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The FDA has granted a fast track designation to IN10018 as a potential therapeutic option for use in patients with platinum-resistant ovarian cancer.
The FDA has granted a fast track designation to IN10018 as a potential therapeutic option for use in patients with platinum-resistant ovarian cancer, according to an announcement from InxMed Co., Ltd.1
A potent and selective ATP-competitive FAK small molecule inhibitor, IN10018 is currently under development in the United States, as well as Australia, and China.
Early data with the agent showcased an acceptable toxicity profile with encouraging efficacy signals in several tumor types. It has also been demonstrated that these kinds of agents possess the potential to overcome fibrotic barrier and immune tolerance and can improve on the benefit observed with targeted therapy, chemotherapy, immunotherapy, and radiation. When paired with chemotherapy, the FAK inhibitor has demonstrated promising efficacy specifically in patients with platinum-resistant ovarian cancer.
“This is an important milestone for InxMed. IN10018 is one of our critical assets to fulfill our ‘Best-in-Disease Combination’ development strategy,” Zaiqi Wang, MD, PhD, chairman and chief executive officer of InxMed, stated in a press release. “We will leverage the advantage of fast track status and work closely with US FDA to speed up further clinical development. InxMed will fully accelerate global clinical development of IN10018 to better meet the patient’s needs.”
Previously, the combination of KRAS G12C inhibition with either sotorasib (Lumakras; formerly AMG 510) or MRTX849 and IN1001 was found to result in synergistic anticancer effects in several cancer cell lines, CDX, and PDX models of KRAS G12C–mutated cancers.2 Moreover, the combination was found to simultaneously decrease the extent of drug resistance.
Other findings from the research showed that the combination of either of the KRAS G12C inhibitors and IN1001 induced stronger anti–KRAS G12C–mutated cancer cell growth than when either agent was used alone. Moreover, by repressing FAK/YAP signaling, the FAK inhibitor enhanced the killing effects of the cancer cells that is observed with KRAS G12C inhibitors. Also, in a KRAS G12C inhibition resistance cell line, the downregulation of the FAK/YAP axis was found to potentiate cancer cell killing mediated by sotorasib.
Using KRAS G12C inhibition–sensitive CDX models of pancreatic cancer (Mia PaCa-2) and non–small cell lung cancer (NSCLC; NCI-H358), investigators set out to further examine the potential utility of sotorasib plus IN10018. In their experiments, they also evaluated both products as monotherapies and noted that the combination resulted in synergistic activity with respect to tumor growth inhibition.
Additionally, tumor regression was noted in the pancreatic cancer model with the double and sotorasib alone. As such, investigators stopped treatment dosing at day 12. Subsequently, tumor regrowth was observed to be delayed in the model that received the combination regimen vs the model that was given sotorasib alone.
In the lung cancer model, the doublet performed better than both agents as monotherapies with regard to inhibiting cancer growth.
In a KRAS G12C–resistant NSCLC CDX model (NCI-H2122 cell line), investigators noted that IN1001 again synergized with sotorasib for tumor growth inhibition without any abnormalities reported. Additionally, the tumors that received treatment with sotorasib were found to have elevated TAP signaling activity, as evaluated via YAP immunohistochemistry, which reinforced the findings from analyses of NCI-H1792 cells.
Investigators also examined the combination of KRAS inhibitors and IN1001 in 2 colorectal cancer PDX models (CO-04-0315 and CO-04-0070). The CO-04-0315 model was found to be relatively sensitive to 30 mg/kg-1 of sotorasib. Moreover, the doublet of sotorasib and IN1001 at 25 mg/kg-1 demonstrated stronger antitumor effects vs either of the agents alone. Notably, the mice tolerated the treatment well during the dosing period of the research.
However, in the second model, CO-04,0070, the vehicle control and the IN1001 at 25 mg/kg-1 groups were taken down on day 21 because of excessive tumor burdens. The group given sotorasib at 30 mg/kg-1 demonstrated persistent cancer growth, underscoring the impact of drug resistance to sotorasib. When dissecting tumor weights, investigators found that the tumors that received the combination regimen were significantly smaller than the ones that received single-agent sotorasib.
IN1001 is also under evaluation in combination with chemotherapy for patients with gastric cancer. In uveal melanoma and melanoma with a new biomarker, IN1001 is being evaluated in combination with targeted therapy.3 The agent is being investigated in combination with immunotherapy in patients with pancreatic cancer and those with NSCLC with a new biomarker. Moreover, IN1001 plus radiotherapy in being investigated preclinically as a potential therapeutic approach in head and neck cancer.