Sunvozertinib: shining light on lung cancer’s exon 20 fight

Non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) gene usually demonstrates significant sensitivity to EGFR tyrosine kinase inhibitors (TKIs), exemplifying a prototype of precision medicine in cancer treatment. The most prevalent EGFR mutations are small deletions in exon 19 and leucine to arginine substitution at codon 858 (L858R), which are collectively referred to as classical EGFR mutations, accounting for 70–80% of all EGFR mutations. However, a range of rarer mutations exists, such as G719X, S768I, L747P/S, E709_T710delinsD, referred to as uncommon EGFR mutations and exon 20 insertion mutations (Ex20ins) (1). Ex20ins mutations were originally described by two groups including ours (2,3), and later, it turned out that they account for about 10% of the EGFR mutations (1,4,5). Although over 100 distinct Ex20ins have been identified (6), A767_V769 dup¹, S768_D770dup, and N771_H773dup collectively comprise more than 45% of the 636 Ex20ins according to the compilation of the five databases (6). Thus, it is crucial to efficiently diagnose the diverse range of Ex20ins without missing any of them, as polymerase chain reaction (PCR)-based kits may miss as high as 40–50% of Ex20ins (6,7). This is also true for the EGFR exon 19 deletion as there are many variants for this subtype, too (8) as well as other driver genes (ALK/RET/ROS1, etc.) (9). The timely use of comprehensive genomic testing using a next generation sequencing is shown to prolong overall survival and to avoid ineffective and costly treatment (9) On the other hand, when considering the next-generation sequencing, we have to also be aware of several pitfalls related to tissue sample quality and quantity, or cost and accessibility (10).

Greulich et al. were the first to experimentally demonstrate that the Ex20ins, D770_771ins NPG has a strong transforming capacity (11). Yet, it is unresponsive to first-generation EGFR-TKI, such as gefitinib or erlotinib. Yasuda et al. characterized specifically Ex20ins for the first time and found that D770_771ins NPG has an unaltered adenosine triphosphate-binding pocket and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation without enhancing affinity to EGFR TKI, resulting in insensitivity to the conventional EGFR-TKIs (12). However, there is heterogeneity in the degree of insensitivity within Ex20ins mutations. Although exon 20 of the EGFR gene spans from codon 762 to 823, insertion mutations usually occur between codon 762 and 775. These mutations can be classified into three main categories based on the location of the inserted amino acids. Insertion in the αC helix (between codon 762 and 766 such as A763_Y764insFQEA) is known to be very sensitive to all generations of EGFR-TKIs (12). On the other hand, Ex20ins occurring at the loop region between codons 767 and 775 following the αC helix is insensitive. However, Ex20ins at codons between 767 and 772 (near-loop region) show intermediate sensitivity to second-generation or Ex20ins-active TKIs compared with those at codons between 773 and 775 (far loop region) (13). In addition, Ex20 ins such as 767_S768insTLA, D770_N771insG, D770_N771insGT, N771_P772insH, or N771_P772insN are sensitive to osimertinib at least in vitro (14). Another study found that Ex20ins mutations that have glycine at position 770, such as D770insGY, are sensitive to second generation EGFR-TKI such as afatinib or dacomitinib (15). Zwierenga et al., have recently reported that computational molecular modeling can predict treatment outcome in patients with NSCLC harboring several EGFR exon 20 mutations (16). Furthermore, there may be potential effect of co-occurring mutations such as TP53 genes on patients’ outcome (17) as seen in classical EGFR mutations.

Due to their general resistance to EGFR-TKIs, NSCLC patients with Ex20ins have a median survival of 16.2 months, significantly shorter than 25.5 months observed in patients with classical EGFR mutations by conventional therapies in the real-world retrospective study (18). To address this unmet medical need, drugs for Ex20ins are being actively developed (Table 1).

Notably, amivantamab (EGFR-cMET bispecific antibody) and mobocertinib were the first two drugs that were granted accelerated approval by US Food and Drug Administration (FDA) in 2021 for NSCLC patients with Ex20ins as a second-line treatment. However, because of the failure of the phase 3 study, mobocertinib was withdrawn from the market (34), as discussed later.

Sunvozertinib, an oral, small-molecule, irreversible selective EGFR-TKI, targets Ex20ins as well as EGFR classical, T790M, and uncommon mutations (35). Starting with osimertinib scaffold, sunvozertinib was synthesized after extensive optimization by substituting various moieties based on its potency against Ex20ins and in vitro drug metabolism and pharmacokinetics parameters (Figure 1) (35).

Figure 1 Structures of EGFR-TKIs developed for Ex20ins are compared with osimertinib. Poziotinib features an anilino-quinazoline moiety with an acrylamide group, similar to second-generation EGFR-TKIs such as afatinib and dacomitinib. Other drugs contain a pyrimidine ring and an acrylamide group. Made at MolView website (https://molview.org/). EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors.

In the March 2024 issue of the Lancet Respiratory Medicine, Wang et al. reported the results of the WU-KONG 6 phase 2 study of sunvozertinib (DZD9008) conducted in China, demonstrating that among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved a confirmed objective response rate (ORR) [95% confidence interval (CI): 50–71%] (19). Responses were consistent across various demographics including age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, number of previous lines of therapy, and history of immunotherapy. Sunvozertinib was well tolerated at a dosage of 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were increased blood creatine phosphokinase (17%), diarrhea (8%), and anemia (6%). Serious treatment-related adverse events included interstitial lung disease (5%), anemia (3%), vomiting (2%), nausea (2%), and pneumonia (2%). The authors concluded that sunvozertinib demonstrated anti-tumor efficacy for patients with Ex20ins following platinum-doublet chemotherapy with acceptable toxicities, leading to breakthrough therapy designations from both US FDA and China National Medical Products Administration (NMPA) in 2022 and approval in China in 2023. In addition, the primary analysis of WU-KONG 1B study, a global pivotal study similarly designed to WU-KONG 6, reported an ORR of 44.9% (95% CI: 34.0–56.1%) with responses regardless of previous amivantamab treatment (20). These results appear more favorable comparing other Ex20ins drugs in development (Table 1).

Looking ahead, the PAPILLON study is the first phase 3 trial to demonstrate the superiority of targeted therapy over platinum-based chemotherapy in the first-line setting for patients with EGFR Ex20ins (31). The study randomized 308 patients, showing a progression-free survival (PFS) of 11.4 months for the amivantamab plus chemotherapy arm compared to 6.7 months for the chemotherapy-only group [hazard ratio (HR) 0.40, 95% CI: 0.30–0.53]. The ORR was 73% in the combination arm versus 47% in the control group. Notably, 75% of patients in the amivantamab-chemotherapy arm experienced grade 3 or higher adverse events (31). Frequent non-hematologic adverse events observed ≥30% of the patients in the amivantamab-chemotherapy arm include paronychia (all grade 56%/grade 3 ≤7%), rash (54%/11%), infusion-related reaction (42%/1%), hypoalbuminemia (41%/4%), increased glutamic oxaloacetic transaminase (ALT) (33%/4%), increased glutamic pyruvic transaminase (AST) (31%/1%) and peripheral edema (30%/1%) (31). On the other hand, the phase 3 EXCLAIM-2 trial in previously untreated NSCLC patients with EGFR exon 20ins showed no superiority of mobocertinib monotherapy over platinum-based chemotherapy, with a median PFS of 9.6 months for both treatment arms (36).

Sunvozertinib monotherapy in the first-line setting demonstrated promising results with an ORR of 79% and a median PFS of 12 months for patients treated at a 300 mg dosage in the combined analysis of WU-KONG 1A and WU-KONG 15 (32). Although the number of patients was small, the FDA granted breakthrough therapy designation to first-line sunvozertinib for Ex20ins NSCLC in April 2024. Similarly, Furmonertinib also showed a promising ORR of 79% in the first-line cohort of the FAVOUR study. WU-KONG28 (NCT05668988), FURVENT (NCT05607550) and REZILENT3 (NCT05973773) are ongoing phase 3 studies evaluating sunvozertinib monotherapy, furmonertinib monotherapy or zipalertinib in combination with pemetrexed plus carboplatin, respectively, against platinum-doublet chemotherapy as a first-line treatment for patients with NSCLC harboring EGFR exon20ins.

In summary, the development of treatments for Ex20ins is advancing very rapidly, with many promising agents now available, which was unimaginable a decade ago. However, for the NSCLC patients with classical EGFR mutations, median PFS of osimertinib monotherapy in FLAURA (37), osimertinib combined with chemotherapy in FLAURA 2 (38) and lazertinib combined with amivantamab in MARIPOSA (39) are 18.9, 25.5 and 23.7 months, respectively. This level of efficacy could be ideally achieved for Ex20ins as better agents will be developed in the future, considering the high oncogene-dependent nature of Ex20ins in general.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-907/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-907/coif). T.M. has received research funding from Boehringer Ingelheim, AstraZeneca, Taiho, Ono Pharmaceuticals, Merck Sharp & Dohme, Eli Lilly, Chugai Pharmaceuticals, and Bridge Biopharma. Additionally, he has received lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceuticals, Pfizer, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Merck Biopharma, Ono Pharmaceuticals, Amgen, and Daiichi-Sankyo. He also participated in advisory board of Regeneron, Bristol Myers Squibb, Janssen and Taiho. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

¹A767_V769dup, where dup is short for duplication, represents a change in amino acid sequence from …MASVDNPHV… to MASVASVDNP…. Please note that this mutation can also be described either as M766_A767insASV or V769_D770insASV. Be aware that all these three represent the same mutation and the Human Genome Variation Society recommends the first description.

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