Certain Toxicities Could Be Correlated With mTOR Efficacy in Metastatic RCC

A new study published in BMC Cancer has shown a link between metabolic toxicities and the efficacy of mammalian target of rapamycin (mTOR) inhibitors for the treatment of metastatic renal cell carcinoma (RCC). Specifically, clinical benefit occurred more frequently when liver transaminases and serum creatinine level increased, and when absolute changes in glycemia, phosphatemia, and liver transaminases were higher, the study showed. Conversely, lymphopenia was associated with a lack of efficacy.

“Given this preliminary result, it seems difficult to use a single biological parameter or a single descriptive method to predict treatment efficacy on the basis of toxicity,” wrote Mohamed Jebali, MD, of the department of medical oncology at Hôpital Européen Georges-Pompidou in Paris, and colleagues. “The relationship between a greater number of toxicities and clinical benefit should be investigated but we did not assess these relationships because of the sample size in our series.”

Prior studies of mTOR inhibitors have shown the most frequent adverse events to be skin rash, nausea, mucositis, and diarrhea. The most common metabolic toxicities were anemia, hypercholesterolemia, hypertriglyceridemia, increase in serum creatinine level, and lymphopenia. Some toxicities have been shown to be correlated with drug efficacy.

In this study, the researchers retrospectively collected data on metabolic toxicities that occurred in patients treated with the mTOR inhibitors everolimus and temsirolimus for metastatic RCC to determine if they were associated with efficacy. The study included data from 75 patients. All patients had to have received the medication for at least 28 days.

Of the study participants, 6 had a partial response, 42 had stable disease, and 15 had progressive disease. With a median follow-up of 12.8 months, the median progression-free survival was 6.7 months. The most common all-grade toxicities were lymphopenia, increase in serum creatinine level, hypertriglyceridemia, hypercholesterolemia, and hyperglycemia. The median time to the highest-grade metabolic toxicities ranged from 28 to 90 days.

The researchers found a significant association between clinical benefit and all-grade increase in serum creatinine level and liver transaminases. Ninety-two percent of patients with clinical benefit had an increase in serum creatinine compared with 46% of patients with progressive disease. Similarly, 94% of patients with clinical benefit had an increase in liver transaminases compared with 66% of those with progressive disease.

“There were some discrepancies between our results and those published in the literature,” the researchers wrote. “The rates of grade 3–4 hyperglycemia and lymphopenia were higher in our everolimus subgroup than those described in the literature (13% vs 4%; 20% vs 3%, respectively), whereas the rates of grade 3–4 hyperglycemia were lower in the temsirolimus subgroup than those reported in the literature (6% vs 11%). These discrepancies may be due on the one hand to the small sample size, and on the other hand to a high proportion of patients (64%) who were treated in third-line or more.”

The patients who had clinical benefit from the drugs had a significantly more severe absolute increase of glycemia (P = .002) and absolute decrease in phosphatemia (P = .02). Finally, progression-free survival was significantly higher with the onset rate of hypophosphatemia (P = .03) and hyperglycemia (P = .001) and lower with the onset rate of lymphopenia (P = .004).

The researchers noted several limitations to the study, including its small sample size, the retrospective nature of the study, and the withdrawal of 12 patients.