Ridaforolimus Shows Promise as Maintenance Therapy for Patients With Advanced Sarcoma

Patients with metastatic soft-tissue sarcoma had statistically significant improvement in progression-free survival (PFS) when treated with mTOR inhibitor ridaforolimus, results of a multicenter trial showed.

Median PFS improved from 14.6 weeks with placebo to 17.7 weeks among patients treated with ridaforolimus. The 3- and 6-month PFS also showed advantages for the active treatment, according to a report presented in June at the ASCO annual meeting.

“The study met the primary endpoint in progression-free survival improvement,” said Sant Chawla, MD, a medical oncologist at the Sarcoma Oncology Center in Santa Monica, California. “There was a trend toward a benefit for overall survival, with a hazard ratio of 0.88 for ridaforolimus compared with placebo.

“Ridaforolimus provided better tumor control, and the treatment had no adverse impact on survival following disease progression. We observed no major unexpected adverse events and toxicities, which were similar to other mTOR inhibitors.”

Multiples types of sarcomas exhibit dysregulated mTOR signaling. Ridaforolimus is a rapamycin analog that possesses potent mTOR inhibition, and phase I/II clinical trials demonstrated clinical activity in sarcomas.

Table. SUCCEED Trial: Progression-Free Survival Rates

Independent Radiology Review

HR = 0.72; P = .0001

Median PFS

3-Month PFS Rate

6-Month PFS Rate

Ridaforolimus

17.7 weeks

70%

34%

Placebo

14.6 weeks

54%

23%

Investigator Assessment

HR = 0.69; P = .0001

Median PFS

3-Month PFS Rate

6-Month PFS Rate

Ridaforolimus

22.4 weeks

72%

37%

Placebo

14.7 weeks

55%

23%

HR indicates hazard ratio; PFS, progression-free survival.

Adapted from Chawla et al. J Clin Oncol. 2011;29(suppl; abstr 10005).

Chawla presented results of a phase III trial involving 711 patients with metastatic sarcomas that had progressed after initial benefit (response or stable disease) during treatment with as many as 3 prior chemotherapy regimens. Patients were randomized to ridaforolimus or placebo and treated until disease progression. Response was assessed by an independent radiology review.

The primary endpoint was PFS. Secondary endpoints included overall survival, objective response, cancer-related symptoms, and safety.

When the trial ended, the 3.1-week improvement in PFS with ridaforolimus translated into a 28% reduction in the hazard for progression (P = .0001). Ridaforolimustreated patients had a 3-month PFS of 70% compared with 54% for the placebo group, and 6-month PFS was 34% and 23% with ridaforolimus and placebo, respectively (Table).

Investigator-assessed PFS showed a larger advantage for ridaforolimus, reflected in a median PFS of 22.4 weeks versus 14.7 weeks with placebo, representing a 31% reduction in the hazard for progression (P = .0001).

Subgroup analysis showed a consistent advantage for ridaforolimus across all prespecified patients subgroups.

Analysis of the secondary endpoint of overall survival yielded a median of 21.4 months with ridaforolimus versus 19.2 months with placebo, a 12% reduction in the hazard (P = .2256).

Significantly more patients derived clinical benefit from treatment with ridaforolimus. The total clinical benefit rate was 40.6% with ridaforolimus and 28.6% with placebo (P = .0009).

“

Ridaforolimus provided better tumor control, and the treatment had no adverse impact on survival following disease progression. We observed no major unexpected adverse events and toxicities, which were similar to other mTOR inhibitors.”

—Sant Chawla, MD

Assessment of tumor growth also showed a significant difference in favor of ridaforolimus. The best target lesion response averaged —1.3% with ridaforolimus, whereas placebo-treated patients had a 10.3% increase in target lesion size as best response (P <.0001).

Post-progression survival was similar in the 2 treatment arms, suggesting no adverse effect of treatment with the mTOR inhibitor.

All ridaforolimus-treated patients had grade 1 or higher toxicity, and 64% had grade 3 or higher toxicity. The most commonly reported adverse events were stomatitis (61%), infections (52%), fatigue (36%), thrombocytopenia (34%), diarrhea (32%), cough (31%), and rash (28%). Only thrombocytopenia had as much as a 10% incidence of grade 3 or worse severity.

“It is important and interesting to note that 94% of the patients in the placebo arm had at least grade 1 toxicity and 26% had grade 3 or more,” said Chawla. “This was clearly reflective of patients’ disease and prior chemotherapy and background activity.”

The effect of treatment on cancer-related symptoms could not be assessed due to missing data for a substantial proportion of patients in each group.

Chawla SP, Blay J, Ray-Coquard IL, et al. Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy. J Clin Oncol. 2011;29(suppl; abstr 10005).