Sarcoma: New data on ripretinib, regorafenib, sunitinib and nivolumab

Sarcomas are relatively rare tumors that can occur on the soft tissue or bone. New study data on their treatment was presented by Javier Martin-Broto, Virgen del Rocio University Hospital, Seville, Spain.

INVICTUS Study with ripretinib application in GIST cases

Sarcomas are relatively rare tumors that can occur on the soft tissue or bone. New study data on their treatment was presented at the ESMO Congress 2019 by Javier Martin-Broto, Virgen del Rocio University Hospital, Seville, Spain.

Martin-Broto from the Virgen del Rocio University Hospital, Seville, Spain, described the INVICTUS study with the KIT switch control inhibitor ripretinib in intensively pretreated patients with advanced gastrointestinal stromal tumors (GIST)1 as very important. Ripretinib inhibits KIT- and PDGFRA-mutated kinases. In the randomized phase 3 INVICTUS study, 120 patients received 2:1 randomized ripretinib or placebo. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate and overall survival (OS). Progression allowed dose escalation or cross-over.

The primary endpoint was met, PFS was significantly extended from 1.0 months under placebo to 6.3 months under ripretinib (p < 0.0001). Martin-Broto described the hazard ratio of 0.15 as impressive. After 6 months, 51% of patients under ripretinib and 3.2% under placebo were without recurrence of progression - "that's a huge difference,'' Martin-Broto remarked. Ripretinib also significantly reduced the secondary endpoint of OS by 64% with a median OS of 15.1 months under verum and 6.6 months under placebo. After 1 year, 65.4% of patients in the ripretinib group were still alive and 25.9% in the placebo group.

Ripretinib resulted in alopecia in 51% of patients and hand-foot syndrome in 21%. 

Ripretinib represents a potential new therapeutic standard for severely pretreated patients with GIST. "It is a relevant milestone that will change clinical practice," commented Martin-Broto.

Regorafenib in chondrosarcoma

The metastatic chondrosarcoma is currently difficult to treat, it is only slightly sensitive to chemotherapy. Multicinase inhibitors with anti-angiogenic effects have, however, shown activity. In the Phase 2 study REGOBONE, the oral tyrosine kinase inhibitor regorafenib was investigated in various bone sarcomas. In Barcelona, the investigators presented data on chondrosarcoma2. Patients with metastatic or locally advanced chondrosarcoma were included in the study after 1 or 2 pre-therapies and treated randomly with regorafenib plus best supportive care (BSC) (n = 24) or placebo plus BSC (n = 16). After 12 weeks, 13 patients (54.2%) in the regorafenib arm and 6 patients (37.5%) in the placebo arm were without recurrence of progression. The median PFS was extended from 8 to 19.4 weeks with regorafenib. Despite a lower PFS rate than expected, this study signaled that regorafenib may have a benefit in patients with relapsed chondrosarcoma.

TAPPAS study in angiosarcoma

The Phase 3 study TAPPAS investigated the combination of the angiogenesis inhibitor pazopanib and endoglin inhibitor TRC105 in patients with angiosarcoma. Endoglin is an essential angiogenesis receptor expressed on angiosarcoma cells and upregulated by VEGF inhibitors3. "This is the first comparative study in patients with angiosarcoma," said Martin-Broto. 129 patients with unresectable angiosarcoma and a maximum of two pre-treatments without VEGF inhibitor received randomized pazopanib or pazopanib plus TRC105. The combination was less tolerated with increased headache, anemia and nosebleeds compared to pazopanib monotherapy. The PFS did not differ between the two arms with 4.3 months of pazopanib and 4.2 months of pazopanib plus TRC105. There were also no significant differences in all other efficacy endpoints. Endoglin may not be a central target in angiosarcoma. The treatment of this disease is therefore still an "unmet need".

IMMUNOSARC: Sunitinib plus nivolumab in soft tissue and bone sarcomas

The IMMUNOSARC Phase 2 study investigated the combination of the angiogenesis inhibitor sunitinib with the PD-1 inhibitor nivolumab in patients with soft tissue sarcoma4. After induction therapy with sunitinib, patients received sunitinib plus nivolumab until progression or intolerance. The primary endpoint was the PFS rate at 6 months, which was 50%. Median PFS was 5.9 months. Thus, the combination achieved higher PFS rates than reported for monotherapy with nivolumab or sunitinib.

Sources:
1. By Mehren M, et al. INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥ 4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA87
2. Duffaud F, et al. Results of the randomized, placebo (PL)-controlled phase II study evaluating the efficacy and safety of regorafenib (REG) in patients (pts) with locally advanced (LA) or metastatic relapsed chondrosarcoma (CS), on behalf of the French Sarcoma Group (FSG) and UNICANCER. ). ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA88
3. Jones RL, et al. Results of the TAPPAS trial: An adaptive enrichment Phase 3 trial of TRC105 and pazopanib (P) versus pazopanib alone in patients with advanced angiosarcoma. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 16670
4. Martin-Broto J, et al. IMMUNOSARC: A collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib plus nivolumab in advanced soft tissue and bone sarcomas: Results of the phase II- soft-tissue sarcoma cohort. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 16690

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