Background Results of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy. Methods This open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1. Results 43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths. Conclusions Although the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS. Trial registration number NCT03359018.

Background: Antiangiogenesis tyrosine kinase inhibitors (TKIs) have been shown to prolong progression-free survival (PFS) in advanced osteosarcoma. Methylsulfonic apatinib is a TKI that specifically inhibits vascular endothelial growth factor receptor-2. We aim to assess apatinib in patients with advanced high-grade osteosarcoma progressing upon chemotherapy. Materials and Methods: This phase II trial was conducted at Peking University People's Hospital. We enrolled participants (≥16 years of age) with progressive relapsed or unresectable osteosarcoma. Participants received 750 mg or 500 mg of apatinib according to body surface area once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate and PFS at 4 months. Results: A total of 37 participants were finally included into the analysis. Until final follow-up, the objective response rate (complete response + partial response) was 43.24% (16/37). The 4-month PFS rate was 56.76% (95% confidence interval [CI], 39.43%–70.84%). Median PFS and overall survival were 4.50 (95% CI, 3.47–6.27) and 9.87 (95% CI 7.97–18.93) months, respectively. Toxic effects led to dose reductions or interruptions in a total of 25 of 37 (67.57%) patients. The most common grade 3–4 adverse events were pneumothorax in six (16.22%) patients, wound dehiscence in four (10.81%), proteinuria in three (8.11%), diarrhea in three (8.11%), and palmar-plantar erythrodysesthesia syndrome in three (8.11%). No other serious adverse events were reported during the trial. There were no treatment-related deaths. Conclusion: Apatinib is a sensitive drug for advanced osteosarcoma with a high response rate after failure of chemotherapy, with similar duration of response compared to other TKIs.

Purpose: To explore the efficacy and safety of TQB2450 combined with anlotinib in patients with locally advanced or metastatic soft-tissue sarcoma (LA/M STS). Patients and Methods: This was a single arm phase II study (TQB2450-Ib-02 study) performed at two hospitals in China to assess the potency of TQB2450 combined with anlotinib in patients with LA/M STS. Patients were previously unresponsive to at least one chemotherapy regimen. Anlotinib (12 mg every day) was administered orally from day 1 to day 14 every 3 weeks. TQB2450 was administered by intravenous infusion at 1,200 mg on day 1 every 3 weeks. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: Between January 2019 and June 2020, 30 patients were enrolled. The ORR was 36.67% and the DCR was 76.67%. The median PFS was 7.85 months [95% confidence interval (CI), 2.89–23.06] and the median OS was not reached [95% CI, 10.58–not estimable (NE)]. Among the patients with alveolar soft part sarcoma (ASPS; 12/30, 40%), the ORR was 75% and the median PFS was 23.06 months (95% CI, 8.97–NE). The most common treatment related adverse events were hypothyroidism (76.67%), hypertriglyceridemia (63.33%), hypercholesterolemia (60.00%), and elevated blood lactate dehydrogenase (53.33%). Conclusions: The study showed the promising activity in patients with ASPS, also indicating the trend of treatment efficacy in other sarcomas. The toxicity was tolerable. More studies with larger sample size and controlled arm were warranted.

Background: Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy is the most-frequently employed strategy for patients with high-grade osteosarcoma. However, the contribution of neoadjuvant chemotherapy compared with postoperative adjuvant chemotherapy has not been tested rigorously in patients with nonmetastatic high-grade pelvic osteosarcoma. Questions/purposes: (1) Does neoadjuvant chemotherapy followed by delayed surgery offer a survival benefit to patients with nonmetastatic high-grade pelvic osteosarcoma compared with immediate surgery and adjuvant chemotherapy? (2) Is the timing of chemotherapy and surgery associated with a difference in the survivorship free from local recurrence and the risk of complications? (3) Is the threshold of 90% necrosis after neoadjuvant chemotherapy appropriate to distinguish responders from nonresponders in patients with pelvic osteosarcoma? Methods: Between 2000 and 2015, our center treated 112 patients with nonmetastatic high-grade primary pelvic osteosarcoma, of whom 93 underwent tumor resection with chemotherapy. Four patients (4%) were lost to followup before 24 months but were not known to have died; the remaining 89 patients were included in this retrospective study. Based on the timing of surgery and chemotherapy, patients were analyzed in two groups: (1) neoadjuvant chemotherapy followed by delayed surgery and adjuvant chemotherapy (n = 56; mean followup of 61 months, range 27-137 months), and (2) immediate surgery followed by adjuvant chemotherapy (n = 33; mean followup of 77 months, range 25-193 months). The total duration and intensity of chemotherapy was similar in both groups. During the period in question, we generally used neoadjuvant therapy followed by delayed surgery and adjuvant chemotherapy when patients received their biopsies in our center. We typically used immediate surgery with adjuvant chemotherapy when patients initially refused chemotherapy or when they had severe pain or poor walking function. Patients in the neoadjuvant chemotherapy group had a higher proportion of sacral infiltration; other factors such as sex, age and tumor size were well balanced between groups. We compared overall survival and local recurrence-free survival rates between the two groups. We completed univariate log-rank tests and multivariate Cox analyses in all patients to identify factors associated with survival and local recurrence using the Kaplan-Meier method. Results: No survival benefit was found in the patients treated with neoadjuvant chemotherapy followed by delayed surgery compared with the group treated with immediate surgery and adjuvant chemotherapy. At 5 years, the overall survival (OS) was 42% (95% CI, 33–52) for all patients in this study, 43% (95% CI, 30–56) for the neoadjuvant group, and 40% (95% CI, 25–55) for the immediate surgery group; p = 0.709. With the numbers available, there was no difference in the likelihood of successful limb salvage (five of 56 patients [89%] in the neoadjuvant chemotherapy group versus three of 33 patients [91%] in the immediate surgery group; p = 0.557). The 5-year local recurrence-free survival was 67% (95% CI, 59–76) with no difference between the two groups (68%; 95% CI, 57–78% versus 67%; 95% CI, 52–81; p = 0.595). With the numbers available, there was no difference in survival between patients whose tumors demonstrated more than 90% necrosis; however, only four of 56 patients in the neoadjuvant chemotherapy group demonstrated 90% necrosis. Conclusions: We found no survival advantage with chemotherapy before surgery compared with immediate surgery in patients with nonmetastatic high-grade pelvic osteosarcoma. The decision on chemotherapy timing should be made for reasons other than survival. A prospective trial is needed to confirm this conclusion. Level of Evidence: Level III, therapeutic study.

Aim: Apatinib, a specific tyrosine kinase inhibitor (TKI) that targets mainly vascular endothelial growth factor receptor-2 (VEGFR-2) as well as Ret, c-Kit and c-Src, has been assessed in patients with advanced osteosarcoma (phase II), the primary report of which has been published in PMID 30559126. This sub-study explored the potential signs of Adverse Events (AEs) for apatinib-treated osteosarcoma. Methods: Participants with advanced osteosarcoma progressing upon chemotherapy received apatinib until disease progression or unacceptable toxicity. Toxicities, progression-free survival (PFS), and clinical benefit rate (CBR) following treatment were evaluated. Results: Of the 41 patients recruited to the study, 37 received treatment and constituted the safety population. At data cut-off (December 30, 2017), median follow-up for safety was 7.37 (IQR, 6.33–11.07) months. The most common grade 3–4 AEs were pneumothorax (16.22%), wound dehiscence (10.81%), proteinuria (8.11%), diarrhea (8.11%), and skin reaction (8.11%). Only hypertension was an independent predictive factor for both PFS (hazard ratio [HR], 0.44; P = 0.07) and CBR (P = 0.07). Anorexia was also significantly related to a longer PFS in a Cox regression model (HR, 0.35; P =0.01). For CBR, pneumothorax and hypothyroidism showed more clinical benefit (P = 0.07 and 0.00, respectively). Conclusion: The results of this study suggest that anorexia, hypertension, pneumothorax, and hypothyroidism might be markers for a favorable clinical outcome following apatinib-treated refractory osteosarcoma.