Dr Haddox Discusses Novel, Targeted Therapies in Soft Tissue Sarcomas
Candace L. Haddox, MD, Dana-Farber Cancer Institute, discusses novel and targeted therapies in soft tissue sarcomas at the virtual 2022 Rare Cancer Series from Great Debates & Updates.
According to Dr Haddox, sarcomas have unique behaviors and biology, taking up 1% of cancers in adults with over 100+ distinct histological subtypes.
Recent histology-driven drug approvals in soft tissue sarcomas include ripretinib and avapritinib for gastrointestinal stromal tumors (GIST), nab-sirolimus for perivascular epithelioid cell tumor (PEComa), tazemetostat for epithelioid sarcoma, pexidartinib for tenosynovial giant cell tumor (TGCT), denosumab for giant cell tumor of bone, imatinib for dermatofibrosarcoma protuberans (DFSP), and pomalidomide for Kaposi sarcoma.
GISTs are the most common sarcoma subtype ad the most common sarcoma treated with targeted tyrosine kinase inhibitors (TKIs), explained Dr Haddox. Out of all patients with GIST, 75% have activating mutations in the KIT oncogene. Other mutations include PDGFRA, NF1, SDH-deficient, BRAF, and NKRK. Most are susceptible to imatinib.
Ripretinib is a switch control TKI now approved for GIST in the 4th line, Dr Haddox said. It has a unique mechanism of action that stabilizes the inactive conformation.
In two clinical trials, ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients previously treated with 3 or more TKIs.
Beyond ripretinib (150 mg BID, > 4 lines of therapy [L] with an median progression-free survival [mPFS] of 3.7 months), there are off label options for patients with GIST in later lines of treatment, Dr Haddox said, including cabozantinib (60 mg daily, > 2L, mPFS 5.5 months), avapritinib (300 mg daily, > 3L, mPFS 3.7 months), pazopanib (800mg daily, > 2L, mPFS 3.4 months), and more.
Avapritinib is a novel TKI inhibiting PDGFRA D842V mutant GIST. In a phase 1 dose expansion trial, for 56 patients, the mPFS was 34 months (95% CI, 22.9-NR) when given avapritinib. Cognitive impairments were seen in 1/3 of the patients.
Looking ahead to the future of GIST, Dr Haddox said there’s an emerging role for circulating tumor DNA (ctDNA) for disease mentoring and tailoring therapy.
For PEComa, nab-sirolimus provides activity in patients with malignant PEComa, an ultrarare sarcoma often harboring TSC1/2 inactivating mutation. The drug was recently FDA approved and is commercially available.
In the AMPECT trial, nab-sirolimus improved intratumor drug accumulation and target suppression in patients with malignant PEComa, Dr Haddox said. The response rate, durability of response, disease control rate, and safety profiles support the use of nab-sirolimus as a treatment option for this disease.
Tazmetostat is typically used for epithelioid sarcoma, a rare and aggressive soft-tissue sarcoma subtype primarily affecting young adults. Over 90% of tumors have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2.
Results from an open-label, phase 2 study on the clinical activity and safety of tazmetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma, found it was well tolerated and showed clinical activity, and has the potential to improve outcomes, in patients with advanced epithelioid sarcoma.
Emerging targets for patients with leiomyosarcoma (LMS), a common soft tissue sarcoma subtype with smooth muscle differentiation, include DNA damage repair and olaparib plus temozolomide, Dr Haddox said.
In one study, patients with LMS with homologous recombination pathway gene alterations had poor clinical outcomes, particularly those with non-BRCA gene alterations. In another study, olaparib plus temozolomide demonstrated an overall objective response rate of 27%, had a median PFS of 6.9 months, and had a duration of response of 12 months.
Dr Haddox said there are many other DNA damage response drugs and combinations currently being explored.
For patients with well-differentiated/dedifferentiated liposarcomas (WD/DDLS), a common sarcoma subtype, MDM2 and CDK4 are emerging targets, Dr Haddox said.
A study looking at CDK4/6 in patients with advanced WD/DDLS, treatment with palbociclib, a selective CDK4 and CDK6 inhibitor, was associated with a favorable PFS and occasional tumor response. The median PFS was 17.9 weeks (95% CI, 11.9-24 weeks).
In conclusion, Dr Haddox said there are exciting advancements in sarcoma targeted therapies, with recent FDA approvals in common and ultra-rare soft tissue sarcoma subtypes.—Emily Bader
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