Abstract
Patients with alveolar soft part sarcoma (ASPS) are rare and have few treatment options. We assessed the activity of geptanolimab (GB226), a fully humanized programmed cell death protein 1 antibody, for patients with unresectable, recurrent, or metastatic ASPS.
We conducted this multicenter, single-arm, phase II study (Gxplore-005, NCT03623581) in patients aged 18–75 years who had unresectable, recurrent, or metastatic ASPS at 11 sites in China. Patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by independent review committee (IRC) per RECIST 1.1 in the full analysis set population.
Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. Fourteen [37.8%; 95% confidence interval (CI), 22.5–55.2] of 37 patients had an objective response assessed by IRC with a 6-month duration of response rate of 91.7%. Median progression-free survival was 6.9 months (95% CI, 5.0–not reached) and disease control was achieved in 32 (86.5%; 95% CI, 71.2–95.5) patients. Three of 37 patients reported grade 3 treatment-related adverse events (TRAEs), including anemia, hypophysitis, and proteinuria [one each (2.7%)]. No grade 4 TRAEs were observed. Two (5.4%) patients discontinued treatment due to TRAEs (one with hypophysitis and one with Mobitz type I atrioventricular block). The baseline percentage of CD4+ T cells was adversely associated with patient response (P = 0.031).
Geptanolimab has clinically meaningful activity and a manageable safety profile in unresectable, recurrent, or metastatic ASPS.
This study demonstrates geptanolimab (GB226) is clinically active in patients with unresectable, recurrent, or metastatic alveolar soft part sarcoma (ASPS). This phase II study (Gxplore-005, NCT03623581) evaluated geptanolimab, a genetically engineered mAb targeting programmed cell death protein 1, in patients with unresectable, recurrent, or metastatic ASPS. Geptanolimab monotherapy showed clinically meaningful benefit, with an independent review committee assessed overall response rate of 37.8% and 6-month duration of response rate of 91.7%. Disease control rate was 86.5% and 91.9% per RECIST 1.1 and RECIST for immune-based therapeutics criteria, respectively. Toxicities were overall manageable. On the basis of the biomarker analysis, no correlation was identified between programmed death-ligand 1 expression and patient response, and we suggested ASPS as a microsatellite stable and low tumor mutation burden tumor. This study established that the baseline percentage of CD4+ T cells was adversely associated with patient response, which may serve as a predictor in patients with ASPS treated with geptanolimab.
Introduction
Alveolar soft part sarcoma (ASPS) is a rare and distinctive subtype representing only 0.5%–1.0% of soft-tissue sarcomas (STSs), and STSs account for approximately 0.8% of all malignancy types with about 39,900 new cases in China, 2014 (1, 2). The treatment usually involved surgical resection while conventional anthracycline-based chemotherapy was inactive (3, 4).
High risk of metastases commonly developed up to 85% in 20 years, and the median overall survival (OS) for patients initially diagnosed with metastases is only 3 years (5). Given the rarity of the disease, most data are retrospective and treatment options are limited. Two recommended VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) for ASPS per National Comprehensive Cancer Network (NCCN) guideline (6), sunitinib and pazopanib, have both produced dimensional and durable response in patients with advanced ASPS (7–9). The objective response rate (ORR) of previous studies of sunitinib ranged from 40% to 62.5%, and pazopanib from 16.7% to 27.6%. Recently, a phase II study has revealed an ORR of 19% of another VEGFR inhibitor cediranib, in 31 patients with metastatic ASPS (10). However, disease progression commonly developed with VEGFR-TKI treatment and demonstrated a median progression-free survival (PFS) of 13–19 months with sunitinib, 5.5–13.6 months with pazopanib, and 10.1 months with cediranib (7, 9–13).
Immune checkpoint inhibitors (ICIs) represented encouraging effects in patients with ASPS (14–16). Groisberg and colleagues reported two of four patients, diagnosed with ASPS and enrolled in immunotherapy trials, who achieved a partial response (PR) lasting 8 and 12 months after previous two to four lines of treatment failure (15). Response to combination treatment has also been reported. Wilky and colleagues presented a single-center phase II study with axitinib combined with pembrolizumab, among which 11 patients had a diagnosis of ASPS. Objective response was observed in six (54.5%) of the 11 patients and the median PFS was 12.4 months (95% CI, 2.7–22.3; ref. 16). A recent phase I study of toripalimab, an antiprogrammed cell death protein 1 (PD-1) antibody, demonstrated an ORR of 25% in 12 patients with ASPS (17). Despite of the substantial benefit of anti–PD-1 treatment in ASPS in previous reports, all studies to date investigated anti–PD-1 antibody containing treatment in all-comer patients with STS, instead of ASPS alone. Thus, we conducted this multicenter, single-arm, phase II study to evaluate the activity and safety of geptanolimab, a recombinant anti–PD-1 humanized mAb, in patients with unresectable, recurrent, or metastatic ASPS (Gxplore-005, NCT03623581) with a dosing regimen determined in a phase I study (NCT03374007).
Patients and Methods
Patients
Patients with histologically confirmed ASPS by local pathologists were eligible with at least one measurable lesion according to standard RECIST 1.1 (18), an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, adequate hematologic, renal, and hepatic function, available tumor tissue sample at study entry and a predicted life expectancy of greater than 3 months. Participants had to have adequate organ functions: absolute neutrophil count ≥1.5 × 109/L, platelet count ≥100 × 109/L, hemoglobin ≥80 g/L, total bilirubin ≤1.5 × the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × ULN (if liver metastases were present, ALT and AST up to 5 × ULN), serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/minute (calculated by Cockcroft and Gault equation). Four or more weeks were required before treatment initiation from the prior radiotherapy. At least 6 weeks must have elapsed from last treatment of nitrosoureas, mitomycin C, and receptor activator of NFκB ligand inhibitor. A minimum period of 4 weeks (or 5 or more half-life) were required between any prior treatment and the first dose of study drug geptanolimab.
The main exclusion criteria included disease requiring immunosuppressive treatment or systematic corticosteroids (>10 mg daily prednisone equivalent); prior treatment of ICIs, clinically active central nervous system (CNS) involvement (no presentation of neurologic symptom following surgical resection and asymptomatic brain metastasis without progression for 4 weeks or longer following radiotherapy were allowed); positive for human immunodeficiency virus, hepatitis B, hepatitis C, or anti-treponema pallidum antibody (TPAb); grade >1 adverse events (AEs) associated with previous therapy before enrollment per the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03, except for alopecia or neuropathy. More detailed eligibility criteria are available in the Supplementary Materials.
The study protocol has obtained approval from institutional review boards and independent ethics committees of each participating site (details in Supplementary Table S1). The study was designed and conducted according to Declaration of Helsinki and the good clinical practice guidelines. All patients provided written informed consent before enrollment.
Study design, treatment, and assessment
We conducted this multicenter, single-arm, phase II study at 11 sites in China with patients who had unresectable, recurrent, or metastatic ASPS. Eligible patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression, unacceptable toxicity, or end of the study (i.e., a maximum treatment duration of 1 year of the last subject, termination of treatment, consent withdrawal, lost to follow-up or death, whichever occurs first). Treatment was permitted to continue beyond the first progressive disease (PD) defined by RECIST 1.1, with assessed clinical benefit and acceptable toxicity. Dose modifications were not permitted, but delays of dose were allowed for up to 6 weeks for the occurrence of grade 3 or worse treatment-related nonhematologic AEs (except for fatigue) defined by protocol.
Treatment response was assessed by contrast-enhanced CT and/or MRI every 6 weeks until end of the study, consent withdrawal, disease progression, unacceptable toxicity, initiation of a subsequent anticancer treatment, death or loss of follow-up. For patients who discontinued treatment for reasons other than disease progression and did not achieve a subsequent anticancer treatment, response was assessed every 6 weeks until 3 months and every 12 weeks thereafter. The radiological assessment was reviewed by both independent review committee (IRC) and investigator by RECIST 1.1 and RECIST for immune-based therapeutics (iRECIST; ref. 19). The response assessments were required to be confirmed 6 weeks after the initial evaluation. Survival follow-up was done every 3 months until patient death, lost to follow-up, or end of the study.
Safety was captured for all patients receiving at least one dose of the study drug geptanolimab, until 30 days after treatment discontinuation and 90 days for those who did not start next anticancer therapy. AEs were assessed in accordance with NCI CTCAE 4.03. Immune-related AEs (irAEs) were identified and managed according to the NCCN guideline for Management of Immunotherapy-Related Toxicities (20).
Outcomes
The primary endpoint was ORR, defined as the proportion of patients with a best overall response of complete or partial remission, as assessed by IRC using RECIST 1.1. The secondary endpoints were ORR per iRECIST, OS, safety, and immunogenicity. Other secondary efficacy endpoints included disease control rate (DCR), duration of response (DOR), and PFS assessed per RECIST 1.1 and iRECIST. The proportion of patients with an objective response by lymphocyte composition and programmed death-ligand 1 (PD-L1) expression were exploratory endpoints.
DCR was the percentage of patients achieving either a complete response (CR) or PR or stable disease (SD); DOR was the duration of time from first documented response to the date of first documented disease progression or death from any cause; PFS was defined as the first date of geptanolimab administration to progression or death from any cause; OS was defined as the period from the start of geptanolimab treatment to death. Detailed response definitions according to iRECIST guideline are presented in the Supplementary Materials.
Statistical analysis
With the null hypothesis of ORR at 10% and a one-sided type I error rate of 2.5% assuming a valid ORR of 30%, at least 30 patients were required to ensure an 85% power for detecting 20% difference in ORR. Given a possible drop-off rate of 15%, 35 patients were planned to enroll.
Patients receiving at least one dose of geptanolimab were included in full analysis set (FAS) and analyzed for efficacy and safety. Exact binominal confidence intervals (CIs) were calculated for response outcomes. The distributions of all time-to-event endpoints were estimated using the Kaplan–Meier method. Wilcoxon rank-sum tests were applied to compare pretreatment T-cell subpopulation between groups [responders (CR/PR) vs. nonresponders (SD/PD)]. Wilcoxon signed-rank tests were computed to assess changes of T-cell subpopulation from baseline in sequential samples in the same patient. All statistical analyses were performed by using SAS version 9.4. A two-sided P value of less than 0.05 was considered statistically significant.
This study was registered with ClinicalTrials.gov, number NCT03623581.
Biomarker assessment
Immunogenicity was evaluated in patients for antidrug antibody (ADA) positive. An immunologic ligand-binding assay was developed and validated for the detection and quantitation of anti-geptanolimab antibodies in serum collected at baseline, week 1/2/6 and every 6 weeks after week 6 according to the ADA collection schedule. Peripheral blood collected from patients prior to first dose of geptanolimab and during treatment (every 6 weeks at response evaluation) were analyzed for lymphocyte subpopulation by flow cytometry (details in Supplementary Materials).
Archival tumor tissues were obtained from patients prior to treatment initiation. Expression of PD-L1 was assessed by IHC using Ventana PD-L1 (SP263; Roche) rabbit monoclonal primary antibody. Patients were considered PD-L1 positive using a combined positive score (CPS) cut-off ≥1. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor samples using ReliaPrep FFPE gDNA Miniprep System (Promega) following the manufacturer's instructions. Microsatellite instability (MSI) analysis was performed using MSI analysis System Version 1.2 (Promega) across five mononucleotide-repeat markers (NR21, BAT25, NR24, BAT26, MONO27). Tumor mutation burden (TMB) was assessed with hybridization capture of exons from 440 cancer-related genes, interrogating single-nucleotide variants, small insertions and deletions, copy-number variation, and fusion (details in Supplementary Materials).
Results
Patients and treatment
Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. The median time from initial diagnosis of ASPS to the first dose of geptanolimab was 1.9 (range, 0.3–20.0) years. Among the 31 patients who had undergone surgery, 24 (77.4%) had received radical surgery (surgical resection margins negative on final pathology). The median time from surgery to study drug geptanolimab administration was 15.2 (range, 1.7–61.9) months. Of the 37 patients, 19 (51.4%) patients had prior use of VEGFR-TKI and 12 (32.4%) patients had received radiotherapy. At study entry, 35 (94.6%) patients developed metastatic disease and seven (18.9%) patients had brain metastases. Baseline characteristics of patients are summarized in Table 1. By the cut-off date of September 6, 2019, 23 patients are in study and 14 patients have discontinued treatment. Discontinuation was related to disease progression or clinical deterioration (n = 11; 29.7%), unacceptable toxicity (n = 2; 5.4%), and withdraw of consent (n = 1; 2.7%; Fig. 1).
. | n (%) or median (range) . |
---|---|
Patient characteristics . | (n = 37) . |
Age | |
Median, years (range) | 30 (19–52) |
Gender | |
Male | 15 (40.5) |
Female | 22 (59.5) |
ECOG PS | |
0 | 17 (45.9) |
1 | 20 (54.1) |
Disease clinical stage | |
IV | 35 (94.6) |
Not available | 2 (5.4) |
Brain metastases | |
Yes | 7 (18.9) |
No | 30 (81.1) |
Prior surgery | |
Yes | 31 (83.8) |
No | 6 (16.2) |
Prior radiotherapy | |
Yes | 12 (32.4) |
No | 25 (67.6) |
Prior systemic treatment lines | |
0 | 14 (37.8) |
1 | 15 (40.5) |
2 | 5 (13.5) |
3 or above | 3 (8.1) |
Prior VEGFR-TKI treatment | |
Yes | 19 (51.4) |
No | 18 (48.6) |
PD-L1 CPS | |
≥1 | 12 (32.4) |
<1 | 25 (67.6) |
. | n (%) or median (range) . |
---|---|
Patient characteristics . | (n = 37) . |
Age | |
Median, years (range) | 30 (19–52) |
Gender | |
Male | 15 (40.5) |
Female | 22 (59.5) |
ECOG PS | |
0 | 17 (45.9) |
1 | 20 (54.1) |
Disease clinical stage | |
IV | 35 (94.6) |
Not available | 2 (5.4) |
Brain metastases | |
Yes | 7 (18.9) |
No | 30 (81.1) |
Prior surgery | |
Yes | 31 (83.8) |
No | 6 (16.2) |
Prior radiotherapy | |
Yes | 12 (32.4) |
No | 25 (67.6) |
Prior systemic treatment lines | |
0 | 14 (37.8) |
1 | 15 (40.5) |
2 | 5 (13.5) |
3 or above | 3 (8.1) |
Prior VEGFR-TKI treatment | |
Yes | 19 (51.4) |
No | 18 (48.6) |
PD-L1 CPS | |
≥1 | 12 (32.4) |
<1 | 25 (67.6) |
Abbreviations: CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death-ligand 1; PS, performance status; VEGFR-TKI, vascular endothelial growth factor receptor tyrosine kinase inhibitor.
Efficacy
The median follow-up was 7.8 (range, 2.2–12.0) months and patients received a median of 17 (range, 4–26) doses of geptanolimab treatment. Objective response was confirmed in 14 (37.8%; 95% CI, 22.5–55.2) of 37 patients by IRC. Disease control was achieved in 32 (86.5%; 95% CI, 71.2–95.5) patients (Fig. 2A). Median DOR was not reached by the cut-off date and the 6 months DOR was 91.7% (Fig. 2B). Median PFS was 6.9 months [95% CI, 5.0–not reached (NR)] with 3-month and 6-month PFS rates of 70.3% (95% CI, 52.8–82.3) and 56.1% (95% CI, 38.6–70.4), respectively (Fig. 3A). Median OS data were immature (Fig. 3B).
Per iRECIST criteria, disease control was observed in 34 (91.9%) patients, with 37.8% (n = 14) of patients having iPR and 54.1% (n = 20) having iSD. One patient had immune unconfirmed PD and two had immune-confirmed PD. Table 2 and Supplementary Table S2 summarized the responses to therapy at the data cut-off date per IRC and investigator assessment. Other efficacy outcomes including ORR, DOR, and PFS were comparable by IRC and investigator assessment.
. | RECIST 1.1 . | iRECIST . |
---|---|---|
Endpoint . | (n = 37) . | (n = 37) . |
(i)ORRa | ||
Number of patients | 14 | 14 |
Percentage (%) of patients (95% CI) | 37.8 (22.5–55.2) | 37.8 (22.5–55.2) |
(i)DCRb | ||
Number of patients | 32 | 34 |
Percentage (%) of patients (95% CI) | 86.5 (71.2–95.5) | 91.9 (78.1–98.3) |
Response, n (%) | ||
(i)CR | 0 | 0 |
(i)PR | 14 (37.8) | 14 (37.8) |
(i)SD | 18 (48.6) | 20 (54.1) |
PD | 5 (13.5) | |
iUPD | — | 1 (2.7) |
iCPD | — | 2 (5.4) |
(i)PFS, months | ||
Median (95% CI) | 6.9 (5.03–NR) | NR (NR–NR) |
3-month PFS rate (%) (95% CI) | 70.3 (52.8–82.3) | 91.7 (76.5–97.3) |
6-month PFS rate (%) (95% CI) | 56.1 (38.6–70.4) | 76.7 (58.7–87.7) |
. | RECIST 1.1 . | iRECIST . |
---|---|---|
Endpoint . | (n = 37) . | (n = 37) . |
(i)ORRa | ||
Number of patients | 14 | 14 |
Percentage (%) of patients (95% CI) | 37.8 (22.5–55.2) | 37.8 (22.5–55.2) |
(i)DCRb | ||
Number of patients | 32 | 34 |
Percentage (%) of patients (95% CI) | 86.5 (71.2–95.5) | 91.9 (78.1–98.3) |
Response, n (%) | ||
(i)CR | 0 | 0 |
(i)PR | 14 (37.8) | 14 (37.8) |
(i)SD | 18 (48.6) | 20 (54.1) |
PD | 5 (13.5) | |
iUPD | — | 1 (2.7) |
iCPD | — | 2 (5.4) |
(i)PFS, months | ||
Median (95% CI) | 6.9 (5.03–NR) | NR (NR–NR) |
3-month PFS rate (%) (95% CI) | 70.3 (52.8–82.3) | 91.7 (76.5–97.3) |
6-month PFS rate (%) (95% CI) | 56.1 (38.6–70.4) | 76.7 (58.7–87.7) |
Abbreviations: CI, confidence interval; (i)CR, (immune) complete response; (i)DCR, (immune) disease control rate; iCPD, immune-confirmed progressive disease; iUPD, immune unconfirmed progressive disease; iRECIST, Response Evaluation Criteria In Solid Tumors for immune-based therapeutics; NR, not reached; (i) ORR, (immune) overall response rates; PD, progressive disease; (i)PFS, (immune) progression-free survival; (i)PR, (immune) partial response; RECIST, Response Evaluation Criteria in Solid Tumors; (i)SD, (immune) stable disease.
aComplete or partial response.
bComplete response, partial response, or stable disease.
Post hoc, we compared first and second endpoints between patient baseline characteristics (gender, ECOG PS), prior treatment (treatment lines, VEGFR-TKIs exposure) and other biomarkers (PD-L1 and baseline lymphocyte composition). A response was observed in seven of 19 patients who had prior exposure to VEGFR-TKIs (36.8%; 95% CI, 16.3–61.6) and disease control was observed in 14 patients (73.7%; 95% CI, 48.8–90.9; Supplementary Table S3). Of the 37 patients, 23 (62.2%) patients with at least one line of prior systemic therapy had an ORR of 39.1% (n = 9; 95% CI, 19.7–61.5), while response was observed in 12.5% (n = 1; 95% CI, 0.3–52.7) of the eight patients who have failed two or more lines of systemic treatment. The ORR for the 14 patients without prior treatment was 35.7%. Notably, disease control was observed in all 14 (100.0%) patients.
Safety
Thirty-five (94.6%) of the 37 patients reported at least one AE and six (16.2%) patients had grade ≥3 AEs (Supplementary Table S4). Treatment-related AEs (TRAEs) were reported in 32 (86.5%) patients. The most common TRAEs (incidence ≥10%) were rash (n = 7; 18.9%) and blood thyroid stimulating hormone increased (n = 7; 18.9%), hypothyroidism (n = 6; 16.2%), followed by white blood cell count decreased (n = 5; 13.5%), anemia (n = 5; 13.5%), blood bilirubin increased (n = 5; 13.5%), neutrophil count decreased (n = 5; 13.5%), ALT increased (n = 4; 10.8%), fever (n = 4; 10.8%), and hyperuricemia (n = 4; 10.8%). Three (8.1%) of 37 patients reported grade ≥3 TRAEs, including anaemia (n = 1; 2.7%), hypophysitis (n = 1; 2.7%), and proteinuria (n = 1; 2.7%). No grade 4 TRAE was reported (Table 3). Treatment-related serious AEs occurred in three patients (8.1%), including anemia (n = 1; 2.7%), fever (n = 1; 2.7%), and hypophysitis (n = 1; 2.7%). Seventeen (45.9%) of 37 patients reported irAEs, commonly rash (16.2%) and hypothyroidism (16.2%). Two (5.4%) patients reported grade ≥3 irAEs, one (2.7%) anemia, and one (2.7%) hypophysitis (Supplementary Table S5). Overall, five (29.4%) of 17 patients had their irAEs resolved without interruption of treatment, while the other 12 patients received treatment for irAEs, and four of them received corticosteroids. Two patients (5.4%) discontinued treatment due to one Mobitz type I atrioventricular block and one hypophysitis, which were both determined treatment-related. Among the seven patients with baseline brain metastases, no CNS disorder was identified. No death occurred at the time of this analysis.
Adverse event . | Grade 1, n (%) . | Grade 2, n (%) . | Grade 3, n (%) . |
---|---|---|---|
Rash | 5 (13.5) | 2 (5.4) | 0 |
Blood thyroid stimulating hormone increased | 7 (18.9) | 0 | 0 |
Hypothyroidism | 4 (10.8) | 2 (5.4) | 0 |
White blood cell count decreased | 2 (5.4) | 3 (8.1) | 0 |
Anaemia | 3 (8.1) | 1 (2.7) | 1 (2.7) |
Blood bilirubin increased | 3 (8.1) | 2 (5.4) | 0 |
Neutrophil count decreased | 3 (8.1) | 2 (5.4) | 0 |
Alanine aminotransferase increased | 3 (8.1) | 1 (2.7) | 0 |
Fever | 3 (8.1) | 1 (2.7) | 0 |
Hyperuricemia | 4 (10.8) | 0 | 0 |
Hypophysitis | 0 | 0 | 1 (2.7) |
Proteinuria | 0 | 0 | 1 (2.7) |
Adverse event . | Grade 1, n (%) . | Grade 2, n (%) . | Grade 3, n (%) . |
---|---|---|---|
Rash | 5 (13.5) | 2 (5.4) | 0 |
Blood thyroid stimulating hormone increased | 7 (18.9) | 0 | 0 |
Hypothyroidism | 4 (10.8) | 2 (5.4) | 0 |
White blood cell count decreased | 2 (5.4) | 3 (8.1) | 0 |
Anaemia | 3 (8.1) | 1 (2.7) | 1 (2.7) |
Blood bilirubin increased | 3 (8.1) | 2 (5.4) | 0 |
Neutrophil count decreased | 3 (8.1) | 2 (5.4) | 0 |
Alanine aminotransferase increased | 3 (8.1) | 1 (2.7) | 0 |
Fever | 3 (8.1) | 1 (2.7) | 0 |
Hyperuricemia | 4 (10.8) | 0 | 0 |
Hypophysitis | 0 | 0 | 1 (2.7) |
Proteinuria | 0 | 0 | 1 (2.7) |
aTreatment-related adverse events were defined as an adverse event related or possibly related to treatment, as assessed by the investigator. The total number of patients was 37 in this study. This table included all grade treatment-related adverse events occurring in at least 10% of patients and all grade 3 events. No grade 4 or 5 adverse event occurred.
Biomarker analysis
Of 37 patients, 12 (32.4%) patients were classified as PD-L1 positive (CPS ≥1) and 11 (29.7%) of 37 patients had PD-L1 expression (≥1%) in tumor cells. No difference in response was observed between patients with CPS ≥1 (33.3%; 95% CI, 9.9–65.1) and CPS<1 (40.0%; 95% CI, 21.1–61.3). Archival FFPE tissue samples were available for MSI testing in 29 of 37 patients and all of them were microsatellite stable (MSS). TMB was assessed in 27 patients and all had TMB less than one mutation/Mb.
We assessed the correlation between the baseline lymphocyte composition and treatment response. We found that the percentage of CD4+ T cells was significantly higher in nonresponders compared with responders per RECIST 1.1 (P = 0.031). In addition, we observed an influence of geptanolimab on T-cell subpopulation, with CD4+ T-cell count significantly decreased in the first assessment (week 6 vs. baseline; P = 0.021; Supplementary Table S6).
There were four (10.8%) patients in the entire cohort tested positive for ADAs after the geptanolimab treatment, with three patients detected positive before the treatment and one turned positive during treatment. All four patients achieved disease control following geptanolimab treatment and two of them showed response.
Discussion
The treatment options for patients with ASPS remain limited because of the rarity of this disease and the scarcity of clinical studies. For metastatic patients, anti–PD-1 treatment possessed potential clinical benefit, especially for patient refractory to VEGFR-TKIs treatment. To our knowledge, this study represented the first multicenter, phase II study of anti–PD-1 antibody in patients with unresectable, recurrent, or metastatic ASPS. Objective response was achieved in 14 (37.8%) of 37 patients, significantly higher than 10% expected for chemotherapy, indicating meaningful clinical benefit of geptanolimab. Noticeably, pseudoprogression followed by SD per iRECIST was observed in two patients and no hyperprogression occurred in this cohort.
Patients with solid tumors have an overall ORR around 35% (21), and a response to monoimmunotherapy ranged from 11.2% to 70.0% (22). In this study, the overall ORR was 37.8% in FAS and 39.1% for patients with prior treatment. Nineteen patients with prior VEGFR-TKI treatment had an ORR of 36.8% and a median PFS of 6.9 months. The ORR for the 14 patients without prior treatment was 35.7%, and all these patients achieved disease control. The median PFS of this study was 6.9 months, which was numerically lower than the previous studies treated with sunitinib (range, 13–19 months) in patients with ASPS (7, 11, 12), but comparable with those treated with pazopanib (range, 5.5–13.6 months; refs. 9, 13). More recently, a phase II study investigating atezolizumab in patients with ASPS reported an ORR of 32%, which is comparable with the response rate of this study (23). Notably, 36.8% of patients with prior VEGFR-TKI treatment responded to geptanolimab in this study. The findings of this study indicate geptanolimab is active in patients with unresectable, recurrent, or metastatic ASPS who have failed VEGFR-TKI treatment.
Prediction of a patient's response to anti–PD-1 antibody is critical to inform the treatment. Generally, PD-L1 expression by IHC is the most widely used approach with robust data on the clinical usefulness to guide anti–PD-1 treatment in various solid tumors. Previously, in a phase II study assessing axitinib plus pembrolizumab in advanced sarcomas, all tested biopsy samples from patients with ASPS were PD-L1 expression and tumor lymphocyte infiltration was high by IHC in six of nine (66%) patients (16). In this study, only 11 (29.7%) of 37 patients were PD-L1 positive in tumor cells and no statistically significant difference was identified between PD-L1 positive group versus negative group with a CPS cut-off of 1. Besides, MSI and TMB are also used as prognostic biomarkers of ICIs in solid tumors, but in this study, all patients were MSS with low TMB. Despite the sensitivity of ASPS to ICIs, the mechanism behind this response remains elusive. Further investigations of the immune microenvironment will be crucial to understand the response and resistance mechanism, which would serve for better patient selection and immunotherapy optimization in patients with ASPS.
Geptanolimab did not significantly increase the safety risk comparing with VEGFR-TKI treatment. 32 (86.5%) of patients reported TRAEs and 3 (8.1%) reported grade ≥3 TRAEs. In one pazopanib study, TRAEs were reported in all patients. Grade 3 TRAEs were reported in 16.7% patients (13). In another sunitinib study with metastatic patients with ASPS, AEs were 100% and 53% were grade 3/4 (12). It should also be noted that this study incorporated seven patients with baseline brain metastases and no CNS disorders occurred during treatment, while two (40%) of five patients with ASPS with baseline brain metastases were reported to present grade 3 seizures on pembrolizumab and axitinib combination treatment (16).
As a rare disease, few treatment options are available for unresectable, recurrent, or metastatic patient with ASPS without determined standard of care. Thus, despite of limitations including the short follow-up period, limited sample size, and preliminary results of exploratory analysis, this study showed clinical meaningful activity and a manageable safety profile of geptanolimab in this patient population.
Disclosure of Potential Conflicts of Interest
Q. Guo and C. Gao are employees of Genor Biopharma Co, Ltd, China. The other authors declared no conflicts of interest.
Authors' Contributions
Y. Shi: Conceptualization, data curation, supervision, funding acquisition, investigation, methodology, writing-original draft, writing-review and editing. Q. Cai: Data curation, investigation, methodology, writing-review and editing. Y. Jiang: Data curation, investigation, methodology, writing-review and editing. G. Huang: Data curation, investigation, methodology, writing-review and editing. M. Bi: Data curation, investigation, methodology, writing-review and editing. B. Wang: Data curation, investigation, methodology, writing-review and editing. Y. Zhou: Data curation, investigation, methodology, writing-review and editing. G. Wang: Data curation, investigation, methodology, writing-review and editing. H. Ying: Data curation, investigation, methodology, writing-review and editing. Z. Tao: Data curation, investigation, methodology, writing-review and editing. C. Shi: Data curation, investigation, methodology, writing-review and editing. Q. Guo: Resources, data curation, project administration, writing-review and editing. C. Gao: Data curation, formal analysis, methodology, writing-review and editing.
Acknowledgments
This study was sponsored by Genor Biopharma Co, Ltd, China. This study was also supported by China National Major Project for New Drug Innovation (grant no. 2017ZX09304015) and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS; grant no. 2016-I2M-1-001). We thank all the study sites, the investigators, patients, and their families who participated in this study. Authors also appreciate the contributions from the following key members: Joe Zhou, Yu Wang (consulting), Huiyang Cheng, Haige Shen (consulting), Shengbin Ren, Si Chen, Di Qiao, Yue Kang, Fan Xie, Yan Yang, Yi Zheng, Ming Tong, Chunyan Yuan, Gaijing Xue, Cuncun Li, Jing Zhang, Jie Guo, Ziyi Kan, Zhen Gao, Jun Lin, Ke Tan, and Hongbin Yan. Finally, we thank Shiyu Jiang (National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, China) for the medical writing assistance.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.