What happened, in summary

This 43-year-old never-smoker was referred in September 2021 with metastatic lung adenocarcinoma. The contralateral lung was the only metastatic site. Tumor testing showed PD-L1 tumor proportion score of 50%. Next-generation sequencing identified a HER2 exon 20 insertion, later confirmed as HER2 p.(Y772_A775dup), along with TP53 p.(R248W). Broader profiling also showed microsatellite stability, low tumor mutational burden, and low genomic instability status. Although no anti-HER2 agent was available in Italy for this setting and PD-L1 overexpression could have supported immunotherapy alone, her molecular and clinical profile led the treating team to choose front-line chemoimmunotherapy. After 4 cycles, the primary lung lesion had a partial response and all secondary nodules in the left lung disappeared. She continued maintenance therapy until April 2023, when mild renal toxicity occurred. At reassessment, the disease remained unchanged except for persistence of the primary lesion. The patient strongly wanted removal of the residual mass, even though the multidisciplinary board did not recommend surgery. In November 2023, she underwent right lower lobectomy with radical lymphadenectomy. Pathology showed a complete response, meaning no residual viable tumor was found in the resected specimen. After surgery, no additional therapy was offered. The first sequencing panel found the HER2 exon 20 insertion, and broader testing confirmed both HER2 and TP53 mutations, with similar variant allele frequencies in a sample with 38% tumor cellularity. This molecular profile mattered because the patient was young and a never-smoker, and it shaped the choice to use a combined systemic approach before considering local surgery.