Targeted Drug, Chemo Similar for Older STS Patients

Older patients with advanced or metastatic soft-tissue sarcoma (STS) had similar progression-free survival (PFS) whether they initially received standard chemotherapy or the angiogenesis inhibitor pazopanib (Votrient), which was better tolerated, a randomized trial showed.

Patients allocated to doxorubicin had a median PFS of 5.3 months as compared with 4.4 months with pazopanib. The outcome resulted in a hazard ratio of 1.00, and the PFS values had overlapping confidence intervals (CI). Objective response rate (ORR) and overall survival (OS) also did not differ significantly between the two treatment groups.

Severe neutropenia and febrile neutropenia, key secondary endpoints, occurred less often with pazopanib, although overall toxicity was similar between the treatments, reported Viktor Grünwald, MD, PhD, of University Hospital Essen in Germany, and colleagues in the Journal of Clinical Oncology.

"To accommodate the rarity of the subgroup of elderly patients with STS, a relaxed noninferiority margin (hazard ratio) of 1.8 was used," the authors noted. "As expected, wide CI margins were reported, but within these limits, pazopanib was noninferior to doxorubicin for PFS and the anticipated superior outcome prevailed for grade 4 neutropenia and febrile neutropenia. Sensitivity analyses were consistent with these findings, indicating no clinically meaningful difference, which was in concordance with a similar OS between arms."

"Overall incidence of toxicity remained similar for both treatment types, but there were differences in the AE [adverse event] profiles that may help guide the choice of treatment for elderly patients," they continued. "Our current trial procedure predominantly selects fit elderly patients to participate in our trials. Future studies should focus on frail patients determined by GA [geriatric assessment] to help develop a therapeutic strategy for this vulnerable patient population."

Long-Time Chemo Standard

Doxorubicin has represented standard-of-care systemic therapy for advanced or metastatic STS since the 1970s, even though the drug has well-recognized toxicity. In one study involving patients ages ≤65, doxorubicin caused grade 4 neutropenia in a third of the patients and febrile neutropenia in 9%. Geriatric patients frequently require hospitalization as a result of doxorubicin-associated toxicity, Grünwald and colleagues noted.

Pazopanib, which targets vascular endothelial growth factor, produces limited hematologic toxicity and has a global health status comparable to placebo, the authors continued. In the U.S., the drug has FDA approval as second-line therapy for advanced/metastatic STS. The drug's lack of severe hematologic toxicity provided the basis for a randomized trial to determine whether pazopanib is noninferior to doxorubicin as first-line therapy for older patients with advanced/metastatic STS.

Investigators in the German Sarcoma Working Group enrolled patients ages ≥60 with previously untreated chemotherapy-sensitive types of STS: fibrosarcoma, pleomorphic high-grade sarcoma, leiomyosarcoma, liposarcoma, alveolar or pleomorphic rhabdomyosarcoma, vascular sarcoma, synovial sarcoma not otherwise specified, and malignant peripheral nerve sheath tumors.

Patients were randomized 2:1 to daily pazopanib or to doxorubicin q3w for a maximum of six cycles. The primary endpoint was PFS and noninferiority was defined by CIs with an upper limit of 1.8.

Tolerability, Efficacy Data

Data analysis included 120 patients, who had a median age of 71. A fourth of patients in each group had dose reductions. In the subgroup of patients older than age 71, 13 (27.1%) randomized to pazopanib and six (40%) to doxorubicin had dose reductions.

About a third of patients in each group discontinued treatment, including 17 (35.4%) in the pazopanib arm and six (40.0%) in the doxorubicin arm who were older than age 71. The rates of discontinuation for toxicity were 22% with pazopanib and 7.7% with doxorubicin.

The entire study population had a median PFS of 4.4 months. The 0.9-month difference between the pazopanib and doxorubicin groups did not achieve statistical significance, and the CIs did not exceed the upper limit of the noninferiority margin (95% CI 0.65-1.53). PFS rates at 12 and 26 weeks did not differ significantly between the groups.

No patient in the pazopanib arm developed grade 4 neutropenia versus 56.4% of patients in the doxorubicin arm (P<0.0001), and febrile neutropenia occurred in 0% and 10.3%, respectively. ORR was 12.3% with pazopanib and 15.4% with doxorubicin. Median OS was 13.9 months for the entire study population, 12.3 months for the pazopanib group, and 14.3 months for the doxorubicin subgroup (HR 1.08, 95% CI 0.68-1.72).

Safety and tolerability data showed distinct AE profiles for pazopanib and doxorubicin. AEs, regardless of origin, and treatment-related AEs occurred in a similar proportion of patients in each treatment arm. The most common AEs (≥10% of patients) associated with pazopanib were diarrhea, hypertension, hypothyroidism, and general physical health deterioration. In contrast, the most common AEs in the doxorubicin arm were alopecia, neutropenia, stomatitis, anemia, leukopenia, and mucosal inflammation.

The authors stated that tolerability parameters beyond neutropenia may help determine the best treatment option for a given patient in the clinic setting. Additionally, comorbidities and patient preference "should be aligned with characteristic AEs of a given therapy."

Available data suggest a specific group of patients for which pazopanib is appropriate, said Brian A. van Tine, MD, of Washington University in St. Louis, who participated in a recent trial of dose-escalated pazopanib in older patients with STS and ineligible for chemotherapy.

"For debilitated older patients who want therapy, you can find out how well they do on therapy by starting them on pazopanib," he told MedPage Today. "In our study, we did dose escalation of pazopanib and found that it was much better tolerated. I think that doxorubicin versus pazopanib as front-line therapy doesn't matter so much as the patients who are being treated. The older patients get, the more likely I am to not want to use doxorubicin."

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