Clinical trial ineligibility tied to poor renal cell carcinoma outcomes

Phase III clinical trials have led to the approval of several targeted mRCC therapies.

"These clinical trials had strict eligibility criteria to maintain internal validity," said lead investigator Daniel Heng, MD, MPH, medical oncologist at the Tom Baker Cancer Center, University of Calgary in Calgary, Alberta.

To estimate the number of trial-ineligible patients treated with targeted therapy and to evaluate the outcomes of trial-ineligible patients compared with trial-eligible patients, Dr. Heng and co-authors analyzed data from 17 international cancer centers on consecutive series of patients with mRCC. Dr. Heng presented the results at the 2012 Genitourinary Cancers Symposium in San Francisco.

Patients were treated with anti-vascular endothelial growth factor (VEGF) targeted therapy for mRCC, which included sunitinib (Sutent), sorafenib (Nexavar), bevacizumab (Avastin), pazopanib (Votrient), and axitinib (Inlyta).

Commonly used exclusion criteria were a Karnofsky Performance Status <70%, brain metastases, non-clear cell histology, hemoglobin ≤9 grams/dL, creatinine >2x the upper limit of normal, platelet count of <100x10³ /uL, neutrophil count <1500/mm³ , or corrected calcium ≤12 mg/dL.

Of 2,076 mRCC patients treated with targeted therapy, 894 (43%) were deemed ineligible. The most common reason for exclusion was a Karnofsky score <70% (13.4% of patients were excluded due to this parameter), followed by a non-clear cell histology (11.2%), brain metastases (8.3%), and anemia (7.4%).

The median age of the 2,076 patients was 61 years, and the median Karnofsky score was 80%. Nineteen percent had a favorable prognosis, 55% had an intermediate prognosis, and 26% had poor prognosis using the Heng et al prognostic categories. Fifty-eight percent had anemia and 10% had hypercalcemia. Brain metastases were present in 8%, and 11% had a non-clear cell histology. Seventy-nine percent had prior nephrectomy.

More than twice as many patients who were deemed ineligible had a poor prognosis compared with those potentially eligible for clinical trials (43% vs. 16%; p<.0001), said Dr. Heng. In addition, one-fourth of eligible patients had favorable-risk disease compared with only 9% of ineligible patients (p<.0001).

The response rate to therapy was significantly worse in ineligible patients versus eligible patients (21% vs. 29%; p<.0001). Response rates were worse in ineligible patients for all Heng et al prognostic categories.

The median progression-free survival and median overall survival of first-line targeted therapy for ineligible versus eligible patients was 5.2 versus 8.8 months and 14.5 versus 28.8 months (all p<.0001), respectively.

Of the 896 patients who went on to second-line therapy, progression-free survival was 3.2 months in the trial-ineligible versus 4.4 months in the trial-eligible patients (p=.0074).

When adjusted by the Heng et al prognostic categories, the hazard ratio for death between the trial-ineligible and trial-eligible patients was 1.511 (p<.0001).

"The discrepancies in clinical outcome should be taken into account when applying protocol therapies to protocol-ineligible patients," said Dr. Heng. "These patients should still be treated with targeted therapy, but when it comes to patient counseling and prognostication, we should temper those discussions with these data."

Specific trials addressing the needs of protocol-ineligible patients and assessing overall survival are required, he said.