Objective Patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations have a poor prognosis and few therapeutic alternatives. We conducted a review of scientific evidence about therapies in NSCLC with EGFR exon 20 insertion mutations. Data Sources A systematic review in PubMed® database was performed up to November 19, 2022. Clinical trials (CTs) about treatments of patients diagnosed with advanced or metastatic NSCLC harbouring EGFR exon 20 insertions who had previously received platinum-based chemotherapy were selected. CTs with a sample size of less than 10 patients were discarded. Efficacy results were used to determine the most interesting drugs. Subsequently, a more exhaustive analysis of the design of the CTs and safety of the most interesting schemes was conducted. Comparisons were attempted to develop. Data Summary A total of 40 records were found in the systematic search. Twelve selected CTs included the following therapies: poziotinib, osimertinib, pertuzumab–trastuzumab–docetaxel scheme, mobocertinib, amivantamab, erlotinib–onalespib regimen, luminespib, ado-trastuzumab emtansine and dacomitinib. Mobocertinib, amivantamab and poziotinib were determined as the most interesting treatments according to efficacy data. Gastrointestinal and dermatological adverse reactions were relevant in these regimens. All CTs presented a non-randomised design. No reliable comparisons could be developed. Conclusions The efficacy of mobocertinib, amivantamab and poziotinib in NSCLC with EGFR exon 20 insertion mutations is promising. However, therapies were assessed in single-arm CTs with low-quality evidence. Comparative studies with more extensive patient follow-up, larger sample size and better design are needed to reliably quantify the effect of these drugs.