With the development of KIT mutation and KIT tyrosine kinase inhibitor imatinib (GlivecTM, Novartis), survival of patients with advanced and/or metastatic gastrointestinal stromal tumor (GIST) has significantly improved. Recently, sunitinib (SuteneTM, Pfizer) and regorafenib (StivargaTM, Bayer) have been proven to be effective as second- and third-line treatment, respectively in GIST patients who failed to imatinib treatment. However, almost all patients eventually experience disease progression due to the development of drug resistance to first-line imatinib, second-line sunitinib treatment, and third-line regorafenib. As a fourth-line treatment, ripretinib was proven to prolong progression-free survival as compared to placebo with a median progression-free survival of 6.3 months in the Phase 3 INVICTUS study. However, ripretinib is not available in many regions including Korea, making it difficult to use. Therefore, a new treatment options are needed in the clinical setting post-imatinib, sunitinib and regorafenib.

Historic data suggest that GISTs do not respond to conventional cytotoxic chemotherapy, but systematic unbiased screening has not been performed. A recent large-scaled chemotherapy susceptibility screening with GIST cells showed that among a total of 89 chemotherapies, 37 have anti-cancer effect in at least one type of GIST cells. It was suggested that of these agents, transcriptional inhibitors and chemotherapies such as topoisomerase II, paclitaxel, and bortezomib would be effective. Based on these results, our group has recently performed a phase II study for evaluating efficacy and safety of paclitaxel in patients with advanced and/or metastatic GIST after failure of at least imatinib and sunitinib. Although paclitaxel showed overall limited anti-tumor efficacy, it was more effective in patients with low P-glycoprotein expression. Based on these study results, it was hypothesized that paclitaxel would also be effective in GIST patients, and a phase II study was conducted to evaluate the efficacy and safety of paclitaxel in 25 patients with advanced and/or metastatic GIST who failed imatinib and sunitinib treatment. At week 16, the disease control rate (DCR; response + stable lesion) was 16.7%, showing a limited anticancer effect. However, in patients with a low level of P-glycoprotein expression, the DCR was 25% at 16 weeks, suggesting that paclitaxel may be efficacious in this clinical setting. Subsequently, a phase II clinical trial of paclitaxel is currentl ongoing in patients with metastatic or progressive GIST with low P-glycoprotein expression who have failed imatinib, sunitinib, and regorafenib treatment in patients with a low P-glycoprotein expression level. However, data from Asan Medical Center suggest that only about 20% of GISTs have a low P-glycoprotein expression level (IHC score 3 points or less) in this clinical setting.

P-glycoprotein is a plasma membrane protein that acts as an efflux pump for drugs and is implicated in multidrug resistance. In particular, hydrophobic chemotherapeutic agents such as paclitaxel are known to be substrates of P-glycoprotein, supporting the concept that GIST patients with high P-glycoprotein expression may be resistant to paclitaxel. This raise the possibility that paclitaxel-based combination treatment may be considered when the function of P-glycoprotein is inhibited.

Ricoveranib is a mutikinase inhibitor with anti-angiogenic activity. In a phase 3 study conducted in China, rivoceranib improved overall survival compared to placebo as a 3rd-line treatment for metastatic gastric cancer. In addition, an improvement in progression-free survival compared to placebo was confirmed in the multinational phase 3 ANGEL study. Recently, the combination therapy of rivoceranib and camrelizumab, an immune checkpoint inhibitor, in unresectable liver cancer has been proven to improve survival results compared to sorafenib. When it comes to the treatment of GIST, the anti-angiogenic activity and inhibition of P-glycoprotein by rivoceranib suggest its potential use in GIST patients. In particular, when used in combination with paclitaxel in GIST whose P-glycoprotien expression level is high, rivoceranib is expected to have an additional or synergistic anti-tumor activity. In a phase 1 clinical study of metastatic gastric cancer, the combination therapy of rivoceranib and palclitaxel was confirmed to be safe as well as showing clinical efficacy. The recommended dose for phase 2 study was rivoceranib 400mg and paclitaxel 80mg/m2 (days 1,8 and 15, 4-week cycle).

The objective of this study is to evaluate the safety and efficacy of paclitaxel in combination with rivoceranib in patients with metastatic or advanced GIST with a high P-glycoprotein expression level after failure of at least imatinib, sunitinib and regorafenib.