Recent data indicate that EGFR-TKIs combined with TRT are effective for patients with advanced non-squamous cell lung cancer; however, the combined use of these two treatment strategies increases the incidence rate of RP.
The 1G EGFR TKIs demonstrated an objective response rate of 56%–83%, with a median progression-free survival (PFS) of 9.7-13.1 months [4, 10-12]. However, most patients inevitably develop progressive disease within 1 year of treatment due to acquired resistance. The most dominant mechanism is the development of acquired EGFR T790M mutation [13]. Afatinib is an oral irreversible ErbB family blocker that has demonstrated efficacy and tolerable toxicity in EGFR mutation-positive advanced lung adenocarcinoma, with a median PFS of 11.0-13.4 months [5, 14]. This is a significantly improved outcome in treatment-naive patients with EGFR-mutated NSCLC compared with 1G EGFR-TKIs [15]. Notably, afatinib demonstrated activity against major uncommon mutations, with a median time to treatment failure of 10.8-14.7 months for compound mutations [16]. Nevertheless, EGFR T790M is also the dominant resistance mechanism in afatinib. As a first-line treatment for EGFR mutations, the 3G EGFR-TKI osimertinib specifically and irreversibly binds to the EGFR kinase domain, especially EGFR T790M resistance mutations, while sparing wild-type EGFR and the toxicities associated with its inhibition, with a median PFS (mPFS) of 18.9–20.5 months. Thus, osimertinib is a standard therapy for patients with previously untreated EGFR mutation-positive advanced NSCLC [17, 18]. Currently, three generations of EGFR-TKIs are recommended for the treatment of EGFR mutation-positive patients according to the National Comprehensive Cancer Network guidelines (version3.2022)[33].
A previous study on gefitinib and erlotinib with simultaneous TRT showed that the incidence of RP was approximately 84% (21/25) and the incidence rate of grade ≥3 RP reached 12% [19]. Recently, phase 2 trials on the combination of erlotinib and TRT in locally advanced or metastatic NSCLC have shown feasibility and a favorable safety profile, with an incidence of grade ≥3 RP of approximately 16% [20]. A study of osimertinib combined with TRT reported RP in all 11 patients, and the grade ≥3 RP rate reached 55% [21]. This phenomenon may be related to the small sample size, which leads to bias that might influence the results, and the lack of a unified imaging evaluation of RP. In contrast with the high incidence of RP in the above studies, a retrospective study showed a low incidence of RP (7.7% of cases) in patients treated with a combination of gefitinib, icontinib, erlotinib, and TRT [22]. Another prospective study suggested that 1G EGFR-TKI simultaneous with TRT caused a 39% incidence of RP (10/26) and a 4% incidence of grade ≥3 RP [9]. In a phase II study, 32.1% (9/28) of the patients experienced grade 1 or 2 pneumonitis, and there was no grade 3 acute irradiation pneumonitis in patients treated with radiotherapy combined with gefitinib [8]. Furthermore, a clinical trial also showed a low frequency of symptomatic RP, with an incidence of 10.3% (7/68), and the grade ≥3 RP rate reached 5.9% (4/68) [23]. Based on literature, we found that the data on RP have been inconclusive and that a small sample size has been used in current studies of the simultaneous use of EGFR-TKIs and TRT, limiting further analysis and causing a lack of data comparing the combination of TRT with three generations of EGFR-TKIs. To the best of our knowledge, this study is the first to compare the incidence of RP among the three types of EGFR-TKIs combined with TRT and represents the largest study to date. Our study showed that 2G EGFR-TKIs combined with TRT resulted in a higher rate of RP than 1G or 3G EGFR-TKIs combined with TRT, indicating that the latter two are safe options for patients with EGFR mutations.
The pathogenesis of RP induced by EGFR-TKIs combined with TRT remains unclear. EGFR-TKIs may enhance lung injury by blocking EGFR transactivation, thereby enhancing lung epithelial cell apoptosis and lymphocytic inflammation and preventing their self-repair in response to radiation damage, leading to inflammatory cell recruitment and consequent tissue injury [24]. Thus, the addition of TRT may suppress the proliferation of alveolar epithelial cell self-repair. In the present study, we found that afatinib, which can covalently modify EGFR, had the highest incidence of RP. Afatinib is an orally bioavailable ErbB family blocker that irreversibly blocks signaling from EGFR/ErbB1, human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4, and has wide-spectrum preclinical activity against EGFR mutations [25-27]. Owing to their covalent bond binding mechanism, 2G EGFR-TKIs have a higher binding power and are difficult to dissociate from EGFR, which may be one of the mechanisms underlying the high occurrence of adverse reactions to afatinib [28]. Future research could be based upon a larger survey sample at the individual level by a prospective study, providing a theoretical reference for further study on the mechanism of RP.
Several observations are worth highlighting. First, our study showed that 58 (29%) patients with both clinical symptoms and imaging diagnosis showed RP after radiotherapy, and we used the Kaplan-Meier test to compare the difference in the time of RP after radiotherapy in the three groups. We found that the imaging occurrence of RP presented earlier than the clinical symptoms (p=0.0397), indicating that serial radiological assessment, such as high-resolution computed tomography during EGFR-TKI treatment, is an effective method for the early detection of RP-related changes as well as the prediction of clinical symptoms of RP, which can alleviate or prevent patient discomfort. Second, a recent study showed that overlap time was an independent risk factor for RP in patients treated with simultaneous EGFR-TKI and TRT, suggesting that shortening the overlap time might reduce the rate of RP [29]. In the current study, we found that an overlap time of EGFR-TKI and TRT within 30 d significantly decreased the incidence of clinical and imaging RP, which may be because of the reduced interaction between drugs, radiation, and lung tissue due to shorter exposure time. Third, SBRT plays a major role in the treatment of oligometastatic disease in the lungs due to its high local control and low toxicity, and most patients who undergo SBRT have smaller lesions than those who undergo CFRT [30-32]. Univariate logistic regression analysis showed that the incidence of RP was higher in patients undergoing CFRT than in those receiving SBRT, and this phenomenon may be attributed to the lower dose to the OARs and significantly reduced treatment time with SBRT.
Univariate and multivariate logistic regressions showed that the GTV was an independent predictive factor, indicating that a smaller GTV may lower the incidence of RP. Based on our results, the use of SBRT and TRT within 30 d, smaller GTV, and V20 can significantly reduce the chances of RP; thus, we speculate that when patients got the smallest tumor volume under the EGFR-TKIs treatment, at this moment TRT which may be the best timing to reduce the incidence of RP.
Despite these findings, the present study had some limitations. Its retrospective nature may have introduced bias in patient selection; thus, further prospective and randomized trials that directly compare treatments are warranted.