Vivek Subbiah, MD

Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics department, discusses the adverse events (AEs) that come with the use of kinase inhibitors to treat patients with thyroid cancer.

or other mutations that involve the kinase pathway and make kinase targeted inhibitors important for this patient population. However, kinase inhibitors can have significant AEs that impact how long the patient can be on the treatment to achieve a response.

Subbiah, medical director of the Clinical Center for Targeted Therapy, Cancer Medicine division at The University of Texas MD Anderson Cancer Center, discusses then how to manage these but also how new treatments like selpercatinib (Retevmo) can impact AEs in this patient population.

These multi-targeted kinase inhibtors simultaneously target 

, in addition to a lot of other kinases [in thyrpid cancer]. Although the percentage of patients who had a response to these multikinase inhibitors were in anywhere from 12% to 65%, the safety and durability of the responses to these agents are partially limited by the off target AEs. These AEs like rash, diarrhea, and hypertension, lead to dose reductions in these patients, and these AEs are primarily attributed to more potent inhibition of non-RET kinases, as I said, the VGFR2. Previous to the entry of selective RET-inhibitors, no selective RET-inhibitor was approved for treating those patients.

Selpercatanib is a novel ADP competitive, highly selective small molecule RET-kinase inhibitor. In preclinical models it showed nanomolar potential against diverse 

-alterations that included an acquired gatekeeper assistant mutation as well as anti-tumor activity in the brain. This acquired gatekeeper mutation is interesting because this can develop as a resistance mechanism to multi kinase inhibitors, or it is also seen in rare cases in germline patients with medullary thyroid cancer.

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Vivek Subbiah, MD, discusses the adverse events that come with the use of kinase inhibitors to treat patients with thyroid cancer.

Addressing Adverse Events from Kinase Inhibitors in Thyroid Cancer

Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics department, and medical director of the Clinical Center for Targeted Therapy, Cancer Medicine division at The University of Texas MD Anderson Cancer Center, discusses what sets medullary thyroid cancer (MTC) apart from other thyroid histologies.

 proto-oncogene encodes a transmembrane receptor tyrosine kinase which is activated by 2 mechanisms. These include mutations that involve the system glitch or kinase domains, and structural rearrangements which then allow for the fusion of 

 mutations which are more closely linked to aggressive disease. A large number of patients with metastatic MTC have these mutations and make up a great number of diagnosed cases.

 proto-oncogene encodes a transmembrane receptor tyrosine kinase that is constantly activated by 2 distinct mechanisms. One is mutations involving the system glitch or kinase domains, and structural rearrangements that lead to fusion of 

 to a prime partner. Collectively, these alterations result in ligand dependent signaling and oncogenesis.

 mutations. Overall, more than 60% of patients with metastatic MTC harbor that mutation and in germline patients who are also identified as multiple endocrine neoplasia [MEN] type 1/2, almost 100% have this lead mutation. The germline mutations result in hereditary MEN, type 2A, and type 2B. Collectively these hereditary cancer syndromes account for 25% of all diagnosed cases of MTC of the remaining 75% of sporadic MTC, and as I said, over 60% harbored the 

 mutations are associated with more aggressive disease in MTC, and thus, tumors in a majority of patients need a 

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Vivek Subbiah, MD, discusses what sets medullary thyroid cancer apart from other thyroid histologies. 

Targeting RET in Medullary Thyroid Cancer 

, Vivek Subbiah, an associate professor in the Investigational Cancer Therapeutics department, and medical director of the Clinical Center for Targeted Therapy, Cancer Medicine division at The University of Texas MD Anderson Cancer Center, explains the structure and end points of the LIBRETTO-001 trial (NCT03157128).

The phase 1/2 LIBRETTO-001 study sought to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of selpercatinib (LOXO-292). Participants with advanced solid tumors, including rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation were administered selpercatinib orally.

-altered thyroid tumors heavily pretreated and treatment-naïve patients. Overall response rate (ORR) was 79% in patients with previously treated 

 fusion-positive thyroid cancer and in the treatment-naïve group, response rate was 100%, according to Subbiah. According to the findings of that response rate, 71% were ongoing and 64% stayed progression-free. The approval of selpercatinib capsules for the treatment of thyroid cancer harboring 

 alterations by the FDA was supported by these findings.

 | A total of 441 patients with RET fusion-positive cancers were enrolled in the study as of the data cutoff Of March 19, 2021. In this specific presentation, I discussed the 38 patients who have 

 fusion-positive cancer, excluding those with lung or thyroid as data from these patients have been previously published. The efficacy evaluable population included 32 patients who enrolled on or before September 19, 2020, long enough to allow a 6-month follow-up after the first dose of selpercatinib. The patients were required to be at least 12 years of age with a diagnosis of an advanced or metastatic solid tumor and an equal performance status of 0 to 2.

The primary endpoint was ORR, and secondary end points included duration of response, progression-free survival, safety, and others. 

 fusions occur predominantly in 1% to 2% of lung cancers, and 10% to 20% of thyroid cancers. They have a very low frequency in an increasing number of diverse cancers like pancreatic cancer, salivary gland cancer, and colorectal cancer. The therapeutic relevance of 

 fusions occurring outside the lung and thyroid has not been well established, and that was the purpose of this analysis.

Vivek Subbiah discusses the phase 1/2 LIBRETTO-001 study which sought to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of selpercatinib in patients with advanced solid tumors.

Key Objectives With Selpercatinib Use in RET Fusion-Positive Thyroid Cancer 

Vivek Subbiah, MD, an associate professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, and executive medical director, Department of Medical Oncology Research at the University of Texas MD Anderson Cancer Center, explains what sets medullary thyroid cancer apart from other thyroid cancer histologies.

Over 60% of patients with metastatic MTC harbor the 

 mutations, says Subbiah. In addition, a large proportion of patients also harbor germline 

 mutations. The presence of these germline 

 mutations account for 20% of all cases of MTC.

 mutations lead to more aggressive disease, Subbiah explains. The majority of these patients need to be treated with a RET inhibitor. In contrast, in papillary, anaplastic, and differentiation thyroid cancer, the presence of a 

Vivek Subbiah, MD, explains what sets medullary thyroid cancer apart from other thyroid cancer histologies.









The Impact of Somatic and Germline RET Mutations in Medullary Thyroid Cancer

Vivek Subbiah, MD, of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses how the data from selpercatinib have generated excitement for precision medicine in the treatment landscape for patients with 

The LIBRETTO-001 study demonstrated promising activity with selpercatinib, the selective RET inhibitor, as treatment of patients with 

-mutant non-small cell lung cancer (NSCLC). Subbiah says that this study generated the enthusiasm in precision oncology for 

This opens up new areas of precision oncology, as well as the opportunity for precision medicine in patients with 

Approval of this agent furthers the use of selpercatinib

 in the community setting, Subbiah notes. This now demonstrates proof of principal for selective RET inhibition, so we need to know when patients will receive the most benefit from specific RET targeting, which is upfront, in Subbiah’s personal opinion.

Vivek Subbiah, MD, discusses how the data from selpercatinib have generated excitement for precision medicine in the treatment landscape for patients with RET-driven lung cancer.

Selpercatinib Data Underscore Value of Precision Medicine in RET-Driven Lung Cancer

Vivek Subbiah, MD, of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, shares his take home message regarding the treatment of patients with non–small cell lung cancer (NSCLC) who harbor a 

The main challenge lies in identifying patients who harbor a 

 accounts for 1% to 2% of all cases of NSCLC. Testing for this in NSCLC is important now following the 

FDA’s recent approval of selpercatinib (Retevmo) as treatment of patients with lung cancer harboring 

Subbiah’s main message is that NSCLC is the poster child of precision oncology. The more physicians test for, the more we find. In order to win the war against lung cancer, Subbiah says we need to completely understand the disease, and comprehensive next-generation sequencing that includes all fusions and mutations is the first step.

Vivek Subbiah, MD, shares his take home message regarding the treatment of patients with non–small cell lung cancer who harbor a RET fusion.