Sanjay Goel, MD, MS, director, Phase I/Investigational Therapeutics, Rutgers Cancer Institute of New Jersey; professor, medicine, Division of Medical Oncology, Section of Solid Tumors, Rutgers Robert Wood Johnson Medical School, discusses the safety profile of the TKI tinengotinib (TT-00420) as a monotherapy and in combination with chemotherapy in patients with solid tumors.

A phase 1b/2 trial (NCT04742959) evaluated tinengotinib in 2 monotherapy arms, as well as in 1 combination arm alongside nab-paclitaxel (Abraxane), in adult patients with pretreated solid tumors who have no available standard therapeutic treatment options. Tinengotinib is a multi-kinase inhibitor, with targets such as JAK, Aurora kinases A/B, FGFRs, and VEGFRs.

Since tinengotinib targets multiple kinases, it is associated with several common treatment-related adverse effects (TRAEs), Goel says. Among the 172 patients in the trial’s 2 monotherapy arms, 73.8% experienced any-grade TRAEs. Grade 1, 2, and 3 TRAEs were observed in 14.5%, 22.1%, and 36.0% of patients in the monotherapy arms, respectively. In addition, 1.2% of patients had grade 4 TRAEs, and no grade 5 TRAEs occurred. The grade 4 TRAEs included increased alanine transaminase, increased aspartate transaminase, and perforation of the large intestine. The investigators reported no treatment-related deaths. Overall, the most common TRAEs in the monotherapy arms were hypertension (32.0%), stomatitis (22.1%), diarrhea (16.3%), palmar-plantar erythrodysesthesia syndrome (14.0%), nausea (12.8%), and fatigue (10.5%).

The 5 patients who received tinengotinib plus nab-paclitaxel experienced more myelosuppression than those in the monotherapy arms, Goel notes. In total, 80.0% of patients in this arm experienced tinengotinib-related adverse effects. Common TRAEs in this arm included neutropenia and stomatitis, which each occurred in 60% of patients, as well as hyponatremia, hypokalemia, and hypertension, which each occurred in 40% of patients. One patient in the combination arm died from a pulmonary hemorrhage, which was not considered related to the study drug.

The AEs seen across both arms are commonly associated with TKIs and were expected, Goel concludes.

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Sanjay Goel, MD, MS, discusses the safety profile of the TKI tinengotinib as a monotherapy and in combination with chemotherapy in patients with solid tumors.

Dr Goel on the Safety Profile of Tinengotinib in Solid Tumors

Sanjay Goel, MD, MS, director, Phase I/Investigational Therapeutics, Rutgers Cancer Institute of New Jersey; professor, medicine, Division of Medical Oncology, Section of Solid Tumors, Rutgers Robert Wood Johnson Medical School, discusses the mechanism of action of tinengotinib (TT-00420) and the efficacy of this agent in patients with cholangiocarcinoma.

A phase 1b/2 trial (NCT04742959) investigated the TKI tinengotinib in adult patients with pretreated solid tumors who have no available standard therapeutic treatment options and adequate organ function. This included 17 patients with cholangiocarcinoma. The 3-arm trial evaluated the agent as a monotherapy, in combination with nab-paclitaxel, and as monotherapy in a pharmacokinetics run-in arm. The end points of this trial were safety and tolerability per CTCAE v5.0, preliminary efficacy per RECIST v1.1, clinical pharmacokinetics analyses, and biomarkers. In the overall evaluable trial population, the best overall response rate was 14.5%, the disease control rate was 64.5%, and the clinical benefit rate was 25%.

The small molecule inhibitor tinengotinib is a spectrum-selective multi-kinase inhibitor, Goel says. Its common targets include Aurora kinase A/B, JAK, FGFRs, and VEGFRs, Goel explains. By inhibiting these kinases, this agent targets angiogenesis, cell proliferation, and immune-oncologic pathways, Goel emphasizes.

In the subgroup of patients with cholangiocarcinoma, 17.6% (n = 3) achieved a partial response. Five patients in the cholangiocarcinoma subgroup had disease harboring an 

 alterations in cholangiocarcinoma are not common, they are important to test for because patients with these alterations may be eligible for FDA-approved therapies, according to Goel. Among the 5 patients with 

-altered cholangiocarcinoma, 40% (n = 2) responded with tinengotinib. Moreover, 4 of those 5 patients had previously been exposed to prior FGFR-targeted therapy. These findings indicate that tinengotinib can benefit patients with 

-altered cholangiocarcinoma, including those who have received a prior FGFR-targeted agent, Goel concludes.

Dr Goel reports receiving honoraria from Amgen and Merck; he has stock and other ownership interests with Johnson and Johnson, Merck, and Moderna Therapeutics; he received institutional research funding from BeiGene, Deciphera, Dragonfly Therapeutics, EMD Serono, PharmaMar, Takeda, and TLC PharmaChem; he has a patent with co-inventor, John Mariadason, Ph.D, entitled "Method Of Determining The Sensitivity Of Cancer Cells To EGFR Inhibitors Including Cetuximab, Panitumumab And Erlotinib.", Patent No. 20090258364.

Sanjay Goel, MD, MS, discusses the mechanism of action of tinengotinib and the efficacy of this agent in patients with cholangiocarcinoma.

Dr Goel on the Mechanism of Action of Tinengotinib in Solid Tumors

Sanjay Goel, MD, MS, director of Phase I/Investigational Therapeutics, medical oncologist, professor of medicine, Division of Medical Oncology, Section of Solid Tumor, Rutgers Robert Wood Johnson Medical School, discusses the preliminary efficacy of tinengotinib (TT-00420)monotherapy in advanced solid tumors according to data from a phase 1b/2 trial (NCT04742959).

The phase 1b/2 trial was conducted to evaluate the safety, pharmacokinetics, and efficacy of the spectrum-selective multi-kinase inhibitor tinengotinib as a monotherapy in patients with advanced or metastatic solid tumors with no available standard treatment options. Patients enrolled in the study were assigned to 1 of 3 arms. In arm A, tinengotinib was administered orally at 12 mg once daily. In arm B, tinengotinib was administered at 8 mg, 10 mg, or 12 mg once a day alongside 100 mg of nab-paclitaxel (Abraxane) to patients with HER2-negative breast cancer. Arm C was the pharmacokinetic run-in, and involved administering tinengotinib at either 5 mg, 8 mg, 10 mg, or 12 mg once a day, or 4 mg or 6 mg twice a day to all-comers.

As of April 3, 2023, 177 patients were enrolled and treated on the study. Of the 124 efficacy evaluable patients in the monotherapy arms, the overall response rate (ORR) was 14.5% and was composed entirely of partial responses (PRs), Goel reports. The disease control rate (DCR) was 64.5%. Additionally, 25% of patients experienced clinical benefit with single-agent tinengotinib, which was defined as a complete response (CR), PR, or stable disease (SD) lasting more than 6 months, Goel states. Responses were observed across a wide range of tumor types, including cholangiocarcinoma, prostate cancer, hormone receptor (HR)–positive/HER2-negative breast cancer, and triple-negative breast cancer, he notes. Best ORR in patients with cholangiocarcinoma (n = 17) was 17.6%. Notably, this rate was 40% in those who expressed 

alterations. Best ORRs in the remaining 3 tumor types were 50% (n = 5/10), 33.3% (n = 2/6) and 37.5% (n = 3/8), respectively.

Clinical benefit with oral tinengotinib was also seen in patients with ovarian, squamous oropharynx, fallopian tube, urothelial, cervical, bladder, endometrial, leiomyosarcoma, melanoma, colon, duodenum, and lung cancer, Goel concludes.

Sanjay Goel, MD, MS, discusses the preliminary efficacy of tinengotinib monotherapy in advanced solid tumors according to data from a phase 1b/2 trial (NCT04742959). 

Dr Goel on the Preliminary Efficacy of Tinengotinib Monotherapy in Advanced Solid Tumors

Sanjay Goel, MD, MS, director of Phase I/Investigational Therapeutics, medical oncologist, professor of Medicine, Division of Medical Oncology, Section of Solid Tumor, Rutgers Robert Wood Johnson Medical School, discusses the evolution of precision and personalized medicine in cancer care.

Precision and personalized medicine share some similar characteristics, as both represent a medical model where a patient’s treatment is based on something specific that is found within their tumor, Goel says. However, there are some inherent differences between precision and personalized medicine. Precision medicine is more mathematically based compared with personalized medicine, whereas personalized medicine focuses on tailoring a particular therapy to a specific patient, Goel adds.

Ultimately, the terminology most commonly used regarding precision and personalized medicine is biomarkers, as both are consistently driven by the presence of these markers in the tumor of an individual patient, Goel continues. The use of genetic and molecular profiling in cancer care has defined precision medicine in the space, and the implementation of precision medicine has grown over the past two decades, Goel says.

The inception of precision medicine dates back approximately 20 years, Goel says. The Human Genome Project was completed in 2003, and in 2015, United States President Barack Obama announced the launch of the Precision Medicine Initiative.

The start of this initiative coincided with the initiation of the phase 2 NCI MATCH trial (NCT02465060), and this study utilized targeted therapy directed by genetic testing for the treatment of patients with advanced refractory solid tumors, lymphomas, or multiple myeloma. The study aimed to identify patients with genetic abnormalities, such as mutations, amplifications, or translocations, who might benefit more from treatment which targets their tumor's particular genetic abnormality.

In recent years, the oncology community has observed successes with the use of precision medicine, and one of the best examples is the use of a pembrolizumab (Keytruda) in patients who have microsatellite instability or a high tumor mutational burden, Goel concludes.

Sanjay Goel, MD, MS, discusses the evolution of precision and personalized medicine in cancer care.

Dr. Goel on the Evolution of Precision and Personalized Medicine in Cancer Care

Sanjay Goel, MD, MS, director of Phase I / Investigational Therapeutics, medical oncologist, professor of Medicine, Division of Medical Oncology, Section of Solid Tumor, Rutgers Robert Wood Johnson Medical School, discusses the need for diverse representation in clinical trials.

The population in the United States continues to get more diverse, and nearly half of the population identifies as non-Hispanic white, Goel says. Although Hispanic and Black communities are both growing, non-Hispanic White patients still comprise approximately 85%-90% of clinical trial enrollment, Goel adds. Due to disproportionate enrollment in clinical trials, some patients in the community are being treated with therapeutic interventions and decisions based on data generated from patients that may have different presentations of cancer, Goel explains.

Genetic differences exist between races, which can influence how patients respond to therapy in terms of efficacy and toxicity, Goel emphasizes. Having equitable representation of the community in clinical trials can help address these issues, Goel says. Though it will take time to get to this point, it is important to address these problems now, Goel concludes.

Sanjay Goel, MD, MS, discusses the need for diverse representation in clinical trials.


Sanjay Goel, MD, MS

Articles

Dr Goel on the Safety Profile of Tinengotinib in Solid Tumors

Dr Goel on the Mechanism of Action of Tinengotinib in Solid Tumors

Dr Goel on the Preliminary Efficacy of Tinengotinib Monotherapy in Advanced Solid Tumors

Dr. Goel on the Evolution of Precision and Personalized Medicine in Cancer Care

Dr. Goel on the Need for Diverse Representation in Clinical Trials