In this open-label, multi-center study, larotinib demonstrated promising anti-tumor activity and manageable toxicity profiles in previously treated patients with advanced and metastatic ESCC with EGFR overexpression or amplification. Although about 61.7% of patients underwent 2 or more prior therapies, larotinib showed encouraging efficacy, especially at the dose of 350 mg, with a confirmed ORR of 20.0%, median PFS of 3.4 months, and median OS of 8.0 months.
Over the past decades, there were few options for patients with advanced ESCC who have progressed after first-line chemotherapy. Despite systemic chemotherapeutic agents such as docetaxel, paclitaxel, and irinotecan being used for this patient population, clinical benefits were limited. Recently, immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and camrelizumab, showed promising efficacy and were approved as second-line ESCC therapy. These PD-1 antibodies demonstrated better efficacy in pivotal phase 3 studies when compared with chemotherapy in ESCC. The median OS was from 8.2 months to 10.9 months, and ORR ranged from 16.7–20.2% (Kojima et al. 2020; Kato et al. 2019; Huang et al. 2020). Larotinib at 350 mg demonstrated a similar antitumor activity as immune therapy. Even in patients who had undergone 2 or more prior therapies, encouraging antitumor activity was also observed. The ORR was 14.3% at 350 mg, near to that of pembrolizumab (9/63, 14.3%) reported in KEYNOTE-180 (Shah et al. 2019). Moreover, 5 of 9 patients who had progressed after immunotherapy had tumor reduction (one had a partial response), suggesting larotinib might represent a new treatment option for patients with ESCC. However, the lack of statistical rigor associated with small sample sizes was problematic, and this study was a single-arm, non-randomized study; these findings should be interpreted with caution because of the different patient compositions in our study.
Even though several studies regarding first-generation EGFR TKIs, including gefitinb, erlotinib, and icotinib, have been conducted in advanced esophageal carcinoma, limited benefits were observed. As mentioned in the introduction section, the main possible reasons behind the failure of gefitinib and erlotinib studies in esophageal carcinoma were: no population screening was conducted, with most of the recruited subjects were diagnosed with adenocarcinoma or no EGFR biomarker screening was performed. The phase II study of Icotinib in esophageal cancer learned lessons from the gefitinib and erlotinib studies, subjects enrolled were ESCC with EGFR overexpression (an immunohistochemical [IHC] staining score of 3 matriculations) or EGFR gene amplification (a positive fluorescence in situ hybridization [FISH] result), and the ORR increased to 16.7% (9/54); however, median PFS is only 1.7 months, with a median OS of 5.1 months. In this phase Ib clinical study in ESCC, the subject of EGFR biomarker requirement is almost the same as that of icotinib. More importantly, this study demonstrated a higher ORR and improved survival benefit, in the 350 mg group, the median OS is 8.0 months and median PFS is 3.4 months, with an ORR of up to 20.0% (10/50), which may be attributed to the difference in terms of drug property. This could be also explained in preclinical findings (Additional file 5), in which larotinib showed a stronger inhibition activity against EGFR kinase and higher accumulation in esophageal tissue than icotinib did. Moreover, in comparison with its counterparts, such as gefitinib and erlotinib, larotinib exhibited a similar effect on EGFR kinase but higher accumulation in esophageal tissue (Additional file 1). Besides, larotinib also demonstrated a higher ratio of exposure in tumor/plasma when compared with erlotinib (Additional file 6).
Even though both EGFR overexpression and amplification were selected to be predictors of efficacy in our study, similar survival benefits were observed between patients from two subgroups, with the median OS of both 5.9 months and PFS of 3.6 months versus 3.8 months. The reason was probably that almost all patients with EGFR amplification had EGFR overexpression (only 4 patients showed EGFR amplification but low expression), suggesting that EGFR overexpression might be correlated with EGFR amplification, which corroborated previous findings (Hanawa et al. 2019; Huang et al. 2016). Considering 95% of patients in our study were EGFR-overexpressed, and 10 responses all occurred in this patient population, EGFR overexpression could be used as a predicted biomarker in the future study of larotinib in ESCC.
Larotinib is well-tolerated in patients with ESCC. The toxicity profile in our study was similar to that of other first-generation EGFR-TKIs. Most of the TRAEs were grades 1 or 2, and most of the treatment-related SAEs could be resolved or became tolerable after therapeutic interventions. Although interstitial lung disease (ILD) was observed (five patients) in our study. Among them, two were recently pre-treated with anti-PD-1 monoclonal antibodies. The time intervals from the last dose of PD-1 inhibitor and the first dose of larotinib in the two subjects were 33 days and 34 days, respectively. Interestingly, no ILD was reported in the patients with intervals longer than 50-days, suggesting that the time interval between anti-PD-1 antibody administration and larotinib treatment may be related to the occurrence of ILD. A similar finding was observed in patients with NSCLC treated with sequential anti-PD-(L)1 monoclonal antibody followed by osimertinib (Schoenfeld et al. 2019). The washout period of immunotherapy, anti-PD-(L)1 monoclonal antibody, in particular, should be long enough, at least 50-days, in follow-up studies of larotinib to minimize inadvertent but possible serious toxicity.
Despite the encouraging results in this study, there remain several limitations. The study outcomes might be biased by the small sample size and the single-arm design. Furthermore, quality of life was not assessed in this study. Thus, a randomized, open-label, phase 3 clinical trial of larotinib in over 400 patients is ongoing (ClinicalTrials.gov identifier NCT04415853).