For Advanced Sarcomas, New Agents Prolong Remission but Not Survival


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“We are beginning to understand the molecular biology underlying a portion of the 80 or so subtypes of sarcomas, and we hope this will lead to subtype-specific treatments,” said William D. Tap, MD, of Memorial Sloan-Kettering Cancer Center, New York, at the Best of ASCO Boston meeting.

“And in gastrointestinal stromal tumors (GIST), we are going to move away from just using single-agent tyrosine kinase inhibitors. While it is currently hard to challenge imatinib [Gleevec] in the front-line setting, we will see breakthroughs that will reveal alternative pathways that are involved, and we will use this to create combination strategies that will make a difference to patients. Hopefully, we will be changing GIST from a controllable disease to a curable one,” he said.

Regorafenib Becomes a New Option

A newsmaker at ASCO, the phase III GRID trial found the oral tyrosine kinase inhibitor regorafenib dramatically delayed disease progression in patients with treatment-refractory metastatic GIST.1

GRID was an international trial that quickly accrued 236 patients with metastatic unresectable GIST who were intolerant to or showing disease progression despite tyrosine kinase inhibitor treatment (59% received more than two lines of such therapy). Patients received daily regorafenib or best supportive care.

Median progression-free survival reached 4.8 months with regorafenib but was only 0.9 months in the placebo arm, for a 73% reduction in risk (P < .0001). The disease control rate at 12 months was 52.6% with regorafenib and 9.1% with placebo. Overall survival was similar, presumably because 85% of placebo recipients crossed over to regorafenib. Median overall survival has not yet been reached in either arm.

“Regorafenib has the potential to fulfill an unmet need for this patient population, and it is appropriate to seek FDA approval,” said Dr. Tap. Future studies of new agents, however, should probably not use placebo in the control arm, “since patients may now have options after imatinib and sunitinib (Sutent),” he added. “We have to compare novel drugs against these standards of care,” he added.

Pazopanib in Soft-tissue Sarcoma

In the final analysis of the phase III PALETTE trial, involving 362 patients with metastatic soft-tissue sarcoma, treatment with pazopanib (Votrient) resulted in a median overall survival of 12.5 months, vs 10.7 months with placebo, for a 14% reduction in risk that was not statistically significant.2 The primary endpoint, median progression-free survival, was 20 vs 7 weeks, respectively, a highly significant 69% reduction in risk (P < .0001). Two-thirds of patients receiving pazopanib had stable disease over the 25 months of follow-up. The drug seemed particularly beneficial in leiomyosarcoma patients.

“Pazopanib gives us a new drug for sarcoma, which is very difficult to treat and for which we have not had an FDA-approved drug since [doxorubicin],” Dr. Tap said.

Sarcomas, he noted, are a very heterogeneous group of tumors that lack a well-defined treatment strategy. What is becoming clear is that among the 80 different subtypes, genetic and molecular abnormalities vary considerably. “In the past, we treated all sarcomas as one malignancy, but we need to begin to stratify sarcomas based on their unique molecular characteristics. We are slowly doing this, and we hope to ultimately have histology-specific treatments, as we do with GIST.”

New Target for Liposarcoma

Liposarcoma is one of the most common soft-tissue sarcomas. The typical histology is well-differentiated/dedifferentiated (WD/DD), which reflects maturation arrest in adipocyte differentiation. These tumors are characterized by ring chromosomes and gene amplifications that ultimately affect cellular differentiation and proliferation. Blockade of CDK4, which is amplified in 90% of WD/DD patients, prevents binding to cyclin D1, prevents phosphorylation of the Rb gene, and forces cell-cycle arrest. 

The oral novel CDK4 inhibitor PD0332991 induces G1 cell-cycle arrest and inhibits the growth of liposarcoma cells in preclinical models. In a phase II trial reported at ASCO, daily PD0332991 was evaluated in 27 patients with metastatic or recurrent WD/DD liposarcoma, CDK4 amplification, Rb gene expression, and disease progression after at least one regimen.3 Based on historical data, a promising result was defined as a 12-week progression-free survival ≥ 40%.

The progression-free survival endpoint was reached by 19 patients, yielding a progression-free rate of 65.5%. At data cutoff, four patients remain on study with stable disease after 32 to 60 weeks of follow-up. “The response noted in patients with WD/DD liposarcomas, a difficult disease to treat systemically, shows that CDK4 has an active role in the pathogenesis of some of these tumors,” Dr. Tap said. ■

Disclosure: Dr. Tap reported no potential conflicts of interest.

References

1. Demetri GD, Reichardt P, Kang Y, et al: Randomized phase III trial of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor progressing despite prior treatment with at least imatinib and sunitinib. GRID trial. 2012 ASCO Annual Meeting. Abstract LBA10008. Presented June 4, 2012.

2. Van Der Graaf W, Blay J, Chawla SP, et al: PALETTE: Final overall survival data and predictive factors for OS of EORTC 62072/GSK VEG110727, a randomized double-blind phase III trial of pazopanib versus placebo in advanced soft tissue sarcoma patients. 2012 ASCO Annual Meeting. Abstract 10009. Presented June 2, 2012.

3. Dickson MA, Keohan M, Tap WD et al. Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified liposarcoma. 2012 ASCO Annual Meeting. Abstract 10002. Presented June 4, 2012.



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