Darlene Dobkowski, MA

Findings from a phase 2 study shared during the 2022 ASCO Genitourinary Cancers Symposium showed that neoadjuvant cabozantinib (Cabometyx) was safe and induced a reduction in tumor size in all patients with locally advanced nonmetastatic clear cell renal cell carcinoma (RCC).

Neoadjuvant cabozantinib (Cabometyx) contributed to tumor reduction with no disease progression in patients with locally advanced nonmetastatic clear cell renal cell carcinoma (RCC), according to findings from an analysis presented at the 2022 ASCO Genitourinary Cancers Symposium.

Results from the analysis, which were presented by Mehmet A. Bilen, MD, an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta and director of the Genitourinary Medical Oncology Program at Winship Cancer Institute at Emory University, also demonstrated no treatment-related grade 4 or grade 5 adverse events.

“We showed that cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced nonmetastatic clear-cell RCC,” said Bilen.

In the analysis of this study (NCT04022343), 17 patients with biopsy-proven clear-cell RCC were treated with neoadjuvant cabozantinib at a starting dose of 60 mg once per day for 12 weeks. Of the patients in the study, 82.4% were men with a median age of 58 years (range: 42-86 years).

“In recent years, highly active treatment options become available for patients with metastatic renal cell carcinoma,” Bilen said. “The increased response rates with cabozantinib in metastatic renal cell carcinoma, along with the other neoadjuvant [tyrosine kinase inhibitor] data, we studied the role for cabozantinib in the neoadjuvant setting in this investigator-initiated clinical trial.”

The primary outcome of this study was an objective response rate at 12 weeks per RECIST v1.1, including complete and partial responses. Secondary outcomes included tolerability, safety, surgical outcome, clinical outcome (overall survival and disease-free survival) and quality of life.

All patients had 12 weeks of treatment with cabozantinib, and most patients (n = 16) underwent surgery without delay after completing a 4-week wash-out period. The one patient who did not undergo surgery refused the procedure for personal reasons and received further systemic treatment.

Results from this analysis demonstrated that all patients had tumor reduction. In particular, 5 patients (29.4%) had a partial response (overall response rate = 0.29; 95% CI, 0.1-0.56) and 12 patients had stable disease. Progression of disease was not observed in the patients treated with cabozantinib. The primary renal tumor size was reduced by a median of 23% (range: 6-45).

“Neoadjuvant treatment is well established in different solid tumors such as breast cancer, gastrointestinal cancers and others,” Bilen said. “Effective neoadjuvant treatment options are needed in patients with locally advanced RCC. We try to explore this in this population and show its feasibility. We are hoping with additional clinical trial data, we are able to establish the role of presurgical treatment in this patient population.”

At the end of treatment, 1 patient who was deemed to be unresectable at the start of the study was considered resectable after 12 weeks. Two patients also converted from radial nephrectomy at the start of the study to partial nephrectomy at the end of treatment.

The most common adverse events that occurred throughout treatment included anorexia, diarrhea, hypertension, fatigue and nausea.One serious adverse event occurred that was related to a pulmonary embolism. Some dose reductions did occur as a result of some adverse events; 5 patients decreased to a 40-mg dose and 2 patients decreased to a 20-mg dose. Two patients died at the time this analysis was performed, including 1 patient who died from COVID-19 and 1 patient who died from an unknown cause.

“A larger clinical trial is needed to further establish the role of presurgical treatment in RCC,” Bilen said. “This will allow us to understand the long-term role of those treatments. In addition to that, other agents such as immunotherapy combinations need to be studied in this space as well. Additionally, we also need to investigate the optimum duration of treatment, ideal clinical trial endpoints and additional correlative studies that will help us to understand the biology of RCC.”

1. Bilen MA, Liu Y, Nazha B, et al. Phase 2 Study of Neoadjuvant Cabozantinib in Patients with Locally Advanced Non-metastatic Clear Cell Renal Cell Carcinoma. Presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; Abstract 340.

Articles

Neoadjuvant cabozantinib was safe and induced a reduction in tumor size in all patients with locally advanced nonmetastatic clear cell renal cell carcinoma enrolled in a phase 2 trial.

Neoadjuvant cabozantinib clinically active in renal cell carcinoma

Results of a comprehensive analysis shared at the 2021 ESMO Congress offers additional clues into the genomic makeup and characteristics of clear cell renal cell carcinoma (ccRCC) tumors based on their 

The analysis identified differences and even some similarities between these tumor subtypes that may provide additional insight regarding treatment selection in patients with ccRCC.

 mutations status in the clinical trial setting appears warranted,” Gennady Bratslavsky, MD, of SUNY Upstate University Hospital in Syracuse, New York, and colleagues wrote in the poster.

Researchers performed comprehensive genetic profiling in 948 patients with clinically advanced ccRCC to assess all classes of genomic alternation. Of these patients, 75% had VHL-mutated disease (median age, 62 years; 71% men) and 25% had VHL wild type ccRCC (median age, 63 years; 71% men).

Some of the significant differences in currently “untargetable” genomic alterations included higher TERT genomic alterations in patients with VHL wild type ccRCC (

 = .007) and higher frequencies of SETD2 in those with VHL mutated ccRCC (

 = .04). Patients with VHL mutated or VHL wild type ccRCC had similar frequencies of genomic alterations that could potentially be targeted except for MTAP deletions; these deletions were observed more frequently in patients with VHL wild type ccRCC (

Researchers also assessed patients with genomic alterations associated with immune checkpoint inhibitor efficacy. In these patients, PBRM1 genomic alterations were significantly more frequent in those with VHL wild type disease compared with VHL mutated disease (

 < .0001). Patients with ccRCC had low tumor mutational burden levels, with 1% to 2% of patients having levels above 10 mut/Mb.

Patients with VHL mutated ccRCC and those with VHL wild type disease often had low positive PD-L1 expression (1%-49% tumor cell staining). In addition, both groups rarely had high positive staining (≥ 50% tumor cell staining).

VHL mutation status has become an area of clinical interest in the RCC paradigm. The 

FDA recently approved belzutifan (Welireg) for adult patients with VHL disease who require therapy for associated RCC.

Bratslavsky G, Necchi A, Grivas P, et al. Comprehensive Genomic Profiling of 

Wild Type Clear Cell Renal Cell Carcinoma. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 690P.

Patients with VHL-mutated ccRCC and VHL–wild type disease often had low positive PD-L1 expression. 

Genomic analysis offers clinical insight into VHL-positive vs -negative ccRCC tumors

Data from a phase 2 trial shared during the 2021 Genitourinary Cancers Symposium suggested that among patients receiving lenvatinib (Lenvima) for renal cell carcinoma, using a higher starting dose enhanced health-related quality of life and extended the time to deterioration.1 

“Based on these findings, patients who received lenvatinib 18 mg starting dose had better quality of life and less severe symptoms than those who received lenvatinib 14 mg starting dose,” said Cristiane Decat Bergerot, PhD, MS, BS, a postdoctoral fellow at City of Hope National Medical Center in Duarte, California, during the virtual poster presentation. “In addition, participants who received lenvatinib 18 mg maintained quality of life and symptom control for longer than those who received lenvatinib 14 mg starting dose.”

In this phase 2, randomized, open-label trial, researchers compared the safety and efficacy of two different starting doses of lenvatinib — 18 mg per day (n = 172; median age, 61 years; 77% men) or 14 mg per day (n = 171; median age, 62 years; 75% men) — in patients with renal cell carcinoma who previously received one vascular endothelial growth factor-targeted treatment. Both starting doses of lenvatinib were given in combination with 5 mg of everolimus per day. Patients received treatment until unacceptable toxicity, disease progression, withdrawal of consent or the end of the study.

Researchers used three different instruments to measure health-related quality of life: Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), EQ-5D-3L and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Quality-of-life scores were measured at baseline, first day of the first cycle of treatment and at the end-of-treatment visit.

Average quality-of-life scores in patients assigned the 18 mg dose were higher compared with those assigned the 14 mg dose. In addition, the higher dose group had lower symptom severity compared with the lower dose group.

“Mean differences in favor of lenvatinib 18 mg were seen in most scales,” said Bergerot during the presentation. “However, none of these differences exceeded the minimally important difference for clinical significance.”

The median time to first deterioration was longer in patients assigned the 18 mg starting dose compared with those assigned the 14 mg starting dose in most scales including the FKSI-DRS total score (12 weeks vs. 15.71 weeks; HR = 1.3). This was also observed for EORTC QLQ-C30, which assessed emotional functioning (20.71 weeks vs. 34.86 weeks), social functioning (12.14 weeks vs. 16.29 weeks), dyspnea (20.29 weeks vs. 40.29 weeks), insomnia (15.43 weeks vs. 28.14 weeks) and financial difficulties (36.14 weeks vs. not estimable).

Patients assigned the 18 mg starting dose also had a longer time to definitive deterioration based on the FKSI-DRS total score (HR = 1.46; 56.43 weeks vs. 80.14 weeks). This was also observed for EORTC QLQ-C30 scores, which assessed factors such as physical functioning (HR = 1.65; 56.14 weeks vs. 99.57 weeks), cognitive functioning (HR = 1.44; 56.14 weeks vs. 72.29 weeks) and fatigue (HR = 1.59; 40.14 weeks vs. 72.29 weeks).

“In conclusion, these findings support the approved treatment of lenvatinib 18 mg starting dose in combination with everolimus as an effective treatment option for patients with renal cell carcinoma following one prior VEGF-targeted treatment while maintaining quality of life,” said Bergerot during the presentation.

1. Bergerot CD, Rha SY, Pal SK, et al. Health-related quality-of-life outcomes from a phase II open-label trial of two different starting doses of lenvatinib in combination with everolimus for treatment of renal cell carcinoma following one prior VEGF-targeted treatment. Presented at: 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 11-13, 2021; virtual. Abstract 314.

The higher starting dose of lenvatinib was also associated with a prolonged time to deterioration.

Darlene Dobkowski, MA

Articles

Neoadjuvant cabozantinib clinically active in renal cell carcinoma

Genomic analysis offers clinical insight into VHL-positive vs -negative ccRCC tumors

QoL boost linked to higher lenvatinib dose in kidney cancer