First-line Afatinib in Epidermal Growth Factor Receptor–mutant Metastatic Non-small Cell Lung Cancer: a Clinical Retrospective Study

Hong Kong J Radiol 2022 Sep;25(3):184-91

 

 

¹ Department of Clinical Oncology, Queen Mary Hospital, Hong Kong

² Department of Clinical Oncology, The University of Hong Kong, Hong Kong

 

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Patients with non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor mutation (EGFR-MT) are currently treated with tyrosine kinase inhibitors (TKIs).[1] Activating mutations in the EGFR gene causes aberrant EGFR signalling, which sensitises tumours to targeted TKI treatment. The Food and Drug Administration has currently approved five TKIs, with gefitinib and erlotinib being first-generation, afatinib and dacomitinib in the second generation, and osimertinib in the third generation.[2]

 

Afatinib is an irreversible blocker of the ErbB family of receptors (inhibiting signalling via heterodimers and homodimers formed by ErbB₁ (EGFR), ErbB₂ (human epidermal growth factor receptor 2 [HER₂]), ErbB₃ (HER₃), and ErbB₄ (HER4).[3] Randomised controlled trials (RCTs) have shown that afatinib significantly improved progression-free survival (PFS) compared with standard chemotherapy.[4] [5] Adverse events (AEs) were tolerable with few treatment discontinuations.

 

Post-hoc analysis of the LUX-Lung trials[6] found afatinib had significant activity against certain uncommon mutations, including G719X, L861Q, and S768I. Preclinical data showed that afatinib was less effective against tumours with exon 20 insertions, or de novo T790M mutations alone or in combination with other mutations.

 

There are not as much prospective clinical data on other EGFR TKIs targeting uncommon mutations. As a result, afatinib is the TKI of choice in the first-line setting for more than 80 countries to treat patients with NSCLC with EGFR-MT.

 

Clinical trials typically have strict inclusion criteria, and certain patient subgroups are frequently excluded, such as elderly patients, patients with brain metastases, or with an Eastern Cooperative Oncology Group (ECOG) performance status ≥2. Given the lack of prospective data in these patients, the goal of this study was to analyse the available data of EGFR-MT patients treated with afatinib in an environment similar to daily clinical practice, and to examine and compare outcomes of individuals with uncommon mutations.

 

Cases of patients aged ≥18 years with histologically proven metastatic NSCLC that were treated with first-line afatinib from 1 January 2015 to 30 June 2021 at Queen Mary Hospital Hong Kong were retrospectively reviewed. Median follow-up time was 23 months. The data cut-off was on 31 July 2021. Those that had received prior anticancer treatment or had primary tumours other than in the lung were excluded. Cases were categorised into four key groups: tumours harbouring major uncommon point mutations (G719X, L861Q, and S768I); exon 20 insertions; other uncommon mutations; and common mutations (exon 19 deletion, exon 21 L858R). Cases with brain metastasis and poor performance status were not excluded.

 

The primary objective was to evaluate the safety and efficacy of afatinib in these groups. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Efficacy endpoints included: PFS (time from first afatinib administration to date of progression or to date of death, whichever came first) and overall survival (OS) [time from diagnosis to date of death]. ‘Progression’ was defined as a worsening radiological appearance as per standard of care at the participating institution via Response Evaluation Criteria in Solid Tumours (RECIST) or by clinical symptomatic progression. Computed tomography (CT) and magnetic resonance imaging were used for patients that underwent baseline brain imaging assessment. Reassessment imaging was arranged every 3 to 6 months using CT or positron emission tomography/CT when feasible. Objective response rates (ORRs) were judged by the authors based on available imaging information via RECIST criteria. EGFR mutations were detected using real-time polymerase chain reactions.

 

Patients received afatinib at starting doses of 40 mg, 30 mg, or 20 mg once daily based on perceived tolerance to treatment by the clinician. Treatment was continued until disease progression, poor tolerability, or other reasons requiring withdrawal. Treatment-related adverse events (TRAEs) were managed using tolerance-guided dose modifications. When TRAEs reversed to Grade 1 or back to baseline, treatments could be resumed at a lower dose (in 10 mg decrements). If patients could not tolerate 20 mg afatinib daily or if TRAEs did not return to Grade 1 or to baseline within 6 weeks, treatment was discontinued. The optimum dose of afatinib was defined as the final dose that a patient received without need for further decrements due to TRAEs.

 

Data were analysed using SPSS (Windows version 23.0; IBM Corp., Armonk [NY], United States). Kaplan–Meier estimates were used for median OS (mOS) and median PFS (mPFS). Univariable and multivariable analyses for prognostic factors of PFS and OS were performed by Cox proportional hazard models. A p value of <0.05 was considered statistically significant. All cases were included in safety and efficacy analyses. Exploratory subgroup analysis was conducted post hoc and descriptive statistics are presented.

 

A total of 85 patients (median age 63 years, range 37-90) were treated with afatinib within the listed period (Table 1). Within the dataset, 50 (58.8%) patients had common mutations, whereas 35 (41.2%) patients were harbouring uncommon mutations. Two patients with L858R mutations had de novo T790M mutations. Major uncommon point mutations such as G719X, L861Q and S768I were the most frequent group, accounting for 68.6% of all uncommon mutations.

 

Table 1. Baseline demographics and disease characteristics of patients with NSCLC treated with first-line afatinib (n = 85).

 

The mPFS was 14.9 months (95% confidence interval [CI]=10.7-19.0), with 63 cases having progressed at the time of analysis. The mPFS according to clinical and treatment characteristics are shown in Tables 2 and 3. On both univariable and multivariable analyses, cases with the exon L858R point mutation had significantly shorter mPFS compared with those with the exon 19 deletion (5.3 months vs. 16.4 months; HR=2.34, 95% CI=1.01-5.62; p = 0.048) [Figure 1]. Patients aged ≥65 years (12.0 months vs. 16.8 months; HR=1.49, 95% CI=1.02-2.48; p = 0.034) had worse mPFS than those of younger age (Figure 2). Patients with ECOG performance status 2-3 (2.7 months vs. 16.4 months; HR=7.28, 95% CI=3.23-16.42; p < 0.001) had a worse mPFS than those with better ECOG performance status (Figure 3).

 

Table 2. Univariable analyses and multivariable analyses for progression-free survival.

 

Table 3. Univariable analyses and multivariable analyses for overall survival

 

Figure 1. PFS according to type of EGFR mutation

 

 

Figure 2. PFS according to age

 

 

Figure 3. PFS according to ECOG performance status

 

Final OS data was largely congruent with PFS findings. mOS was 33.9 months (95% CI=20.6-47.2) for all cases. Cases with exon L858R point mutation had significantly shorter mOS compared with cases with the exon 19 deletion (11.3 months vs. 45.2 months; HR=2.51, 95% CI=1.03-6.08; p = 0.042).

 

TRAEs were common among patients, with up to 91.8% of all patients experiencing some form of TRAE (Table 4). Dose adjustments were required for patients, with up to 54 (63.5%) patients requiring dose reductions. In total, 11.8% of all patients had dose increments. No TRAEs resulted in death.

 

Table 4. Overall summary of TRAEs (n = 85)

 

Most cases started with afatinib 40 mg daily (54.1%), followed by 30 mg daily (36.5%) and 20 mg daily (9.4%). Initial starting dose was maintained for 49 (57.6%) patients (Table 5). Dose reductions were largely due to AEs from treatment whereas dose increments were due to initially perceived poor tolerance to treatment. The optimum dose for most cases was 30 mg daily and most cases with brain metastasis on diagnosis often had surgery or radiotherapy in conjunction with afatinib treatment.

 

Table 5. Afatinib starting dose, dose adjustment, and optimal dose and treatment of baseline brain metastases (n = 85)

 

Overall, 38 of 85 cases (44.7%) had an objective response, including one (1.2%) complete response and 37 (43.5%) partial responses. In all, 27 (31.8%) cases had stable disease. Disease control rate was 76.5%.

 

Sixty-three cases eventually developed progressive disease on afatinib. Forty-eight were retested for T790M mutations, with 39 undergoing plasma EGFR testing and nine with tissue sample testing. Fourteen (29.2%) cases developed exon 20 T790M mutations. All cases that developed T790M mutations had adenocarcinoma exclusively. For cases that had common mutations, 19 received osimertinib as second-line treatment and nine others received chemotherapy. Within the uncommon mutation group, four cases received osimertinib, eight received chemotherapy, and one continued second-line treatment with mobocertinib.

 

This study was a retrospective review of a single-centre experience of cases of metastatic NSCLC EGFR-MT treated with first-line afatinib. Case demographics and population subsets are comparable to other reported studies with EGFR TKIs being used in daily clinical practice.[7] Typically underrepresented subgroups such as the elderly people, cases with brain metastasis, cases with uncommon mutations, and those with ECOG performance status ≥2 were also included in this review. A majority of cases harboured exon 19 deletions and up to 41.2% of all cases were harbouring uncommon mutations. This is likely due to selection bias whereby clinicians were influenced by the mOS results of the LUX-Lung 3 and 6 trials, which favoured afatinib over chemotherapy in the first-line setting,[8] and a tendency to prescribe afatinib for patients harbouring uncommon mutations as well.

 

The mPFS in this review was consistent with other clinical studies (mPFS 11.8-11.9 months) and the LUX Lung trials (mPFS 11.0-11.1 months).[8] [9] Other studies, such as that of Kim et al,[10] have found a substantially longer mPFS of 19.1 months using first-line afatinib, which could be partly due to the fact that only ECOG performance status 0-2 cases were involved.

 

Our results also showed that cases with the exon 19 deletion had a significantly longer mPFS compared with those that had exon 21 L858R mutations. Although Kim et al[10] and Liang et al[9] have highlighted similar outcomes where cases with exon 19 deletions had longer mPFS and improved ORR compared to those having exon 21 L858R mutations, two out of the nine patients that had L858R mutations in our subgroup also harboured de novo T790M, which may have skewed results unfavourably.

 

Cases with unfavourable clinical characteristics, such as poor ECOG performance status or advanced age showed decreased mPFS compared to those without, reaching statistical significance on univariable and multivariable analysis. Cases with brain metastasis on screening, however, did not show significantly worse mPFS, contrary to the findings of Tan et al.[11]

 

Afatinib was demonstrated to be effective in cases with major uncommon point mutations (G719X, L861Q and S768I) with a response rate and mPFS comparable to those with common EGFR mutations. This is consistent with findings from Passaro et al[12] and Yang et al,[13] implying that afatinib may be a suitable choice of treatment for patients harbouring these mutations. The Food and Drug Administration has recently expanded the front-line indication for afatinib to cover NSCLC with these three EGFR mutations. In contrast, exon 20 insertions had a much shorter mPFS. Recently approved treatments, including amivantamab and mobocertinib have shown promise in early-phase clinical studies for exon 20 insertions and could play a role in this subgroup of patients in the future.[14] [15]

 

This study showed a much lower incidence of grade >3 AEs due to afatinib compared with an incidence of 36.0% to 57.0% reported by RCTs.[4] [5] This is likely due to the lower starting doses given within this patient group. Early dose reductions in patients before developing grade 3 AEs in daily practice would also explain these findings. Of note, the incidence of the acquired T790M mutation was lower than the rates reported in several studies (32.1%-47.6%).[10] [16] This could possibly be due to the fact that not all cases progressing on afatinib were retested for T790M. Another reason could be that certain cases that had uncommon mutations were already resistant to afatinib, and therefore did not develop resistance via T790M mutations.

 

In-vitro analysis of EGFR mutations, including uncommon and compound mutations against different EGFR TKIs, showed that afatinib had activity against almost all mutations tested and was more potent than erlotinib and gefitinib. When compared with osimertinib, afatinib also demonstrated a greater spectrum of efficacy against uncommon EGFR mutations, while it was less effective against T790M, as expected.[17] Clinical data, however, are limited. Recent literature demonstrated favourable activity with manageable toxicity in patients with NSCLC harbouring uncommon EGFR mutations treated with first-line osimertinib. A phase II study by Cho et al[18] demonstrated an ORR and PFS of 53% and 8.2 months, respectively, for patients with G719X mutations. For afatinib, an ORR of 77.8% and a PFS of 13.8 months were reported by Yang et al.[6] Although cross-trial comparisons should be done with caution, osimertinib showed a response rate in cases with G719X mutations that was comparable to that of other EGFR TKIs.[6]

 

Numerous factors need to be considered when choosing a therapy, including central nervous system activity, toxicities, and types of EGFR mutations. Clinical efficacy of EGFR TKIs in patients with uncommon mutations should be assessed prospectively, due to the small number and heterogeneity of patients studied thus far.

 

Clinical analyses of afatinib that include patient characteristics such as poor ECOG performance status, brain metastasis, old age, and uncommon mutations are limited. This study is one of the few retrospective reviews that examined a population similar to that encountered in daily clinical practice. The results of our study provide additional data on these subgroups, especially in patients with uncommon mutations.

 

A few limitations should be noted. Given their retrospective nature, data may be prone to bias during measurement. Because radiological assessments were performed at different radiology centres, with potentially different methodologies, response rates and progression were not solely measured based on RECIST criteria. Caution is therefore needed when comparing with published data. As there may have been inadequate follow-up duration for patients, a fair amount of data regarding patients’ PFS and OS were censored. The number of patients with exon 21 L858R was also relatively small compared to exon 19 mutations, with exploratory subgroup analysis performed, limiting the strength of conclusions.

 

In summary, afatinib is an effective first-line treatment for patients with EGFR-MT NSCLC. The drug is generally well-tolerated and response rates and PFS are consistent with previous RCTs and other clinical analyses. Given its high efficacy in major uncommon point mutations, it should be considered as first-line treatment for patients harbouring these mutations.