TKI Dose Escalation Reduces Tumor Burden in mRCC

Roxanne Nelson, BSN, RN

November 10, 2015

MIAMI — Dose escalation of tyrosine kinase inhibitors (TKIs) after disease progression in select patients with metastatic renal cell carcinoma (mRCC) can lead to a reduction in tumor burden and extend the duration of therapy, according to research presented here at the 14th International Kidney Cancer Symposium (IKCS).

One of the problems clinicians face when administering oral TKIs to patients with mRCC is that drug levels of TKIs are highly variable in these patients, explained lead author Moshe Ornstein, MD, of the Cleveland Clinic Taussig Cancer Institute, in Ohio.

"That provides a dilemma to providers who are prescribing the same drug at the same dose to similar patients and potentially seeing different effects," said Dr Ornstein during his presentation. "For that reason, there are dose modifications and adjustments that have been incorporated into TKI dosing, but little is known about the role of dose escalation at the time of disease progression."

Dr Ornstein and his colleagues at the Cleveland Clinic conducted a retrospective review of mRCC patients who experienced disease progression while being treated with TKIs and who underwent dose escalation.

A total of 22 patients were identified. The majority (82%) were men; the median age at diagnosis was 58 years (range, 40-71 years). The most common histologic finding was clear cell (77%), all but one patient had undergone prior nephrectomy, and 77% of patients were at intermediate risk.

"Our patient population was fairly representative of the typical metastatic renal cell carcinoma population," Dr Ornstein noted.

Axitinib (Inlyta, Pfizer Inc) was the most frequently escalated agent following disease progression (17 patients). Patients were receiving different doses at the time of disease progression; doses were escalated on the basis of current dose and tolerability.

Dr Ornstein noted that of those 17 patients, 11 were receiving 5 mg BID at the time of progression, and the dose was generally escalated to 6 or 7 mg.

Of the remaining five patients, three were receiving sunitinib (Sutent, Pfizer Inc), and two were receiving pazopanib (Votrient, Novartis Pharmaceuticals Inc).

Dr Ornstein point out that prior to disease progression and dose escalation, the best response was a partial response, seen in eight patients (36%), and stable disease, seen in 14 patients (64%); median duration of treatment was 6.8 months (range, 1.6 - 50.6 months).

"In terms of the TKI that was dose-escalated, it was first-line therapy in 32% of the patients and second-line in 27% of patients," he said.

Tumor Burden Reduced

After dose escalation, the researchers looked at the effect on tumor burden. In 17 patients with evaluable tumor measurements after TKI dose escalation, 82% experienced a reduction in tumor burden, with a median decrease of 14%.

However, 24% of these responders experienced a decrease in tumor burden of more than 30%, which is RESIST partial response, Dr Ornstein point out.

Thus, these patients had a significant decrease in tumor burden; prior to disease progression and dose escalation, three of the patients in this subgroup had only had stable disease. "This suggests that upon progressive disease and dose escalation, you can actually improve the RECIST response," he said.

You can actually improve the RECIST response. Dr Moshe Ornstein

As an example, Dr Ornstein pointed to one patient who had significant disease in his liver and retroperitoneum. Therapy was initiated with axitinib at 5 mg. The patient's disease progressed, and the dose was escalated to 7 mg. Ten months later, there has been significant shrinking of metastatic sites.

At the time of this analysis, seven patients were continuing to be treated at escalated TKI doses. Numerically, this translates to a median duration of treatment of 6.8 months prior to disease progression and dose escalation; the median treatment duration of escalated therapy was 6.7 months.

On the downside, 14 patients discontinued therapy, including five who discontinued therapy because of tolerability, primarily toxicities of fatigue and diarrhea, and eight because of disease progression.

"These data suggest that patients with metastatic disease who develop resistance on TKI treatment will derive significant clinical benefit from dose escalation in terms of extending the duration of TKI therapy and decrease tumor burden," Dr Ornstein concluded.

14th International Kidney Cancer Symposium (IKCS). Presented November 7, 2015.


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