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First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non–Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
Corresponding author. Address for correspondence: Li Zhang, MD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510060, People's Republic of China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
AC0010 is a mutation-selective, third-generation EGFR tyrosine kinase inhibitor (TKI). This aim of this first-in-human phase I trial was to determine the maximum tolerated dose, recommended phase II dose, schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AC0010 in patients with advanced or recurrent NSCLC and acquired resistance to a first-generation EGFR TKI.
Methods
Patients received escalating daily doses of AC0010 (50–600 mg) throughout 28-day cycles. A modified three-plus-three design was applied. Patients with EGFR T790M mutation were selected by dose expansion. Next-generation sequencing of plasma cell-free DNA was performed before and after treatment to determine mechanisms of anticancer activity and underlying acquired resistance.
Results
Data from 52 patients were reported. Common treatment-emergent adverse events were diarrhea (75%), skin rash (48%), and increased alanine transaminase level (44%); adverse events of grade 3 or higher were seen for increased transaminase level (12%) and skin rash (4%). The maximum tolerated dose was not reached. When all evaluated doses and patients negative for T790M were included, the overall response rate was 36.5%. At daily doses of 350 mg or higher, the overall response rate was 50.0% and the median progression-free survival estimated by the Kaplan-Meier method ranged from 14.0 to 35.6 weeks across a daily dose level from 350 mg to 600 mg. On the basis of pharmacokinetics data analysis, twice-daily administration is recommended and 300 mg twice daily is suggested as the recommended phase II dose. The cell-free DNA sequencing results from 17 patients indicate that T790M allele frequency decreased significantly after treatment with AC0010 (from 2.24 at baseline to 0 with a partial response or stable disease [p < .001]). In patients with development of resistance to AC0010, BRAF V600E mutation, ROS1 fusion, MNNG HOS Transforming gene (c-Met), and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification were detected but EGFR C797S mutation was not detected.
Conclusions
AC0010 had a well-tolerated safety profile and promising antitumor activity in patients with NSCLC with acquired resistance to a first-generation EGFR TKI, supporting its continued development.
EGFR active mutations are common in Asian patients with NSCLC, 30% to 40% of whom exhibit such mutations (compared with 10%–20% of non-Asian patients).
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial.
Recent studies have suggested several mechanisms of resistance acquisition, including the T790M “gate keeping” mutation in exon 20, amplification of MNNG HOS Transforming gene (c-Met) or EGFR, transformation to SCLC, and so forth.
Third-generation EGFR TKIs have provided promising results in patients with the EGFR T790M mutation, with osimertinib exhibiting an overall response rate (ORR) greater than 60%.
AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients.
Preclinical studies have suggested that AC0010 selectively inhibits EGFR activating and T790M mutations while leaving wild-type EGFR unaffected, which strongly supported use of AC0010 as a new third-generation EGFR TKI.
We conducted this first-in-human phase I trial to assess the maximum tolerated dose (MTD), recommended phase II dose (RP2D), dosing schedule, safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AC0010 in patients with NSCLC who failed treatment with a first-generation EGFR TKI. We also performed capture-based deep sequencing of plasma cell-free DNA (cf-DNA) during treatment to better understand both the anticancer properties and development of resistance to AC0010.
Patients and Methods
Patients
This phase I trial was conducted between October 2014 and December 2016 (data cutoff). To be eligible, patients had to (1) be 18 to 75 years old; (2) have advanced or recurrent NSCLC; and (3) have disease progression after at least one treatment with a first-generation EGFR TKI (including gefitinib, erlotinib, and icotinib), which was defined as acquired resistance according to the Jackman criteria.
Additional eligibility criteria included an Eastern Cooperative Oncology Group performance score of 0 or 1 and at least one lesion measurable by computed tomography or magnetic resonance imaging according to the Response Evaluation Criteria in Solid Tumors (version 1.1) (see the Supplementary Data for details). Patients were permitted to continue the study after isolated progressions (e.g., to brain or bone) and receive radiotherapy if the investigators deemed the patients still able to derive benefit.
An assessment of EGFR T790M mutation status by using either blood or tissue samples was also required for eligibility (see the Supplementary Data for details). Patient screening was performed in Sun Yat-sen University Cancer Center (with protocol and amendment approvals granted by the local ethics committee) and conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization. Written informed consent was obtained for each patient individually before enrollment in the study. The trial was registered at ClinicalTrials.gov. (NCT02274337).
Study Design and Drug Treatment
The primary objective of this trial was to assess the MTD, RP2D, dosing schedule, and safety of AC0010. Secondary objectives included examination of AC0010 PK, pharmacodynamics, and antitumor activity.
In the dose escalation stage, sequential patient cohorts received AC0010 starting at a dose of 50 mg and increasing sequentially to 100, 200, 350, 500, 550, and 600 mg. The starting dose of 50 mg was determined by the level at which there were no observed adverse effects and the biological effect of AC0010 anticipated on the basis of preclinical data in tumor xenograft mice and a cynomolgus model was minimal.
AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients.
Patients were administered a single dose of AC0010 and received 7 days of PK evaluation; continuous dosing was applied thereafter. A modified three-plus-three Fibonacci method was applied. PK, single dose escalation, drug accumulation, and effects of interaction of food with AC0010 were studied at this stage. Dose escalation would stop if the MTD was reached or if the PK data (maximum blood concentration and area under the concentration-time curve) reached saturation. The dose expansion stage was designed to accrue additional patients and was to be initiated if dose-limiting toxicities (DLTs) occurred or more PK data were needed at a specific dose level. The dose expansion stage was conducted by using the continual reassessment method after a dose level was confirmed to be tolerated, guided primarily by the results from the PK analyses (Fig 1). Different dosing schedules, such as twice-daily and thrice-daily dosing regimens, would be applied mainly on the basis of the PK analysis results, such as determination of half-life (t½) and the area under the drug/blood concentration–time curve (AUC). Each cycle of AC0010 treatment was 28 days.
Figure 1Patient inclusion diagram and dose escalation and expansion scheme.
Adverse events (AEs) were assessed and graded by the investigators and documented from the time of informed consent to 28 days after retreat from the study according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.02. Any grade 4 or higher hematological toxicities or grade 3 or higher nonhematological toxicities were regarded as DLTs. Tumor imaging was performed at baseline, at the end of the first cycle, and every two cycles thereafter by using either computed tomography or magnetic resonance imaging. For each patient, the imaging method in follow-up was consistent with that at baseline. Tumor response was assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Assessment of antitumor activity was based on (1) ORR, defined as the proportion of patients who displayed a partial response (PR) or complete response (CR), and (2) disease control rate (DCR), which was defined as the proportion of patients who achieved PR or CR or stable disease. Best overall response (BOR) (either CR or PR) was confirmed after 4 weeks.
Assessment of Pharmacokinetics and Pharmacodynamics
Serial peripheral blood samples were collected at before the dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the dose for the single-dose PK test. For the continuous PK test, serial peripheral blood samples were collected at before the dose on days 1, 8, 15, 22, and 28 and after the dose on day 28 at hours 0.5, 1, 2, 3, 4, 6, 8, 12, and 24. Plasma concentrations of AC0010 were measured by using a validated liquid chromatography–tandem mass spectrometry method with a 0.2-ng/mL lower limit of quantification. PK parameters, including maximum concentration (Cmax), AUC, time to reach maximum plasma concentration (Tmax), and t½ were calculated by using noncompartmental methods with Phoenix 6.4 software (Pharsight, Mountain View, CA). Descriptive statistics (mean and SD) were estimated for PK parameters in each cohort. Peripheral blood samples were collected at time points synchronized with assessment by tumor imaging and at the time of discontinuation of AC0010 treatment. Capture-based deep sequencing of patient’s plasma cf-DNA was performed by using a lung plasma panel spanning 168 critical genes and covering 160 kb of human genomic regions; 13 genes were sequenced for all exons, 143 genes were selected exons, six were selected exons and introns, two were introns only, three were single-nucleotide polymorphisms, and one was a promoter. The median depth of sequencing was 10,000×. For more details, see the Supplementary Data (Supplementary Table 1).
Patients in the intention-to-treat population who received at least one dose of AC0010 were included in the full analysis set (FAS). Efficacy analysis was conducted in the FAS. Patients who were in the FAS and had recorded safety assessment were included in the safety set. Descriptive statistics were used to summarize qualitative and quantitative data. All data tests were two sided. Fisher's exact testing was used to compare the response rate in the various subgroups. Nonparametric analysis was used to evaluate the correlation between T790M allele frequencies (AFs) and target lesion shrinkage rate and to compare AFs between groups. AFs were plotted as scatter plots. All statistics were analyzed with SAS software (version 9.13, SAS Institute Inc, Cary, NC).
Results
Patients
A total of 52 patients (21 in the dose escalation stage and 31 in the dose expansion stage) were included. Their demographics are shown in Table 1. Most of the patients (63%) harbored an exon 19 deletion. All patients were tested for the T790M mutation before treatment; 87% (45 of 52) tested positive for a T790M mutation; 90% (47 of 52) had a T790M mutation on the basis of tissue testing by polymerase chain reaction sequencing or amplification refractory mutation system analysis (a detectable lower limit of mutation abundance of 1%), and 10% had a T790M mutation according to analysis of their peripheral blood by next-generation sequencing (AF cutoff 1% also) (Supplementary Tables 2 and 3). The inclusion scheme is summarized in Figure 1.
Table 1Demographics and Clinical Characteristics of the 52 Patients
In all, 17 patients received two or more lines of prior EGFR TKIs, 16 patients received first-generation TKI rechallenge, and one patient received afatinib treatment after a first-generation TKI.
Detected by using either blood or tumor tissue within 28 days; direct sequencing, amplification refractory mutation system, or next-generation sequencing by a local or central laboratory were acceptable.
Dosing was guided on the basis of pharmacokinetic results during the trial.
n (%)
Once day
25 (48)
Twice daily
21 (40)
Thrice daily
6 (12)
TKI, tyrosine kinase inhibitor.
a In all, 17 patients received two or more lines of prior EGFR TKIs, 16 patients received first-generation TKI rechallenge, and one patient received afatinib treatment after a first-generation TKI.
b Detected by using either blood or tumor tissue within 28 days; direct sequencing, amplification refractory mutation system, or next-generation sequencing by a local or central laboratory were acceptable.
c Seven patients with negative T790M statues were not analyzed for resistance mechanism.
d Dosing was guided on the basis of pharmacokinetic results during the trial.
PK analyses after single and continuous dose administration (once-daily dosing) showed that the mean AUC and Cmax of AC0010 followed a dose-proportional pattern across the dosing range (50–350 mg): approximately fourfold with single administration (991 versus 3264 ng/mL of the Cmax and 6.1 versus 22.7 h·mg/L of the AUC0–24h) and fourfold to fivefold in continuous dosing (875 versus 3352 ng/mL of Cmax and 5.5 versus 28.1 h·mg/L of the AUC0–24h) compared with 50 mg to 350 mg. The AUC and Cmax reached saturation at 350 mg with single and continuous dose administration (see Fig. 1 and Supplementary Fig. 1). The PK data are shown in Supplementary Tables 4 and 5. The median time to Cmax for AC0010 was 3.0 hours (range 1.0–6.0 hours), the mean t½ was 7.76 hours (range 7.15–8.12 hours), and the observed accumulation ratio of continuous dosing at day 28 ranged from 0.97 to 1.74. On the basis of t½, a steady-state concentration of AC0010 was reached within 7 days. A standard diet (700 Cal/meal, fat energy ratio approximately 20%) had no effect on absorption of AC0010 in the dose groups receiving more than 200 mg of the drug as compared with administration during fasting (Supplementary Table 6).
Safety
AEs were evaluated by the investigators and were observed in all 52 patients (Table 2). The most common treatment-emergent AEs across all doses were diarrhea (75%), skin rash (48%), increased alanine transaminase (ALT) level (44%), and increased aspartate transaminase (AST) level (38%). The median durations of AEs were 4 days for diarrhea, 23 days for skin rash, and 16 days for increased transaminase levels. For increased transaminase levels, most cases (74%) were grade 1 or 2 and transient and 78% of patients recovered within 30 days without treatment, with the increases occurring more frequently in patients with baseline liver impairment, such as testing positive for hepatitis B virus infection, liver metastasis, and so forth (a rate of increased ALT level 49% versus 22% and a rate of increased AST level of 44% versus 11%) (Supplementary Table 7). Only two patients experienced a concomitant grade 1 increase in bilirubin level. The rates of AEs in the 36 patients who received a daily dose 350 mg or higher (which are also shown in Table 2) were generally higher.
Table 2Summary of Safety Profiles and the Most Common Any-Cause AEs due to AC0010 by Dosing
As shown in Table 2, grade 3 or higher AEs were reported in 14 patients (27%), with 10 patients (19%) experiencing grade 3 or higher AEs that were suspected of being drug related. Ten patients (19%) experienced AEs leading to dose interruption; two (4%) of them accepted dose reduction and eight (15%) discontinued treatment. Eleven patients (21%) experienced serious AEs, four of which were suspected of being drug related, including those in two patients experiencing a grade 3 skin rash and in two patients whose disease was clinically diagnosed as interstitial lung disease and who recovered upon corticosteroid treatment (Supplementary Table 8 and Supplementary Fig. 2). Two patients (4%) displayed grade 1 QT interval prolongation. No hyperglycemia was observed.
MTD and RP2D
MTD
Three DLTs were observed, including grade 3 increases in ALT/AST level (n = 2 [at 200 and 500 mg]) and a grade 3 skin rash (n = 1 [at 550 mg]). After interruption of the AC0010 dose and concomitant treatment, these DLTs were reversed. The MTD was not reached. The dose escalation stopped at 600 mg (mainly on the basis of the PK analysis results). The results of single and continuous dose administration (a once-daily schedule) showed that 500 mg, 550 mg, and 600 mg did not significantly increase Cmax or AUC0–24h compared with 350 mg (the data are presented in Supplementary Tables 4 and 5).
RP2D Determination
Exposure to AC0010 (AUC0–24h and Cmax) reached saturation at 350 mg after administration of a single dose (a once-daily schedule) (Fig. 2 and Supplementary Fig. 1). This finding was based on the fact that the t½ of AC0010 was short (approximately 8 hours) and the AUC (0–24 hours at day 28) and trough plasma concentration (Ctrough at day 15) were significantly correlated with ORR and DCR (Supplementary Table 9). A twice-daily or thrice-daily schedule provided a higher AUC and Ctrough than a once-daily dosing schedule did (Supplementary Table 10); no significant differences were observed between twice-daily and thrice-daily dosing at the same dose level (600 mg). On the basis of the aforementioned PK analysis results, twice-daily administration is recommended and 300 mg twice-daily is suggested as RP2D; however, these recommendations need to be further supported by efficacy and safety data.
Figure 2Pharmacokinetic (PK) analyses of AC0010. (A) Mean AC0010 plasma concentration–time profile by dose level after administration of a single dose. Patients were administered a single dose of AC0010 once daily and received 7 days of PK evaluation before continuous dosing (cycle 0). (B) Mean AC0010 plasma concentration–time profile by dose level after continuous dose administration at cycle 1 day 28. Both linear and semilog curves are presented. Five patients did not have PK data at cycle 1 day 28 (three dose-limiting toxicities and two cases of early disease progression). QD, once daily; BID, twice daily; TID, thrice daily.
According to a preliminary assessment of tumor response in all 52 patients, no CR was observed and 19 patients (36.5%) displayed confirmed PR. The ORR was 36.5% (19 of 52 patients) and the DCR was 75.0% (39 of 52 patients). Thirteen patients (25%) had disease progression (two were not assessable), as shown in Fig 3A. A total of 34 patients (65.4%) had their tumor burden reduced (a target lesions size that was smaller at the BOR than at baseline).
Figure 3Best change in the target lesion compared with baseline at the best overall response to AC0010 treatment. Waterfall plots for best change in the target lesion for all patients (A) and patients receiving a daily dose of 350 mg or higher (B). The colored bars represent different daily doses of AC0010. The dashed lines at 20% and −30% represent the boundary for determination of progressive disease (PD) and partial response (PR). Imputed values represent the values for two patients whose target lesions were not evaluable and were defined as 20%. Asterisks represent PRs that have not been confirmed yet. Stable disease and PD represent the confirmed results for two patients.
The ORR in patients with a daily dose of 350 mg or higher (50.0% [18 of 36]) was significantly higher than in those with a daily dose less than 350 mg (6.25% [one of 16]) (p = 0.002) (Fig. 3B). Patients who received a dose of 350 mg or more exhibited a higher ORR with the twice-daily or thrice-daily dosing schedule than with once-daily dosing (ORRs of 52.4%, 50.0%, and 44.4%, respectively). The ORR in patients with the T790 mutation (42.2% [19 of 45]) was significantly higher than in those lacking this mutation (0% [0 of 7]) (p = 0.031). No significant difference in ORR was observed between patients who were and were not treated with an EGFR TKI immediately before the study, or in patients with different activating EGFR mutations (L858R and 19del) (Supplementary Table 11). The median PFS estimated by Kaplan-Meier method ranged from 14.0 to 35.6 weeks for patients who received a daily dose of 350 mg or higher (350–600 mg/d).
The rates of shrinkage of the target lesions (against baseline) at each imaging follow-up are showed in Supplementary Figure 3. By the time of data cutoff, eight patients remained on study; three were with treatment beyond isolated progression and five were without treatment.
Plasma cf-DNA Sequencing
Patients with development of acquired resistance to AC0010 (those who achieved a PR or stable disease for ≥6 months) were included in this analysis.
A total of 17 patients were enrolled (BOR of 12 patients with a PR and five with stable disease). The baseline mutation spectrum is shown in Fig 4A and Supplementary Figure 4. All 17 patients had an EGFR-sensitizing mutation (19del or 21L858R) in combination with EGFR T790M. The baseline EGFR T790M AFs in patients with a BOR of PR (12 patients) were marginally higher than those of patients who had a BOR of stable disease (five patients), with median values of 10.5% and 5.4%, respectively (p = 0.058) (see Fig. 4A). The EGFR T790M AFs at baseline were significantly correlated with the best target lesion shrinkage rate (a correlation coefficient of −0.704 [p = 0.002, Spearman rank correlation]); higher T790M AFs at baseline were indicative of more substantial tumor shrinkage. After the start of AC0010 administration, declines in mutation AFs or amplification CNVs were observed in 15 of 17 patients (88.2%). For 23.5% of patients (4 of 17), no mutation/amplification was detected at their first follow-up after treatment. All patients had either a decline or a complete eviction of the subclone harboring T790M during treatment, whereas other mutation AFs or amplification CNVs rebounded in most of patients (14 of 16 [87.5%]) before or at the time of disease progression (Supplementary Fig. 5). The AFs of T790M at the BOR were significantly lower than the baseline level (median 2.24% versus 0% [p < 0.001, Mann-Whitney U test]), suggesting that AC0010 may have specificity for T790M (Fig. 4B).
Figure 4Plasma cell-free DNA sequencing results for 17 patients with acquired drug resistance. (A) Heat map of baseline mutations/copy number variations (CNVs), which were sorted by the best overall response of patients after AC0010 treatment. Each column represents a distinct patient. The shades of color represent the allele frequencies (AFs) or copy numbers. Best overall responses are shown at the top: 12 patients with a partial response (PR) and five patients with stable disease. (B) Scatter plot of T790M AFs. The red dashed line represents the median (2.24 at baseline, 0 at PR/stable disease, and 0 at disease progression [PD]). (C) Pie chart depicting the different AC0010-resistant variants. TP53, tumor protein p53 gene; RB1, retinoblastoma gene; ERBB, erb-b2 receptor tyrosine kinase gene; amp, amplification; TAB2, TGF-beta activated kinase 1 (MAP3K7) binding protein 2 gene; OR5L2, olfactory receptor family 5 subfamily L member 2 gene; NLRP4, NLR family pyrin domain containing 4 gene; BRCA2, BRCA2, DNA repair associated gene; CTNNA2, catenin alpha 2 gene; CTNNB1, catenin beta 1 gene; CDKN2A, cyclin-dependent kinase inhibitor 2A gene; FGFR1, fibroblast growth factor receptor 1 gene; CDK4, cyclin-dependent kinase 4 gene; del, deletion; PTEN, phosphatase and tensin homolog gene; CSMD3, CUB and Sushi multiple domains 3 gene; CCND1, cyclin D1 gene; FGF19, fibroblast growth factor 19 gene; FGF3, fibroblast growth factor 3 gene; FGF4, fibroblast growth factor gene; MET, MNNG HOS Transforming gene; freq, frequency.
The evaluation of the 16 patients (one unqualified sample was excluded) who displayed disease progression after commencement of AC0010 treatment suggested a few potential resistance mechanisms. These putative mechanisms include BRAF V600E (one of 16), ROS1 fusion (one of 16), MET amplification (one of 16), erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification (two of 16), and retinoblastoma 1 gene (RB1) (two of 16) and tumor protein p53 gene (TP53) (three of 16) mutations. No EGFR C797S mutations were observed in any patients, and seven patients showed no molecular resistance mechanism according to this panel (Fig 4C).
Discussion
In this study, we evaluated the safety, PK, and efficacy of AC0010 in patients with NSCLC with development of resistance to first-generation EGFR TKIs.
Our results suggest that AC0010 was well tolerated at daily doses ranging from 50 to 600 mg. As with other EGFR TKIs, the most common AEs caused by AC0010 were diarrhea, skin rash, and increased transaminase level.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial.
In most cases, diarrhea, skin rashes, and increased liver transaminase levels were mild and transient, with the low rate of grade 3 to grade 5 drug-related AEs (skin rash and diarrhea) suggesting that AC0010 selectively targets mutant forms of EGFR while sparing wild-type EGFR.
The rate of AEs leading to drug discontinuation is 15% (8 patients), with 6% considered drug-related and 9% considered disease progression–related, which compared well with the rate of osimertinib (3%) (the first U.S. Food and Drug Administration–approved third-generation EGFR TKI). The relationship between transient increased transaminase levels and previous liver impairments in patients treated with AC0010 will be evaluated in a future study. Interstitial lung disease occurred at a low incidence rate (4%), and it was manageable with regular symptomatic and radiological surveillance and prompt treatment. No hyperglycemia or cardiovascular injury was observed, indicating no off-target effects (e.g., Insulin Like Growth Factor Receptor inhibition).
For the patients who received higher doses (≥350 mg) of AC0010, the ORR was 50.0%. PK analysis indicates that when compared with the once-daily dosing regimen, the twice-daily and thrice-daily dosing regimens produced an increased Ctrough and AUC. The twice-daily and thrice-daily dosing regimens increased the ORR to 52.4% and 50.0%, respectively. In this study, AC0010 exhibited a high tumor response rate and well-tolerated safety profile, which could provide another choice for patients after the failure of first-generation EGFR TKIs.
In cf-DNA sequencing analyses during AC0010 treatment, the AFs of T790M decreased significantly, which is consistent with our preclinical findings,
AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients.
thus providing evidence of AC0010 being an EGFR T790M mutation–selective inhibitor. Further studies on tissue sequencing are still needed.
Amplification of MET and ERBB2 emerged at disease progression during AC0010 treatment. These common EGFR TKI resistance mechanisms enable a bypass of inhibited EGFR, resulting in reactivation of common downstream pathways. Previous studies of acquired resistance to EGFR TKI showed that MET amplification acts as an independent driver that is responsible for 3% to 5% of cases of resistance and may account for up to 20% of relapses.
The amplification of ERBB2 and/or MET has been reported as a potential resistance mechanism of third-generation EGFR TKIs, which may support the bypass theory.
The BRAF mutations and ROS1 fusion that also emerged during the treatment are generally regarded as independent driver mutations of acquired resistance to first- and third-generation EGFR TKIs.
High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression.
Recent studies have suggested that concomitant inactivation of both RB1 and TP53 was significantly related to transformation into SCLC from lung adenocarcinoma, which is a major resistance mechanism of EGFR TKI treatment.
In our study, concomitant RB1 and TP53 inactivation at the time of acquired resistance developed in two patients. But the substantial biopsy samples indicated that neither of them had SCLC transformation. With regard to potential acquired resistance mechanisms of AC0010, more cases are needed to investigate the function of RB1 and TP53 mutation during the treatment. Notably, the EGFR C797S mutation, which is a well-known cause of resistance to osimertinib, was not observed.
AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients.
Collectively, although tissue analysis before and after treatment is lacking, our data highlight the value of cf-DNA for tracking patient response and elucidating drug resistance mechanisms.
The limitations of this trial should be noted. The sample size in this study was small. Consequently, the results of this study may not be thoroughly representative, particularly, with regard to safety (in particular, long-term toxicity) and survival assessments, such as PFS (especially with the RP2D). Those results will be confirmed in an ongoing larger expansion cohort and in phase II trials (NCT02448251 and NCT03058094). Also, the FLAURA trial shows that third-generation TKI osimertinib is significantly better than gefitinib for first-line therapy in patients with NSCLC with EGFR-activating mutation and may change the guideline and become the standard treatment. A clinical trial comparing AC0010 with a first-generation EGFR TKI clinical trial is also being considered.
In summary, AC0010 has comparable antitumor activity and tolerated toxicity with other third-generation TKIs. Further development of AC0010 as a novel third-generation EGFR TKI in patients with NSCLC is warranted.
Acknowledgments
This work was supported by National Key R&D Program of China (grant 2016YFC0905500), Chinese National Natural Science Foundation project (grant 81372502), Science and Technology Program of Guangzhou, People's Republic of China (201607020031) and ACEA Pharmaceutical Research, ACEA Biosciences, Inc., and Burning Rock Biotech. We would like to thank all the patients, patient families, study investigators, and personnel who participated in this trial.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial.
AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients.
High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression.
Drs. Ma, Zheng, and Zhao equally contributed to this work.
Disclosure: Dr. Li Zhang has received research funding from Bristol-Myers Squibb, Pfizer, Eli Lilly and Company, and ACEA Pharmaceutical Research. Dr. Ma has received compensation for travel expenses from ACEA Pharmaceutical Research. Dr. Chuai and Dr. Zhou Zhang are employees and stock owners of Burning Rock Biotech. Dr. Xu is an employee and stock owner of ACEA Pharmaceutical Research. Dr. Xu is chief executive officer and cofounder and stock owner of ACEA Biosciences, Inc. The remaining authors declare no conflict of interest.
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