Phase 1b Trial Evaluates Combined Treatment for Renal Cell Carcinoma

Overview of Renal Cell Carcinoma

A phase 1b trial, funded by Merck and Pfizer, has been initiated to assess the effectiveness of a combination of two drugs in treating renal cell carcinoma (RCC), which accounts for 95% of kidney cancer cases. Annually, approximately 338,000 new cases of RCC are diagnosed worldwide. This specific cancer originates in the small tubules of the kidney responsible for filtering and transporting urine.

When detected early, treatment options include the surgical removal of either the tumor or the affected kidney to halt the cancer’s progression. However, about 30% of patients present with advanced or metastatic disease at diagnosis, where the cancer has spread to other body parts.

Treatment Options for Advanced Renal Cell Carcinoma

In cases of advanced RCC, patients are often treated with drugs such as bevacizumab, pazopanib, and sunitinib. These medications work by inhibiting the formation of a blood supply network necessary for tumor growth.

Comparative Analysis of Drug Types

VEGF inhibitors represent a class of drugs that interfere with the vascular endothelial growth factor (VEGF) or its receptor, both crucial for establishing and maintaining blood supply networks around tumors. While these drugs show initial promise, many patients may experience relapse or develop resistance, along with severe side effects.

Another prevalent treatment involves immune checkpoint inhibitors. Although both VEGF inhibitors and immune checkpoint inhibitors are utilized for RCC, neither class is universally effective alone. Hence, there is a pressing need for research into the synergistic effects of combining anti-angiogenic agents and emerging immune checkpoint inhibitors to find safer treatment alternatives for RCC patients.

Study Findings Published in Lancet Oncology

A recent study published in *Lancet Oncology* investigated the safety of combining axitinib (a VEGF inhibitor) and avelumab (an immune checkpoint inhibitor). Conducted across 14 centers in the U.S., U.K., and Japan, the study aimed to establish appropriate dosages through a process known as “dose-finding” and “dose-escalation.” These studies primarily focus on monitoring safety profiles and adverse effects in participants.

From October 30, 2015, to September 2016, the study enrolled six patients during the dose-finding phase, followed by 49 patients in the dose-expansion phase. The open-label design allowed both researchers and patients to be aware of the administered treatments.

Effectiveness and Safety Profile of the Combination

The combination treatment showed promising results, with 58% of participants experiencing a reduction in tumor size. Researchers evaluated the safety profile by categorizing the frequency of severe side effects, termed “adverse events,” which are classified by severity.

Despite the positive outcomes in tumor reduction, 58% of patients also reported grade 3 or worse adverse effects, with increased blood pressure being the most common complication. Notably, 2% of patients experienced treatment-related myocarditis.

The results from the dose-finding phase identified a dosage of 10 mg/kg for avelumab administered bi-weekly, alongside axitinib dosed at 5 mg twice daily. Ongoing phase 3 testing aims to compare the safety profile of this combination with other anti-angiogenic treatments.

Overall, the safety profile of the combined treatment appears comparable to that of each drug administered individually, suggesting no additional risk associated with their combination. Preliminary effectiveness data is encouraging, and further research is underway to validate the use of avelumab plus axitinib in treating renal cell carcinoma.

Conclusion

The findings from this trial indicate potential advancements in the treatment of renal cell carcinoma, with ongoing investigations expected to provide deeper insights into effective and safe treatment combinations.

Written by Vinayak Khattar, Ph.D., M.B.A.
Reference: Choueiri, Toni K., et al. “Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial.” *The Lancet Oncology* 19.4 (2018): 451-460.