Sunvozertinib (DZD9008), an oral, irreversible EGFR tyrosine kinase inhibitor specifically designed to target EGFR exon 20 insertion mutations, has demonstrated encouraging clinical activity in heavily pretreated non-small cell lung cancer (NSCLC) patients, according to results from two ongoing phase I studies.
Clinical Trial Results Show Meaningful Activity
In a pooled analysis of 102 patients from the WU-KONG1 and WU-KONG2 studies, sunvozertinib achieved a confirmed objective response rate (ORR) of 37.5% among 56 evaluable patients with EGFR exon 20 insertion mutations. The best ORR reached 41.1% across all dose levels, with partial responses observed at doses of 100 mg and higher.
At the recommended phase II doses of 200 mg and 300 mg once daily, the confirmed ORRs were 45.5% and 41.9%, respectively. In the dose-expansion cohorts, the best and confirmed ORRs were 47.4% and 44.7%, respectively, across the 200-400 mg dose range.
The median duration of response exceeded 3.5 months and had not been reached at the data cutoff, with the longest duration of response extending beyond 8 months. Notably, 65.2% of responding patients were still receiving treatment and maintaining their response at the time of analysis.
Improved Safety Profile Compared to Existing Options
Sunvozertinib demonstrated a more favorable safety profile compared to other approved EGFR exon 20 insertion inhibitors. While diarrhea occurred in 53.9% of patients overall, only 4.9% experienced grade 3 or higher diarrhea, substantially lower than the 21% rate reported with mobocertinib in its pivotal phase II study.
Rash affected 40.2% of patients, but no patients experienced grade 3 or higher rash. The maximum tolerated dose was established at 400 mg once daily, though this dose was not selected for future development due to the high rate of dose reductions required.
Dr. Sandip P. Patel noted that for patients with exon 20 insertion mutations who are refractory to platinum-based chemotherapy, current standard-of-care options include carboplatin-pemetrexed, mobocertinib, or amivantamab, which is a bispecific antibody against EGFR and MET.
Activity Across Multiple Patient Subgroups
The drug showed antitumor efficacy across different EGFR exon 20 insertion subtypes, with more than 39 distinct subtypes reported in NSCLC. Importantly, partial responses were observed in patients with baseline brain metastases and in those who had received prior amivantamab treatment, suggesting potential utility in previously treated populations.
The study enrolled heavily pretreated patients, with a median of three prior lines of therapy, and 91.2% had received at least one line of prior chemotherapy. Among four patients who had received prior amivantamab treatment, two achieved partial responses.
Pharmacokinetic Properties Support Once-Daily Dosing
Sunvozertinib exhibited dose-proportional pharmacokinetics across the 50-400 mg dose range, with a half-life of approximately 50 hours enabling once-daily dosing. The drug showed approximately 3-fold accumulation after repeat dosing compared to single dosing, reaching steady state within 15 days.
At doses of 200 mg and higher, plasma concentrations consistently exceeded the IC50 values for the majority of EGFR exon 20 insertion subtypes, supporting the rationale for the selected dose levels in expansion cohorts.
Addressing an Unmet Medical Need
EGFR exon 20 insertion mutations comprise approximately 2% of NSCLC cases but have historically been challenging to treat effectively. With available therapies such as platinum-based chemotherapy, patients typically achieve median progression-free survival and overall survival rates of only around 6 months and 24 months, respectively.
The recent approvals of amivantamab and mobocertinib have provided new options, but with objective response rates of approximately 40% and 28%, respectively, and significant toxicity concerns with mobocertinib, there remains room for improvement in treating this patient population.
Based on these encouraging results, sunvozertinib has received Breakthrough Therapy designation from the FDA for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
