Clinical features and outcomes of unresectable locally advanced lung adenocarcinoma with uncommon EGFR mutations: a retrospective multi-center Chinese study

Introduction

The phase 3 PACIFIC trial established a new standard of care for unresectable stage III non-small cell lung cancer (NSCLC) patients, particularly those receiving durvalumab consolidation therapy following definitive chemoradiotherapy (CRT) (1). However, the identification of epidermal growth factor receptor (EGFR) mutations, which have shown significant responsiveness to tyrosine kinase inhibitors (TKIs), presents a challenge in therapeutic decision-making for locally advanced NSCLC (2-5). In patients with EGFR mutations, the combination of EGFR-TKIs with radiotherapy (RT) has demonstrated superior survival outcomes compared to CRT with durvalumab or CRT alone (6-9).

Approximately 40–50% of Chinese patients with advanced non-squamous lung cancer harbor EGFR mutations (10-11). The most common mutations, exon 19 deletion(19DEL) and exon 21-L858R mutation, exhibit a superior response and survival rate compared to traditionally chemotherapy treatment (2-5). However, most clinical trials have excluded uncommon EGFR mutations, a highly heterogeneous group of mutations within exons 18–21, including T790M, G719X, and L861Q. Studies have demonstrated varying sensitivities to first, second, and third-generation EGFR-TKIs among patients with these uncommon mutations, with first-generation EGFR-TKIs being notably less effective (12-14).

Previously, our REFRACT program revealed that the frequency of EGFR mutations was significantly lower than that reported in advanced-stage Asian patients (6). Additional evidence indicates that the prevalence of EGFR-mutant stage III lung adenocarcinoma is lower (17–31%) compared to advanced-stage disease (40–50%), with limited reporting on uncommon mutations (15-22). Furthermore, uncommon mutations were not included in the phase 3 LAURA trial, which has reshaped treatment standards for locally advanced NSCLC with common mutations (9). The low incidence and wide variety of these mutations have constrained the development of clinical trials targeting uncommon EGFR mutations. To address this gap, we conducted a multi-center study focusing on patients with locally advanced lung adenocarcinoma harboring uncommon EGFR mutations to elucidate their clinical demographics and survival outcomes under different treatment modalities. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-751/rc).

Methods

Data sources and treatment cohorts

This study included data from the multi-center REFRACT program (trial number: NCT04304638). We extracted information from this database, including mutation type, treatment details, and survival endpoints. Patients with unknown EGFR mutations or mutations in other genes were excluded from enrollment. The data analysis flow is presented in Figure 1. Patients were stratified into three cohorts based on their initial treatment strategy involving RT or EGFR-TKIs therapy. Those who received concurrent or sequential CRT were included in the study. EGFR mutations were assessed using either polymerase chain reaction (PCR) amplification or next-generation sequencing. The follow-up strategy and RT plans have been previously described in detail (6).

Figure 1 Flow diagram of the included patients. EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; BED, biological effective dose; 19DEL, exon 19 deletion.

Definition of endpoints

Overall survival (OS) was defined as the time from histological diagnosis to death or the last follow-up. Progression-free survival (PFS) was defined as the time from histological diagnosis to the first event of tumor progression or death. Locoregional recurrence was defined as disease recurrence in the ipsilateral lung and regional lymph nodes, while new lesions outside of the loco-regional areas were considered distant recurrences.

Statistical analysis

Data comparisons were conducted using Chi-squared tests, t-tests, and non-parametric Mann-Whitney U tests. Survival data were evaluated using the Kaplan-Meier method, and differences were examined using the log-rank test. Hazard ratios were estimated using the Cox proportional hazards model. Variables with a univariable significance of P<0.10 were entered into the multivariable Cox model, and a two-sided P value <0.05 was considered statistically significant. Statistical analyses were performed using STATA 16.0 or SPSS 26.0.

Ethical statement

The study was conducted in accordance with the standards set forth in Good Clinical Practice guidelines and the principles of outlined in the Declaration of Helsinki (as revised in 2013). This study protocol was approved by the Medical Research Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (2020042915382802), and the other participant units were also agreed the study. Written informed consent was waived since this is a retrospective analysis.

Results

Clinical characteristics

A total of 511 patients were identified in the current cohorts, including 245 patients (47.9%) with an exon 19 deletion, 217 patients (42.5%) with the L858R exon mutation, and 49 patients (9.6%) with an uncommon mutation. Among these, 162 patients (31.7%) were smokers, 349 (68.3%) were non-smokers, and 306 (59.9%) were female. The median age was 60 years, with a range of 30–89 years. Of the total cohort, 168 patients (32.9%) were diagnosed with stage IIIA and 343 patients (67.1%) with stage IIIB. Additionally, 482 patients (94.3%) were in good physical condition.

The median age at diagnosis was 57 years (range, 37–80 years) for patients with common EGFR mutations and 61 years (range, 30–89 years) for those with uncommon mutations. The baseline characteristics, including sex, performance status, smoking status, and stage, were similar between the two groups. Detailed baseline information was presented in Table 1.

Frequencies

Among patients with uncommon EGFR mutations, 9 (18.4%) had a single exon 20 insertion (EX20 Ins), while 11 (22.4%) had the G719X point mutation occurring in exon 18. The L861Q and S768I mutations were each found in 4 patients (eight patients in total), and the T790M mutation was identified in 2 patients. Complex mutations were observed in 17 patients (34.7%), including 19DEL + L858R in 3 patients and 19DEL or L858R + T790M in 6 patients. Other infrequently reported uncommon mutations included G719S (n=1), G718S (n=1), G719X + S768I (n=1), G719X + L861Q (n=1), L861Q + S768I (n=1), S768I + G719S (n=1), 19DEL + L861Q (n=1), L858R + G719S (n=1), L858R + S768I (n=1), and G719X + T790M (n=1). The frequencies of the uncommon and common subtypes were presented in Figure 2.

Figure 2 Distribution of EGFR mutations (A) and the frequency of uncommon EGFR mutations (B) in unresectable stage III lung adenocarcinoma. EGFR, epidermal growth factor receptor; 19DEL, exon 19 deletion.

Treatment

At the time of analysis, 440 of the 511 patients with EGFR mutations had received systemic anticancer treatment and had adequate follow-up (baseline clinical characteristics are shown in Table S1). In the uncommon mutation group, 9 patients (23.4%) received a combination of EGFR-TKIs and RT (EGFR-TKIs + RT), while 16 patients (43.2%) were treated with EGFR-TKIs. In the CRT subgroup (N=12), with 9 patients (24.3%) receiving concurrent CRT and 3 patients (8.1%) receiving sequential CRT. The RT dose ranged from 54.0 to 61.6 Gy, with the most common concurrent chemotherapy regimen being pemetrexed and cisplatin (n=8, 88.9%). In EGFR-TKIs group, 14 patients (87.5%) received first-generation TKIs (10 gefitinib, 3 icotinib, and 1 erlotinib), 1 patient received a second-generation TKI (afatinib), and 1 patient received a third-generation EGFR-TKIs (osimertinib). In the EGFR-TKIs + RT subgroup, 8 patients (88.9%) received first-generation TKIs (5 gefitinib, 2 icotinib, and 1 erlotinib), and 1 patient received experimental EGFR-TKI. The RT dose in this subgroup ranged from 50.0 to 60.0 Gy. One patient received concurrent EGFR-TKIs without chemotherapy, 8 patients received pemetrexed and cisplatin before RT, 2 patients received sequential EGFR-TKIs before RT, and 6 patients received EGFR-TKIs after CRT. In the common mutation group, 93 patients (23.4%) received EGFR-TKIs + RT, 214 patients (53.8%) were treated with EGFR-TKIs alone, and 91 patients (22.9%) received CRT.

Survival

The median follow-up period was 35.9 months [95% confidence interval (CI), 32.5–39.3]. During this time, 320 patients (72.7%) experienced tumor recurrence, and 164 patients (37.2%) died. A significant difference in PFS for uncommon and common mutation group [median 11.9 (95% CI: 8.1–15.7) vs. 17.5 (95% CI: 15.7–19.4) months; P=0.005, Figure 3A]. Multivariable Cox regression analysis confirmed this difference [P=0.006, hazard ratio (HR): 1.67, 95% CI: 1.16–2.40]. However, there was no significant difference in OS for uncommon and common mutation group [median 42.6 (95% CI: 29.3–55.9) vs. 54.2 (95% CI: 46.6–61.7) months; P=0.14, Figure 3B].

Figure 3 Kaplan-Meier curves of progression-free survival and overall survival for different mutation types (A,B) and different treatment groups in EGFR-mutant locally advanced lung adenocarcinoma (C,D). CRT, chemoradiotherapy; EGFR, epidermal growth factor receptor; RT, radiotherapy; TKIs, tyrosine kinase inhibitors.

For the uncommon mutation group, the median PFS for the CRT, EGFR-TKIs, and EGFR-TKIs + RT subgroups were 11.9 months (95% CI, 6.5–17.3), 5.0 months (95% CI, 3.3–6.6), and 14.8 months (95% CI, 9.8–19.8), respectively (P=0.03; Figure 3C). The median OS for the three subgroups was 43.6 months (95% CI, 9.0–78.2), 30.9 months (95% CI, 19.8–42.0), and not reached (NR), respectively (P=0.18; Figure 3D). Patients who received CRT or EGFR-TKIs showed significantly superior PFS compared to those who received TKIs alone (P=0.02, 0.04, respectively). The EGFR-TKIs + RT regimen did not result in increased PFS compared to CRT alone (P=0.90). Similarly, the CRT (P=0.49) and EGFR-TKIs + RT (P=0.07) groups showed a trend toward superior OS compared to the EGFR-TKIs group, though the difference was not statistically significant. There was no difference in OS between EGFR-TKIs + RT and CRT alone (P=0.21).

The median PFS was significantly shorter in patients with uncommon EGFR mutations compared to those with common mutations who were treated with EGFR-TKIs [median 5.0 (95% CI: 3.3–6.6) vs. 16.9 (95% CI: 14.0–19.8) months, P<0.001]. However, PFS was similar in patients treated with CRT (P=0.39) and EGFR-TKIs + RT (P=0.09). OS was shorter in patients with uncommon EGFR mutations compared to those with common mutations treated with TKIs [median 30.9 (95% CI: 19.8–49.3) vs. 49.3 (95% CI: 36.8–61.7), P=0.09, Figure 3]. However, OS was similar in the CRT (P=0.48) and EGFR-TKIs + RT (P=0.73) groups. The survival outcomes for patients with uncommon EGFR mutations were shown in Figure 4.

Figure 4 Display PFS and OS of individual patient’s mutation type. CRT, chemoradiotherapy; EGFR, epidermal growth factor receptor; RT, radiotherapy; TKIs, tyrosine kinase inhibitors; OS, overall survival; PFS, progression-free survival.

Recurrence patterns

Among the 37 patients with uncommon mutations, tumor recurrence was identified in 34 patients (91.9%), compared to 286 patients (71.0%) with common mutations (P=0.006). Distant metastases or loco-regional failure as the first site of recurrence were similar between the uncommon and common mutation groups (P>0.99, P=0.27, respectively). Brain metastases were also comparable between the two groups (24.3% vs. 24.1%, P>0.99, Table 2).

Compound mutations

Of the 17 patients with compound mutations, 9 were male, and all were current or former smokers, with an age range of 37–79 years (median, 58 years). Six patients were diagnosed with stage IIIA, and 11 with stage IIIB. Patients with compound mutations had similar OS [median 42.6 (95% CI: 29.8–55.4) vs. 26.7 (95% CI: 21.8–31.7), P=0.32] and PFS [median 10.0 (95% CI: 2.3–17.7) vs. 11.9 (95% CI: 6.2–17.6) months, P=0.30] compared to patients with common mutations. The baseline characteristics of patients between the two groups were balanced with respect to sex, performance status, smoking status, and stage (Tables S2,S3). Recurrence rates were similar between the two groups (P=0.26, Table S4).

Discussion

In this study, we analyzed the frequency and characteristics of EGFR mutations in patients with unresectable locally advanced adenocarcinoma. We found that uncommon mutations accounted for 9.6% of all EGFR mutations, with G719X (2.2%, 11/511) and EX20 Ins (1.7%, 9/511) being the most common single uncommon mutation sites. Additionally, we observed that 3.3% (17/511) of the patients had EGFR compound mutations, including combinations of G719X, L858R, and S768I. These findings were consistent with prevalence rates reported in other studies (11,23-26). The demographic and clinical characteristics of the two groups in our study those with uncommon and common mutations were similar regarding sex, age, smoking status, and disease stage.

The uncommon EGFR mutations generally exhibited lower responses rates to TKI than observed in common mutations, especially for first-generation EGFR-TKIs. The first-line chemotherapy remains relatively effective for NSCLC, especially with uncommon EGFR mutations (13,27). Our results indicated that patients receiving standard CRT as first-line treatment had significantly longer PFS compared to those who received EGFR-TKIs. Furthermore, there was no significant difference in survival between patients with uncommon and common mutations within the CRT group (median PFS 11.9 vs. 12.6 months, P=0.39; median OS 43.6 vs. 53.9 months, P=0.48). These findings aligned with those from a small retrospective study on CRT for patients with uncommon mutations (18). These results suggest that CRT remains the standard of care for this patient subgroup.

Previous real-world data and clinical trials have suggested that patients with uncommon EGFR mutations generally have a poorer treatment response to EGFR-TKIs compared to those with common mutations, particularly with first-generation EGFR-TKIs (12-14,23). Our data corroborated these findings, showing that PFS and OS were significantly shorter in patients with uncommon mutations treated with EGFR-TKIs (median PFS 5.0 vs. 16.9 months, P<0.001; median OS 30.9 vs. 49.3 months, P=0.14) compared to those with common mutations. However, afatinib has demonstrated a favorable response in patients with certain uncommon mutations, including G719X, L861Q, and S768I, according to the LUX-Lung 2, 3, and 6 studies (12). Similarly, a phase II clinical trial of osimertinib reported favorable outcomes and tolerable toxicity in patients with G719X (n=19; 53%), L861Q (n=9; 25%), and S768I (n=8; 22%) mutations. Notably, EX20 Ins mutations have shown poor responses to both first- and second-generation EGFR-TKIs (28). Few patients with EX20 Ins have responded to EGFR-TKIs, and these patients were excluded from trials involving third-generation EGFR-TKIs (osimertinib) (14,29). Based on our findings, EGFR-TKIs should not be recommended as the first choice for locally advanced NSCLC with uncommon mutations. The LAURA trial established that osimertinib combined with CRT significantly prolonged PFS compared to placebo in unresectable stage III EGFR-common mutation NSCLCs (9). A systematic review supported the use of second-generation TKI afatinib for G719X, S768I, E709X, and L747X mutations and for compound uncommon mutations. For other uncommon mutations such as L861Q, exhibited 75% (95% CI: 56.6–88.5%) response rates to osimertinib (27). Therefore, the optimal treatment strategy for patients with uncommon mutations remains a challenge, and a combination of RT and sensitivity EGFR-TKIs may be a promising option depending on the specific mutation genotype.

Few studies have specifically examined the prevalence and survival outcomes of compound mutations. In our cohort, the frequency of EGFR compound mutations was 3.3% (n=17/511), slightly lower than reported in a previous study (30). In subgroup analyses, patients with EGFR compound mutations had similar PFS compared to those with individual uncommon mutations (median PFS 10.0 vs. 11.9 months, P=0.30). Previous research has indicated that the PFS for patients with EGFR compound mutations was significantly higher than for those with individual uncommon mutations (median PFS 11.9 vs. 6.5 months, P=0.01) among patients receiving EGFR-TKIs alone (31). Another study reported different results for PFS (median 9.3 vs. 7.0 months, P=0.45) but found a significant difference in OS (median 31.4 vs. 12.4 months, P<0.001) (32). Due to the limited sample size, these results require validation through further studies.

Several limitations of this study should be acknowledged. The selection bias could not be excluded owing to retrospectively design. The most significant limitation was the small size of the uncommon mutation cohort. In particular, 88.0% of patients with uncommon mutation was treated with the first generation of EGFR-TKIs, which are known to be less effective. This highlighted the need for further data on the next generation of EGFR-TKIs. Moreover, it is necessary to conduct prospective data validation to facilitate a comparison of the results obtained from the different treatment. Additionally, the detection of uncommon mutations was constrained by sequencing methods and sample availability. PCR-based or direct sequencing methods may have underestimated the prevalence of EGFR uncommon mutations compared to next-generation sequencing. Plasma genetic testing was feasible but less accurate and sensitive than tissue biopsy. Moreover, clinical decision-making for locally advanced NSCLC with EGFR mutations varies among institutions and physicians. Finally, concurrent RT and EGFR-TKIs pose concerns regarding pulmonary toxicity. A systematic literature review indicated that the rate of severe lung pneumonitis was 4.9% (95% CI, 2.4–8.1%) for concurrent EGFR-TKIs and RT, significantly higher than the 0.4% (95% CI, 0.0–3.1%) rate for sequential therapy (33).

Conclusions

In conclusion, this study provided a comprehensive overview of the prevalence and outcomes of uncommon EGFR mutations in unresectable locally advanced lung adenocarcinoma patients. Our findings suggested that uncommon mutations are associated with worse survival outcomes when treated with EGFR-TKIs. However, CRT remained the primary treatment, with RT combined with EGFR-TKIs emerging as a promising approach. Future studies are needed to validate these results and refine treatment strategies for patients with uncommon EGFR mutations.

Acknowledgments

Funding: This work was supported by the Shenzhen Key Medical Discipline Construction Fund (No. SZXK013); the Sanming Project of Medicine in Shenzhen (No. SZSM202211030); the Shenzhen High-level Hospital Construction Fund; the Shenzhen Clinical Research Center for Cancer (No. [2021]287); and the Hospital Research Project (No. E010322032).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-751/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-751/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-751/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-751/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the standards set forth in Good Clinical Practice guidelines and the principles of outlined in the Declaration of Helsinki (as revised in 2013), and the participant hospitals were also informed and agreed the study. This study was registered with Clinical Trials.gov. (trial number: NCT04304638). This study protocol was approved by the Medical Research Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (2020042915382802). Written informed consent was waived since this is a retrospective analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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