In patients receiving everolimus in clinical trials, stomatitis frequently occurred in the initial weeks of treatment, but this did not compromise clinical outcomes, according to Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.
In fact, there was some indication that the occurrence of stomatitis was actually predictive of greater treatment benefit, she noted at the American Society of Clinical Oncology’s 2014 Breast Cancer Symposium.
“In this retrospective analysis, stomatitis appeared to be associated with longer progression-free survival [PFS]” in most of the trials, Rugo indicated, though she cautioned that this was an unplanned analysis.
“In many patients with stomatitis, we reduced or held doses. We can’t say the outcome is better in patients who got stomatitis, but it’s certainly not worse. It tells us that patients who get stomatitis, even though we hold or reduce doses, have at least the same PFS, and in some patients, stomatitis may be a marker [of prognosis],” Rugo said.
Meta-Analysis of Key Trials
The relationship between stomatitis and clinical outcomes in patients treated with mTOR inhibitors had not been evaluated prior to this meta-analysis. The study also aimed to assess the incidence, time to occurrence, and severity of stomatitis in patients treated with everolimus.
The researchers examined data from 7 randomized, double-blind, phase 3 clinical trials of everolimus in patients with advanced breast cancer (BOLERO-2 and -3), neuroendocrine tumors (RADIANT-2 and -3), renal cell carcinoma (RECORD-1), and tuberous sclerosis complex (EXIST-1 and -2).
Altogether, of the 1455 cancer patients treated with everolimus, 67% experienced stomatitis of any grade. A second episode was reported in 40% of these patients, with the episodes tending to be less severe. The incidence was highest (71%) in the breast cancer trials. Most stomatitis was grade 1/2, with grade 3/4 observed in only 8.6%. Only 25 patients (1.7%) discontinued treatment as the result of stomatitis.
“Stomatitis occurred rapidly,” Rugo noted. More than 60% of the 973 patients reporting this toxicity developed it by 2 months; median time to the first episode was 0.82 months and 89% of all first episodes were observed within 8 weeks.
“Sixty percent of patients who experienced stomatitis experienced only 1 episode. Regardless of whether a patient experienced 1 or 2 episodes, most were of grade 1 or 2 severity,” Rugo indicated. Dose reductions and interruptions were necessary for approximately one-quarter of patients, usually those with grade 3 or 4 stomatitis. Adjustments were most likely during the breast cancer trials.
Progression-Free Survival Improved?
Development of stomatitis within 8 weeks of everolimus treatment initiation, compared with everolimus-treated patients without this toxicity, was associated with longer PFS in the BOLERO-2 (hazard ratio [HR] = 0.78) and RADIANT-3 (HR = 0.70) trials. A similar trend was observed for the RECORD-1 (HR = 0.90) and RADIANT-2 (HR = 0.87), but not for BOLERO-3, the analysis showed.
In BOLERO-2, median PFS was 8.48 months in everolimus-treated patients who developed stomatitis, 6.90 months for patients without stomatitis, and 3.17 months for the control arms. In RADIANT-3, median PFS was 13.86 months, 8.31 months, and 4.60 months, respectively.
“A big issue with everolimus is toxicity. Grade 2 stomatitis is actually very unpleasant. Altogether, about 30% of our breast cancer patients are bothered by this, the majority within the first 6 weeks, but it doesn’t impact efficacy,” Rugo said.
“These findings support continuing everolimus with dose adjustments and management according to the approved prescribing information in patients who experience stomatitis,” she said.
Rugo recommended checking on patients 2 weeks after the start of treatment, and managing grade 2 or higher toxicity with dose delays or reductions. She treats stomatitis with steroid mouthwash and is studying the mouthwash as prophylaxis as well.
“My personal experience is that you have to stop the drug for grade 2 stomatitis, use the steroids, then restart everolimus with the patient on the mouthwash. Many patients can escalate back up to the same dose. Patient education is also critical,” Rugo said.
Rugo HS, Yao JC, Pavel M, et al. Stomatitis incidence and its relationship with efficacy: a meta-analysis of everolimus clinical studies. J Clin Oncol. 2014;32(suppl 26):abstract 151. Poster presented at: American Society of Clinical Oncology 2014 Breast Cancer Symposium; September 4-6, 2014; San Francisco, CA.