Phase 2 findings show that adding a tyrosine kinase inhibitor to dual immunotherapy curbed disease progression in patients with metastatic soft tissue sarcoma.
Cabozantinib (Cabometyx), a multi-targeted tyrosine kinase inhibitor (TKI), improved progression-free survival (PFS) and disease control rates (DCR), when used in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) among patients with metastatic soft tissue sarcoma in a phase 2 trial (NCT04551430) presented at the 2023 ASCO Annual Meeting.
The median PFS for the 4-drug group was 5.4 months, compared with 3.8 months in the cabozantinib-only arm (HR, 0.57; 0.35-0.91; P = .016).
The DCR for the cabozantinib/nivolumab/ipilimumab arm was 80%, including 41 patients who had stable disease, and then the 5 partial and 2 complete responses (CRs). Meanwhile, in the cabozantinib monotherapy group, the DCR was 42%, including 11 stable disease and 2 partial responses (PRs; P = .0004).
“The combination of cabozantinib plus ipilimumab/nivolumab when compared to cabozantinib alone was statistically significant for improved DCR and PFS for the treatment of non-translocation soft-tissue sarcoma.,” study author, Brian Van Tine, MD, PhD, professor of medicine, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine in St. Louis, Missouri, said while presenting the findings.
According to Van Tine, PD-1 and CTLA4 inhibition has been studied in other solid tumors and has been shown to be safe in phase 1 studies. Investigators therefore sought to assess this combination alongside multi-targeted TKI inhibitor that has demonstrated clinical activity in soft tissue sarcoma as a single agent.
Patients in the trial were randomly assigned 2:1 to receive cabozantinib (40 mg, daily) plus ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) for 4 doses Q3W and then maintenance nivolumab at 480g Q4W (n = 69) or 60 mg of cabozantinib alone (n = 36). The trial design allowed for crossover, and 19 patients crossed over to the triplet arm after disease progression.
To be eligible for the trial, patients needed to have an ECOG score of 0-1; have undergone 1-2 prior lines of therapy; and be diagnosed with sarcomas that lack translocations. Median age was 59 (range, 35-77) and 61 (range, 19-77) in the triplet and single-agent arms, respectively. On average, patients had 1.7 (range, 1-4) and 1.5 (range, 1-3) prior therapies, respectively among the 2 groups.
Regarding tumor subtype, 39 and 19 patients in the triplet and single-agent arms, respectively, had a diagnosis of leiomyosarcoma; 2 and 1 patient had dedifferentiated liposarcoma; 2 and 3 patients had undifferentiated pleomorphic sarcoma; and 26 and 13 patients had a disease histology classified as “other.”
There was no statistically significant difference in response rates between the two arms. They were 11% in the immunotherapy-containing arm, which included 5 PRs and 2 CRs; and 6% in the cabozantinib-only arm, including 2 PRs and no CRs.
“What becomes interesting is the crossover arm — it's allowed after RECIST (-determined) progression — we added ipilimumab and nivolumab and we had an additional 2 PRs in leiomyosarcoma,” Van Tine explained.
Patients who responded to the cabozantinib/nivolumab/ipilimumab regimen had angiosarcoma, epitheliod sarcoma, and myxofibrosarcoma. Both patients who responded to cabozantinib had leiomyosarcoma.
The most common grade 3-4 adverse events (AEs) affecting 10% or more of patients in the three-drug group included hypothyroidism, diarrhea, mucositis, oral dysesthesia, nausea, vomiting, elevated AST and ALT, anorexia, dysgeusia, headache, pruritis, maculopapular rash, and hypertension. For the cabozantinib-only arm, common grade 3-4 AEs were hypothyroidism, diarrhea, oral dysesthesia, fatigue, palmar-plantar erythrodysesthesia, and hypertension.
“As of this first early data cutoff, this trial has not yet met its primary response rate objective,” Van Tine concluded. “Correlative work is ongoing, and updated response data will be presented soon.”
Editor’s Note: Dr Van Tine reported relationships with a number of pharmaceutical companies.
Van Tine BA, Eulo V, Toeniskoetter J, et. al. Randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition versus cabozantinib in metastatic soft tissue sarcoma. J Clin Oncol. 2023;41(suppl 17):LBA11504. doi:10.1200/JCO.2023.41.17_suppl.LBA11504