Although the mechanisms underlying acquired resistance are
Although the mechanisms underlying acquired resistance are diverse, approximately 60% of the tumors with EGFR mutations acquire resistance after progression on a first-line EGFR-TKI through target modification following the substitution of threonine for methionine at amino Ac-DEVD-CHO 790 in the EGFR sequence . To target the resistance mechanisms, researchers have tried target-specific inhibitors or blocking other relevant pathways in a resistance model. In our preclinical study, we demonstrated that afatinib activated the IL-6 receptor/JAK1/STAT3 signaling pathway in NSCLC cell lines harboring the T790 M mutation, and that the inhibition of JAK improved the efficacy of the irreversible EGFR-TKI . Therefore, we embarked on evaluating the safety and efficacy of the combination of JAK inhibitor and irreversible EGFR-TKI in EGFR-mutant NSCLC patients. In this study, we did not observe any DLT up to the highest dose level and established the RP2D as 50 mg afatinib once daily combined with 25 mg ruxolitinib twice daily, taking efficacy and safety into consideration. The most frequent and significant toxicities were anemia and diarrhea. However, G3 toxicities were observed in four patients (three patients with G3 diarrhea and one patient with G3 anemia). Because diarrhea was caused by afatinib, the dose of afatinib was reduced in three patients during this study. Although anemia was thought to be caused by ruxolitinib, we did not reduce the ruxolitinib dose. Further, the anemia was asymptomatic and spontaneously improved. Recently, Yu et al. conducted a phase I/II clinical trial that evaluated the combination therapy of ruxolitinib and erlotinib in patients with EGFR-mutant lung adenocarcinomas resistant to erlotinib . They observed one patient with PR among 22 patients (including four patients with T790 M), and the median PFS was 2.2 months (95% CI, 1.4–4.1) . In the current study, the median PFS of all patients was 4.9 months (95% CI, 2.4–7.5) and the ORR was 23.3%. Among the 30 patients, including 20 patients with T790 M mutations, we observed PR in seven patients, SD in 21, and PD in two patients. The seven patients with PR maintained the afatinib and ruxolitinib combination treatment for a median of 8.5 months (95% CI, 3.9–13.1). Among the seven patients with PR, five harbored the T790 M mutation. The higher clinical efficacy observed in our study could be related to afatinib, which has also been shown to have modest activity against the T790 M mutation in a few cases [19,20]. In the LUX-Lung 1 trial, the ORR was 7% (all cases exhibited PR), the DCR was 58%, and the median PFS was 3.3 months (95% CI, 2.79–4.40) in the afatinib group . Additionally, in the LUX-Lung 4 trial, afatinib monotherapy yielded an ORR of 8.2%, a DCR of 65.6%, and a median PFS of 4.4 months in patients with NSCLC who progressed on erlotinib and/or gefitinib . In the study, two patients with T790 M mutations had SD for 1 month and 9 months, respectively . Because the LUX-Lung 1 and LUX-Lung 4 trials demonstrated the modest efficacy of afatinib in EGFR-mutant NSCLC patients previously treated with erlotinib and/or gefitinib [9,19], we believe substituting erlotinib with afatinib could be potentially responsible for the higher clinical efficacy observed in this study. In the current study, we hypothesized that a treatment that targeted JAK/STAT3 could improve the clinical efficacy of afatinib in NSCLC patients with the T790 M mutation, for which osimertinib has become the standard of care [21,22]. Actually, the clinical efficacy achieved by the combination of irreversible EGFR TKI and JAK1/2 inhibitor seems to be lower than those of osimertinib. In this study, 20 patients with T790 M mutation showed a median PFS of 4.9 months (95% CI, 2.5–7.3), which was inferior to those of osimertinib in AURA study (9.6 months) , in AURA study phase II extension component (12.3 months) , and in AURA3 study (10.1 months) . In addition, among 20 T790M + patients in our study, 7 patients were treated with osimertinib after failure of this study, and their median PFS to osimertinib was 6.5 months (95% CI, 0–13.7). Given these evidences, the combination of afatinib and ruxolitinib might fail to achieve sufficient suppression on EGFR T790 M mutation of the NSCLC patients, compared to osimertinib. Although JAK/STAT3 activation is one of the important resistance mechanisms to irreversible EGFR TKI in T790 M mutant NSCLC, which is not enough to solely inhibit the proliferation of T790 M mutant NSCLC. Therefore, we are trying to find the role of JAK/STAT3 signaling inhibition in combination with osimertinib or in patients with resistance to osimertinib. To this end, AZD4205, a novel JAK1 inhibitor, is being investigated to determine if JAK inhibition improves the efficacy of osimertinib in preclinical and clinical settings [25,26]. In our study, two patients were previously treated with osimertinib. A patient with the exon 19 deletion and small-cell carcinoma transformation in a re-biopsied tumor prior to study enrollment showed rapid progression on the afatinib and ruxolitinib combination. Although the other patient with a T790 M mutation who was treated with osimertinib exhibited a modest decrease in tumor burden (shrinkage of 8.0% of target lesions), the patient withdrew from the study due to G2 diarrhea and general weakness.