Pazopanib Effective and Safe in Poor-Risk Metastatic Clear Cell Renal Cell Carcinoma

Pazopanib, a tyrosine kinase inhibitor (TKI), is active and well-tolerated in patients with poor-risk metastatic clear cell renal cell carcinoma (ccRCC) with no new safety signal observed, according to results from the phase 4 FLIPPER clinical trial.

In the metastatic RCC paradigm, patients with advanced disease are usually treated temsirolimus which has long been the standard-of-care (SOC) therapy in this patient population. For treatment-naïve patients, however, research is limited. In addition, pazopanib is FDA-approved as treatment of treatment-naive or cytokine-pretreated patients with advanced or metastatic RCC, but the trial leading to this approval included only 4 poor-risk patients. Thus, even with 2 SOCs available for metastatic ccRCC, an effective and safe therapies for patients with poor-risk disease remains an unmet medical need, rationalizing the execution of the FLIPPER trial. The study evaluated the efficacy and safety of frontline pazopanib in 60 patients with poor-risk metastatic RCC.

"High-risk metastatic RCC is a condition with very limited therapeutic options. It remained unclear whether TKI were effective and the standard of care was seen in mTOR inhibition using temsirolimus. As we have seen efficacy in some of our high-risk patients with pazopanib we were highly encouraged to prospectively test our idea of a higher efficacy of TKI therapy versus mTOR inhibition in these highly selected patients, Michael Staehler, MD, of the Department of Urology, Interdisciplinary Center of Renal Tumors, Ludwig-Maximilians-University of Munich, in Munich, Germany and lead investigator of the study told Targeted Oncology, in an interview.

Following enrollment in the study, 9 patients were excluded due to information obtained during the screening process, and 8 patients were not treated as part of the study. Overall, 43 patients received pazopanib 800 mg orally once daily in FLIPPER. Treatment was continued until disease progression, unacceptable toxicity, development of another malignancy requiring treatment or withdrawal of patient consent. Patients were assessed for the primary end point of 6-month progression-free survival (PFS) rate, as well as secondary end points, including PFS, overall survival (OS), objective response rate (ORR), and duration of response (DOR).

In treated patients, tumor responses were assessed per RECIST version 1.1 with evaluations conducted every 8 weeks until week 24. Efficacy was assessed in the modified intention-to-treat (mITT) population, which included 34 patients who mostly had clear cell histology, 80% of whom underwent prior nephrectomy. Notably, at the time patients were included in the study 67.4% of the general population and 64.7% of the mITT population were defined as poor-risk according to Memorial Sloan Kettering Cancer Center criteria, whereas 25.6% of the overall population had intermediate-risk disease as did 26.5% of the mITT population.

Treatment with frontline pazopanib led to a 6-month PFS rate of 35.3% (95% CI 19.7-53.5). The median PFS observed with the agent was 4.5 months (95% CI, 3.6-7.8). In addition, front line pazopanib therapy achieved a median OS of 9.3 months (95% CI, 6.6-22.2).

In terms of response, the ORR observed in the study was 32.4% (95% CI, 17.4-50.5) with no patients achieving a complete response and 32.4% achieving a partial response. The median DOR with frontline pazopanib was 9.7 months (95% CI, 1.8-12.4). It was also shown that 50.0% of the population had stable disease while 14.7% had progressive disease. Response data were missing for 1 patient.

Overall, treatment on frontline pazopanib lasted for a median of 17.0 weeks (range,

1.6-92.0) with a mean relative dose intensity of 98.2%. Just over 4% of the patients treated required dose reductions, and 4.7% discontinued treatment due to treatment-related adverse events (AEs).

AEs of any grade were observed in 93.0% of the study population with the most common AEs being hypothyroidism (30.2%), diarrhea (30.2%), and fatigue (18.6%). Grade 3/4 AEs were seen in 32.6%, which included fatigue, pleural effusion, and hypertension in 4.7% of patients, each.

Any-grade AEs deemed to be related to pazopanib treatment were observed in 79.1% of patients. The most common pazopanib-related AEs were hypothyroidism (30.2%), diarrhea (25.6%), and fatigue (18.6%). The most common grade 3/4 pazopanib-related was hypertension (4.7%).

Regarding the safety results, Staehler stated in the interview: "Usually pazopanib has a later onset of side effects than other TKIs, thus making it a drug for metastatic and or symptomatic patients who have a high need for systemic therapy but a low tolerance for side effects, maybe due to thier symptoms."

Staehler et al determined that the results of pazopanib as frontline treatment for patients with poor-risk metastatic ccRCC were similar to what was observed in the TemPa trial of temsirolimus versus pazopanib in patients with poor-risk advanced ccRCC. Based on these data Staehler et al consider pazopanib reasonable for use as treatment of poor-risk metastatic ccRCC in the frontline setting.

"We believe that we could show a solid basis for TKI therapy in high-risk metastatic RCC patients. Although immunotherapy now has risen to be the standard of care in this subgroup of patients, some still might need or benefit from non-TKI therapy. For these patients pazopanib can be offered as a standard of care based on our positive efficacy data," Staehler told Targeted Oncology.

_Reference:

_{Staehler M, Panic A, Goebell PJ, et al. First-line pazopanib in intermediate- and poor-risk patients with metastatic renal cell carcinoma: Final results of the FLIPPER trial. Int. J. Cancer. 2021. 148(4):950–960.}