Background and Importance Patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations have poor prognosis and few therapeutic alternatives.

Aim and Objectives To develop a systematic review of platinum pre-treated NSCLC harbouring eGFR exon 20 insertions to assess efficacy of treatments and scientific quality of studies.

Material and Methods Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines was applied in bibliographic review. Search was conducted in PubMed^® database up to 15 September 2022. Filter ‘clinical trial’ on types of articles was applied to the following review strategy: (exon 20 insertion) AND (Therapy/broad[filter]). Inclusion criteria: Randomised clinical trials (RCTs) evaluating treatments in patients diagnosed with advanced or metastatic NSCLC harbouring EGFR exon 20 insertions who had previously received platinum-based chemotherapy. Efficacy endpoints considered were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Data recorded: publication date, study design, comparator arm, therapies, sample size, treatment line, efficacy data.

Results Forty search results were found in review. Twelve RCTs were included. Publication dates of studies were between April 2015 and July 2022. Design of studies: 9 (75%) phase II RCT (one was basket trial) and 3 (25%) phase I/II. None of them presented a comparator arm. Therapies assessed: poziotinib, osimertinib (high and low doses), pertuzumab-trastuzumab combination, mobocertinib, amivantamab, erlotinib-onalespib combination, luminespib, ado-trastuzumab emtansine and dacomitinib. Sample size of RCTs ranged from 10 to 114 patients. Both untreated and platinum-pretreated patients were recruited in 4 (25%) RCTs and the rest comprised exclusively platinum-pretreated population. Ado-trastuzumab emtansine showed the best numerical results according to ORR (54.5%), but the worst PFS (2.8 months; 95% CI 1.4-4.4) and OS (8.1 months; 95% CI 3.5-13.2) of all therapeutic alternatives. The highest numerical efficacy results were achieved by amivantamab [PFS = 8.3 months (95% CI 6.5-10.9); OS = 22.8 months (95% CI 14.6 to not reached)] and mobocertinib [PFS = 7.3 months (95% CI 5.5-9.2); OS = 24.0 months (95% CI, 14.6-28.8)].

Conclusion and Relevance Results of amivantamab and mobocertinib suggested a higher numerical efficacy for clinically relevant endpoints in platinum pre-treated NSCLC harbouring EGFR exon 20 insertions. However, comparative RCTs with larger sample sizes are necessary to obtain reliable data.

Conflict of Interest No conflict of interest.