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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The fact that sunitinib targets many different receptors leads to a number of side effects, including GI (e.g., abdominal pain, diarrhea, constipation, anorexia, taste disturbances, and gastrointestinal perforation) and skin (e.g., classic hand-foot syndrome, stomatitis, dry skin, and rash) disturbances. Other side effects include hypertension, edema, dyspnea, fatigue, and peripheral neuropathy. Sunitinib cannot be used whilst breastfeeding.
The Contribution of Pets to Human and Veterinary Medicine
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Toceranib (SU11654) is a receptor tyrosine kinase (RTK) inhibitor that is used to treat canine mast cell tumors. Toceranib phosphate was approved by the FDA for animal use in 2009, under the tradename Palladia™ (Zoetis, Parsippany, NJ). Sunitinib (SU11248) is a receptor tyrosine kinase inhibitor closely related to SU11654 that is used to treat renal cell carcinoma in people as well as specific types of gastrointestinal cancer. Sunitinib was approved by the FDA in 2006 as Sutent®. These two molecules are structural cousins. Pharmaceutical company Sugen conducted the original research on both of these molecules and became interested in targeting KIT receptor tyrosine kinases found in certain human cancers (gastrointestinal stromal tumors, small lung cancers, acute myeloid leukemia) during the late 1990s. At that time, the company became aware of the role of KIT mutations in canine mast cell tumors (a common cancer type found in dogs). A small clinical trial was performed in canine patients with mast cell tumors and results were promising, thereby providing useful proof of concept data to encourage translational research in humans. Furthermore, SU11654 demonstrated pharmacokinetic (PK) properties comparable to SU11248 in dogs. In fact, Sutent does not have a high therapeutic index and the PK properties seen in dogs are much better approximations of human PK properties than that seen in murine models. The fact that some of the same mutations identified in human gastrointestinal stroma tumors were present in canine mast cell tumors made this research especially informative.
Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Key sunitinib toxicities included hypertension, fatigue, diarrhea, hand–foot sensitivity, stomatitis, and skin color changes. Mild pancytopenia is common but rarely dose-limiting. Post-marketing surveillance and expanded access programs have also revealed drug-induced hypothyroidism to be common, and routine monitoring of thyroid function and supplementation when required while on treatment with sunitinib (and related agents) are recommended.
Therapeutic options in thymomas and thymic carcinomas
Published in Expert Review of Anticancer Therapy, 2022
Sunitinib targets VEGFR-1, -2, and -3, PDGFR, RET, FMS-like tyrosine kinase, colony-stimulating factor 1 receptor, and KIT. Sunitinib inhibits a wider range of kinases than sorafenib, and its inhibition is stronger than that of sorafenib [58]. Sunitinib is approved for use in renal cell carcinoma and pancreatic NETs and is effective for GISTs even after failure or discontinuation of imatinib. A Phase 2 study including 23 patients with chemotherapy-pretreated thymic carcinoma showed that oral sunitinib (50 mg once daily for four weeks followed by two weeks without treatment) yielded an ORR of 26% and PFS of 7.2 months [59]. However, 70% of the participants experienced Grade 3–4 treatment-related adverse events (AEs) including leukocytopenia, fatigue, and oral mucositis. A retrospective study based on the French RYMTHMIC network prospective database also showed a relatively good RR of 29% for thymoma and of 20% for thymic carcinoma [60]. Since toxicity was problematic, another study using sunitinib (50 mg once daily for two weeks followed by one week without treatment) was conducted as a part of the Phase 2 study above. However, the ORR was only 8% and PFS was only five months in 13 patients with pretreated thymic carcinoma [61].
Pembrolizumab for the treatment of renal cell carcinoma
Published in Expert Opinion on Biological Therapy, 2021
Carlo Di Bona, Viktoria Stühler, Steffen Rausch, Arnulf Stenzl, Jens Bedke
The phase III open-label KEYNOTE-426 trial compared the standard treatment sunitinib to the combination of axitinib plus pembrolizumab in patients with advanced, untreated clear cell RCC [29], leading to FDA approval of this therapeutic regimen. Eight hundred and sixty-one patients were randomized between the two arms. Pembrolizumab was administered intravenously in doses of 200 mg every 3 weeks, axitinib was given orally at 5 mg twice daily. Sunitinib was administered orally in 50 mg doses once a day for the first 4 weeks of each 6-week cycle. Pembrolizumab was administered up to a maximum of 35 cycles. The primary end points were OS and PFS, secondary endpoints were ORR, duration of response and safety. Control imaging was performed at baseline and at week 12, then every 6 weeks until week 54 and later every 12 weeks. The combination of axitinib plus pembrolizumab resulted in a significantly longer OS (HR for death 0.53, 95% CI 0.38–0.74; p < 0.0001) and PFS (HR for disease progression or death 0.69, 95% CI 0.57–0.84; p < 0.001) and a significantly higher ORR (59.3% vs. 35.7%; p < 0.001) than sunitinib. The combination of axitinib plus pembrolizumab showed higher liver toxicity than the individual drugs used in monotherapy, although the frequency of toxic effects was similar in both treatment arms (AEs of any grade 98.4% with the combination vs. 99.5% with sunitinib, AEs grade 3–4 75.8% with the combination vs. 70.6% with sunitinib).
MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma
Published in Expert Opinion on Investigational Drugs, 2021
In another phase II study, 31 patients with VHL disease were treated with pazopanib [17]. The co-primary endpoints of the study were objective response rate and safety. Sixty-nine percent of patients had RCC with a total of 59 renal tumors. 2/59 (3%) RCC tumors had a complete response, and 29/59 (49%) had a partial response. Regarding other VHL associated lesions, 2/49 (4%) of hemangioblastomas and 9/17 (53%) pancreatic tumors achieved partial response with pazopanib treatment. Overall, in this study, the response rate was 42%. Similar to the sunitinib study, diarrhea, fatigue, HTN and nausea were the most common adverse events. Additionally, elevated transaminases were commonly observed, which is known as a typical pazopanib-related toxicity. 21/31 (67%) of the patients had a dose reduction due to toxicity.