Introduction:
- EGFR mutations are common in pulmonary adenocarcinomas (10-44%).
- The best available treatment for EGFR-mutated lung cancers is tyrosine kinase
inhibitors (TKIs).
- EGFR-TKIs have shown improved survival outcomes as compared to platinum-based
chemotherapy.
- The reversible TKIs like gefitinib selectively target EGFR, while the irreversible TKIs
like dacomitinib target EGFR/HER1, HER2, and HER4, the 3 kinase-active members
of the ErbB family.
ARCHER 1050 Trial:
- ARCHER 1050 was a randomized, phase III trial, across different countries.
- The study included stage III/IV NSCLC patients who had a recurrence after a year
post-chemotherapy and at least 1 EGFR mutation.
Methodology:
- A total of 452 patients were randomized to receive gefitinib (n=225) or dacomitinib
(n=227).
- Patients in the dacomitinib received 45 mg once daily in 28-day cycles and patients in
the gefitinib group received 250 mg once daily in 28-day cycles.
- Two dacomitinib dose reductions were permitted (30 mg/day and 15 mg/day) in the
case of grade 2-3 toxicities.
- The primary endpoint was PFS, while the secondary outcomes included objective
response rate and duration, and OS.
- Dacomitinib was discontinued in 161 patients, while gefitinib was discontinued in 186
patients.
- According to the masked independent review, the median PFS in the dacomitinib
group was higher than in the gefitinib group.
- Best overall response (complete or partial) was achieved in 75% of the Asian
population and 68% of the non-Asian population.
- Proportion of treatment failure in the dacomitinib group was lesser than the gefitinib
group.
- The overall survival was better in the dacomitinib group.
- The adverse events in both groups were similar. Diarrhea, paronychia, dermatitis
acneiform, and stomatitis were common in the dacomitinib group, whereas diarrhea,
increased alanine aminotransferase, and aspartate aminotransferase occurred
commonly in the gefitinib group.
- Dacomitinib-associated serious adverse events were higher than those caused by
gefitinib.
- Skin and subcutaneous tissue disorders, gastrointestinal disorders, and interstitial lung
disease or pneumonitis were responsible for the termination of dacomitinib, whereas
increased aspartate aminotransferase and interstitial lung disease or pneumonitis were
responsible for gefitinib discontinuation.
Discussion:
- Unlike the LUX-Lung 7 trial, which compared the efficacy of afatinib and gefitinib,
ARCHER 1050 supports the use of dacomitinib.
- The PFS benefit associated with dacomitinib was superior to afatinib.
- The prolonged PFS can be explained by a greater reduction in the tumor size.
- The irreversible binding of dacomitinib indicates the longer duration of response.
- There is insufficient evidence to conclude the difference between responses by the
Asian and non-Asian populations.
- ARCHER 1050 reported no difference in the efficacy of both drugs in patients with
either exon 19 deletion or Leu858Arg mutation. On the contrary, a Chinese study
comparing erlotinib and gefitinib indicated that EGFR TKIs have greater efficacy in
patients with exon 19 deletion than in patients with Leu858Arg mutation.
- Limitations like introduction bias, exclusion of patients with brain metastases, a
higher proportion of females in the dacomitinib group, and a greater number of
patients with ECOG score 0 in the gefitinib group are acknowledged and considered
in the analysis.
- In conclusion, dacomitinib was better than gefitinib in NSCLC patients with an EGFR
mutation. Dacomitinib can be considered in the management of these patients.