Background: Overall survival after first-line chemotherapy for metastatic or recurrent gastroenteropancreatic poorly differentiated neuroendocrine carcinoma (GEP-NEC) is reported to be less than 1 year. Platinum drugs in combination with etoposide or irinotecan have been used as first-line chemotherapy for GEP-NEC patients, but no standard treatment has been established for second-line and subsequent chemotherapy. Recently, however, we have seen patients with a good prognosis after treatment based on comprehensive cancer genomic profiling (CGP). We retrospectively reviewed GEP-NEC patients treated with chemotherapy. Methods: Patient background, treatment regimen, overall survival, and toxicity were evaluated in 20 GEP-NEC patients who started first-line platinum combination chemotherapy at our hospital between October 2016 and September 2022. Results: Median age was 71 (48 to 81) years, 16 were male, and primary sites were esophagus in 2 patients, stomach in 7 patients, small intestine in 2 patients, large intestine in 6 patients, and pancreas in 3 patients. Five patients had an adenocarcinoma component. Stage III, IV, and recurrence were observed in 2, 16, and 2 patients, respectively. Progression-free survival and overall survival after first-line chemotherapy were 4.0 (2.3 to 7.0) and 8.1 (4.7 to 17.0) months, respectively. Grade 3 or higher toxicity was observed in 13 patients. No differences in overall survival were observed in chemotherapy regimen including etoposide or irinotecan and cisplatin or carboplatin. Patients who underwent CGP had significantly longer survival. After second-line chemotherapy, a regimen containing irinotecan, 5-FU, paclitaxel, ramucirumab, and nivolumab was used, and overall survival was 5.2 (1.8 to NA) months. There were 4 of 20 patients who survived for more than 1000 days after first-line chemotherapy. Durable responses were observed in colonic NEC patients harboring the POLE P286R mutation treated with nivolumab and in those harboring the BRAF V600E mutation treated with cetuximab and encorafenib. Conclusions: Overall survival of GEP-NEC patients treated with platinum combination chemotherapy was very poor at only 8 months. However, in some cases, long-term survival has been achieved with molecular targeted therapy based on CGP results.