Genetic Profiling Suggests Rationale for Limited Response to Immunotherapy in Osteosarcoma
February 22, 2020 01:00am
By Nichole Tucker
The combination of talimogene laherparepvec plus pembrolizumab led to a promising objective response rate in patients with advanced sarcoma who typically have limited treatment options, according to a phase II clinical trial published in JAMA Oncology.
The combination of talimogene laherparepvec (T-VEC) plus pembrolizumab (Keytruda) led to a promising objective response rate (ORR) in patients with advanced sarcoma who typically have limited treatment options, according to a phase II clinical trial published in JAMA Oncology.
The primary end point of the study was ORR at 24 weeks, determined by RECIST v1.1 criteria. The authors noted that a 30% ORR would be considered promising; the primary end point was met. Secondary end points also included the best ORR determined by immune-related RECIST criteria, progression-free survival (PFS) rate at 24 weeks, and overall survival (OS), as well as safety.
All 20 patients enrolled were evaluable for response, and the ORR at 24 weeks was 30% (95% CI, 12%-54%). The best overall response was a partial response in 7 patients (35%) determined by RECIST v1.1. Seven patients (35%) also had stable disease (SD), and 6 patients (30%) had progressive disease (PD). The median time to response was 14.4 weeks (range, 6.6-31.9), and the median duration of response was 56.1 weeks (range, 49.4-87.0). The disease control rate was 70%.
“To our knowledge, this is one of the highest ORRs reported in an unselected sarcoma-specific study population evaluating the efficacy of combination immunotherapy,” study authors wrote in their paper.
At the time of analysis, 5 patients reached the maximum duration of therapy, and 4 patients remained on the study, 2 of whom were progression-free. Among patients who responded, the average number of prior lines of therapy was 1 (range, 0-3), and the median duration of therapy was 16 weeks (range, 7-67). The median follow-up time for survival was 56.2 weeks. Two patients discontinued T-VEC treatment because of the resolution of palpable disease, and 2 discontinued pembrolizumab because of toxic effects.
The median PFS was 17.1 weeks (95% CI, 12.6-not estimable). The 12-week PFS rate was 70% (2-sided; 95% CI, 52.5%-93.3%), and the 24-week PFS rate was 39.4% (2-sided; 95% CI, 22.7%-68.3%). The median disease-specific survival was 74.7 weeks (3-sided; 95% CI, 49.0-not estimable), and 8 patients had died by the data cutoff.
The combination was well-tolerated, according to investigators. The most common treatment-related adverse events (TRAEs) of any grade, which occurred in 20% of patients or more, included fatigue (80%), fever (45%), chills (45%), nausea (30%), anemia (25%), vomiting (20%), hypothyroidism (20%), pruritis (20%), and an increase in aspartate aminotransferase level (20%). The most common grade 3 TRAEs included pneumonitis, anemia, and fever, observed in 5% of patients each.
In terms of immune-mediated TRAEs, the most common of any grade included pneumonitis (10%), uveitis (5%), hypothyroidism (20%), and thrombocytopenia (5%). Grade 3 pneumonitis occurred in 1 patient, and another patient had recurrent grade 2 uveitis, which led to study discontinuation.
PD-L1positive sarcoma was observed at baseline in 1 patient with epithelioid sarcoma, who obtained a PR on the study after previously experiencing disease progression on prior treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) concurrently with radiotherapy. Six out of the 11 patients with paired evaluable tumor samples had converted from PD-L1–negative to -positive from baseline to after treatment.
In the 6 out of 7 evaluable patients who achieved a response, 1 patient was PD-L1positive at baseline versus 4 patients after treatment. In the 13 patients with refractory disease, no patients were PD-L1–positive at baseline versus 5 posttreatment. The mean tumor-infiltrating lymphocyte (TIL) score was higher in the responsive versus refractory arms, and the mean TIL score was 3 among the responsive patients versus 2 in the refractory patients.
Both T-VEC and pembrolizumab were administered to all patients on day 1 of each 21-day cycle. T-VEC was given by intertumoral injection at ≤4 mL × 106plaque-forming units [PFU]/mL for the first dose and ≤4 mL × 108PFU/mL for all subsequent doses. Pembrolizumab was given at a dose of 200 mg intravenously. Patients continued on treatment until a complete response (CR) was achieved, until progressive disease or unacceptable toxicity occurred, or the maximum duration of therapy of 12 months was reached.
The single-institution trial included patients with a histologically confirmed locally advanced or metastatic sarcoma with at least 1 injectable subcutaneous, cutaneous, or nodal lesions of 10 mm or greater. Patients also had to have measurable disease determined by RECIST v1.1, at least 1 or more prior lines of standard systemic therapy, an ECOG performance status of 0 or 1, and adequate organ function to be included in the study. If patients had known active central nervous system metastases, symptomatic autoimmune disease, clinically significant immunosuppression, or active herpetic skin lesions, they could not be included in the study.
“Expansion of this study is in progress for angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and myofibroblastic sarcoma (MFS), and epithelioid sarcoma. In addition, a neoadjuvant cohort of patients with localized, operable UPS and MFS is being explored,” study authors concluded. “Continued exploration of immune-related biomarkers to inform the future selection of patients with sarcomas most likely to benefit from this treatment remains a priority for the expansion cohort.”
Kelly CM, Antonescu CR, Bowler T, et al. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab.JAMAOncol.[Published Online January 23, 2020]. doi:10.1001/jamaoncol.2019.6152.