Renal cell carcinoma: Phase-1 trial finds effective drug combination with high risks

Clinical Trials & Research
renal cell carcinoma

A phase-1b trial funded by Merck and Pfizer combined two drugs to evaluate their effectiveness in treating renal cell carcinoma.

Renal cell carcinoma makes up 95% of kidney cancer cases. About 338,000 cases of renal cell carcinoma are detected worldwide every year.

Renal cell carcinoma is a form of cancer that starts in the small tubules of the kidney.  These tubules filter and transport urine. When renal cell carcinoma is detected at an early stage, either the tumor or kidney itself can be removed to prevent the spread of cancer to other organs of the body. However, during diagnosis, about 30% of patients have advanced or metastatic cases. Metastatic cancer is when the cancer spreads to another part of the body.

In advanced cases, drugs like bevacizumab, pazopanib, and sunitinib are recommended to patients. These drugs block the development of a blood supply network that supplies key nutrients for tumor growth.

Comparing drug types for renal cell carcinoma

VEGF inhibitors are a class of drugs that block either the growth factor called vascular endothelial growth factor (VEGF) or its receptor. These growth factors are required for the start and development of a blood supply network around tumors. Despite initial success, many patients experience relapse and some of these therapies are met with resistance and severe side effects.

Another class of drug that is commonly used to treat renal cell carcinoma is immune checkpoint inhibitors. Both VEGF inhibitors and immune checkpoint inhibitors have been used to treat renal cell carcinoma. However, neither of these drug classes is effective against all cancers alone. There is a need to test a combination of the anti-angiogenic and recently emerging arsenal of immune checkpoint inhibitors to identify a safer combination of drugs for renal cell carcinoma patients.

A recent study published in Lancet Oncology evaluated the safety profile for a combination of axitinib (a VEGF inhibitor,) and avelumab (an immune checkpoint inhibitor).

Researchers conducted the study across 14 centers in the U.S., U.K., and Japan. The study design was geared to identify a relevant dose of each drug, which is a process known as “dose-finding” and “dose-escalation”. These types of studies primarily monitor the safety profile and the adverse effects in patients following treatment.

From October 30, 2015, to September 2016, researchers enrolled six patients in the dose-finding phase and then 49 patients were enrolled in the dose-expansion phase. The study was open-label, implying that both researchers and patients were aware of which drugs were administered.

The combination was effective but the risks were high

Among the patients, 58% experienced a reduction in the size of their tumours. The researchers quantified the safety profile of the drugs by assessing the frequency of extreme side effects. These side effects are also referred to as “adverse events” and classified grade-wise, with grade 3 and grade 4 considered very severe.

Despite the encouraging results in tumor size reduction, as much as 58% of the patients also exhibited adverse events of grade 3 or worse, with increased blood pressure being the most common side effect.

Unfortunately, 2% of patients also succumbed to treatment-related myocarditis. The results of dose-finding phase revealed a dose of 10mg/kg for Avelumab to be administered once every two weeks, and axitinib administration at 5mg twice a day. The safety profile of these drugs is currently in phase 3 testing to compare them with other anti-angiogenic drugs.

Altogether, the safety profile of the combination of drugs seemed comparable to the safety profiles of each treatment alone, indicating that there is no increased risk associated with combining these treatments. The preliminary data on the effectiveness of the treatment is encouraging, and further ongoing research is in progress to further confirm the combination of avelumab plus axitinib in the treatment of renal cell carcinoma.

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. 

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