LUAC harboring EGFR mutation is highly sensitive to Osimertinib with a median progression free survival circa 20 months in first line. Nevertheless, drug resistance eventually develops. A variety of acquired resistance mechanisms have been reported, including secondary resistance mutations, alternative pathway activation and histological transformation to small cell lung cancer or squamous cell lung cancer (LUSC). Here we report the case of a 68-year-old female with recurrent EGFR mutated-LUAC (L858R). She received Osimertinib in first line but presented disease progression after only 6 months. Besides, she did not experience any signs of clinical benefit and lost almost 10 kg while on treatment. After disease progression, a biopsy was performed in a new adrenal lesion, confirming the histological transformation to LUSC with persistence of L858R mutation. She received carboplatin/paclitaxel/pembrolizumab for 4 cycles followed by maintenance with pembrolizumab (200mg IV 21/21d). CT scans revealed partial response and she experienced clinical benefit, recovering weight and resuming her daily activities and social life. After 14 months of treatment, she is still on immunotherapy and her last CT scans from May/2020 reveal sustained partial response.