Treatment with camrelizumab plus apatinib showcased antitumor activity with an acceptable toxicity profile in patients with refractory chordoma, according to results from a phase 2 investigator-initiated trial (ChiCTR2100042938) published in the Journal of Clinical Oncology.1
The objective response rate (ORR) achieved with the doublet (n = 33) was 24.2% (8/33; 95% CI, 11.1%-42.3%) per RECIST criteria, with a disease control rate (DCR) of 90.9% (30/33; 95% CI, 75.7%-98.1%). No complete responses were observed; all 8 responders achieved partial responses (PRs). These data exceeded previously reported ORRs for anti–PD-1 monotherapy (approximately 12%)2 and antiangiogenic monotherapy (approximately 3.7%)3 in advanced chordoma. The median PFS was 28.4 months (95% CI, 13.53-43.28); the 6- and 12-month PFS rates were 84.4% (95% CI, 66.3%-93.2%) and 70.0% (95% CI, 47.8%-84.2%), respectively.1
At a median follow-up of 20.8 months (IQR, 13.35-26.55), the median time to response was 6 months (IQR, 4-9.25 months), and the median DOR per RECIST 1.1 was not reached (NR). Tumor lesion shrinkage was observed in 23 patients (69.7%). The median OS was NR at the time of data cutoff; 4 deaths occurred during follow-up—2 from tumor progression and 2 from postoperative complications following salvage surgery after treatment discontinuation.1
“[The] combination of camrelizumab and apatinib offered encouraging efficacy with manageable toxicity in chordoma treatment. CDKN2A alterations are associated with worse prognosis and may prove to be a potential biomarker for treatment selection.”
-Jianru Xiao, MD, and coinvestigators
Xiao is affiliated with the Department of Orthopedic Oncology at Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, in Shanghai, China.
What is the treatment landscape for refractory chordoma?
Chordoma is a rare malignant tumor arising predominantly in the clivus, sacrum, and spine. Despite its typically indolent behavior, chordoma is locally aggressive and characterized by a locoregional recurrence rate exceeding 50% even after macroscopic complete resection, with a 5-year survival rate ranging from 65% to 70%.4 Cytotoxic chemotherapy has limited efficacy, and targeted therapies have demonstrated modest antitumor activity in clinical trials, with the highest reported ORR of 3.7% per RECIST 1.1.3
Prior data suggested isolated activity for immune checkpoint inhibitors (ICIs) in chordoma—a phase 2 trial reported an ORR of 12% with pembrolizumab (Keytruda),2 and a single PR was observed among 5 patients treated with durvalumab (Imfinzi) plus tremelimumab (Imjudo).5 Building on the investigators’ prior phase 2 study of apatinib monotherapy in advanced chordoma, this trial was designed to evaluate the synergistic potential of combining a PD-1 inhibitor with an antiangiogenic agent in this refractory setting. Camrelizumab is a humanized monoclonal anti–PD-1 antibody; apatinib is a selective VEGFR2 tyrosine kinase inhibitor.1
How were patients treated with camrelizumab plus apatinib in the trial?
This investigator-initiated, single-arm, single-center phase 2 trial enrolled patients aged 18 to 75 years with histologically confirmed refractory chordoma (unresectable or not amenable to radical surgery) at a tertiary hospital in Shanghai.1 Key eligibility requirements included measurable disease per RECIST 1.1, documented disease progression per Choi criteria on contrast-enhanced CT or MRI within 6 months prior to enrollment, ECOG performance status of 0 to 2, and life expectancy exceeding 3 months. Patients with prior antiangiogenic or anti–PD-1/PD-L1 therapy were excluded.
Patients received intravenous camrelizumab at 200 mg once every 2 weeks combined with oral apatinib at alternating doses of 250 mg and 500 mg on consecutive days, in 4-week cycles. Treatment continued until unacceptable toxicity, spinal cord compression, consent withdrawal, or loss of clinical benefit as assessed by the investigator. The primary end point was ORR per RECIST 1.1; secondary end points included ORR per Choi criteria, PFS, overall survival (OS), DCR, duration of response (DOR), safety, and quality of life.
Of 38 patients screened between September 2021 and October 2024, 33 were enrolled and included in efficacy and safety analyses. The cohort comprised 20 male (60.6%) and 13 female (39.4%) patients, with a median age of 56 years (IQR, 49-61). Sixteen patients (48.5%) had sacral primaries, and 17 (51.5%) had mobile spine tumors. Twenty-seven patients (81.8%) had a history of surgery, and 10 (30.3%) had received prior radiotherapy. All patients had conventional chordoma histology. The cutoff date for the published data was May 31, 2025.
Camrelizumab Plus Apatinib in Refractory Chordoma: Key Findings
• The combination achieved an ORR of 24.2% per RECIST 1.1 and 48.5% per Choi criteria, with a DCR of 90.9% and median PFS of 28.4 months.
• CDKN2A copy-number deletion or homozygous deletion was significantly associated with inferior response rates and shorter PFS compared with patients with normal CDKN2A status.
• All 20 patients who underwent successful NGS exhibited PD-L1–negative, microsatellite-stable, and tumor mutational burden–low profiles.
• Grade 3 or 4 hepatotoxicity (elevated AST and ALT levels) was the most common severe adverse effect; no treatment-related deaths occurred.
What additional efficacy did camrelizumab plus apatinib demonstrate in chordoma?
Per Choi criteria, the ORR was 48.5% (16/33; 95% CI, 30.8%-66.5%), the DCR was 81.8% (27/33; 95% CI, 64.5%-93.0%), and the median DOR was 22.2 months (95% CI, 12.5-NR). The median PFS per Choi criteria was 15.3 months (95% CI, 7.03-23.57). Investigators noted that Choi criteria, which account for changes in tumor density rather than size alone, may offer earlier and more sensitive efficacy evaluation for chordoma, given the indolent growth pattern of the disease and the mechanism of antiangiogenic agents.1
Post hoc biomarker analyses identified CDKN2A copy-number deletion (CND) as the most common genomic alteration detected by next-generation sequencing (NGS), occurring in 6 of 20 evaluable patients (30%). Among patients with CDKN2A CND (n = 6), 66.7% had progressive disease and 33.3% had stable disease per Choi criteria, compared with 71.4% PR rates among patients with normal CDKN2A status (n = 14; P < .001). PFS was significantly shorter in the CND subgroup vs the normal subgroup (P < .001).1
Fluorescence in situ hybridization analysis of CDKN2A in 26 patients revealed homozygous deletion (HD) in 10 patients (38.5%). In the HD subgroup, the PR rate was 10.0% vs 75.0% in the non-HD subgroup (P = .004), and PFS was significantly shorter in the HD subgroup vs the non-HD subgroup (P = .014). The median PFS was 4.3 months (95% CI, 2.37-6.23) in the combined CDKN2A CND/HD subgroup (n = 8) vs NR in the non-CND and non-HD subgroup (n = 10; P = .046). All 20 patients who completed NGS testing exhibited PD-L1–negative (<1%), microsatellite-stable, and tumor mutational burden–low profiles.1
What is the safety profile of camrelizumab plus apatinib in chordoma?
Treatment-related adverse effects (TRAEs) occurred in 31 patients (93.9%), with grade 3 to 4 TRAEs observed in 20 patients (60.6%).1 Elevated aspartate aminotransferase (AST) level was the most common any-grade TRAE (n = 25; 75.8%) and the most common grade 3 or 4 TRAE (n = 13; 39.4%). Elevated alanine aminotransferase (ALT) levels occurred in 24 patients (72.7%) overall and at grade 3 or 4 severity in 11 patients (33.3%). Additionally, any-grade TRAEs included proteinuria (n = 17; 51.5%), elevated gamma-glutamyltransferase (n = 16; 48.5%), hypothyroidism (n = 12; 36.4%), and hypertension (n = 11; 33.3%).
TRAEs led to apatinib dose interruptions in 13 patients (39.4%), of whom 6 (18.2%) required dose reductions. Camrelizumab dose interruptions occurred in 7 patients (21.2%), primarily due to AST/ALT elevation (n = 5) and reactive cutaneous capillary endothelial proliferation (RCCEP; n = 2). Both drugs were permanently discontinued in 4 patients (12.1%) due to recurrent liver dysfunction. No treatment-related deaths occurred. Investigators noted that the incidence of RCCEP was markedly lower than that reported with camrelizumab monotherapy (21.3% vs approximately 80%), which they attributed to a potential moderating effect of VEGFR inhibition on this camrelizumab-associated skin toxicity.6,7
What are the limitations of the camrelizumab plus apatinib chordoma trial?
The authors acknowledged several limitations, including the single-center, single-arm design with its inherent potential for selection bias; biomarker testing in only a subset of patients, limiting statistical power; treatment delivery disruptions in some first-stage patients due to the COVID-19 pandemic; and the preclusion of definitively attributing the prognostic effect of CDKN2A alterations to either individual agent, given the single-arm design.1
The investigators proposed that a multicenter, prospective phase 3 study stratified by CDKN2A status may be warranted to validate the biomarker’s predictive role.
References
- Yang C, Jia Q, Zhao C, et al. Efficacy and safety of camrelizumab plus apatinib in patients with refractory chordoma: a phase II clinical trial. J Clin Oncol. Published online May 13, 2026. doi:10.1200/JCO-25-02719
- Blay JY, Chevret S, Le Cesne A, et al. Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. Lancet Oncol. 2023;24(8):892-902. doi:10.1016/S1470-2045(23)00282-6
- Liu C, Jia Q, Wei H, et al. Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2020;21(9):1244-1252. doi:10.1016/S1470-2045(20)30466-6
- Agner KE, Larkins MC. Population-based survival analysis of primary spinal chordoma in the US from 2000 to 2020. J Neurooncol. 2024;170(2):397-405. doi:10.1007/s11060-024-04807-y
- Somaiah N, Conley AP, Parra ER, et al. Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. Lancet Oncol. 2022;23(9):1156-1166. doi:10.1016/S1470-2045(22)00392-8
- Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19(10):1338-1350. doi:10.1016/S1470-2045(18)30495-9
- Mo Y, Pan Y, Zhang B, et al. Apatinib combined with camrelizumab in the treatment of recurrent/metastatic nasopharyngeal carcinoma: a prospective multicenter phase II study. Front Immunol. 2023;14:1298418. doi:10.3389/fimmu.2023.1298418
