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Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study

Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study

Patients

Between March 6, 2019 and September 14, 2020, 171 NPC patients were screened and 130 (median age 49.5 years and men 76.0%) were included, forming the intention-to-treat population. Four patients without measurable lesions according to the Independent Radiological Review Committee (IRRC) and one patient who had received only one prior line of chemotherapy were excluded from the efficacy analysis. The FAS per IRRC included 125 patients. In addition, one patient who the investigators determined had no measurable lesion at baseline and one patient who had not received at least two prior lines of chemotherapy were excluded. The FAS per investigators included 128 patients. Forty-six (36.8%) patients in the FAS by IRRC were PD-L1 positive. Serum EBV copy number at baseline was ≥500 IU/ml in 103 (82.4%) patients. Seventy-seven (61.6%) patients had lung metastases, 62 (49.6%) had bone metastases, and 60 (48.0%) had liver metastases. For prior targeted therapies, 36 patients (27.7%) previously received nimotuzumab, 4 (3.1%) endostatin, and 2 (1.5%) cetuximab. Forty-six (36.8%) patients had received at least three prior lines of systemic therapy (Table 1).

Table 1 Patient demographics and baseline characteristics-ITT

The data cut-off date was September 28, 2022. The median follow-up was 29.6 months. The median treatment duration was 4.1 months (range: 0.03-40.9 months). Eight (6.4%) patients continued to receive treatment. One hundred seventeen (93.6%) patients discontinued treatment due to radiological disease progression (n = 82), clinical worsening without radiological evidence (n = 3), adverse events (n = 5), withdrawal of consent (n = 4), loss to follow-up (n = 2), death (n = 4), and other causes (n = 17) (Fig. 1). Sixty-five of 93 patients (69.9%) with disease progression continued treatment with penpulimab and 53.9% subsequently received additional anticancer treatment.

figure 1
Figure 1

The study flowchart. Progressive Parkinson’s disease

Efficacy measures

In the FAS per IRRC, 1 patient (0.8%, 95% CI = 0.0–4.4%) achieved a complete response (CR) and 34 (27.2%, 95% CI = 19.6–35 .9%) a partial response (PR). 2a). The ORR was 28.0% (95% CI = 20.3–36.7%). The median time to response was 1.8 months (95% CI = 1.6–7.4 months) and the median duration of response was 14.8 months (95% CI = 8.9–25.3 months). At 9 months, 66.8% (95% CI = 48.1–80.0%) of patients responded (Fig. 2b). At the time of data cutoff, 10.4% of patients were still in remission. In addition, 27 patients had SD and 51 developed PD. The disease control rate (DCR) was 49.6% (95% CI = 40.5–58.7%).

Fig. 2
Figure 2

Treatment response and survival outcomes. a Waterfall plot of the best percent changes for the sum of target lesion diameters for patients who underwent radiographic evaluation at least once. *This patient had a >20% increase in the sum of the diameter, but with an absolute increase <5 mm, according to the IRRC, and therefore stable disease (SD) rather than progressive disease (PD) was documented. ^The indicated lesion in this patient is the lymph node. b Swimmer plots of time to tumor response (months) of individual patients with metastatic nasopharyngeal carcinoma as assessed by the Independent Radiological Review Committee (IRCC) according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Each swim lane represents one patient in the full analysis set (FAS) per IRRC. Patient responses are color coded. CR complete response, NE not evaluable, PD progressive disease, PR partial response, SD stable disease. Kaplan-Meier estimated progression-free survival curves (PFS) (c) and overall survival (OS) curves (D) of NPC patients in the FAS per IRRC

Eighty-six PFS events occurred and the median PFS was 3.6 months (95% CI = 1.9–7.3 months) (Fig. 2c). The PFS rate at 6 months and 12 months was 42.1% (95% CI = 32.9–51.0%) and 24.7% (95% CI = 17.0–33.1%), respectively. At data cutoff, 48 (36.9%) deaths were reported in the FAS. Median OS was 22.8 months (95% CI = 17.1 months to not reached) (Fig. 2d). The OS rate at 12 and 24 months was 66.1% (95% CI = 56.7–74.0%) and 48.6% (95% CI = 38.9–57.7%), respectively.

Safety

All 130 patients were included in the safety analysis. TRAEs occurred in 71.5% of patients. The three most common TRAEs of any grade were hypothyroidism (30.0%), anemia (15.4%), and elevated aspartate aminotransferase (AST) (14.6%). Fourteen (10.8%) patients experienced grade ≥ 3 TRAEs (Table 2). The rate of irAEs was 48.5% (63/130). The most common irAEs were hypothyroidism (20.8%), elevated blood thyroid-stimulating hormone (12.3%), rash (6.2%), and elevated AST (6.2%). Ten (10/130, 7.6%) patients experienced grade 3 or higher irAEs, including grade 4 abnormal liver function in 1 patient. No grade 5 irAEs were reported (Supplementary Table 1). Four (3.1%) patients permanently discontinued penpulimab due to TRAEs/irAEs, including elevated transaminase levels, disseminated herpes zoster, pemphigoid, and pleural effusion.

Table 2 Treatment-related adverse reactions, all grades (occurring in ≥5% of patients) and grades 3-5

Subgroup analysis

In the subgroup analysis of 60 patients with liver metastases at baseline, the ORR and DCR were 30.0% (95% CI = 18.8–43.2%) and 40.0% (95% CI = 27.6–53, respectively). 5%). Median PFS and OS were 1.9 months (95% CI = 1.8–6.6 months) and 18.6 months (95% CI = 9.4 – not estimable), respectively. Objective response was observed in all subgroups stratified by demographic and clinical characteristics, except in patients ≥65 years (only two patients).

Of 122 patients assessed for PD-L1 expression, the ORR was 43.5% (95% CI = 28.9–58.9%) vs. 19.7% (95% CI = 11.5–30.5%) in patients with a tumor proportion score (TPS) ≥ 50% (n = 46) vs. <50% (n=76) (Supplementary Table 2). Higher PD-L1 expression was also associated with longer median PFS (7.6 months, 95% CI = 3.6–12.0 months). vs. 1.9 months, 95% CI = 1.8–5.6 months; HR = 0.61, 95% CI = 0.40–0.93) and OS (not reached, 95% CI = 22.4 months to not estimable vs. TPS < 50%: 18.6 months, 95% CI = 11.5–24.3 months; HR = 0.52, 95% CI = 0.30–0.92) (Fig. 3a, b).

Fig. 3
figure 3

Survival outcomes stratified by key baseline characteristics. Kaplan-Meier estimated progression-free survival (PFS) and overall survival (OS) curves of NPC patients stratified by PD-L1 expression (TPS ≥ 50% vs. <50%) (a, b) and (TPS ≥ 1% vs. < 1%) (c, D), EBV DNA levels (≥500 IU/ml vs <500 IU/ml) (e, F), and lactate dehydrogenase (LDH) levels at baseline (≥the upper limit, ULN vs.G, H)

Furthermore, 89.3% of patients had TPS ≥ 1% and had a significantly higher ORR than those with TPS < 1% (32.1%, 95% CI = 23.5–41.7% vs. 0%). They also had longer median PFS (3.8 months, 95% CI = 1.9–7.6 months vs. 1.8 months, 95% CI = 1.6–1.9 months; HR = 0.41, 95% CI = 0.22–0.74) and OS (24.2 months vs. 11.5 months; HR = 0.44, 95% CI = 0.22–0.90) (Fig. 3c and d).

Lower EBV DNA levels at baseline predicted better efficacy.24 Patients with an EBV DNA level < 500 IU/ml (n = 22) had a higher ORR than patients with an EBV DNA level ≥ 500 IU/ml (45.5%, 95% CI = 24.4–67, 8% vs. 24.3%, 95% CI = 16.4–33.7%). A lower baseline EBV DNA level was also associated with longer PFS (11.3 months, 95% CI = 1.8 months to inestimable vs. 2.3 months, 95% CI = 1.9–3.8 months; HR, 0.45, 95% CI = 0.25–0.81) and OS (not reached, 95% CI = 23.1 months to not estimable vs. 18.6 months, 95% CI = 11.5 to 25.7 months; HR = 0.32, 95% CI = 0.14–0.74) (Fig. 3e, f). Eighty-eight patients were assessed for EBV DNA levels after two treatment cycles and 46.6% experienced a >50% decrease in EBV DNA levels. Nevertheless, they experienced no significant improvement in PFS and OS compared to those with a ≤50% decrease or increase in EBV DNA levels (PFS: 9.1 months). vs. 1.9 months; Operating system: not reached vs. 30.7 months).

Sixty-one (48.8%) patients had higher lactate dehydrogenase (LDH) levels (≥the upper limit, ULN) at baseline. A higher baseline LDH level was associated with poor response (ORR = 16.4%, 95% CI = 8.2–28.1% vs. 39.1%, 95% CI = 27.1–52.1%), shorter median PFS (1.8 months vs. 7.5 months; P< 0.001) and OS (9.9 months vs. not reached) (Fig. 3g, h).