More Data Supporting Temsirolimus in Advanced Kidney Cancer

Allison Gandey

June 29, 2007

June 29, 2007 (Chicago) -- Two new analyses of a phase 3 trial of temsirolimus ( Torisel, Wyeth) show the drug improves overall survival in patients with clear cell and other tumor cell types, and patients report enhanced quality-adjusted survival. Findings were presented here at the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting. "The results of these analyses expand our understanding of temsirolimus in patients with advanced kidney cancer," Janice Dutcher, MD, from Our Lady of Mercy Medical Center, in the Bronx, and New York Medical College, in Valhalla, told reporters. "The data also improve our knowledge of patients’ perception of their health during this time on therapy."

Phase 3 results of the major temsirolimus trial were published last month (Hudes G et al. N Engl J Med. 2007;356:2271-2281). As reported by Medscape, the study showed the targeted therapy extended median overall survival vs interferon alpha in patients with advance renal cell carcinoma. Temsirolimus is a specific inhibitor of mammalian target of rapamycin (mTOR), a signaling protein that regulates cell growth and angiogenesis.

In an interview with Medscape at the time the study was published, Gary Hudes, MD, director of the genitourinary malignancies program at the Fox Chase Cancer Center, in Philadelphia, said the trial was unique in that all of the patients had advanced metastatic disease, and it was specifically designed for patients with poor prognostic indicators. "This is a group that hasn't been well studied," he said. "The majority of modern studies may include only a small handful of patients with disease this advanced."

The researchers looked at 626 previously untreated patients with metastatic renal cell carcinoma and a poor prognosis. Patients were randomized to 1 of 3 groups and received either 25 mg of intravenous temsirolimus once a week, subcutaneous injections of interferon alpha beginning at 3 million U and increased to a maximum of 18 million U 3 times weekly, or combination therapy of 15 mg of temsirolimus and 6 million U of interferon at the standard routes and schedules.

Patients randomized to receive temsirolimus experienced the greatest increase in median survival. Patients using temsirolimus as monotherapy had an overall survival of 10.9 months compared with 8.4 months for combination temsirolimus and interferon therapy and 7.3 months for those treated with interferon. Combining the 2 agents did not improve overall survival, but patients who received combination therapy had the greatest number of grade 3 and 4 adverse events, which led to subsequent delays and reductions in treatment.

Improves Overall Survival in Clear Cell and Other Tumor Types and Enhances Quality-Adjusted Survival

During poster discussions at ASCO, investigators presented 2 new analyses of the trial. Sponsored by Wyeth Pharmaceuticals, the first study looked at the link between tumor histology, age, and prognostic risk group and survival. The second study evaluated quality-adjusted survival -- a measure that incorporates patient feedback on time without symptoms and adverse effects.

Led by Dr. Dutcher, the investigators of the first study found that temsirolimus benefits patients regardless of histology or age. And they suggest that patients in both poor- and intermediate-risk groups might also benefit. The proportion of patients with different histologies was balanced across all groups (82% clear cell; 18% other histologies, including non-clear cell and indeterminate). Of those with additional subtype data, 75% were papillary.

For patients with clear-cell tumors, median overall survival and progression-free survival were greater for temsirolimus vs interferon, with a hazard ratio of 0.85 and 0.84. For patients with other tumor histologies, the median overall survival and progression-free survival were also greater fortemsirolimus vs interferon, with a hazard ratio of 0.55 and 0.36.

In the second study, led by Rajiv Mallick, PhD, from Wyeth Pharmaceuticals in Collegeville, Pennsylvania, the group looked at a predefined secondary end point of the larger phase 3 temsirolimus trial. To evaluate quality-adjusted survival, the researchers asked patients to complete questionnaires at several points, including weeks 12 and 32 of the study, when they experienced a serious adverse event, and upon relapse, progression of disease, or withdrawal from the study.

All 626 randomized patients in the study were included in computation of health states. Questionnaires were completed by:

  • 601 of 626 (96%) patients at baseline.

  • 260 of 300 (87%) patients upon progression.

  • 230 of 570 (40%) of patients during a grade 3/4 adverse event.

Among patients with advanced renal cell carcinoma and poor prognostic features, single-agent temsirolimus was associated with significantly longer overall survival compared with interferon alpha. This longer survival almost entirely consisted of time spent without symptoms of progression or toxicity. The researchers conclude that patients treated with temsirolimus had significantly greater quality-adjusted survival than those treated with interferon alpha.

Temsirolimus Adverse Reactions and Warnings

The most common adverse reactions observed with temsirolimus are rash, asthenia, mucositis, nausea, edema, and anorexia. The incidence of these reactions is 30% or more. This is also the case for the most common laboratory abnormalities, which include anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated aspartate aminotransferase, and leukopenia.

The use of temsirolimus is likely to lead to increases in serum glucose, the manufacturer warns. This may result in the need for an increase in the dose or initiation of insulin or an oral hypoglycemic agent. Temsirolimus use is likely to lead to increases in serum triglycerides and cholesterol. This may require initiation or increase in the dose of lipid-lowering agents. And the product has been linked to immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

Cases of interstitial lung disease, some resulting in death, have been reported with temsirolimus. Bowel perforation or renal failure may also occur. Clinicians are asked to promptly evaluate fever, abdominal pain, bloody stools, or acute abdomen. Due to abnormal wound healing, experts warn temsirolimus should be used with caution during the perioperative period.

American Society of Clinical Oncology 43rd Annual Meeting: Poster discussions 5033 and 5049. Presented June 2, 2007.

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