An evaluation of aumolertinib for the treatment of EGFR T790M mutation-positive non-small cell lung cancer

ABSTRACT

Introduction

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can significantly improve patient prognosis when used on patients with EGFR-mutant non-small cell lung cancer (NSCLC), but those patients often develop acquired resistance after 9–14 months of treatment. These resistance mechanisms are complex and diverse, with the EGFR T790M mutation being the most common. Aumolertinib is a new third-generation EGFR-TKI that is highly selective for EGFR-sensitizing mutations and EGFR T790M resistance mutation.

Areas covered

This review summarizes the mechanism of action, efficacy, and safety of aumolertinib for EGFR T790M mutation-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects.

Expert opinion

Aumolertinib has shown good efficacy and safety for advanced EGFR T790M mutation-positive NSCLC patients who have progressed after EGFR-TKI treatment. It is expected to become a new treatment option, and to aid the establishment of new treatment standards. A phase III clinical study is currently underway to evaluate the suitability of aumolertinib as a first-line treatment. At present, more drug combinations and different applicable populations are being further explored. Future challenges include exploring mechanisms of aumolertinib resistance and determining its efficacy in European and American populations.

KEYWORDS:

• NSCLC
• targeted therapy
• aumolertinib
• EGFR T790M mutation

1. Introduction

Lung cancer has the second highest incidence (11.4%) and the highest mortality (18%) of all cancers [1], among which non-small cell lung cancer (NSCLC) accounts for approximately 85%. Molecular targeted therapy has led to a new era of precision therapy for NSCLC. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are one of the most commonly used drug types for the treatment of NSCLC. A series of clinical studies have confirmed that, compared with traditional platinum-containing dual-drug chemotherapy, both first-generation (gefitinib [2], erlotinib [3,4], and icotinib [5]) and second-generation EGFR-TKIs (afatinib [6,7] and dacomitinib [8,9]) can deliver clinical benefits for patients with EGFR-mutant advanced NSCLC. However, patients often develop acquired resistance after a median of 9–14 months of treatment. These resistance mechanisms are complex and diverse, with the EGFR T790M mutation being the most common; it accounts for approximately 50% [10,11]. The third-generation EGFR-TKI osimertinib was first approved for the treatment of patients with acquired resistance mediated by the EGFR T790M mutation [12]. Aumolertinib, which is the second third-generation EGFR-TKI in the world, is an innovative drug that was independently developed in China; it has high selectivity for EGFR-sensitizing and EGFR T790M resistance mutation.

2. Overview of the market

Osimertinib was approved by the United States of America (USA) Food and Drug Administration (FDA) in 2015 for EGFR T790M mutation-positive patients with locally advanced or metastatic NSCLC; it was approved in China in March 2017. In March 2020, aumolertinib became the second third-generation EGFR-TKI to be approved for use in EGFR T790M-positive advanced NSCLC patients; it was approved for marketing by the National Medical Products Administration (NMPA) in China. Subsequently, in 2021, the third-generation EGFR-TKIs furmonertinib and lazertinib were approved for listing in China and South Korea, respectively. In addition to these approved third-generation EGFR-TKIs, many other third-generation EGFR-TKIs are currently being studied, such as ASK120069, SH-1028, D-0316, rezivertinib, and abivertinib [13].

3. Introduction of the compound

The T790M mutation involves a change in the 790^th amino acid of exon 20 of the EGFR gene, with methionine replacing threonine. This mutation structurally inhibits first- and second-generation EGFR-TKIs by changing the crystal structure of the adenosine tri-phosphate (ATP) binding pocket and inhibiting binding to the ATP binding site. This in turn leads to drug resistance to EGFR-TKIs. Aumolertinib is a new and irreversible small molecule third-generation EGFR-TKI that has high selectivity for EGFR-sensitizing mutations and EGFR T790M resistance mutation (Box 1).

3.1. Chemistry

Aumolertinib’s chemical formula is N-[5-[[4-(1-cyclopropylindol-3-yl)-pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide. Aumolertinib is similar to other third-generation EGFR-TKIs. Aminopyrimidine is used as their core, while the Michael addition receptor is introduced. Based on this structural foundation, aumolertinib can interact with and irreversibly bind to cysteine-797 (Cys797) through an unsaturated acrylamide bond at the ATP binding site of the EGFR tyrosine kinase domain. Thus, it can selectively act on EGFR-sensitive mutations and EGFR T790M-resistant mutation. Aumolertinib is optimized based on the structure of osimertinib, in which the methyl group is replaced with a cyclopropyl group on the indole nitrogen ring [14,15]. Cyclopropyl group has been shown to improve the metabolic stability and receptor subtype selectivity of aumolertinib, while avoiding the production of nonselective metabolites that strongly inhibit wild-type EGFR (WT-EGFR) during drug metabolism. Meanwhile, the addition of cyclopropyl group increases the blood-brain barrier permeability of aumolertinib [16].

3.2. Pharmacodynamics and pharmacokinetics

Aumolertinib has demonstrated great inhibitory activity against T790M, T790M/L858R, and T790M/Del19, with half maximal inhibitory concentrations (IC₅₀) of 0.37 ± 0.04, 0.29 ± 0.10, and 0.21 ± 0.10 nM, respectively. However, its inhibitory activity against WT-EGFR only exhibited an IC₅₀ of 3.39 ± 0.53 nM, an approximately tenfold difference . Preclinical studies have shown that a course of 14 days of administration of aumolertinib (20 mg·kg⁻¹ per os [PO] quaque die [QD]), when applied to treat tumor-bearing mice transplanted with NCI-H1975 tumor cells (L858R/T790M mutation positive), effectively inhibited the growth of transplanted tumors. It exhibited a tumor growth inhibition rate of 194.4%, which is equivalent to that of osimertinib. Aumolertinib’s clearance half-life (T _1/2) is approximately 30 to 35 hours. In the dose range of 55–220 mg, the maximum plasma concentration of aumolertinib and its the area under the curve showed a dose-dependent linear increase, reaching saturation in the dose range of 260 mg [14,17]. Preclinical studies have shown that the brain-to-plasma concentration ratios of aumolertinib rangs from 4.4 to 19.1 while the brain-to-plasma concentration ratios of osimertinib rangs from 1.8 to 2.8. Compared with osimertinib, the addition of cyclopropyl in aumolertinib can increase the penetration of the blood-brain barrier [18,19].

4. Clinical efficacy

4.1. Phase I trial

The phase I study of aumolertinib was an international multicentre trial involving 120 patients who progressed after receiving EGFR-TKIs (gefitinib or erlotinib). Among them, 44 were from mainland China, 69 were from Taiwan, and seven were from the USA. Twenty-six patients in the dose-escalation cohort received 55–260 mg (55, 110, 220, or 260 mg) of aumolertinib per day to determine the maximum tolerated dose (MTD) and the recommended dose for the extended cohort; these doses were determined to be 55 and 110 mg, respectively, with no dose-limiting toxicity (DLT) occurring at these doses. At doses of 220 and 260 mg, two patients had DLT events. The 94 patients in the dose expansion cohort were confirmed to have EGFR T790M mutation by tumor biopsies; they received 55–220 mg (55, 110, or 220 mg) of aumolertinib daily to determine the recommended dose for the phase II study. All 120 patients were included in the efficacy analysis, which showed that the overall objective response rate (ORR) was 50%, the disease control rate (DCR) was 89%, the median duration of response (DoR) was 9.5 months, and the median progression-free survival (PFS) was 9.6 months. Among patients in the dose expansion cohort (who were confirmed to have EGFR T790M), ORR and DCR were determined to be 52 and 92%, respectively, the median DoR was 9.7 months, and the median PFS was determined to be 11.0 months. In the dose expansion cohort, the 110 mg cohort exhibited the highest DCR (55 mg: 83%, 110 mg: 97%, and 220 mg: 94%). The ORR of 110 mg was similar to that of the 55 mg cohort (55 mg: 60%; 110 mg: 55%); both were higher than that of the 220 mg cohort [42%]). Furthermore, there was an increasing trend toward the longest PFS, so 110 mg QD was selected as the recommended dose for the phase II trial [14,20].

4.2. Phase II Trial

The phase II study featured 244 Chinese patients with EGFR T790M mutations and locally advanced or metastatic NSCLC, who had previously progressed after treatment with EGFR-TKIs. These patients each received 110 mg of aumolertinib orally, once a day, which resulted in an ORR of 68.9%, a DCR of 93.4%, a median DoR of 15.1 months, a median PFS of 12.4 months, and a median OS of not reached (NR) (95% confidence interval [CI]: 22.9-NR) [18,21–23].

In subgroup analysis, for patients with EGFR exon 19 deletion, ORR and DCR were 72.2% and 96.1% respectively, the median DoR was 15.1 months, the median PFS was 12.4 months, the median OS was NR (95% CI: NR-NR). For patients with EGFR L858R mutation, ORR and DCR were 63.5% and 89.4% respectively, the median DoR was 16.5 months, the median PFS was 12.3 months, the median OS was NR (95% CI: 22.9-NR) [18].

The study included 88 patients with asymptomatic brain metastases. Among them, 23 patients had assessable central nervous system (CNS) metastases. For these 23 patients, CNS-ORR and CNS-DCR were 60.9 and 91.3% respectively, the median CNS-DoR was 12.5 months, the median CNS-PFS was 11.8 months, and the median CNS-OS was 16.2 months [18].

5. Safety and tolerability

During the phase I study of aumolertinib, 91 patients (76%) experienced treatment-related adverse events (TRAEs). The most common TRAEs were increased blood creatine phosphokinase (CPK) level (20%), rash (15%), increased aspartate aminotransferase (AST) level (12%), increased alanine aminotransferase (ALT) level (11%), decreased white blood cell (WBC) count (11%), diarrhea (10%), and pruritus (10%). The reported rate of TRAEs increased in a dose-dependent manner (55–220 mg). Twenty-three patients (19%) experienced TRAEs of grade ≥3, among which increased blood CPK (10%) and increased ALT (3%) levels were the most common. Seven patients (6%) suffered treatment-related serious adverse events (SAEs), with the most common treatment-related SAE being increased blood CPK level (2%). No grade 5 adverse events (AEs) were reported in the study. In terms of cardiotoxicity, only grade 1 TRAEs were observed. Four patients (3%) had sinus bradycardia, three patients (3%) had ventricular premature beats, and two patients (2%) had rapid heartbeats. In terms of interstitial lung disease, one case of grade 4 treatment-related interstitial lung disease was recorded in the 260 mg cohort [14,20].

In the phase II study of aumolertinib, the safety profile of the drug was consistent with the report of the phase I study. Ninety-one patients (76%) experienced TRAEs.The most common TRAEs (≥10%) were increased blood CPK level (20.9%), increased AST level (12.3%), decreased WBC count (12.3%), increased ALT level (11.9%) and pruritus (10.7%). Eighty-two patients (33.6%) had AEs of grade ≥3, among whom forty patients (16.4%) were evaluated as grade ≥3 TRAEs. The most common grade ≥3 TRAEs were increased blood CPK level (7.0%) and increased ALT level (1.2%). QT prolongation were reported in 15 patients (6.1%), among whom 12 patients (5.0%) had TRAEs of grade 1 or 2. There were no reports of interstitial lung disease during the study period [18,21–23].

6. Regulatory affairs

On 17 March 2020 aumolertinib passed the NMPA priority review and approval procedure in China. Thus, it was approved as second-line treatment for patients with EGFR T790M mutation-positive NSCLC. Aumolertinib is also currently under review for approval by the FDA [18].

7. Conclusion

For EGFR T790M-positive patients with locally advanced or metastatic NSCLC who have progressed after treatment of first- or second-generation EGFR-TKIs, aumolertinib has shown good clinical benefits. The addition of cyclopropyl group enhances the metabolic stability and receptor subtype selectivity of aumolertinib, while reducing the incidences of adverse reactions such as rash or diarrhea. The most common TRAEs of grade 3 or 4 that have been recorded are increased blood CPK level and increased ALT level, which mainly manifested as asymptomatic abnormal biochemical indicators. They did not cause treatment discontinuation, and were reversible and manageable. These findings suggest that from a clinical point of view, relevant biochemical indicators should be monitored regularly. At the same time, aumolertinib has also demonstrated a good ability to penetrate the blood-brain barrier, and it can maintain an excellent curative effect for patients with CNS metastases.

8. Expert opinion

Aumolertinib, which is the world’s second and China’s first self-developed third-generation EGFR-TKI, was approved by the NMPA as second-line treatment for patients with EGFR T790M mutation-positive NSCLC on 17 March 2020. Aumolertinib has opened a new chapter for the targeted therapy of EGFR mutations in China and is also currently under review for approval by the FDA.

The structures of third-generation EGFR-TKIs have been optimized based on first- and second-generation EGFR-TKIs. Aminopyrimidine is used as their core, while the Michael addition receptor is introduced; this receptor has a strong inhibitory effect on the EGFR T790M resistance mutation. Aumolertinib is optimized based on the structure of osimertinib, in which the methyl group is replaced with a cyclopropyl group on the indole nitrogen ring. At present, the third-generation EGFR-TKIs that have been approved in China are osimertinib, aumolertinib, and furmonertinib. AURA 17 [24–27], APOLLO [18,21–23], and ALSC003 [28] are both single-arm, phase II clinical studies, which have explored the efficacy and safety of osimertinib, aumolertinib, and furmonertinib, respectively, for patients with EGFR T790M mutation-positive NSCLC who have progressed from previous EGFR-TKI treatments. Though the data between different studies cannot be directly compared, these three studies are mainly focused on the Chinese population, so some trends can be obtained through comparison.

In terms of efficacy (Table 1), the results of these studies showed that the ORR and DCR of the osimertinib group were 63 and 89%, respectively; the median DoR was 9.9 months, the median PFS was 9.7 months, and the median OS was 23.2 months. The ORR and DCR of the aumolertinib group were 68.9 and 93.4%, respectively; the median DoR was 15.1 months, the median PFS was 12.4 months, and the median OS was NR. Finally, the ORR and DCR of the furmonertinib group were 74 and 94%, respectively, the median DoR was 8.3 months, the median PFS was 9.6 months, and the median OS was NR. The median PFS of the aumolertinib group was >1 year, which represents the longest median PFS of any third-generation EGFR-TKI that has been obtained in second-line studies. This may be related to the enhanced efficacy provided by the cyclopropyl structure of aumolertinib.

Table 1. Comparison of efficacy of the third-generation EGFR-TKIs

	Osimertinib (AURA 17) N = 171 [24–27]	Aumolertinib (APOLLO) N = 244 [18,21–23]	Furmonertinib (ALSC003) N = 220 [28]
ORR	63%	68.9%	74%
DCR	89%	93.4%	94%
mPFS	9.7 months	12.4 months	9.6 months
mDoR	9.9 months	15.1 months	8.3 months
mOS	23.2 months	NR	NR

objective response rate, ORR; disease control rate, DCR; median progression-free survival, mPFS; median duration of response, mDoR; median overall survival, mOS; not reached, NR.

The lipophilic properties of aumolertinib cyclopropyl also ensure that it can penetrate the blood-brain barrier, and it can maintain excellent efficacy for patients with CNS metastases. Its CNS-ORR and CNS-DCR were 60.9 and 91.3%, respectively, the median CNS-DoR was 12.5 months, the median CNS-PFS was 11.8 months, and the median CNS-OS reached as high as 19.1 months.

In terms of safety, aumolertinib, osimertinib, and furmonertinib have exhibited similar overall incidences of adverse reactions; their overall safety is also good (Table 2). However, aumolertinib has an innovative structure, in which the introduction of cyclopropyl prevents the production of metabolites that strongly inhibit WT-EGFR. This was found to significantly reduce diarrhea, rashes and other side effects caused by the inhibition of WT-EGFR. Aumolertinib also has relatively low blood toxicity and cardiotoxicity (as evidenced by its prolonged QT interval), and to date there have been no associated occurrences of interstitial pneumonia. Most CPK conditions have not been reported in studies of osimertinib and furmonertinib. Although aumolertinib was found to lead to a certain degree of increased CPK levels, no SAEs occurred that caused patients to stop treatment. Increased CPK levels are mainly manifested as asymptomatic abnormal biochemical indicators that are both reversible and manageable. There were no clinically significant increases in blood creatinine, blood urea nitrogen, or blood potassium.

Table 2. Comparison of safety of the third-generation EGFR-TKIs

	Osimertinib (AURA 17) N = 171 [24–27]	Aumolertinib (APOLLO) N = 244 [18,21–23]	Furmonertinib (ALSC003) N = 220 [28]
Any AE	165 (96%)	229 (93.9%)	214 (97%)
Treatment-related AE	142 (83%)	187 (76.6%)	171 (78%)
Any AE grade≥3	43 (25%)	82 (33.6%)	58 (26%)
Treatment-related AE grade≥3	18 (11%)	40 (16.4%)	25 (11%)
SAE	28 (16%)	NA	52 (24%)
Treatment-related SAE	6 (4%)	NA	12 (5%)
Any AE leading to dose interruption	10 (6%)	32 (13.1%)	24 (11%)
Any AE leading to dose reduction	1 (1%)	5 (2.0%)	5 (2%)
Any AE leading to discontinuation	6 (4%)	13 (5.3%)	8 (4%)
Treatment-related AE leading to discontinuation	2 (1%)	7 (2.9%)	4 (2%)
Any AE leading to death	8 (5%)	NA	4 (2%)
Treatment-related AE leading to death	2 (1%)	NA	1 (<1%)

adverse event, AE; serious adverse event, SAE; not applicable, NA.

Based on the excellent efficacy, survival data, and safety of aumolertinib as revealed in the APOLLO study, it has become a new choice for the second-line treatment of advanced EGFR T790M mutation-positive NSCLC patients in China. Aumolertinib will also help to establish new standards for the second-line treatment of NSCLC, though its safety and efficacy in European and American populations need to be further explored. The AENEAS study, meanwhile, explored aumolertinib as a first-line treatment for patients with EGFR mutation-positive advanced NSCLC; this study has now reached its primary endpoint. Compared with gefitinib, the PFS of aumolertinib was found to be significantly prolonged in this study (19.3 vs 9.9 months, HR = 0.46, p < 0.0001). Thus, it may provide more options for first-line treatment in the future [29]. The resistance mechanism of aumolertinib and the optimal selection of treatment options after resistance remain unclear, however, so future studies should aim to elucidate these points. Aumolertinib is also currently being studied in the context of other areas of NSCLC, such as first-line combination therapy for advanced NSCLC, perioperative treatment of early NSCLC, and maintenance treatment after radical concurrent chemo radiotherapy for locally advanced NSCLC (Table 3). It is hoped that with the development of more clinical studies and the accumulation of real-world clinical experience, the value of aumolertinib in the field of lung cancer will be more actively explored, ultimately benefiting more NSCLC patients.

Box 1. Drug summary

Drug name	Aumolertinib
Phase	Launched
Indication	Second-line treatment for EGFR T790M mutation-positive NSCLC
Pharmacology description	The third generation EGFR-TKI
Route of administration	Oral
Chemical structure
Pivotal trial(s)	NCT0298110 [14], NCT02981108 [18]

Pharmaprojects – copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

Table 3. Clinical trials of Aumolertinib in NSCLC (https://www.clinicaltrials.gov)

Clinical trial	Treatment	Patients	Design
Aumolertinib as Neo-adjuvant or postoperative adjuvant treatment in stage IA-IIIB NSCLC
NCT04455594	Aumolertinib Vs. Erlotinib/Platinum doublet chemotherapy	Neo-adjuvant Treatment of Stage IIIA-N2 EGFR-mutated NSCLC	Phase II,randomized, open-lable
NCT04922138	Aumolertinib	postoperative adjuvant treatment of stage IA NSCLC patients with EGFR 19del/21L858R.	Phase II,single group,open-label
NCT04687241	Aumolertinib Vs. Placebo	stage II–IIIB EGFR-mutated NSCLC following complete tumor resection with or without adjuvant chemotherapy	Phase III,randomized, double-blind
Aumolertinib as maintenance therapy in stage III unresectable NSCLC after chemoradiotherapy
NCT04951635	Aumolertinib Vs. Placebo	stage III unresectable NSCLC with sensitizing EGFR mutation following chemoradiation	Phase III,randomized, double-blind
Aumolertinib as first-line treatment in advanced NSCLC
NCT03904823	Aumolertinib+Famitinib	Advanced EGFR-mutated NSCLC	Phase II,single group,open-label
NCT04951648	Aumolertinib Vs. Platinum-based chemotherapy	Locally advanced or metastatic NSCLC with uncommon EGFR Mutation	Phase III,randomized, open-lable
NCT03849768	Aumolertinib Vs. Gefitinib	Locally advanced or metastatic EGFR-mutated NSCLC	Phase III,randomized, open-lable
NCT04923906	Aumolertinib Vs. Aumolertinib+chemotherapy	Locally advanced or metastatic NSCLC with sensitizing EGFR mutation	Phase III,randomized, open-lable
NCT04643847	Aumolertinib+Upfront radiotherapy	Advanced EGFR-mutated NSCLC with brain metastases	Phase II,single group,open-label
NCT04808752	Aumolertinib	Advanced NSCLC with sensitizing EGFR mutation and brain metastases	Phase II,single group,open-label
Aumolertinib as second-line or beyond treatment in advanced NSCLC
NCT02981108	Aumolertinib	Locally advanced or metastatic EGFR-mutated NSCLC after failure of EGFR-TKIs	Phase I/II,single group,open-label
NCT04870190	Aumolertinib Vs. Osimertinib	Advanced EGFR-mutated NSCLC with brain metastases after failure of EGFR-TKIs	Phase III,randomized, double-blind
NCT04882345	Aumolertinib	Advanced EGFR-mutated NSCLC who are intolerant to the safety of osimertinib treatment	Phase II,single group,open-label

non-small cell lung cancer,NSCLC.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This manuscript was funded by the Hunan Provincial Natural Science Foundation of China(2021JJ30430), the Hunan Cancer Hospital Climb Plan (ZX2020005-5) and the Hunan Provincial Health Commission (No.B2019090).