Phase 2 data show that tyrosine kinase inhibitors can be combined with chemotherapy to improve outcomes in patients with relapsed or refractory osteosarcoma.
Encouraging anti-tumor activity has been observed with the combination of lenvatinib (Lenvima) with etoposide plus ifosfamid in patients with relapsed or refractory osteosarcoma, according to findings from a phase 2 study published in Lancet Oncology.
For relapsed/refractory osteosarcoma, no standard-of-care therapy has been established, and prognosis for this patient population remains poor. Outcomes are worse among patients who are unable to undergo survival-extending surgery for their disease, and the systemic agents that have been administered as second-line treatment for osteosarcoma have shown modest survival benefits.
Ensuant to guidelines from the European Society for Medical Oncology, etoposide is among one of the recommended chemotherapy agents for the treatment of relapsed/refractory osteosarcoma. Guidelines from the National Comprehensive Cancer Network also recommend using high-dose ifosfamide with or without etoposide, regorafenib (Stivarga), or sorafenib (Nexavar) with or without the mTOR inhibitor everolimus (Afinitor). Preclinical research also supports the decision to explore the combination of lenvatinib and etoposide plus ifosfamid in a phase 2 study of patients with relapsed/refractory osteosarcoma.
Following a multicenter, open-label, multicohort design, 17 hospitals across 6 countries screened 30 patients for inclusion in phase 1 or 2 of the study (NCT02432274). Patients treated in phase 1 are identified as cohort 3A from which 15 out of 30 patients were eligible to be treated and were assigned to treatment. These patients were pooled and included in cohort 3B. Those treated in phase 2 are referred to as cohort 3B and in this cohort, 20 patients were treated. For the full analysis set, all 35 patients from cohorts 3A and 3B were included.
The study was 80% powered to detect improvement in progression-free survival in the phase 2 portion at 4 months per RECIST and by investigator assessment. The secondary end points of the study included PFS, time to progression, best overall response, objective response rate (ORR), disease control rate (DCR), duration of response, clinical benefit rate (CBR), and safety.
Lenvatinib was administered to patients at 11 mg/m2 with etoposide plus ifosfamid.
Results showed that patients treated in phase 1 who received the recommended phase 2 dose had a PFS of s 51% (95% CI, 34-69) at 4 months, achieving the binomial estimate. In all 35 patients, the PFS at 4 months was 80% (95% CI, 60-90), according to the Kaplan-Meier analysis. A median follow-up of 5.8 months (interquartile range, 4.1-9.7), the median PFS observed in the study was 8.7 months (95% CI, 4.5-12.0,) which corresponded with 15 PFS events.
Out of 32 patients who were evaluable for response, the ORR observed was 9% (95% CI, 2-25), which were all partial responses. Further, stable disease was achieved in 59% of patients while 19% had progressive disease, and 13% were not evaluable. The median DOR was no estimable. The DCR in all 35 patients was 71% (95% CI, 54-85), and the CBR was 37% (95% CI, 21-55).
Duration of treatment with lenvatinib lasted a median of 4.96 months (IQR, 2.69-9.46). The median percent of the intended lenvatinib received by patients was 87.1% (IQR, 63.1-100). The study patients received a median of 7.0 cycles of lenvatinib (IQR, 4.0-13.0), 5.0 cycles of ifosfamid (IQR, 4.0-5.0), and 5.0 cycles of etoposide (IQR, 4.0-5.0).
All patients in the 3B cohort experienced treatment-emergent AEs (TEAEs) from lenvatinib and 95% experienced treatment-related AEs. No serious were reported from cohort 3B, but 9% of patients withdrew from the study due to AEs, and there were dose reductions and interruptions in 60% and 54% of patients, respectively. TEAEs related to chemotherapy led to study withdrawals from 9% of patients, dose reductions from 20%, and dose interruptions from 3%.
“Overall, the safety profile aligned with safety profiles of each study drug, and no unexpected adverse events were observed, “wrote the study authors led by Nathalie Gaspar, MD, of Gustave Roussy Cancer Centre.
The most common AEs of any grade were anemia (100%), diarrhea (100%), and neutropenia (86%). The most common ≥3 AEs were the same as the grade common AEs with the addition of febrile neutropenia occurring in 57%.
Looking at the population of pooled patients analyzing in cohort 3B, the median age was 15 years (range, 13-17). The group was predominantly male (66%), and most had a Karnofsky or Lansky performance score of 100 (43%). The number of prior anticancer therapies received was 1 for most patients in the cohort (40%), however, 34% had 3 prior therapies, and 26% had 3 or more prior therapies. Forty-six percent of patients previously underwent surgery, and 9% had prior radiotherapy. In terms of metastatic sites, 63% of patients had 1 site of metastasis and 31% had 2. The lungs were the most common site of metastasis among the cohort 3b subjects (69%), and the second most common was the lung and bone (20%).
“The manageable safety profile, along with promising activity results, suggests that tyrosine kinase inhibitors could be combined with chemotherapy to possibly treat patients with relapsed or refractory osteosarcoma; however, a direct comparison with chemotherapy is not currently available,” concluded Gaspar et al.
Continued exploration of lenvatinib for the treatment of pediatric and adult patients with relapsed or refractory osteosarcoma is occurring in phase 2 randomized study (NCT04154189).
Gaspar N, Venkatramani R, Hecker-Nolting S, et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study.