Singularity Cake
In February, the latest statistics from the National Cancer Center of China showed that up to 816,000 people are diagnosed with lung cancer (17.9% of all cancers) and 715,000 people die from lung cancer (23.8% of all cancers) each year in China, both ranking first among all cancers [1].
In recent decades, targeted therapies have rewritten the treatment paradigm for non-small cell lung cancer (NSCLC), and as NGS assays continue to innovate, new rare mutations are increasingly being diagnosed. EGFR exon 20 insertional mutations (EGFR exon20ins) are one such mutation.
Although EGFR exon20ins account for only 2% of all NSCLC, due to the large population base, more than 10,000 new lung cancer patients still carry this mutation each year, with a higher prevalence especially in women, non-smokers and Asians [2].
EGFR-TKIs (e.g., gefitinib, afatinib, oseltinib, etc.), a precision-targeted tool for the treatment of lung cancer, are effective in patients with EGFR-sensitive mutation-positive NSCLC, but have nothing to offer to EGFR exon20ins. The reason behind this is that the above drug molecules are difficult to bind effectively to the structural domain encoded by exon 20, so the clinical effect is even inferior to that of pemetrexed + platinum-based chemotherapy or chemotherapy combined with bevacizumab [3].
This results in an extremely alarming prognosis and survival status for patients with EGFR exon20ins, with a 75% increased risk of death, 93% increased risk of disease progression or death, and a five-year survival rate of only 8% compared to EGFR-sensitive mutations [4], with a median survival of only half that of EGFR-sensitive mutation types (16.5 months V.S. 33 months). Even more chilling is that immunotherapy, which has been killing in other tumor fields, is also ineffective against EGFR exon20ins, with poor results [5-7]. It is easy to see that such patients are in urgent need of effective treatments.
Recently, a research team led by Mengzhao Wang of Peking Union Medical College Hospital, Chih-Sin Yang of National Taiwan University School of Medicine, and Pasi A. Jänne of the Dana-Farber Cancer Institute, affiliated with Harvard Medical School, published in the prestigious journalCancer DiscoveryThe important research results were published in [8].
They explored the clinical activity of Sunvozertinib (DZD9008), an oral, potent, irreversible and selective tyrosine kinase inhibitor of EGFR exon20ins. From the results of this early study, the overall population objective remission rate (ORR) was 41.1% [8]. This finding gives new hope to patients with EGFR exon20ins mutations.
Screenshot of thesis home page
Those who follow EGFR exon20ins must know that the US FDA approved Mobocertinib and Amivantamab successively in 2021 for the treatment of adult NSCLC patients with EGFR exon20ins.
However, clinical data show that Amivantamab has an objective remission rate of only 40% [9-10], compared to 28% for Mobocertinib [11], and that 40% of patients treated with Mobocertinib inevitably developed grade 3 and higher side effects, and 21% developed severe diarrheal symptoms of grade 3 and higher that leading to intolerance and discontinuation of the drug [12-13]. Although Mobocertinib and Amivantamab have brought a new light to the treatment of EGFR exon20ins, the less-than-optimal disease remission rates and high incidence of grade 3 and above side effects leave the clinical need for EGFR exon20ins far from being met.
Sunvozertinib, developed with oseltinib as a backbone, is expected to bring new hope to EGFR exon20ins. From the preclinical laboratory data of Sunvozertinib: in A431 cell line, Sunvozertinib showed 1.4-9.6-fold selectivity for EGFR exon20ins compared to wild-type EFGR, and the three subtypes insASV/insSVD/insNPH in particular showed 2.5-3.1-fold of high selectivity [8].
Since the protein structure of EGFR exon20ins mutant is similar to that of wild-type EGFR after conformational changes, targeted drugs inhibiting the mutant protein may also bind and inhibit wild-type EGFR protein in normal cells [14], and high selectivity can avoid dose-limiting toxicity and reduce the incidence of side effects to some extent.
In addition, in a transgenic rat model of EGFR exon20ins (ins ASV subtype), Sunvozertinib also showed better anti-tumor effects compared to the blank control (**P < 0.01). Even if the laboratory data is good, it is only the first step of a long journey.
It was based on the above preclinical study data that the research team led by Mengzhao Wang and others initiated the early clinical study.
During the July 9, 2019-April 3, 2021 study period, researchers enrolled a total of 102 NSCLC with EGFR or HER2 20 exon insertional mutations at 25 centers worldwide (WU-KONG1 study was conducted at 17 centers in the United States, Australia, Korea and Taiwan, China; WU-KONG2 study was conducted simultaneously at 8 centers in mainland China) patients, 62 of whom (60.8%) had EGFR exon20ins, all of whom had received prior treatment in line 2 or higher, including those who had been previously treated with Amivantamab and those with baseline brain metastases.
In the trial population, Sunvozertinib was administered once daily in a dose range of 50-400 mg for the dose-escalation cohort and 200-400 mg for the dose-expansion cohort, with an optimal tolerated dose of 400 mg.
Sunvozertinib Phase I/II clinical trial design
In these two ongoing clinical studies (WU-KONG1 and WU-KONG2), 56 patients carrying EGFR exon20ins were included in this analysis.
Overall, Sunvozertinib treatment doses ≥100 mg/dose were effective in patients with different subtypes, with an overall population objective remission rate (ORR) of 41.1% and a definitive objective remission rate (C-ORR) of 37.5%. In particular, in the 300 mg dose group, where the proportion of patients with baseline brain metastases was as high as 49%, the ORR reached 48.4%, the C-ORR 41.9%, and the disease control rate (DCR) 90.3%, significantly outperforming the efficacy of other commercially available EGFR TKIs [8].
Sunvozertinib remission rates in 56 patients with different dose cohorts of EGFR exon20ins
Notably, Sunvozertinib also demonstrated preliminary anti-tumor effects in some patients with double mutations in EGFR T790M and HER2 exon20ins, warranting in-depth studies in larger samples in the future.
Clinical results of Sunvozertinib in 56 patients with EGFR exon20ins
In terms of safety, the overall tolerability of the patients was good and the adverse effects were manageable. Among the common adverse reactions were diarrhea and rash, with grade 3 or higher adverse reactions being diarrhea (4.9%) and no grade 3 or higher rash reactions occurring. Sunvozertinib demonstrated a lower incidence of permanent discontinuation, dose reduction, and grade ≥3 side effects due to drug-related adverse events compared with afatinib, daclotinib, and Mobocertinib [15-16]
In terms of pharmacokinetics, blood concentration is positively dependent on dose and has a half-life of about 50 hours in humans, which can be maintained with once daily dosing. The PK curve is gentle, and the difference between peak and trough concentrations is small, which helps to reduce the incidence of adverse reactions caused by high fluctuations in peak drug concentrations. In addition, the results of the food effect test showed that there was no clinically significant effect on drug metabolism with or without meals.
Based on the above data, it is easy to see that Sunvozertinib has good safety, tolerability, PK/PD correlation and preliminary efficacy, and has the potential to become a new, more effective targeted oral drug, which provides a basis for its further clinical development.
However, there are some limitations to this study, such as: the anti-tumor activity observed in patients with baseline brain metastases, the assessment did not include intracranial lesions as a target parameter, and the effect of treating brain metastases may not be significantly different from that of the same dose of oseltinib, and future studies will be necessary to confirm this finding. In addition, if Sunvozertinib can significantly outperform Amivantamab and Mobocertinib in the subsequent publication of gold metric data for PFS and OS, then a smooth launch and early benefit to patients is really in sight.
