Targeted agents have started to make inroads in sarcoma therapies, and gastrointestinal stromal tumor (GIST) is the poster child for this success,” Mark Agulnik, MD, stated in summarizing progress in GIST and other sarcomas at the Best of ASCO meeting in Chicago. Dr. Agulnik is Associate Professor, Northwestern University, Feinberg School of Medicine, Chicago.
Ten-year outcomes from the phase III SWOG Intergroup Trial S00331 show that a significant subset of patients with metastatic GIST achieved durable long-term overall survival with single-agent imatinib (Gleevec). The trial was designed to study the impact of two different doses of imatinib among patients with advanced GIST, but long-term survival rates (8 or more years) among 695 eligible patients differed little—27% for those receiving 400 mg/d and 25% for those receiving 800 mg/d.
GIST genotype was available in a subset of 395 patients. Among these patients, 282 (71%) had KIT exon 11 mutations, 67 (17%) had no mutation detected in KIT or PDGFRA, 32 (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA mutations. At 4.5 years’ median follow-up, patients with KIT exon 11 mutations had significantly better overall survival than those with no mutations (P = .011) or with KIT exon 9 mutations (P = .049).
Data from 2014 show significantly worse overall survival for patients with KIT exon 9 mutations—38 months median overall survival vs 66 months for patients with KIT exon 11 mutations (P = .001) and 40 months for patients with no mutations (P = .047).
Evolving Landscape of Options
Information obtained for 137 long-term survivors revealed that 49% received no additional therapy beyond imatinib. Of the 51% who did receive additional therapy, 39% received systemic therapy with the tyrosine kinase inhibitors sunitinib (Sutent, 41 patients or 30%) and sorafenib (Nexavar, 16 patients or 12%), or other agents. A total of 41 patients (30%) received surgery; 10 patients (7%) had radiofrequency ablation; and 6 patients (4%) had radiation therapy.
“The landscape of therapeutic options for GIST has evolved greatly since this early large-scale trial,” Dr. Agulnik said. He mentioned that new tyrosine kinase inhibitor therapies, including regorafenib (Stivarga), have been approved for patients following disease progression on imatinib.
“Multidisciplinary management of GIST, with resection of limited sites of oligoclonal, resistant disease, is a standard option with continuation of [tyrosine kinase inhibitor] therapy to manage residual unresectable disease,” he added. “New options for management of KIT exon 9 mutant and other resistant GIST genotypes are still needed.”
Phase II Ponatinib Trial
Initial analysis of a phase II trial of ponatinib (Iclusig)2 “suggests ponatinib has activity in patients with advanced GIST,” particularly patients with KIT exon 11 mutations in whom prior tyrosine kinase inhibitor therapy has failed, Dr. Agulnik reported.
“Ponatinib is an oral [tyrosine kinase inhibitor] with potent activity against BCR-ABL,” he explained, and “against mutated forms of KIT and PDGFRA, including KIT mutations that confer resistance to approved [tyrosine kinase inhibitors].” Ponatinib has been approved for the treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) or T315I-positive Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL), and for those with CML or Philadelphia chromosome–positive ALL for whom no other tyrosine kinase inhibitor is indicated.
The phase II trial initially included patients with advanced GIST in whom one or more tyrosine kinase inhibitors have failed, but the protocol was amended earlier this year to include only patients for whom all three tyrosine kinase inhibitors approved for GIST—imatinib, sunitinib, and regorafenib—have failed. The 35 enrolled patients received ponatinib at 45 mg once daily, and 14 patients have received treatment for at least 6 months and remain on therapy (1 with a partial response, 11 with stable disease, and 2 with progressive disease).
The primary endpoint of clinical benefit rate (complete response plus partial response plus stable disease) was 50% at 16 weeks for patients with KIT exon 11–mutant GIST. “When we look at overall survival and progression-free survival, we see that the patients with KIT exon 11–mutated disease do better than those without the mutation,” Dr. Agulnik pointed out.
Median overall survival was not reached, but at 6 months was 80% for patients with KIT exon 11 mutations and 71% for those without. Median progression-free survival was 7 months for patients with KIT exon 11 mutations and 4 months for those without. Overall, these data “provide ponatinib proof of concept in resistant GIST and warrant future investigation,” Dr. Agulnik stated.
The safety profile of ponatinib in GIST appears to be consistent with that in CML, except that “myelosuppression is notably less in GIST than in leukemia studies,” Dr. Agulnik noted. Treatment-emergent serious adverse events occurring in two or more patients were abdominal pain (11%), and nausea, vomiting, and fatigue (6% each). The researchers reported that one patient had myocardial ischemia and one died, possibly related to ponatinib therapy.
Predictive Biomarker Profiling
In an attempt to identify predictive biomarkers for potential targeted therapies, a multiplatform profiling study3 looked at more than 1,900 specimens from a variety of sarcomas, although GIST and Kaposi sarcoma were excluded. Explaining the rationale behind this study, Dr. Agulnik noted, “While sarcoma is rare, it is a very heterogeneous tumor, and so, predictive biomarkers may help direct the selection of optimal therapy for an individual patient. And we do know that we need new therapeutics,” he continued. “If we could identify the targets and use these therapeutics, we could make a substantial change for these patients.”
More than 6,000 physicians submitted specimens from 59 countries, and these specimens were reviewed by board-certified pathologists. The median age of the patients was 55, and 62% of the specimens were from females, which Dr. Agulnik said was probably a reflection of the number of uterine sarcomas.
Samples were analyzed using immunohistochemistry, fluorescence or chromogenic in situ hybridization (FISH/CISH), and/or next-generation or Sanger DNA sequencing. For 256 cases, all three platforms of testing were used.
The sequencing results did not reveal many mutations. The most common mutation was in TP53, which was found in 22.4% of all patients with a variety of sarcomas, Dr. Agulnik pointed out. The frequency of other mutations ranged from 1.2% to 3.2%.
TOPO2A was found to be overexpressed in approximately 50% of sarcomas, without associated gene amplification. This overexpression was most common in angiosarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma. The study authors concluded that the utility of TOPO2A should be studied as a biomarker for sensitivity to anthracyclines, especially in relation to TP53 status in a tumor.
“Profiling through protein expression, gene copy variations, and mutations identified alterations in 99% of sarcoma samples,” Dr. Agulnik reported. “Future clinical trials are needed to determine the predictive and/or prognostic nature of these findings.” ■
Disclosure: Dr. Agulnik is a consultant for and receives honoraria from Novartis and GlaxoSmithKline.
References
1. Demetri GD, Rankin CJ, Benjamin RS, et al: Long-term disease control of advanced gastrointestinal stromal tumors (GIST) with imatinib (IM): 10-year outcomes from SWOG phase III intergroup trial S0033. ASCO Annual Meeting. Abstract 10508. Presented June 1, 2014.
2. Heinrich MC, von Mehren M, Demetri GD, et al: A phase 2 study of pontanib in patients (pts) with advanced gastrointestinal stromal tumors (GIST) after failure of tyrosine kinase inhibitor (TKI) therapy: Initial report. ASCO Annual Meeting. Abstract 10506. Presented June 1, 2014.
3. Movva S, Wen W, Chen W, et al: Predictive biomarker profiling of > 1,900 sarcomas: Identification of potential novel treatment modalities. ASCO Annual Meeting. Abstract 10509. Presented June 1, 2014.
