In this retrospective study, dacomitinib showed a durable efficacy and maintained a manageable safety profile but necessitated dose reduction in the majority of patients in patients with EGFR-mutated NSCLC. For the overall population, ORR was 84.3% and the median PFS was 16.7 months, which was quite superior to the survival results represented in ARCHER 10508.
The primary differences in baseline characteristics compared to ARCHER 1050 are the presence of brain metastasis and racial composition. Unlike ARCHER 1050, which demonstrated a relatively diverse racial distribution with 75% Asian, 25% White, and less than 1% Black participants, this retrospective study was only included Asian in South Korea. Furthermore, ARCHER 1050 excluded patients with brain metastasis, while 45.1% of patients had brain metastasis at the initiation of dacomitinib in this study. Survival results are superior in this study compared to ARCHER 1050, despite including patients with brain metastasis. The distribution of smoking status and the prevalence of EGFR mutation, including exon 19 deletion and L858R mutation in exon 21 were comparable between this study and ARCHER 1050.
As mentioned above, the efficacy of dacomitinib in patients with brain metastasis was initially unclear in previous prospective studies. In this study, the inclusion of patients with brain metastasis and survival analysis based on the presence of brain metastasis contributed to obtaining insight regarding this aspect, despite its retrospective nature. The median PFS was 16.7 months despite 45.1% of patients having brain metastasis. Several retrospective studies showed the intracranial efficacy of dacomitinib, with an overall intracranial objective response rate (iORR) of 85%12,13. In a previous prospective study involving 30 patients with brain metastasis, dacomitinib demonstrated an iORR of 96.7% and the median PFS was 17.5 months14.
In subgroup analysis conducted based on EGFR mutation in ARCHER 1050, dacomitinib demonstrated significantly superior survival efficacy compared to gefitinib in patients harboring L858R mutation in exon 21 (hazard ratio: 0.63, 95% CI; 0.44–0.88). The superior survival efficacy of dacomitinib in patients with the L858R mutation in exon 21 represents a unique feature not observed in other EGFR-TKIs, including afatinib, which belongs to the same generation of EGFR TKIs7. Recent in vitro studies revealed that dacomitinib demonstrates the lowest IC50 values for the L858R mutation in exon 21 (IC50 = 2.6) compared to gefitinib (IC50 = 26), erlotinib (IC50 = 16), afatinib (IC50 = 4), and osimertinib (IC50 = 9). The efficacy of dacomitinib in L858R mutation in exon 21 appears to be linked to these IC50 values15. Additionally, in FLAURA, subgroup analysis based on EGFR mutation demonstrates relatively limited OS benefit in L858R mutation in the exon 21 subgroup with osimertinib (hazard ratio: 1.0, 95% CI; 0.71–1.40)16. Dacomitinib may represent a promising treatment option for patients with EGFR-mutant NSCLC harboring L858R mutation in exon 21, when compared to other EGFR TKIs.
The recommended optimal starting dose for dacomitinib is 45 mg per day in ARCHER 1050. However, women, Asians, and patients with lower body weight tend to reduce the dose17. In this study, dose reductions were necessary in most patients (85.6%) owing to adverse events. This study also showed that the reduction to 30 mg took a median time of 1.2 months, while further reduction to 15 mg required a median time of 4.3 months. The relatively early implementation of dose reductions can be attributed to the prevailing belief that a generous reduction is preferable and does not compromise efficacy17. The metabolism of dacomitinib varies individually. In previous study of dacomitinib through plasma concentration, there was no difference among the patients who remained on 45 mg per day, those who had their dose reduced from 45 mg to 30 mg per day, and those who had their dose reduced from 45 mg to 30 mg and then to 15 mg per day. Starting at 45 mg or 30 mg per day and adjusting according to adverse events with close and frequent follow-up is a top-down approach which considered to be optimal17.
It is well-established that T790M mutation in exon 20 occur in 50%-60% of patients treated with EGFR first- or second-generation TKIs18. The clinical data regarding the resistance mechanism of dacomitinib is still limited. In this study, T790M mutations were observed in 40% of cases, which is consistent with previous data from other first- or second-generation EGFR-TKIs.
This study had several limitations. The median OS was not reached owing to the relatively short follow-up time. Additionally, the retrospective nature of this study and the small sample size further constrain its findings.
In conclusion, this study demonstrated a real-world efficacy of dacomitinib in EGFR-mutated NSCLC as a first-line treatment. With a tolerable safety profile and superior survival efficacy compared with previous prospective studies, it is anticipated to be a valuable second-generation EGFR TKI in clinical practice. Additionally, the study highlights its efficacy in patients with brain metastasis, establishing it as one of the viable treatment options for NSCLC patients with brain metastasis.