Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study
Creators: name: Bazhenova, Lyudmila
name: Kim, Dong-Wan
name: Cho, Byoung Chul
name: Goel, Sanjay
name: Heist, Rebecca
name: Werner, Theresa L
name: Eaton, Keith D
name: Wang, Judy S
name: Pant, Shubham
name: Adkins, Douglas R
name: Blakely, Collin M
name: Yan, Xiaohong
name: Neuteboom, Saskia
name: Christensen, James G
name: Chao, Richard
name: Bauer, Todd
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Science Policy
subject: Infectious Diseases
subject: FOS: Health sciences

description: <b>Aim:</b> We report clinical activity and safety of sitravatinib in patients with advanced cancer from basket cohorts with specific molecular alterations, in a Phase Ib study. <b>Materials &amp; methods:</b> Patients with advanced solid tumors harboring amplification, mutation, or rearrangement of <i>MET</i>, <i>AXL</i>, <i>RET</i>, <i>NTRK</i>, <i>DDR2</i>, <i>KDR</i>, <i>PDGFRA</i>, <i>KIT</i> or <i>CBL</i> received sitravatinib once daily. Primary end point was confirmed objective response rate (ORR). <b>Results:</b> In total, 113 patients were enrolled following a median of 3 (range 1–18) prior systemic regimens. Altered <i>RET</i> (n = 31), <i>CBL</i> (n = 31) and <i>MET</i> (n = 17) were most frequent cohorts. Overall, 68.9% had reduced tumor volume and most (61.5%) had a best objective response of stable disease. ORR was highest in patients with <i>RET</i>-rearranged non-small cell lung cancer (21.1%) but did not differ significantly from the null hypothesis (ORR ≤15%; <i>p</i> = 0.316). Median progression-free survival and overall survival (5.7 and 24.2 months, respectively) were also longest in the <i>RET</i>-rearranged non-small cell lung cancer cohort. Diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) were the most frequent treatment-emergent adverse events. Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts. <b>Conclusion:</b> Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors. Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711
 We report findings from a clinical study of sitravatinib which included patients with cancer that could not be removed by surgery or had spread to other parts of the body. The tumors of these patients contained specific molecular changes in one of the following genes: <i>MET</i>, <i>AXL</i>, <i>RET</i>, <i>NTRK</i>, <i>DDR2</i>, <i>KDR</i>, <i>PDGFRA</i>, <i>KIT</i> or <i>CBL</i>. All patients received treatment with sitravatinib once a day. Change in tumor size over time was assessed to see how effective treatment with sitravatinib was. In total, 113 patients joined the study. Most patients had already received a median of three different types of medicines for their cancer (and up to 18 different types of anticancer medicines). Most patients had tumors that contained alterations in <i>RET</i>, <i>CBL</i> or <i>MET</i> genes. During the study, the percentage of patients who had a decrease in the tumor size was highest in the group with non-small cell lung cancer that contained an altered <i>RET</i> gene (21.1%). However, this level of response to sitravatinib was not considered high enough to be medically important. The most common side effects during the study were diarrhea (61.1%), fatigue (50.4%) and high blood pressure (46.9%). Most side effects were mild or moderate in severity. The study provided the opportunity to assess sitravatinib as a treatment for cancers with specific gene mutations that are uncommon; the study closed before the planned number of patients were enrolled. In conclusion, the side effects seen in patients who received sitravatinib were manageable. Signals of how well sitravatinib worked were modest in patients with cancer that had spread to other parts of the body and contained specific molecular changes. Basket trials that enroll cohorts of patients with various tumor types that harbor specific molecular alterations can inform the activity of novel treatments for rare genetic drivers, helping ensure patients receive treatment that is based on the molecular signature of their disease. Sitravatinib (MGCD516) is an oral small molecule inhibitor that targets a spectrum of closely related receptor tyrosine kinases involved in cancer development, predominantly TAM family (TYRO3, AXL, MERTK) and split family (VEGFR2, MET, RET, KIT) receptors. We report clinical activity and safety with sitravatinib in patients with advanced solid tumors that harbored genetic alterations relevant to the mechanism of action of sitravatinib, who participated in the Phase Ib basket study cohorts of the first-in-human study. Overall, 113 heavily pre-treated patients were enrolled; patients with tumors containing alterations in <i>RET</i> (n = 31), <i>CBL</i> (n = 31) and <i>MET</i> (n = 17) were the most frequent cohorts. Overall, the clinical activity of sitravatinib was modest: while most patients (68.9%) experienced a reduction in tumor volume, the majority (61.5%) had a best objective response of stable disease. Objective response rate was highest in patients with <i>RET</i>-rearranged NSCLC (21.1%) but this did not differ significantly from the null hypothesis (ORR ≤15%; <i>p</i> = 0.316). Despite the basket-cohort approach to enrollment, fewer patients than planned were enrolled across the cohorts in the timeframe of the study; this prevented further refinement of molecular alteration subtypes for which sitravatinib may have clinical utility. Sitravatinib had a manageable safety profile: most adverse events were mild-to-moderate in severity, with diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) being most frequently observed.