Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: final analysis of the GioTag study

Three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are now approved in the first-line setting for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC): the first-generation reversible TKIs, erlotinib and gefitinib; the second-generation irreversible ErbB family blockers, afatinib and dacomitinib; and the third-generation EGFR TKI, osimertinib [1–5].

In randomized clinical trials, the second- and third-generation EGFR TKIs have significantly improved progression-free survival versus first-generation TKIs in first-line treatment of EGFR mutation-positive NSCLC [6–8]. Exploratory analysis of the ARCHER-1050 trial indicated that dacomitinib was associated with improved overall survival (OS) versus gefitinib, and LUX-Lung 7 showed a trend toward OS benefit with afatinib [9,10]. Recent data from the FLAURA Phase III trial demonstrated significantly prolonged OS with first-line osimertinib compared with the first-generation EGFR TKIs (gefitinib or erlotinib) in patients with EGFR mutation-positive NSCLC [11]. However, as acquired resistance to first-line EGFR TKI therapy is inevitable, the availability of subsequent treatment options following disease progression is a key consideration when assessing therapeutic choices.

Emergence of the T790M mutation in exon 20 of EGFR is the predominant molecular resistance mechanism to gefitinib, erlotinib and afatinib. This mutation presents in approximately 50–73% of tumors at the time of acquired resistance, with the likelihood being highest in patients with Del19-positive disease [12–16]. Osimertinib has demonstrated impressive activity in T790M-positive patients [17]. In contrast, targeted therapy options following first-line osimertinib treatment remain limited due to the heterogeneity of osimertinib resistance mechanisms, which are still not fully understood [18,19]. Chemotherapy is often the only option for patients who progress on osimertinib treatment in everyday clinical practice.

It has therefore been suggested that, at least in some patients, reserving osimertinib as a second-line therapy option may maximize time on targeted treatment and defer the need for more toxic chemotherapy regimens. The GioTag study was a global, observational, multicenter study designed to assess outcomes in EGFR TKI-naive patients with EGFR mutation-positive (Del19/L858R) NSCLC who received sequential afatinib and osimertinib treatment in a real-world clinical practice setting [20,21]. Importantly, for real-world clinical practice, the study included elderly patients and those with poor prognostic characteristics (Eastern Cooperative Oncology Group performance status [ECOG PS] ≥2 or stable brain metastases) who are often under-represented in or excluded from randomized clinical trials.

At the initial and updated analyses (May 2018 and April 2019, respectively), results were encouraging, particularly for Del19-positive patients and Asian patients [20,21]. Here, we report findings from the final analysis, including updated time on treatment and OS data.

Materials & methods

Study design & patients

The design of the GioTag study has been described previously [20,21]. In brief, GioTag was a global, observational study conducted across ten countries (Austria, Canada, Israel, Italy, Japan, Singapore, Slovenia, Spain, Taiwan and the USA; NCT03370770). Data were collected between December 2017 and December 2019 for patients with EGFR mutation-positive (Del19 and L858R) NSCLC who had T790M-positive disease after first-line afatinib and subsequently received osimertinib. To limit selection bias, each participating center assessed the health records of a maximum of 15 consecutive patients. All patients must have initiated osimertinib ≥10 months prior to enrollment to avoid early censoring and ensure mature data. Data were collected directly from sites via manual medical chart review (n = 77; 38%) or from electronic health records (n = 126; 62%) supplied by Cardinal Health (OH, USA). Verification of source data were undertaken for 30% of patients. Informed consent was provided where required.

Outcomes & assessments

The primary outcome was time on treatment, defined as the time from the first dose of afatinib to that of the last dose of osimertinib or death. The OS analysis was exploratory and was defined as time from start of afatinib treatment to death.

Statistical analysis

Data cut-off for this final analysis was 28 November 2019 and data for all enrolled patients were included. Time on treatment and OS were estimated using the Kaplan–Meier method; for patients still on treatment, time on treatment was censored at the date of data collection.

Results

Baseline demographics and characteristics of the 204 patients included in the analysis have been described previously [20,21]. The GioTag population reflected real-world clinical practice and included patients with ECOG PS ≥2 (15.2%) and those with CNS metastases (10.3%), in addition to the usual patient population included in clinical trials. Patients were predominantly Caucasian (58.8%) but also included Asian (24.5%) and African–American (8.8%) patients. At the start of afatinib treatment, 73.5% of patients had a Del19 mutation and 26.0% had the L858R mutation. One patient had both Del19 and L858R.

Most patients received the approved starting doses of afatinib (40 mg/day; 83.7%) and osimertinib (80 mg/day; 98.0%). One patient was excluded from the analysis due to reports of conflicting data. At the time of this final analysis (December 2019), 120 (59.1%) patients had died, 31 (15.3%) were lost to follow-up and 52 (25.6%) were alive; of these 52, 29 remained on osimertinib treatment and 11 had discontinued osimertinib treatment.

After a median follow-up of 33.9 months, the median time on treatment for sequential afatinib and osimertinib was 27.7 months (90% CI: 26.7–29.9; Figure 1A). For Asian patients (n = 50), median time on treatment was 37.1 months (90% CI: 28.1–40.3) and in patients with Del19-positive tumors (n = 149), median time on treatment was 30.0 months (90% CI: 27.6–31.9) (Table 1 & Figure 1). In the 31 Asian patients with Del19-positive disease, median time on treatment was 40.0 months (90% CI: 36.4–45.0). Clinical benefit was also consistent across patient subgroups often excluded from clinical trials: median time on treatment was 22.2 months in patients with brain metastases, 27.3 months in patients aged ≥65 years and 22.2 months in those with ECOG PS ≥2 (Table 1).

As reported previously, overall median time on afatinib was 11.9 months (90% CI: 10.9–12.2) [20]. Median time on osimertinib treatment was 15.6 months (90% CI: 13.6–17.1) overall, 18.9 months (90% CI: 13.6–23.3) in Asian patients and 16.5 months (90% CI: 14.9–17.9) in patients with Del19-positive tumors.

Overall median OS was 37.6 months (90% CI: 35.5–41.3) with a 2-year survival rate of 80% (Figure 2A). Median OS was 44.8 months (90% CI: 37.0–57.8) in Asian patients and 41.6 months (90% CI: 36.9–45.0) in patients with Del19-positive disease (Figure 2); in Asian patients with Del19-positive disease, OS was 45.7 months (90% CI: 38.2–57.8). Median OS was consistent in patients with poor prognostic characteristics: 31.0 months in patients with brain metastases, 36.9 months in patients aged ≥65 years and 32.0 months in those with ECOG PS ≥2 (Table 1). Median time from discontinuation of osimertinib treatment to death was 5.6 months (90% CI: 4.3–8.0).

For the 168 patients who received the recommended starting dose of afatinib (40 mg), median time on treatment and OS were 27.7 months (90% CI: 26.7–29.9) and 38.0 months (90% CI: 35.9–41.3), respectively. Median time on treatment and OS were 38.2 months (90% CI: 28.9–40.3) and 44.8 months (90% CI: 38.2–57.8) in Asian patients and 29.9 months (90% CI: 27.6–32.7) and 40.3 months (90% CI: 36.8–44.8) in those with Del19-positive disease, respectively. In the 29 Asian patients with Del19-positive disease who started on afatinib 40 mg, median time on treatment and OS were 40.0 months (90% CI: 36.4–46.7) and 45.7 months (90% CI: 38.2–57.8), respectively.

Discussion

These final results of the GioTag study further demonstrate that sequential afatinib and osimertinib treatment is a feasible and effective therapeutic strategy in a broad, real-world population of patients with EGFR mutation-positive NSCLC who acquired T790M, confirming results from the previous analyses [20,21]. Overall, median time on sequential afatinib and osimertinib treatment was 27.7 months for this patient population, consistent with the findings of the primary and interim analyses of the GioTag study (median times on treatment of 27.6 and 28.1 months, respectively) [20,21]. The OS data reported here represent the most mature analysis of OS with sequential afatinib and osimertinib to date. Particularly favorable outcomes were seen in patients with Del19-positive disease and Asian patients, with prolonged median time on treatment and a median OS of over 3.5 years reported for both subgroups. Across the overall population and patient subgroups, time on treatment and OS curves have not changed substantially from the previous analyses [20,21], although some median values have changed, likely due to the capturing of just a single point on the curve and small patient numbers in some of the subgroups.

Importantly, these clinical benefits were consistent across patient subgroups, including those with poor prognostic characteristics such as brain metastases, age ≥65 years or ECOG PS ≥2, who are often excluded from or under-represented in randomized clinical trials. Of note, the clinical benefit seen here in patients aged ≥65 years is consistent with that recently reported in a meta-analysis of clinical trial data, which suggested that EGFR TKIs have substantial benefit in elderly patients [22]. Further, it should be noted that prior afatinib treatment did not appear to diminish time on treatment with second-line osimertinib, with patients remaining on second-line osimertinib treatment for a median of 15.6 months overall and slightly longer in Asian patients and those with Del19-positive tumors.

These data are in agreement with other studies assessing sequential afatinib and osimertinib. In 37 patients who received osimertinib therapy after first-line afatinib in the LUX-Lung 3, 6 and 7 studies, median time on osimertinib was 20.2 months (95% CI: 12.8–31.5) and median OS was not reached after a median follow-up of 4.7 years [23]. Recent observational data also support prolonged osimertinib treatment after first-line afatinib [24]. Retrospective analysis of the few patients treated with dacomitinib or afatinib in the Phase III ARCHER-1050 and Phase IIB Lux-Lung 7 trials who went on to receive osimertinib (n = 22 and n = 20, respectively), demonstrated that median OS was 36.7 months with sequential dacomitinib and osimertinib, and not reached (3-year OS rate of ∼90%) with sequential afatinib and osimertinib, respectively [9,10].

The data presented here raise the question of the most appropriate therapeutic strategy: sequential afatinib and osimertinib or first-line osimertinib. OS is clearly a key consideration when selecting first-line treatment. Since the previous analyses of the GioTag study, OS data from the Phase III FLAURA study of first-line osimertinib have been reported; median OS of 38.6 months with osimertinib compared with 31.8 months with first-generation EGFR TKIs (gefitinib or erlotinib) (hazard ratio [HR]: 0.80; 95% CI: 0.64–1.00; p = 0.046) [11]. Consequently, osimertinib is increasingly used as a first-line treatment of choice. However, it should be noted that the OS benefit of first-line osimertinib in the 347 Asian patients included in the FLAURA study was less clear with a HR of 1.00 (95% CI: 0.75–1.32; median OS 37.1 months with osimertinib and 35.8 months with erlotinib/gefitinib) [11,25]. While direct comparisons are limited, not least because the FLAURA study enrolled patients with Del19 or L858R EGFR mutations at diagnosis, whereas the GioTag study only collected data from patients who acquired the T790M mutation after first-line afatinib treatment, the overall OS (37.6 months) reported for the broad, real-world patient population in the GioTag study is similar to that seen in the FLAURA trial. While further work may be needed to further identify patients likely to acquire the T790M mutation, and to identify therapeutic options for T790M-negative patients, it seems that some patient subgroups, such as those with Del19-positive disease and Asian patients, may benefit from a sequential therapy approach.

Further prospective validation is needed to address the question of the optimum therapeutic approach in patients with EGFR mutation-positive NSCLC. The final OS analysis of the Phase III AURA-3 trial, comparing second-line osimertinib with chemotherapy following first-line progression on EGFR TKIs in 419 patients with EGFR mutation-positive NSCLC demonstrated a numerical OS advantage for osimertinib, although this was not statistically significant (median OS: 26.8 vs 22.5 months; HR: 0.87; 95% CI: 0.67–1.12; p = 0.277) [26]. The Phase II APPLE trial (which compares sequential gefitinib/osimertinib vs first-line osimertinib) [27] should also be informative in terms of comparing the OS benefits of different sequential regimens.

As discussed previously [20], the main limitations of the GioTag study were its retrospective nature, lack of a comparator arm and potential for selection bias. The potential for selection bias was minimized as much as possible, for example by including only consecutive patients who fulfilled all of the inclusion criteria and limiting enrollment to a maximum of 15 patients per site. Nevertheless, this may have inadvertently introduced selection bias by either excluding those who died on first-line afatinib or under-representing those who derived long-term benefit from first-line afatinib; data from the LUX-Lung trials estimate these to be approximately 6 and 10–20% of patients, respectively.

Conclusion

These final data from the real-world GioTag study confirm those of the previous analyses and demonstrate that sequential afatinib followed by osimertinib is a feasible and effective therapeutic strategy in real-world patients with EGFR mutation-positive NSCLC who develop T790M.

Of note, median OS was over 3.5 years in Asian patients and those with Del19-positive disease, suggesting that sequential use of TKIs could potentially allow these EGFR mutation-positive NSCLC patients to receive long-term, chemotherapy-free treatment.