Background: LCNECC is a rare, poorly differentiated neoplasm with a median survival of 13 months. The cell of origin, genetic mediators and optimal clinical management of LCNECC are unknown. Current guidelines recommend treatment with platinum and etoposide, but nearly all patients rapidly fail therapy. Identification of actionable genomic alterations in LCNECC may lead to improved outcomes. Methods: We identified 123 patients (1.1%) with LCNECC or non-small cell high-grade neuroendocrine carcinoma of the colon or rectum, out of 11134 colorectal cancers treated at MSKCC from 1991-2015. Genomic testing had been performed on 8 tumors: 5 using mass spectrometry based genotyping of 8 genes and 3 using hybridization exon capture of 341 cancer-associated genes (MSK IMPACT). Results: BRAF V600E mutations were identified in 5/8 (62.5%) LCNECCs. One patient each had KRAS Q61H and G12V mutations. Only 2/8 patients had TP53 mutations. All 5 patients with BRAF V600E mutations had non-regional lymphadenopathy, consistent with the metastatic pattern seen in BRAF-mutant colorectal adenocarcinoma (CRC). One patient, a 52-year old female with metastatic LCNECC, was first treated with cisplatin/irinotecan but progressed after 2 cycles. She was treated with FOLFOX, with dramatic clinical and radiological response lasting 7 months. BRAFV600E mutation was identified, and she was treated with dabrafenib+trametinib with radiologically stable disease at 2 months. In sum, 4/6 evaluable patients treated with first line FOLFOX, and 3/3 patients receiving second line FOLFOX after disease progression on cisplatin-based therapy achieved radiological responses. Conclusions: BRAF and KRAS hotspot mutations are near universal features of LCNECC, suggesting that LCNECC is an ERK driven tumor. BRAF inhibitor therapy was associated with clinical benefit in one LCNECC patient. Mutations in TP53, RB1 and PTEN, frequent in small cell cancer, are uncommon in LCNECC. Moreover, several patients responded to FOLFOX, a standard of care for CRC. Together, the mutation patterns and therapy responses suggest some similarities between LCNECC and CRC. MSK IMPACT analysis of further LCNECCs is underway and will be reported at the meeting.