Novel Targeted Agents In Soft Tissue Sarcoma.

Welcome to the Oncology Network for Excellence. We are again speaking with Dr. John Eckardt on novel targeted agents in soft tissue sarcoma. Dr. Eckardt, in recent years, several previously unmet needs have been fulfilled as new targeted agents have emerged. Still today, one area of unmet need is sarcoma. Can you tell us what progress has been made in this area recently?

For many years in drug development tumor types such as metastatic renal cell carcinoma, metastatic melanoma, and soft tissue sarcoma  were the mainstay of phase I drug development, due to the  inherent resistance of these tumors to standard cytotoxic chemotherapy .   Recently VEGF tKIs and mTOR inhibitors have demonstrated  significant activity in RCC, and currently  bRAF and CTLA4 inhibitors have  demonstrated activity in melanoma, we now have first, second, and sometimes even third line therapies for RCC and melanoma..

However, sarcoma remains the forgotten stepchild. There has been no new agents approved for sarcoma in over 20 years.  At ASCO this year, there three interesting new trials demonstrating the activity of new targeted therapy in treatment of patients with soft tissue sarcoma. 

QUESTION:   Can you briefly tell us about these trials?

This trial was presented by Dr. Chawla on behalf of the SUCCEED investigators.  Ridaforolimus is a rapamycin analogue and a potent inhibitor of the mTOR pathway.  Prior therapies with ridaforolimus in soft tissue sarcomas has demonstrated regressions of tumors as a single agent and have demonstrated  clinical benefit responses in early phase I and phase II  trials of  27-29% as defined as by CR, PR, or stable disease lasting greater than 4 months.

In the phase III trial, patients who had a CR, PR, or stable disease with standard cytotoxic chemotherapy were randomized to receive either ridaforolimus at dose of 40 mg every day for five days weekly or placebo.  On the trial 711 patients were enrolled. The characteristics of both arms in the trial were well balanced between the ridaforolimus and placebo arms. 

The primary endpoint of this trial was PFS (progression free survival).  In this trial ridaforolimus  demonstrated  a 17.7 week  vs. 14.6 week median PFS.   The 6 month PFS was also improved for the ridaforolimus arm demonstrating a 34% PFS vs.  23% for placebo.   The overall hazard ratio for PFS was .72 with a statistically significant  p value of .0001. For the primary endpoint of PFS, there were no major differences in the subgroups assessed. 

For OS(overall survival), ridaforolimus demonstrated a medium OS of 21.4 weeks vs 19.2 weeks for placebo.   Clinical benefit response was also superior for ridaforolimus arm.  Ridaforolimus demonstrated 40.6%   clinical benefit response compared to 28.6% for placebo with a p value of .0009.

Finally, toxicities were generally well tolerated on ridaforolimus arm. Grade 3 toxicities included thrombocytopenia in 10% of patients and stomatitis in 9% of patients.

Overall, these encouraging data are  expected to lead to filing for ridaforolimus as a maintenance treatment  for soft tissue sarcoma in patients who have an initial response or stable disease to chemotherapy.

Trial II

The second trial I would like to discuss is a phase III trial done by the EORTC evaluating pazopanib vs placebo in patients with soft tissue sarcoma whose disease had progressed during or following prior chemotherapy.

Pazopanib is a multi-kinase angiogenesis inhibitor targeting VEGF, PDGFR, and cKIT.  In earlier phase II trials in soft tissue sarcoma, response rates were seen in 44% of patients with leiomyosarcoma, 49% synovial sarcoma, and 39% of patients with other soft tissue sarcomas.  In this trial, patients with advanced soft tissue sarcoma with performance status of 0 or 1 who have progressed within 6 months of chemotherapy or after. Up to four lines of prior therapy were randomized in a 2:1 fashion to either pazopanib 800 mg a day or matching placebo.

Overall, 369 patients were enrolled on the trial, with 246 on the pazopanib arm and 123 on the placebo arm. The primary endpoint evaluated was progression free survival (PFS).  In this study, patient characteristics were well balanced between the two arms.  In assessment of the primary endpoint, pazopanib was found to have a PFS of 4.6 months vs. 1.5 months in placebo, with a hazard ratio (HR) of .31 and a p-value of less than .0001.

Secondary endpoints included overall survival (OS).  In this trial, OS was improved with the median OS for the placebo group of 10.4 months and the pazopanib group of 11.6 months which gave a HR of .83 and p-value of .17.  Other endpoints included response rate (RR).  Partial responses  (PR) were seen in 6% of patients on the pazopanib arm vs 0 on the placebo arm. Stable disease (SD)  was seen in 67% of patients on the pazopanib arm vs. 38 %  of patients on the placebo arm.

Toxicities seen on this trial were consistent with prior experience with pazopanib. These included grade 3/ 4 fatigue in 13% of patients, grade 3/4 diarrhea in 5% of patients and grade 3/4 hypertension in 7% of patients.  One patient had a drug related death on the pazopanib arm, which was due to multi organ failure.

In conclusion, pazopanib demonstrated significant activity in patients with soft tissue sarcoma previously exposed to chemotherapy with approximately three-fold increase in PFS compared to placebo arm. This trial was stopped on interim analysis and final trial results are expected later this year.

Trial III

Finally, let’s discuss the randomized discontinuation trial of brivanib in patients with advanced soft tissue sarcoma.  Brivanib is a selective duel inhibitor of VEGF and FGF.  In this trial, brivanib was given initially to 251 patients. After 12 weeks of treatment, patients with PR were continued on brivanib open label.  Patients with SD were then randomized to either brivanib or placebo.  Patients with progressive disease were taken off therapy.  Patients who received placebo were eligible to receive brivanib as open-label at the time of progression.

Of the 251 patients who initially began brivanib therapy at 800 mg/ day, 133 patients were removed from study due to progressive disease.  Another 35 patients were removed due to other causes including toxicities, consent withdrawal, or unrelated toxicities to the study drug.  Of the remaining 83 patients, 7 demonstrated PR and were continued on brivanib.  Of these responses, 3 were patients with angiosarcoma which was 15% of all treated angiosarcoma patients.  Of the remaining 76 patients who had SD, 38 were randomized to remain on brivanib and 38 patients were crossed over to placebo.   

The primary endpoint on this trial was PFS in patients with overexpression of FGF2. The trial also looked at secondary exploratory analysis for the activity of brivanib in patients without FGF2 overexpression.  Primary analysis in patients with overexpression of FGF2 demonstrated a doubling of PFS from 1.4 to 2.8 months with a HR of .58 and p-value of .08. This reached the pre-specified 10% alpha level.  In the secondary exploratory analysis in patients who were FGF2 negative, brivanib demonstrated an improvement in PFS from 1.4 to 2.6 with a HR of .8.  This trial was not powered to determine if there is a difference in efficacy of brivanib between FGF2 + and FGF2- patients, though the difference in PFS of  2.8 vs 2.6 months was small.

Of the 38 patients randomized to placebo arm, 30 went on to receive brivanib post progression.  Of these patients, the median PFS was 4.1 months. This is impressive in that these patients had initial SD to brivanib, were taken off therapy and progressed, and went back on therapy and again developed SD.

Toxicities seen on this trial were consistent with prior experience of brivanib including Grade 3-4 fatigue in 10% patients and Grade 3-4 hypertension in 15% of patients.   There were 2 deaths observed on the trial, one due to widespread bleeding and the other from an unknown cause. 

In conclusion, in this randomized discontinuation trial, brivanib appears to have significant activity in heavily pre-treated advanced soft tissue sarcoma patients who overexpress FGF2; however, the trial was not powered to determine if FGF2 is an appropriate biomarker for the use of brivanib in soft tissue sarcoma.  Further evaluation in phase III trials will be required to confirm the activity of brivanib in soft tissue sarcoma patients and to determine if FGF2 is an appropriate biomarker.

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