Sunvozertinib Showcases Early Safety, Efficacy in EGFR Exon 20–Mutated NSCLC

D. Ross Camidge, MD, PhD

Sunvozertinib (DZD9008) elicited promising responses as a second- or later-line treatment in patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to D. Ross Camidge, MD, PhD, who added that further investigation is needed to explore the long-term benefits of the agent, its central nervous system (CNS) activity, and how it performs in a Western population.

Data from the phase 2 WU-KONG6 trial (CTR20211009) presented at the 2022 ESMO Congress showed that patients who received sunvozertinib at 300 mg daily (n = 97) achieved an overall response rate (ORR) of 59.8%. In patients with pretreated baseline CNS metastases (n = 31), the ORR achieved with the agent was 48.4%.

Camidge added that sunvozertinib must be evaluated in patients with untreated brain metastases to fully understand its CNS activity. Since the longest duration of response (DOR) was more than 9.7 months and the median DOR was not reached, he added that further follow-up is required to assess the durability of the agent.

“Because [sunvozertinib] is a drug largely developed in China until recently, it has been flying under the radar,” said Camidge, who is the director of the Thoracic Oncology and Clinical Research Programs at the University of Colorado Anschutz Medical Campus in Aurora, Colorado. “When we list the drugs in development [for EGFR exon 20 insertion [mutations], we sometimes miss out on [sunvozertinib]. However, [the agent] should be on everyone’s list of things to keep an eye on.”

In an interview with OncLive^®, Camidge discussed the potential utility of sunvozertinib in patients with NSCLC harboring EGFR exon 20 insertion mutations, the efficacy and safety data observed with the agent, and future research directions.

OncLive^®: Could you provide background on sunvozertinib and the WU-KONG6 trial?

Camidge: [At the congress,] we discussed recent updates with a new drug called sunvozertinib, which is an inhibitor of EGFR exon 20 insertions. These are not your classical EGFR mutations; [these] are rare, [and they] are traditionally resistant to most of our standard therapies. [WU-KONG6] was largely conducted in China, but it [has] a big dataset.

What was unique about the patient population evaluated in the trial?

[This trial enrolled] patients who had locally advanced or metastatic NSCLC and a centrally confirmed EGFR exon 20 insertion mutation. All patients received prior platinum-based chemotherapy. [Data presented at ESMO involved patients who] were dosed with what is going to be the recommended phase 2 dose of sunvozertinib, [which is] 300 mg once per day. There were data on 97 patients, and we have provocative information in terms of who the drug works in, response, and tolerability.

[Tolerability] has been a challenge for this whole class of [inhibitors]. The reason it has been a challenge is the EGFR exon 20 insertion structure looks similar to the wild-type form of EGFR. It is difficult to [develop] a drug that does not give patients terrible diarrhea and a rash, yet still has efficacy. Sunvozertinib seems to be threading that needle.

Please expand on the efficacy achieved with sunvozertinib in this patient population.

Patients [received] enough of the drug for long enough that they were [experiencing] objective responses. With some of the other drugs that are failing in this class, it is hard to get patients to maintain a dose high enough because of that EGFR wild-type mutation and that thin therapeutic window.

Patients achieved an ORR of 59.8% by a blinded, independent radiology review committee, which is good. However, there are not a lot of data in terms of [DOR]; investigators talked about the median DOR not being reached, but the longest [DOR] in a single patient was more than 9.7 months.

We do not have PFS data, and we do not have a mature median DOR. All we [currently] have is a confirmed ORR.

What was found in patients who had brain metastases at baseline?

The ORR was 48.4% in [31] patients with baseline brain metastases. If you are not careful, that can sound like a CNS response rate, which would be awesome. The trouble is, that it is not [a CNS response rate].

To get into this study, patients had to have treated or absent brain metastases. We know that none of those brain metastases could be evaluable for response. Therefore, the 48.4% ORR is mostly an extracranial response rate, and it is telling you that it is not an overt liability to have had prior treatment for brain metastases. It is not the same thing as showing that [sunvozertinib]has CNS [activity].

Investigators did show an MRI of a CNS lesion, apparently getting smaller, but if that patient had [received] previous radiotherapy, what does that tell us? We must take this apparent CNS activity with a grain of salt and understand that there are proper ways to [evaluate this kind of activity]. [To properly measure this], patients must have untreated and measurable CNS lesions, then have MRIs [to measure] CNS response rate and CNS DOR. We do not have that yet.

Did the location of the EGFR exon 20 insertion mutation affect the efficacy of sunvozertinib?

There are multiple EGFR exon 20 insertion [mutations], and the nice thing is that sunvozertinib seems to work regardless [of the location of the mutation]. There were waterfall plots for near-loop or far-loop insertions [and similar ORRs were observed for both types].

What adverse effects (AEs) were observed in patients who received treatment with sunvozertinib at 300 mg daily?

For [EGFR exon 20 insertion inhibitors], you must look toxicity in the face. If we cannot maintain the dose of the drug because we are inhibiting EGFR wild-type, then we will not maintain efficacy.

However, of the AEs we have seen, [sunvozertinib appears to be tolerable]. Grade 3 [or higher AEs at the 300-mg dose] included diarrhea in 7.3% of patients and rash in 2.8% of patients. Other [grade 3 or higher] AEs included paronychia [at 1.7%] and nausea [at 1.1%]. [Notably, 20.2% of] patients needed a dose reduction at 300 mg, which is, in clinical studies, about the same as [what is seen with] ALK inhibitors.

We appear to have a drug that, unlike many in its class, is tolerable—at least with the degree of follow-up that we have in this study. At the levels that we are achieving tolerability, sunvozertinibis effective. However, [we need to] know how long that efficacy is going to last.

What next steps will be taken with this research?

Studies [need to] include Western patients. These [efforts] are ongoing, [including the phase 1/2 WU-KONG1 trial (NCT03974022)]. I contributed to some of those studies myself, and we will need to see that these signals are robust in terms of tolerability and efficacy. We will need to see the duration of benefit [with the agent]. With long-term follow-up [of WU-KONG6], we will also need to see whether any of those AEs change.

If we start flirting with the idea that there is a CNS signal, we need to generate those data in an appropriate way [by investigating the agent] in patients with untreated measurable CNS lesions and generating a CNS-based end point.

Reference

Wang M, Yang JC-H, Mitchell P, et al. Sunvozertinib for NSCLC patients with EGFR exon 20 insertion mutations: Preliminary analysis of WU-KONG6, the first pivotal study. Ann Oncol. 2022;33(suppl 7):S1003-S1004. doi:10.1016/j.annonc.2022.07.1114