EGFR TKI therapy for NSCLC patients with uncommon EGFR mutations: results of a real-world study (UpSwinG)

While being the established first-line treatment for non-small cell lung cancer (NSCLC) with common EGFR mutations (Del19 or L858R), limited data exist on the efficacy of EGFR TKIs in the subgroup of patients with uncommon EGFR mutations. Results of a large, real-world study presented at ESMO 2021, demonstrate encouraging clinical outcomes with EGFR TKIs in patients with uncommon EGFR mutations. Afatinib was the most used EGFR TKI in this analysis. Efficacy outcomes were best in patients with major uncommon and compound mutations, although some patients with ‘other’ and exon 20 insertion mutations also responded to the EGFR TKI therapy.

Molecular profiling in advanced non-small cell lung cancer (NSCLC) facilitated the detection of actionable mutations, which revolutionised the treatment paradigm for these patients. The pivotal moment in this paradigm shift consisted of the identification of sensitizing mutations in epidermal growth factor receptor (EGFR) that are associated with a clinical response to anti-EGFR-targeted therapy. Exon 19 deletions and exon 21 L858R substitutions are the most common mutations in the EGFR gene and result in high sensitivity to tyrosine kinase inhibitors (TKIs). Apart from these ‘classic mutations’, uncommon EGFR mutations are found in 7-23% of NSCLC patients and for these subgroups of patients, data on EGFR TKIs are much more limited. With the increased use of more sensitive sequencing-based detection methods and liquid biopsies, the detection of uncommon mutations in real-world clinical practice will likely increase in the years to come. As such  the need for a better understanding of the clinical responses to EGFR therapy in these patients remains high.

Study design

To address this issue, the non-interventional, global UpSwinG study investigated existing medical/electronic records for consecutive EGFR TKI-naïve (at diagnosis) patients with uncommon EGFR mutations (T790M de novo mutations, major uncommon mutations [G719X, L861Q or S768I], exon 20 insertions or ‘other’ uncommon mutations), that were treated with erlotinib, gefitinib, afatinib, osimertinib (1st- or 2nd-line). This  study aimed to investigate real-world treatment patterns in patients with uncommon EGFR mutations, assess the efficacy of EGFR TKIs in each uncommon mutation category and assess how EGFR mutations are detected in real-world practice. The primary endpoint for this analysis consisted of time to treatment failure (TTF), with overall response rate (ORR), overall survival (OS), and duration of response (DoR) as secondary endpoints. Of note, patients who were treated in a clinical trial, or had active brain metastases were excluded from the study. The same was true for patients who were treated with osimertinib for an acquired T790M mutation...

Results

In total, 246 patients, with a median age of 69.5 years were enrolled in the study, 56% of whom were female. Most patients in the study (83.7%) were Asian, 6.9% had brain metastases and 12.6% had an ECOG performance status of 2 or more. With respect to the mutation type, 72.8% had a major uncommon mutation (i.e. G719X, S768I, L861Q), 11.8% had an exon 20 insertion, 6.9% had a de novo T790M mutation and 8.5% had  any ‘other’ uncommon mutation. Of study patients, 33.3% had several EGFR mutations of which at least one was an uncommon mutation. Patients in the study were included at 36 sites across nine countries.

EGFR TKIs were the first line treatment of choice in the vast majority of patients (91.9%). Afatinib was the most popular TKI in this setting and was used in 54.1% of patients treated with an EGFR TKI, followed by gefitinib (28.7%), erlotinib (14.3%) and osimertinib (2.9%). Overall, 56.9% of patients with disease progression on first-line therapy received a subsequent line of therapy. In second line, 60.3% of patients were treated with chemotherapy, while 36.9% received an EGFR TKI in second line (40.4% osimertinib, 38.5% gefitinib/erlotinib, 21.2% afatinib).

In patients with uncommon EGFR mutations, EGFR TKIs were associated with an encouraging TTF, with a median of 8.8 months with erlotinib/gefitinib and 11.3 months with afatinib. The median OS for patients treated with first generation TKI’s (erlotinib/gefitinib) or afatinib was reported at 24.2 and 24.5 months, respectively. The ORR to EGFR TKIs was 43.4% (1.4% complete response, 42.1% partial response), with an additional 40.7% of patients experiencing disease stabilization. A detailed overview of TTF, OS, ORR and DoR data in the different mutations subgroups is depicted in slide 4. Interestingly, clinical activity of EGFR TKIs was also observed in patients with poor risk factors. For example, in patients with (non-active) brain metastases, EGFR TKI therapy was associated with a median TTF of 17.3 months and a median OS of 33.9 months (10.7 and 25.7 months, respectively, in patients without brain metastases). In patients with a poor performance status (i.e. ECOG PS ≥2), a median TTF of 8.6 months was reported with a median OS of 14.3 months).

Mutations were still mainly detected using a polymerase chain reaction (PCR) (59.6%), with sequencing only being used in 22.7% of patients. Finally, pathology reports were found to vary in quality with many mutations being marked as ‘undefined’. For example, only 28% of exon 20 insertions and 79% of exon 18 mutations were precisely defined.

Conclusions

EGFR TKIs are the first-line treatment of choice for metastatic NSCLC patients with uncommon EGFR mutations in real-world clinical practice. In the studies cohort, afatinib was the most commonly used EGFR TKI. The ECOG PS remained stable in patients from 1st- to 2nd-line (ECOG PS 0-1 in 66% at the start of first-line therapy vs. 57% at the start of second-line therapy), which enabled more than half of the patients to receive a further treatment. The strongest outcomes were observed in patients with major uncommon and compound mutations. However, some patients with ‘other’ and exon 20 insertion mutations also responded to EGFR TKIs, demonstrating the need for precise information on EGFR mutation type. In conclusion, treatment with an EGFR TKI should be considered for most patients with uncommon mutations.

Reference

Miura S, et al. EGFR TKIs in patients with NSCLC with uncommon EGFR mutations: a real-world study (UpSwinG). Presented at ESMO 2021; Abstract 1217P.

SC-BE-00445 09/2021