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LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma

Combination treatment with immunotherapy agents and/or vascular endothelial growth factor tyrosine kinase inhibitors are a standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Novel therapeutic combinations that include the hypoxia-inducible factor 2α inhibitor belzutifan and the cytotoxic T-lymphocyte-associated protein 4 inhibitor quavonlimab are being investigated for their potential to further improve patient outcomes. This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab as first-line treatment for advanced ccRCC. Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

https://www.merck.com/publication/litespark-012-pembrolizumab-plus-lenvatinib-with-or-without-belzutifan-or-quavonlimab-for-advanced-renal-cell-carcinoma/

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

<p>This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a p-p stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications. </p>

https://www.merck.com/publication/prediction-and-de-risking-of-an-unusual-apiepimer-cocrystal-in-the-commercial-synthesis-of-belzutifan/

Population Pharmacokinetic Analyses for Belzutifan to Inform Dosing Considerations and Labeling

Belzutifan (Welireg, Merck & Co, Inc.) is an oral, potent inhibitor of hypoxia-inducible factor (HIF) 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors (pNET). It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM® v7.3, based on demographics/PK data from 3 clinical pharmacology (food effect, formulation bridging, genotype/race effect) and 2 clinical (phase 1 dose escalation/expansion in RCC and other solid tumors; phase 2 in VHL patients) studies. Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear 2-compartment model with first-order absorption and elimination. For VHL patients, the predicted geometric mean (% coefficient of variation [CV]) apparent clearance (CL/F) was 7.3 L/hr (51%), apparent total volume of distribution (Vd/F) was 130 L (35%); and half-life was 12.39 hours (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve (AUC) compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in overall- and sub-populations for belzutifan labeling.This article is protected by copyright. All rights reserved.

https://www.merck.com/publication/population-pharmacokinetic-analyses-for-belzutifan-to-inform-dosing-considerations-and-labeling/

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study

<br /><h3>BACKGROUND</h3>Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy.<br /><h3>METHODS</h3>This open-label, single-arm, phase 2 study was conducted at ten hospitals and cancer centres in the USA. Patients were enrolled into two cohorts. Patients in cohort 1 had treatment-naive disease (results will be reported separately). In cohort 2, eligible patients were aged 18 years or older with locally advanced or metastatic clear cell renal cell carcinoma, measurable disease according to Response Evaluation Criteria in Solid Tumours version 1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had previously received immunotherapy and up to two systemic treatment regimens. Patients were given belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was confirmed objective response assessed by the investigator. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing.<br /><h3>FINDINGS</h3>Between Sept 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, 52 (44%) of whom were enrolled in cohort 2 and received at least one dose of study treatment. Median age was 63·0 years (IQR 57·5-68·5), 38 (73%) of 52 patients were male, 14 (27%) were female, 48 (92%) were White, two (4%) were Black or African American, and two were Asian (4%). As of data cutoff (Feb 1, 2022), median follow-up was 24·6 months (IQR 22·1-32·2). 16 (30·8% [95% CI 18·7-45·1]) of 52 patients had a confirmed objective response, including one (2%) who had a complete response and 15 (29%) who had partial responses. The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. One death was considered treatment related by the investigator (respiratory failure).<br /><h3>INTERPRETATION</h3>Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor.<br /><h3>FUNDING</h3>Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute.Copyright © 2023 Elsevier Ltd. All rights reserved.

https://www.merck.com/publication/belzutifan-plus-cabozantinib-for-patients-with-advanced-clear-cell-renal-cell-carcinoma-previously-treated-with-immunotherapy-an-open-label-single-arm-phase-2-study/

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy

The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).

https://www.merck.com/publication/litespark-011-belzutifan-plus-lenvatinib-vs-cabozantinib-in-advanced-renal-cell-carcinoma-after-anti-pd-1-pd-l1-therapy/