Nivolumab plus sunitinib meets primary endpoint in IMMUNOSARC study in advanced osteosarcoma

Nivolumab in combination with Sunitinib is active in patients with advanced osteosarcoma, according to results from the phase 1b/2 IMMUNOSARC study (NCT03277924).

Data from the study showed that the 6-month progression-free survival (PFS) rate based on centralized radiological assessment was 42% (95% CI, 27%-58%) in evaluable patients (n=38) who received combination therapy, meeting the trial's primary endpoint. The 6-month progression-free survival rate per local radiographic assessment was 32% (95% CI, 18%-47%), the median follow-up time was 39.8 months (95% CI, 37.9-41.7), and the median progression-free survival per central and local assessments were 3.8 months (95% CI, 2.7-4.8) and 3.7 months (95% CI, 2.7-4.7), respectively.

In addition, according toRECIST 1.1 criteria, the overall response rate (ORR) was 5%, consisting of all partial responses (PR), and 50% of patients had stable disease. The median duration of response was 29 months for PR (range, 8-51) and 7 months for stable disease (range, 1-51). PR occurred in one patient with dedifferentiated chondrosarcoma and one patient with chondroblastic osteosarcoma. These results are consistent with second-line and second-line treatment regimens using drugs thought to be active in osteosarcoma and met the primary endpoint. Despite these results, this was a hypothesis-generating experiment designed to explore activity signals from this combination that could ultimately be integrated into future experiments.

IMMUNOSARC is a multicenter study enrolling patients aged 18 to 80 years with metastatic/advanced osteosarcoma. Eligible patients also needed to have experienced disease progression within 6 months before enrollment; measurable disease according to RECIST 1.1 criteria; ECOG performance status of 0 or 1; adequate laboratory values; left ventricular ejection fraction of at least 50% on echocardiogram or MUGA scan; and adequate liver, kidney, heart and blood function. Patients received 37.5 mg of sunitinib orally on days 1 to 14, followed by 25 mg. Beginning on day 15, 3 mg/kg of nivolumab was administered intravenously every 2 weeks.

The primary endpoint of Phase 2 of the study is 6-month progression-free survival at each central radiology review. Secondary endpoints include PFS, overall survival (OS), RECIST 1.1-compliant ORR, safety, and collection of tissue samples for translational studies.

Other research results show that the median OS is 11.9 months (95%CI, 5.6-18.2); the 6-month, 12-month and 18-month OS rates are 73% (95%CI, 59%-87%), 47% (95%CI30%-65%) and 37% (95%CII20%-54%) respectively. Centrally assessed median PFS for patients with osteosarcoma, traditional chondrosarcoma, Ewing's sarcoma, and dedifferentiated chondrosarcoma were 3.5 months (95% CI, 1.1-6.0), 9.5 months (95% CI, 0.0-19.3), 5.4 months (95% CI, 0.4-10.5), and 1.8 months (95% CI, not applicable), respectively.

The toxicity profile of nivolumab plus sunitinib was relevant;17% of patients discontinued treatment due to toxicity, and there was 1 case of grade 5 pneumonitis. The most common hematologic adverse reactions (AEs) associated with any level of treatment included leukopenia, neutropenia, thrombocytopenia, and anemia. The most common non-hematological adverse events were hypertension, fatigue, and diarrhea. Grade 3 or higher adverse events included neutropenia, hypertension, and anemia.

Overall, further research is needed to better understand the potential benefits of immunotherapy in osteosarcoma and to identify biomarkers of response to these treatments. Based on this Phase 1/2 trial finding, a correlation study with the NanoString PanCancer immunoassay panel in pre- and post-treatment biopsies is underway. An international expansion phase 2 trial in patients with a selected sarcoma tissue type (dedifferentiated chondrosarcoma within osteosarcoma) is currently recruiting [NCT03277924].

References:https://www.onclive.com/view/nivolumab-plus-sunitinib-hits-primary-end-point-in-advanced-bone-sarcoma-immunosarc-study