FDA Grants Breakthrough Therapy Designation to First-Line Sunvozertinib for EGFR Exon 20+ NSCLC

The FDA has granted breakthrough therapy designation to sunvozertinib (DZD9008) as frontline treatment for patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) whose disease harbors an EGFR exon 20 insertion mutation, according to a news release.¹

The breakthrough therapy designation is based on results from the global, multi-center, phase 1/2 WU-KONG1 trial (NCT03974022). Findings from the study, which were presented at the 2023 ESMO Congress with median follow-up of 10.8 months, showed a confirmed objective response rate (ORR) of 78.6% and a median progression-free survival (PFS) of 12.4 months for patients treated in the first line with the 300-mg dose of sunvozertinib (n = 9).^1,2

“We are delighted with the FDA’s decision granting the breakthrough therapy designation to sunvozertinib for first-line treatment, coming on the heels of earlier breakthrough therapy designation approval in later lines of therapy––a clear indication of sunvozertinib’s transformative potential in the treatment of patients with EGFR exon 20 insertion [mutation–positive] NSCLC,” Xiaolin Zhang, PhD, chief executive officer of Dizal Pharma, stated in the press release._¹ “Multiple clinical trials have consistently demonstrated sunvozertinib’s significant clinical benefits to our patients. As a single, oral agent, it offers apparent advantages in both safety and patient compliance over chemotherapies and infusion.”

Affecting up to 4% of patients with NSCLC, EGFR exon 20 insertion mutations pose challenges for treatment due to their unique spatial conformation, diverse subtypes, and high heterogeneity. Sunvozertinib’s innovative molecular structure aims to address these unmet needs in treatment.¹

Notably, the agent previously received breakthrough therapy designation from both the FDA and the Center for Drug Evaluation in China for the treatment of patients with relapsed/refractory EGFR exon 20–mutant NSCLC.3 In 2023, sunvozertinib was approved in China for patients who progressed on first-line treatment. New drug application submissions for United States and European Union approvals are anticipated in the same setting later in 2024, the press release reported.¹

Sunvozertinib’s approval in China was supported by data from the phase 2 WU-KONG6 study (NCT05712902; CTR20211009). In the trial sunvozertinib elicited a 60.8% confirmed ORR in patients with advanced NSCLC with EGFR exon 20 insertion mutations following platinum-based chemotherapy. The agent also demonstrated efficacy across various subtypes, including patients with HER2 exon 20 insertion mutations.¹

In the WU-KONG1 study, investigators are evaluating sunvozertinib in patients with previously treated and treatment-naive EGFR exon 20 insertion mutation–positive NSCLC. The inhibitor was administered orally at 200 mg or 300 mg daily until discontinuation criteria were met.²

The primary outcome measures of the study are safety and tolerability and ORR per RECIST v1.1 criteria. The plasma concentration of sunvozertinib will be evaluated as a secondary end point.²

Regarding safety (n = 57), the most common grade 3 or greater drug-related, treatment-emergent adverse effects (TEAEs) were blood creatine phosphokinase increase (17.5%), diarrhea (7%), lipase increase (5.3%), anemia (5.3%), QT prolongation (3.5%), and amylase increase (3.5%), which were all clinically manageable and reversible. Two patients had a dose reduction and 4 had a discontinuation due to drug-related TEAEs.²

Furthermore, in the data presented at the 2023 ESMO Congress, which also included patients enrolled in the phase 2 WU-KONG15 trial (NCT05559645), the median duration of response was not reached for patients treated with the 300-mg dose. Moreover, 50% of responders who received the 200-mg or 300-mg dose were still undergoing treatment. Furthermore, 100% of patients achieved tumor shrinkage and tumor response was seen in a variety of EGFR exon 20 insertion mutation subtypes.²

“Now enrollment for the global pivotal study in [the] relapsed and refractory setting (WU-KONG1 part B) has been completed, and we are going to report the study results as an oral presentation at the 2024 ASCO Annual Meeting. A randomized, global, phase 3 study in the first-line setting (WU-KONG28 [NCT05668988]) is well underway. This new breakthrough therapy designation will enable us [to] work more closely with the FDA and accelerate its clinical development and regulatory submission,” Zhang noted.¹

References

1. FDA grants breakthrough therapy designation to sunvozertinib for the first-line treatment of patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations. News Release. Dizal Pharma. April 7, 2024. Accessed April 8, 2024. https://www.dizalpharma.com/news/detail?id=70&search=&currentPage=1
2. Yang JCH, Wang M, Chiu CH, et al. Sunvozertinib as first-line treatment in NSCLC patients with EGFR exon20 insertion mutations. Ann Oncol. 2023;34(suppl 2):S765. doi:10.1016/j.annonc.2023.09.2358
3. FDA grants breakthrough therapy designation for Dizal Pharmaceutical’s DZD9008 in patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR exon20 insertion. News release. Dizal Pharmaceutical Co. Ltd. January 28, 2022. Accessed April 8, 2024. https://www.dizalpharma.com/news/detail?id=19