, dab- tal eAppendix 1, available with this article at JNCCN. org), and a BRAF p.V600E mutation was identified. After discussion by the UAB MTB,1 he was started A Pretreatment B 5 months of treatment on targeted therapy with the BRAF inhibitor dab- rafenib and the MEK inhibitor trametinib, in addition to zoledronic acid for his bony metastases (Figure 1). Dabrafenib and trametinib were held approximately a month after initiation due to grade 4 palmar-plantar erythrodysesthesia, and were subsequently restarted at reduced doses, which he tolerated well. Restaging PET/CT was performed after 5 months of treatment and showed marked improvement in his diffuse os- seous metastases (Figure 2A, B). He continued on therapy, and restaging PET/CT after 9 total months of treatment showed essentially stable disease with the exception of a new hypermetabolic lesion in the right C 9 months of treatment D 13 months of treatment ischium, concerning for new metastasis (Figure 2C). He continued on the same regimen due to ineligibil- Figure 2. Marked response to dabrafenib and trametinib demon- strated by restaging imaging. PET/CT scans performed before and after initiation of treatment with dabrafenib and trametinib show a Figure 1. Timeline summary of clinical course. Lines of treatment are robust response to treatment. Pretreatment and posttreatment scans listed above the timeline and changes in disease status by restaging were performed at 6, 13, 17, and 21 months after initial diagnosis imaging are shown below it. Dose reductions, holds, and discontinu- (A–D, respectively). Most strikingly, there is complete resolution of the ations, and palliative radiotherapies are not shown for the sake of vertebral lesions. The new right ischial lesion noted in (C) portended simplicity. the progression of disease through treatment that was demonstrated Abbreviations: LND, lymph node dissection; RT, radiation therapy. 3 months later. © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 16 Number 10 | October 2018 1168 Molecular Insights in Patient Care Lin et al rafenib and trametinib were discontinued and he re- receptor tyrosine kinase (RTK) c-Kit and is known to ceived palliative RT to the hip. be poorly responsive to not only conventional che- At this time, a petition to the manufacturer for motherapy3 but also TKIs with activity against c-Kit, use of nivolumab as part of an expanded access pro- such as imatinib4 and dasatinib.5 In contrast, a recent gram was approved, and he was started on immune retrospective review of patients with SDC suggested a checkpoint blockade after completion of RT. For benefit to treatment with combined carboplatin and additional information, peripheral blood was sent paclitaxel.6 Notably, this cohort of 18 patients was es- for analysis of circulating tumor DNA (ctDNA) by tablished from a retrospective review of >8 years of Guardant360 (Guardant Health, Inc.), revealing clinical records, which exemplifies the difficulty of the known BRAF mutation with a variant allele fre- performing robust prospective clinical trials in this quency (VAF) of 28% and a KRAS p.Q61K mutation type of cancer. A larger retrospective evaluation of with a low VAF of 0.2%, as well as amplifications of 495 patients with SDC listed in the National Cancer MET, EGFR, and CDK6 of unclear clinical signifi- Database indicated that surgical resection was superi- cance. This new information was brought again to or to all other modalities, with insufficient data avail- the UAB MTB for discussion. Tyrosine kinase inhib- able to properly evaluate the role of conventional or itors (TKIs) were considered but not recommend- targeted chemotherapies.7 ed due to the downstream activating mutation of Interestingly, SDC histologically resembles inva- BRAF. CDK inhibitors were also discussed, but not sive ductal carcinoma of the breast,8 but its genomic pursued. He remained on nivolumab for 3 months profile is most similar to that of apocrine breast can-
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