Safety and Efficacy of Nivolumab Plus Recombinant Human Endostatin in Previously Treated Advanced Non-Small-Cell Lung Cancer

Weize Lv; Xiaofeng Pei; Wenhua Zhao; Yunyan Cong; Yajun Wei; Ting Li; Hongyu Zhang; Zhong Lin; Yuichi Saito; Jae Jun Kim; Zibin Liang; Beilong Zhong; Zhihui Wang

Disclosures

Transl Lung Cancer Res. 2022;11(2):201-212.

Abstract and Introduction

Abstract

Background: Evidence of the efficacy of immune checkpoint inhibitors (ICIs) plus antiangiogenic drugs in previously treated patients with advanced non-small-cell lung cancer (NSCLC) is still insufficient, so we investigated the safety and efficacy of nivolumab plus recombinant human (rh)-endostatin in such patients.

Methods: Patients without epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) targetable mutations in advanced NSCLC who did not respond to previous treatment were enrolled. Eligible patients received nivolumab (3 mg/kg, i.v. drip, day 1) every 2 weeks and rh-endostatin (210 mg, continuous i.v. infusion for 168 h) every 4 weeks until disease progression or discontinuation. The primary endpoint was the objective response rate (ORR). The secondary endpoints included disease control rate (DCR), duration of response (DOR), clinical benefit response rate (CBR), progression-free survival (PFS), overall survival (OS) and safety.

Results: A total of 34 patients received a median of 4 cycles of therapy. In all, 14 patients achieved confirmed partial response (PR) with an ORR of 41.2% [14/34; 95% confidence interval (CI): 23.7–58.6%], DCR of 64.7% (22/34; 95% CI: 47.8–81.6%), CBR of 44.1% (95% CI: 26.5–61.7%), and a DOR of 6.9 (95% CI: 4.4–9.4) months. Median follow-up was 12.2 (range, 2.3–18.1) months. Median PFS (mPFS) was 6.8 (95% CI: 1.1–12.1) months, median OS (mOS) was 17.1 (95% CI: 6.6–27.6) months, and 12-month survival rate of 64.4% (95% CI: 46.2–82.6%). In all, 18 (18/34, 52.9%) patients experienced at least one treatment-related adverse event (TRAE), and Grade 3 TRAEs occurred in 4 (4/34, 11.8%) of them.

Conclusions: This study is first to assess nivolumab plus rh-endostatin in previously treated patients with advanced NSCLC. In view of its favorable efficacy and safety profile, this combination represents a promising treatment regimen in this patient population.

Introduction

Immune checkpoint inhibitors (ICIs) play an important role in the treatment of advanced non-small-cell lung cancer (NSCLC). Two phase III trials demonstrated that nivolumab vs. docetaxel improved overall survival (OS) and showed a favorable safety profile in patients with previously treated advanced NSCLC,^[1,2] making nivolumab one of the current new standard second-line treatments in advanced NSCLC. Besides nivolumab, atezolizumab and pembrolizumab also have been approved as second-line treatments. A primary concern about ICI monotherapy as second-line therapy is the unsatisfactory tumor regression in clinical practice. To overcome this problem, combination therapy has been proposed and developed.

A series of preclinical studies suggest that ICIs and anti-angiogenesis therapy may have synergistic antitumor effects.^[3–6] Anti-angiogenesis therapy not only normalizes the tumor vasculature but also optimizes the tumor's immune microenvironment.^[7] Similar to the promising findings from preclinical studies, many clinical trials have shown encouraging clinical benefits and a favorable safety profile for combining ICIs and antiangiogenic drugs in patients with advanced NSCLC.^[8–12] The IMPOWER150 study including atezolizumab, bevacizumab and chemotherapy has unlocked the door of combination therapy of immunotherapy and anti-angiogenic drug for first-line in advanced non-squamous NSCLC.^[10] In view of the high-toxicity from the IMPOWER150 trial, chemotherapy-free treatment combing with PD-1 inhibitor and anti-angiogenic has recently emerged as a novel treat pattern in first-line or later-line advanced NSCLC treatment.^[8,9,11,12] But this choice is based on the evidence of small-size sample phase I/II clinical trials, the effectiveness of the combination therapy should be further confirmed by more well-designed double-blinded randomized controlled trials. In addition, the question of the optimal combination pattern and order of administration, the best candidates, and predictable bio-markers for combination of PD-1 inhibitor and anti-angiogenic remain unresolved. Taken together, more favorable combinations remain to be investigated.

Recombinant human (rh)-endostatin (Endostar®, Simcere Biopharmaceutical Co., Ltd., Jiangsu, China) can inhibit tumor endothelial cell proliferation, angiogenesis and tumor growth by down-regulating expression of vascular endothelial growth factors (VEGFs) and suppressing other important targets like matrix metalloproteinases (MMPs), hypoxia inducible factor 1 alpha (HIF-1α), basic fibroblast growth factor (bFGF).^[13,14] Therefore, rh-endostatin as a multiple-targets angiogenesis inhibitor has its own advantages compared to other anti-angiogenic agents, such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). A phase III trial suggested that rh-endostatin can improve the effect of the NP (vinorelbine and cisplatin) regimen with tolerable adverse effects in patients with untreated advanced NSCLC.^[15] According to previous results, rh-endostatin combined with chemotherapy received approval as a first-line treatment for advanced NSCLC in China. Moreover, preclinical studies have reported that rh-endostatin normalizes the tumor vasculature and improves microenvironment to help carry drug and oxygen to tumor.^[16–18] These processes enhancing the antitumor activity of chemotherapy, as well as having synergistic antitumor effects with PD-1 blockade.^[4] Furthermore, compared to other anti-angiogenic drugs, rh-endostatin has been shown to have less severe toxic profiles and better compliance.^[15,19,20] Especially, its safety and effectiveness in lung squamous cell carcinomas have been demonstrated,^[15,20] where mAbs and TKIs lost approval due to safety concerns. Based on such data, we considered that the combination of rh-endostatin and nivolumab is a feasible treatment for later-line advanced NSCLC therapy, whatever its pathological type. So, we conducted this trial to assess the efficacy and safety of nivolumab plus rh-endostatin continuous intravenous infusion (CIV) as second-line or later treatment for patients with advanced NSCLC. We present the following article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-49/rc).

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Baseline characteristics
Characteristic	Total (n=34)
Age, years
Median [range]	60 [37–72]
Sex, n (%)
Male	23 (67.6)
Female	11 (32.4)
ECOG PS, n (%)
0–1	25 (73.5)
2	9 (26.5)
Tumor histology, n (%)
Adenocarcinoma	22 (64.7)
Squamous	8 (23.5)
Other	4 (11.8)
Smoking status, n (%)
Current or former smoker	17 (50.0)
Never smoker	17 (50.0)
No. of prior systemic therapies, n (%)
1	8 (23.5)
2	15 (44.1)
>2	11 (32.4)
No. of organs with metastasis, n (%)
≤2	24 (70.6)
>2	10 (29.4)
Brain metastasis, n (%)
Yes	8 (23.5)
No	26 (76.5)
Liver metastasis, n (%)
Yes	9 (26.5)
No	25 (73.5)
Prior anti-angiogenesis therapy, n (%)
Yes	16 (47.1)
No	18 (52.9)

ECOG PS, Eastern Cooperative Oncology Group performance status.

Table 2. Best overall tumor response of investigator-evaluation
Outcome	All patients (n=34)	Efficacy-evaluable patients (n=31)
Median follow-up (range), months	12.2 (2.3–18.1)	–
Best overall response, n (%)
CR	0 (0.0)	0 (0.0)
PR	14 (41.2)	14 (45.2)
SD	8 (23.5)	8 (25.8)
PD	12 (35.3)	9 (29.0)
ORR, % (95% CI)	41.2 (23.7–58.6)	45.2 (26.6–63.7)
DCR, % (95% CI)	64.7 (47.8–81.6)	71.0 (54.0–87.9)
CBR, % (95% CI)	44.1 (26.5–61.7)	48.4 (29.8–67.0)
DOR, months (95% CI)	6.9 (4.4–9.4)	6.9 (4.4–9.4)

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; CI, confidence interval; DCR, disease control rate; CBR, clinical benefit response rate; DOR, duration of response.

Table 3. ORR, PFS and OS in all subgroup analyses in FAS
Subgroup [n]	ORR		DCR		mPFS		mOS
Subgroup [n]	N (%)	F value	N (%)	F value	Months, 95% CI	P value	Months, 95% CI	P value
Sex		0.983		0.138		0.272		0.936
Male [23]	10 (43.5)		17 (73.9)		9.4 (1.9–16.9)		17.1 (4.4–29.8)
Female [11]	4 (36.4)		5 (45.5)		3.4 (0.0–7.7)		NR
ECOG PS		0.004*		0.004*		<0.001*		<0.001*
0–1 [25]	14 (56.0)		20 (80.0)		12.5 (7.8–17.2)		17.1 (6.7–27.5)
2 [9]	0 (0.0)		2 (22.2)		1.7 (1.0–2.4)		3.4 (1.9–4.9)
Tumor histology		0.776		0.869		0.618		0.361
Adenocarcinoma [22]	9 (40.9)		15 (68.2)		6.8 (2.4–11.3)		NR
Squamous [8]	4 (50.0)		5 (62.5)		15.3 (NR–NR)		17.1 (NR–NR)
Other [4]	1 (25.0)		2 (50.0)		2.8 (1.6–4.0)		NR
Smoking status		0.728		0.282		0.249		0.573
Smoked [17]	6 (35.3)		9 (52.9)		5.5 (0.9–10.0)		NR
Never smoked [17]	8 (47.1)		13 (76.5)		9.4 (4.1–14.7)		17.1 (4.3–29.9)
No. of prior systemic therapies		0.983		0.459		0.303		0.593
1–2 [23]	10 (43.5)		16 (69.6)		9.4 (2.8–15.9)		17.1 (6.5–27.7)
≥2 [11]	4 (36.4)		6 (54.5)		4.0 (2.2–5.9)		NR
No. of organs with metastasis		0.295		0.459		0.027*		0.006*
≤2 [24]	11 (47.8)		16 (69.6)		9.4 (3.9–14.8)		17.1 (6.6–27.5)
>2 [10]	3 (27.3)		6 (54.5)		3.3 (1.2–5.3)		5.3 (4.6–6.0)
Brain metastasis		0.422		0.098		0.037*		0.029*
Yes [8]	2 (25.0)		3 (37.5)		1.8 (0.1–3.6)		5.3 (1.6–9.0)
No [26]	12 (46.2)		19 (73.1)		7.5 (2.2–12.8)		17.1 (6.6–27.6)
Liver metastasis		0.467		0.271		0.420		0.068
Yes [9]	3 (33.3)		5 (50.0)		3.3 (1.9–4.6)		8.2 (1.1–15.3)
No [25]	11 (44.0)		17 (70.8)		9.3 (5.1–13.5)		NR
Prior anti-angiogenesis therapy		0.315		0.087		0.021*		0.112
Yes [16]	5 (31.3)		7 (43.8)		2.8 (0.4–5.2)		17.1 (4.5–29.7)
No [18]	9 (50.0)		15 (75.0)		12.5 (8.4–16.6)		NR

*, represent P values with significant difference. ORR, objective response rate; PFS, progression-free survival; OS, overall survival; FAS, full analysis set; DCR, disease control rate; mPFS, median PFS; mOS, median OS; ECOG PS, Eastern Cooperative Oncology Group performance status; NR, not reached.

Table 4. TRAEs in SAS
AEs	All patients, n (%)
AEs	Any grade	Grade 1–2	Grade 3–5
Hypothyroidism	7 (20.6)	7 (20.6)	0 (0.0)
Arrhythmia	5 (14.7)	4 (11.8)	1 (2.9)
Atrial premature beats	2 (5.9)	2 (5.9)	0 (0.0)
Atrioventricular block	2 (5.9)	2 (5.9)	0 (0.0)
Atrial fibrillation	1 (2.9)	0 (0.0)	1 (2.9)
Immune-related pneumonitis	3 (8.8)	1 (2.9)	2 (5.9)
Abnormal hepatic function	2 (5.9)	2 (5.9)	0 (0.0)
Blood creatinine increased	2 (5.9)	2 (5.9)	0 (0.0)
Proteinuria	3 (8.8)	3 (8.8)	0 (0.0)
Fatigue	2 (5.9)	2 (5.9)	0 (0.0)
Hyperglycemia	2 (5.9)	2 (5.9)	0 (0.0)
Creatine kinase	2 (5.9)	2 (5.9)	0 (0.0)
Hypertension	2 (5.9)	2 (5.9)	0 (0.0)
Rash	1 (2.9)	1 (2.9)	0 (0.0)
Left ventricular ejection fraction decreased	1 (2.9)	1 (2.9)	0 (0.0)
Catheter-related infection	1 (2.9)	0 (0.0)	1 (2.9)
Any AE	18 (52.9)	14 (41.1)	4 (11.8)