oritinib (SH-1028)

As of August 23, 2023, the first generation EGFR-TKIs, gefitinib, icotinib, and erlotinib; the second generation EGFR-TKIs, afatinib and dacomitinib; and the third generation EGFR-TKIs, osimertinib, almonertinib, furmonertinib and befotertinib were all approved for marketing by China National Medical Products Administration (NMPA). In addition, multiple domestic third-generation EGFR-TKIs are undergoing clinical trials, such as rezivertinib (BPI-7711), limertinib (ASK120067), and oritinib (SH-1028). Meanwhile, mobocertinib and sunvozertinib, which targets EGFR 20ins mutations, were also approved by NMPA. With the increasing variety of EGFR-TKIs approved for marketing subsequently, it brings confusion to clinicians when choosing specific medications, and there is an urgent need to develop relevant treatment guidelines. Hence, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists convened experts to integrate the research results of various EGFR-TKIs, and proposed the "China clinical practice guideline for epidermal growth factor receptor tyrosine kinase inhibitors in stage Ⅳ non-small cell lung cancer (version 2023)", to provide reference for better clinical practice.

P3, N=242, Recruiting, Nanjing Sanhome Pharmaceutical, Co., Ltd.

A phase I drug-drug interaction study in healthy volunteers was performed to evaluate the impact of co-administering rifampicin (a strong CYP3A4 inducer) and itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of SH-1028. In the clinical application of SH-1028, special attention should be paid to the interaction between SH-1028 and drugs or foods that affect the activity of CYP3A4. (Clinical trial registration number: CTR20210558).

After multiple-dose administration, SH-1028 exhibited a slight accumulation, with a mean accumulation ratio (R) of 2.00.4. The study assessed the PK properties of SH-1028 following single and multiple doses in patients with advanced NSCLC and would provide meaningful information for the further development of SH-1028.

Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non-small cell lung cancer accounts for approximately 85% of lung cancer. First- or second-generation EGFR TKIs' weak selectivity often led to the occurrence of treatment-related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year. A dose of 200 mg of SH-1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation.

No abstract available

SH-1028 is efficacious and tolerable in second-line treatment of advanced NSCLC patients with positive EGFR T790M.

No interstitial lung disease were reported. Conclusions Oritinib demonstrated potential clinical benefit and tolerable in advanced NSCLC patients with EGFR T790M mutation.

Conclusion Oritinib demonstrated potential clinical benefit in advanced NSCLC patients with EGFR T790M mutation following prior therapy with EGFR TKIs. The phase II study (n=220 patients) is ongoing to confirm these findings.

Both SH-1028 and osimertinib have a pyrimidine structure (a typical mutant-selective EGFR TKI structure). The main metabolite of SH-1028, Imp3, was tested and showed no wild-type EGFR inhibition or off-target effects. In conclusion, SH-1028 is a new third-generation EGFR inhibitor that exhibits potent activity against EGFR sensitive and resistant (T790 M) mutations.

In this review, we profiled many of the third-generation EGFR TKIs in late stage clinical development (e.g. almonertinib, lazertinib, alflutinib, rezivertinib, ASK120069, SH-1028, D-0316 and abivertinib) of their interim results of phase 1-3 trials and their chemical structures when publicly available. Additionally, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, maverlertinib) including phase 3 results of rociletinib and naquotinib. We further profiled the next-generation combination clinical trial design of third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704) and ACROSS2 (NCT04500717).

P3, N=240, Not yet recruiting, Nanjing Sanhome Pharmaceutical, Co., Ltd.