For patients with disease progression after EGFR-TKI failure, the optimal treatment strategy remains controversial and no consensus has been reached. Our retrospective study found that the therapeutic efficacy of chemotherapy was comparable to that of personalized therapy. Interestingly, we found that when chemotherapy was supplemented with immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs, there was a trend towards providing additional clinical benefits compared to personalized therapy. This highlights the enduring clinical significance of chemotherapy for patients experiencing relapse after prior EGFR-TKI therapy. Moreover, in some cases, combination therapy based on chemotherapy may provide incremental benefits. This emphasizes that chemotherapy is a promising option for treating patients with EGFR-TKI resistance.
PFS with traditional chemotherapy offers a length of 4.4–5.4 months for previously EGFR-TKI treated patients [16]. The data from clinical trials have not shown substantial survival benefits of single-agent ICI [17]. The combination therapy of chemotherapy and ICI or chemotherapy with anti-angiogenesis reported an efficacy with an ORR of 30–60% and a PFS of 5.0-7.0m [18–20]. ICIs combined with chemotherapy and anti-angiogenic drugs showed excellent benefits for patients receiving prior EGFR-TKI treatment, with an ORR of 73.5% and a PFS of 10.2m in the IMpower150 subgroup, and an ORR of 43.9% and a PFS of 6.9m in the ORIENT-31 trail [21–23]. In our study, the efficacy of the combined modality was superior to the chemotherapy alone, particularly in the “quad” model. The patients with EGFR mutations reported a high Treg infiltration, reduced CD8 + T-cell number and decreased tumor mutation burden (TMB) [24–26], which induced a poor clinical efficacy of ICI. EGFR-TKIs can remodel the tumor microenvironment (TME) by increasing CD8+ T cell infiltration and the presentation of MHC class I and II molecules, reducing the infiltration and function of Tregs [27]. So immunotherapy is applied after EGFR-TKIs failure. However, the efficacy and responsiveness of ICI monotherapy are far from satisfactory. Anti‐angiogenic drugs can reduce hypoxia, increase the delivery and efficacy of cytotoxic agents, and reduce immunosuppression through preventing angiogenesis and normalizing the tumor vasculature [28]. Consistent with the previous study, the current study revealed a satisfactory outcome when anti-angiogenics was combined with chemotherapy and immunotherapy.
To date, many efforts have been invested in the search for effective treatment strategies to overcome EGFR-TKI resistance according genetic testing and histologic transformation. In case of EGFR C797S mutation, the follow-up treatment depends on the allelic relationship with T790M: T790M-trans-C797S is sensitive to the combination of first and third-generation of EGFR-TKIs [29], and a combination of brigatinb with cetuximab can achieve a favorable outcome with a PFS of 14 months and an ORR of 60%, in patients with T790M-cis-C797S [30]. The concomitant treatment with Trastuzumab and EGFR-TKIs has been demonstrated to possibly overcome the resistance to EGFR-TKIs as result of ERBB2 amplification [31]. SCLC transformation is responsive to platinum etoposide regimens with a PFS of 3.0-4.0m [10, 32]. In our study, the patients reported a PFS of 4.2m and an ORR of 34%, which is no better than the data in the CG and the data of previous studies, demonstrating that chemotherapy is an acceptable choice after the EGFR-TKIs failure. The above-mentioned findings also suggest that the evidence from personalized treatment is insufficient, for most of the above data are derived from retrospective research, preclinical studies, or small sample trials.
MET amplification has been implicated as one of the bypass resistance mechanisms to EGFR-TKI therapy. Numerous case reports and a growing number of clinical studies have documented the efficacy of the combinatorial regimen of EGFR-TKI and MET-TKI in simultaneously inhibiting both EGFR and MET signaling pathways to overcome EGFR-TKI resistance [33]. The combination of Tepotinib and Gefitinib has reported an amazing efficacy, with an ORR of 66.7% and a PFS of 16.6m in the INSIGHT study [12]. Osimertinib plus savolitinib demonstrates a strong anti-tumor activity, with an ORR of 52% and a median duration of response (DOR) of 7.1 months in the TATTON Phase Ib expansion cohort [34]. In some trials and the real-world study, however, other MET inhibitors combined with EGFR-TKIs report a PFS of only 5-6m [33, 35, 36]. In our research, the PFS was 4.2m and ORR was 40.7% in patients with MET amplification. Therefore, the “quad” model chemotherapy may be a favorable choice to these patients and further studies are awaited to explore the beneficiary group of a personalized therapy.
The analysis of circulating tumor DNA from NSCLC patients reveals that 46% of patients treated with EGFR-TKIs may have multiple resistance mechanisms [37]. Alterations to cell cycle gene and the PI3K pathway were the most common co-occurring resistance mechanism [38]. The multiple resistance mechanisms pose a challenge to personalized therapy. Our study found that 13 patients had the multiple resistance mechanisms; cell cycle gene alterations and EGFR amplification were the most common co-occurring resistance mechanisms; 10 PG patients displayed multiple resistance mechanisms, with an ORR of 20% and a PFS of 4.0m, which indicated no impact on the efficacy of the therapy.
Some limitations remain in this retrospective study. First, the data of overall survival and adverse events were not available, which may affect the benefit elucidation between the CG and PG. Second, only a small number of patients received ICI plus chemotherapy with or without anti-angiogenic drugs, which might limit the interpretation to determine the optimal therapeutic strategy. Third, the data regarding PD-L1 expression were insufficient to determine whether PD-L1 expression was balanced across groups or to analyze the correlation between PD-L1 expression and ICI efficacy.