Tinengotinib Elicits Clinical Benefit in Pretreated Cholangiocarcinoma and Other Advanced Solid Tumors

Sanjay Goel, MD, MS

The use of tinengotinib (TT-00420) monotherapy was well tolerated and displayed signs of antitumor activity in patients with advanced, heavily pretreated solid tumors, according to data from a phase 1b/2 trial (NCT04742959) presented at the 2023 ASCO Annual Meeting.

The phase 1b/2 trial evaluated patients with pretreated solid tumors, including prostate cancer, hormone receptor (HR)–positive/HER2-negative breast cancer, triple-negative breast cancer (TNBC), and cholangiocarcinoma. Of patients evaluable for efficacy in the monotherapy arms (n = 124), the best overall response rate (ORR) was 14.5% with a disease control rate of 64.5%. The clinical benefit rate was 25% in this population.

In evaluable patients with cholangiocarcinoma (n = 17), the ORR was 17.6%. Among those with FGFR-altered cholangiocarcinoma (n = 5), the ORR was 40%. Notably, 4 of 5 patients with FGFR-altered cholangiocarcinoma received prior treatment with a FGFR inhibitor.

Among patients with prostate cancer (n = 10), HR-positive/HER2-negative breast cancer (n = 6), and TNBC (n = 8), the best ORR was 50%, 33.3%, and 37.5%, respectively.

In arm B, 5 patients received treatment with tinengotinib in combination with nab-paclitaxel (Abraxane), and 2 patients achieved stable disease (SD).

No new safety signals were reported in the monotherapy arms, and no dose-limiting toxicities occurred in the combination arm.

“Although several FGFR inhibitors have already been approved [for patients with cholangiocarcinoma], that should not stop the effort of making the next generation [of treatments] that can overcome resistance mechanisms to continue to help these patients. A drug such as [tinengotinib] would serve as a good example of such an effort,” study co-author Sanjay Goel, MD, MS, explained.

In an interview with OncLive^®, Goel, a medical oncologist, director of Phase I / Investigational Therapeutics, and a professor of medicine in the Division of Medical Oncology and Section of Solid Tumor at Rutgers Robert Wood Johnson Medical School and Rutgers Cancer Institute of New Jersey in New Brunswick, expanded on the findings from the phase 1b/2 trial, noting the potential benefit this approach may have for patients with cholangiocarcinoma, and detailed next steps for investigating tinengotinib.

OncLive: What is the mechanism of action of tinengotinib?

Goel: Tinengotinib is a small molecule inhibitor, and it essentially inhibits multiple tyrosine kinases. It is called a spectrum-selective multi-kinase inhibitor. Among its most common targets, it inhibits Aurora kinase A/B, JAK, and, I would say most importantly, multiple receptor tyrosine kinases that include FGFRs and VEGFRs. Essentially, by inhibiting all these kinases, [tinengotinib] targets cell proliferation, angiogenesis, and the immune-oncologic pathways.

What was observed previously with this agent in patients with prostate cancer, HR-positive/HER2-negative breast cancer, TNBC, and cholangiocarcinoma from a phase 1 trial (NCT03654547)?

Considering it was a phase 1 trial, it was actually a very large study. Previously, preliminary data that showed efficacy in prostate cancer, HR-positive/HER2-negative breast cancer, TNBC, and cholangiocarcinoma. Based on [findings from] that phase 1 trial, it was decided to launch this phase 1b/2 study in [patients with] multiple [types of] solid tumors.

Could you expand on the design of the phase 1b/2 trial?

[The phase 1b/2 trial] was essentially divided into 3 different arms. In arm A, [tinengotinib] was given as a monotherapy, and the doses were fixed at 12 mg [per day in continuous 28-day cycles]. Arm B was specifically for patients with [HER2-negative] breast cancer, and [tinengotinib at 8 mg, 10 mg, or 12 mg per day] was combined with a commonly used chemotherapy drug, nab-paclitaxel. Arm C was also a monotherapy arm, but one of the main objectives was to collect extensive pharmacokinetic information. It was divided as either a once-a-day dose, ranging from 5 mg to 12 mg daily, or it was twice-a-day dosing, either at 4 mg or 6 mg.

Overall, [this study had] standard entry criteria for a phase 1 trial. Patients were adults [who received] standard therapy prior to study entry. They needed to have at least 1 measurable lesion, a reasonable performance status, and reasonable organ function.

What efficacy findings from this trial were presented at the 2023 ASCO Annual Meeting?

Overall, there were 124 patients who were eligible for response assessment. Among them, the ORR was 14.5%, with 18 of the 124 patients [achieving] a partial response [PR]. Overall, 64.5% of patients had what is called disease control, meaning that they had either a response or SD. Clinical benefit, which was defined as patients who had a complete response [CR], a PR, or SD that lasted more than 6 months, was observed in 25% of patients.

What is interesting is that these responses were seen across a wide range of tumor types. Not surprisingly, cholangiocarcinoma was one of them, [along with] patients with prostate cancer, HR-positive/HER2-negative breast cancer, and TNBC. Other tumor types where benefit was seen were ovarian cancer, squamous cell cancer of the oropharynx, fallopian tube cancer, urothelial cancer, cervical cancer, bladder cancer, and multiple other tumor types, including colorectal cancer and lung cancer, which are very common cancers.

Lastly, if one looks at patients with cholangiocarcinoma, of which 17 were enrolled and eligible for response evaluation, 3 patients, or 17.6%, had [a PR]. Furthermore, 5 of these patients had a FGFR alteration, which is not very common, but this is something of importance in cholangiocarcinoma because there are drugs approved to use in these patients. Two of these 5 patients, meaning 40%, had a response. Even more interesting, 4 of these 5 patients had received prior FGFR[-targeted] therapy. For patients with cholangiocarcinoma, even though they may have been exposed to a previous FGFR-targeted drug, [tinengotinib] could still provide potential benefit.

What safety findings have been reported with tinengotinib?

This is a typical TKI, and since it targets multiple kinases, there are common treatment-related adverse effects [TRAEs] that are expected with these drugs. Overall, 74% of patients in the monotherapy group [n = 172] experienced [any-grade] TRAEs. The good news is that [36.6%] were grade 1 or 2, 36% were grade 3, and only 1.2% were grade 4. [The patients with grade 4 TRAEs experienced] perforation of the large intestine, increased alanine transaminase, and increased aspartate transaminase. The good news was that no treatment-related deaths were reported.

The most common TRAEs seen in more than 10% of all patients [in the monotherapy arms] included hypertension [32%], stomatitis [22.1%], diarrhea [16.3%], palmar-plantar erythrodysesthesia syndrome [14%], nausea [12.8%], and fatigue [10.5%].

In the combination group with chemotherapy [n = 5], as expected, there was more myelosuppression. Neutropenia was seen in 60% [of patients], and stomatitis [occurred] in 60% [of patients]. Hypertension, hyponatremia, and hypokalemia [were observed] in 40% [of patients]. Of note, there was 1 death reported from a pulmonary hemorrhage, but that was not considered related to the study drug.

Overall, there was nothing surprising. TKIs do have a wide spectrum of AEs, and this essentially just showed the same thing again.

What are some of the next steps for investigating tinengotinib? Will any specific tumor types be the focus?

The activity seen in cholangiocarcinoma is very encouraging. Cholangiocarcinoma is a prime example [for the use of] FGFR-targeted therapy, where there are several drugs now approved. One of the next steps for [tinengotinib] is a [planned] phase 3 trial in patients with cholangiocarcinoma, especially those with an FGFRalteration, typically a gene fusion.

The phase 2 component of the ongoing trial will continue for patients with prostate cancer. What is most exciting is the fact that patients with cholangiocarcinoma who had previously been exposed to FGFR inhibitors did respond to this drug. This is where [tinengotinib] holds the greatest promise, but ultimately, it will all depend on how the phase 3 trial performs.

This trial highlights that even though we may not have a lot of mutations or gene alterations in a certain tumor type—for example, in intrahepatic cholangiocarcinoma, FGFR fusions are only found in about 10% to 15% [patients]—a concerted effort has shown that if you come together as a community and focus on a tumor type such as cholangiocarcinoma, which has not had very good treatment options, we can improve the outcomes of these patients.

Reference

Piha-Paul SA, Goel S, Liao C-Y, et al. Preliminary safety and efficacy of tinengotinib tablets as monotherapy and combination therapy in advanced solid tumors: A phase Ib/II clinical trial. J Clin Oncol. 2023;41(suppl 16):3019. doi:10.1200/JCO.2023.41.16_suppl.3019.