Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Abstract

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.

Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

Figure 1.

Modeling of sunvozertinib with EGFRexon20ins 770_NPG (Protein Data Bank code: 4LRM). Key interactions of sunvozertinib with EGFR proteins include (i) bidentate interactions of aminopyrimidine with a hinge (Met796), (ii) acrylamide group forms an irreversible covalent bond with Cys800, (iii) 2-hydroxypropan-2-yl group occupies space next to the C-helix, and (iv) polar interaction of dimethylaminopyrrolidine with solvent channel residues. Green: carbon; purple: nitrogen; red: oxygen; dark green: chloride; light blue: fluorine. Colors on the protein surface represent the ATP-binding pocket and are for clarity only. DZD9008 = sunvozertinib.

Figure 2.

In vitro and in vivo antitumor activity of sunvozertinib in EGFRexon20ins, sensitizing mutation, uncommon mutation, or resistant mutation cell lines and animal models. A, The cellular activity of sunvozertinib on EGFRexon20ins as well as sensitizing mutation, uncommon mutation, or resistant mutation versus wild-type (WT) EGFR, shown as pEGFR IC₅₀. Cell lines carrying EGFRexon20ins were treated with sunvozertinib at a series of concentrations for 4 hours, and then pEGFR (Tyr1068) was measured with an MSD SECTOR Imager. In the A431 cell line carrying wild-type EGFR, after compound treatment for 4 hours, cells were stimulated with 100 ng/mL of recombinant human EGF for 10 minutes before lysis. The potency in each cell line was the average value from three biologically independent experiments. Data, mean ± SEM. One-way ANOVA test was used for comparison with wild-type EGFR. ****, P < 0.0001. B, Antitumor activity of sunvozertinib in the PDX model LU0387 carrying EGFRexon20ins insNPH. b.i.d., twice daily. C, Antitumor activity of sunvozertinib in the PDX model LU3075 carrying EGFRexon20ins 772_DNP. D, Antitumor activity of sunvozertinib in the A431 xenograft model expressing wild-type EGFR. Tumor volume in the different treatment groups at the endpoint was performed by two-way ANOVA. ****, P < 0.0001. E, PK/PD relationship of sunvozertinib in the PDX LU3075 model. The pEGFR (Tyr1068) and pERK (Thr202/Tyr204) expression in tumor tissues was detected by IHC and normalized to the vehicle control group. Each time point had tumor tissues from three mice to detect pEGFR or pERK signal except the time point of 24 hours in the 50 mg/kg group, which included only one mouse due to complete remission of tumor nodules in some mice. conc., concentration; pERK, phosphorylated ERK. DZD9008 = sunvozertinib.

Figure 3.

Trial profiles. Pooled summary of WU-KONG1 and WU-KONG2 studies. Data cutoff date: April 3, 2021. Sunvozertinib (DZD9008) was dosed once daily. AE, adverse event.

Figure 4.

Clinical activity of sunvozertinib in EGFRexon20ins NSCLC patients with postbaseline target lesion assessments. A, Best percentage change from baseline in target lesions by dose level, molecular subtype, prior amivantamab or poziotinib treatment status, and baseline BM. B, Plot showing percentage change from baseline in target lesion by time on treatment and dose level. Pooled analysis of WU-KONG1 and WU-KONG2 studies was performed. Data cutoff date: April 3, 2021. Tumor response was assessed by investigators according to RECIST 1.1. PD, progressive disease; SD, stable disease. *, confirmed response. EGFRexon20ins subtypes were confirmed by next-generation sequencing using tumor tissue or/and plasma circulating tumor DNA. JNJ-61186372 = amivantamab. Note: Among the 56 patients, a total of 45 subjects had tumor tissue and/or plasma samples tested by a central laboratory using next-generation of sequencing; 41 of 45 were confirmed as EGFRexon20ins-positive, and the overall concordance rate was 91%. However, 31 subjects had only tumor tissue tested by the central laboratory, and the concordance rate between local and central laboratory testing was 97% (30/31).