Purpose:

We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).

Patients and Methods:

This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1.

Results:

Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.

Conclusions:

Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.

See related commentary by Pinato et al., p. 908

This article is featured in Highlights of This Issue, p. 903

Translational Relevance

Combination of anti-programmed death (PD)-1/PD ligand-1(PD-L1) agents with antiangiogenic agents are potential novel treatment options in patients with cancer. In a phase I study, the camrelizumab and apatinib combination demonstrated manageable toxicity and encouraging activity in advanced hepatocellular carcinoma (HCC). On the basis of these results, we launched this phase II study to assess the camrelizumab and apatinib combination in treatment-naïve and pretreated patients with advanced HCC. This combination achieved a substantial number of objective responses, durable responses, prolonged overall survival, and presented reasonable safety profiles. To our knowledge, camrelizumab plus apatinib was the first reported combination strategy of anti-PD-1/PD-L1 and antiangiogenic agents for HCC as second-line treatment. Furthermore, this is the first report of this combination strategy in a population with high infection rate of hepatitis B virus. This study supports camrelizumab plus apatinib as a promising treatment option for advanced HCC in the first-line and second-line settings.

Liver cancer is the sixth most prevalent cancer and the fourth leading cause of cancer mortality worldwide in 2018 (1, 2). Hepatocellular carcinoma (HCC) is the major histologic subtype, accounting for 75%–85% of liver cancers (1). It has been estimated that 72% cases of HCC occur in Asia and more than 50% occur in China (3). The main etiologic risk factors include viral hepatitis, heavy alcohol consumption, exposure to aflatoxin, diabetes, and nonalcoholic fatty liver disease (4). Patients with HCC in Europe, United States, and Japan show a large predominance of hepatitis C virus (HCV) infection, while those in China show a preponderance of hepatitis B virus (HBV) over HCV infection (5). Most patients present with advanced, unresectable disease, with a poor 5-year survival probability of approximately 10%–18% (6, 7).

Currently, there are two first-line targeted treatment options for advanced HCC, namely, sorafenib and lenvatinib, and three second-line targeted treatment options, namely, regorafenib, cabozantinib, and ramucirumab. In recent years, anti-programmed death (PD)-1 antibodies nivolumab and pembrolizumab have received accelerated approval from the FDA for HCC previously treated with sorafenib (8, 9). However, subsequent phase III CheckMate 459 and KEYNOTE-240 studies investigating nivolumab [vs. sorafenib; median overall survival (OS) 16.4 vs. 14.7 months, HR 0.85 (95% CI, 0.72–1.02), P = 0.0752] as first-line treatment and pembrolizumab [vs. placebo; median OS 13.9 vs. 10.6 months, HR 0.781 (95% CI, 0.611–0.998), P = 0.0238] as second-line therapy did not achieve statistical significance for their primary endpoints (10, 11). Thus, the development of new therapies for effective management of advanced HCC is an important unmet medical need.

Dual anti-PD-1/VEGFR 2 (VEGFR-2) therapy has been reported to reprogram the immune microenvironment, and anti-VEGFR-2 blockade induces PD ligand-1 (PD-L1) expression in both endothelial cells and tumor-infiltrating CD4+ cells (12). Therefore, combination therapies of anti-PD-1 inhibitor and antiangiogenic agents have aroused great interest. Recently, the FDA approved the combination of atezolizumab and bevacizumab for patients with unresectable or metastatic HCC who have not received prior systemic therapy on the basis of the phase III IMbrave150 study (13). Lenvatinib plus pembrolizumab showed promising antitumor activity with a tolerable safety profile in treatment-naïve unresectable HCC in the phase Ib KEYNOTE-524 trial (14). However, the above two combination strategies were all evaluated or used in the first-line setting, and there are no data available reported in a larger population with a high proportion of concomitant HBV infection.

In a phase I study launched in October 2016, the combination of camrelizumab (a high-affinity, humanized, IgG4-κ PD-1 mAb) and apatinib (a selective VEGFR-2 tyrosine kinase inhibitor) showed promising antitumor activity and an acceptable safety profile in advanced HCC (15). On the basis of results of this phase I study, we conducted the present phase II study to assess the efficacy and safety of camrelizumab combined with apatinib both in the first-line and second-line settings for advanced HCC.

Study design and patients

This is a nonrandomized, multicenter, open-label, phase II trial of camrelizumab in combination with apatinib in patients with advanced HCC. This trial was conducted across 25 centers in China (Supplementary Table S1).

Eligible patients were ages ≥18 years, had a histologically confirmed diagnosis of unresectable or metastatic advanced HCC, were classified as Barcelona Clinic Liver Cancer stage B or C, were treatment-naïve or had progressed on or were intolerant to first-line targeted therapy, had at least one measurable lesion as defined by RECIST v1.1, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had a predicted life expectancy of greater than 12 weeks, had adequate organ function; and were Child-Pugh class A.

Patients with any history of or active autoimmune disease, or concurrent medical use of immunosuppressive medications or immunosuppressive doses of systemic corticosteroids were excluded. Patients treated previously with any anti-PD-1/PD-L1 mAb or apatinib were also excluded from the study. Patients exhibiting central nervous system metastases or hepatic encephalopathy, tumor occupation ≥50% of the liver volume, liver transplant recipients, hypertension not controlled with antihypertensive agents, and clinically significant cardiovascular or cerebrovascular diseases were also excluded. Patients with positive fecal occult blood at both baseline and reexamination were also excluded if severe esophageal varices were detected by gastroscopy. Full inclusion and exclusion criteria are listed in the Supplementary Methods.

The trial was carried out in accordance with the International Conference on Good Clinical Practice Standards and the Declaration of Helsinki. The Institutional Review Boards or independent ethics committees of all participating centers approved the protocol and amendments, and all patients provided written informed consent.

Procedures

All patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) for 20–60 minutes every 2 weeks plus oral apatinib 250 mg/day in 4-week cycles. Treatment was continued until disease progression, presence unacceptable toxicity, withdrawal of consent, investigator decision, or when patients had received camrelizumab for 2 years, whichever occurred first. Dose reductions of camrelizumab to 3 mg/kg every 2 weeks in patients with bodyweight decreased from ≥50 kg to <50 kg during treatment and dose interruptions of camrelizumab for ≤12 weeks were permitted. Dose discontinuations, interruptions, and modifications in dose frequency of apatinib (to 250 mg/day for 5 days on 2 days off, or 7 days on 7 days off) were allowed.

Tumor assessment by local investigators was performed every 2 cycles (8 weeks) during the first 12 cycles of treatment, and every 3 cycles thereafter in accordance with the RECIST v1.1 guidelines. As determined by the investigator, patients with radiographic progressive disease who were still achieving clinical benefit could continue treatment and be reevaluated to confirm progressive disease after 4–6 weeks. Patients who discontinued treatment for any reason other than disease progression were followed up every 3 months for tumor radiological assessment until disease progression, initiation of new anticancer treatment, or death. Patients were followed up every month after discontinuation of treatment to assess survival. PD-L1 expression was assessed by IHC with PD-L1 IHC 22C3 pharmDx Kit (Agilent Technologies). The expression of PD-L1 was determined by the tumor proportion score (TPS), which is defined as the percentage of viable tumor cells showing partial or complete membrane staining. The detailed protocol for PD-L1 expression detection is provided in the Supplementary Methods.

Adverse events (AE) were collected until 30 days after the last dose, coded according to the Medical Dictionary for Regulatory Activities v22.0 and graded in accordance with the Common Terminology Criteria for Adverse Events v4.03. Serious AEs and immune-related AEs (irAE) were followed up to 90 days after the last dose of camrelizumab or the start of a new anticancer treatment, whichever occurred first. IrAEs were managed in accordance with a previous study and treatment could be reinitiated after clinical improvement (16).

Outcomes

The primary endpoint was the objective response rate (ORR), which was defined as the proportion of patients who achieved confirmed complete response or partial response assessed by an independent review committee (IRC) as per RECIST v1.1 guidelines. Secondary endpoints included ORR [assessed by investigators per RECIST v1.1 and IRC per modified RECIST (mRECIST) guidelines], the disease control rate (DCR, the proportion of patients who achieved complete response, partial response, or stable disease as their best overall response), the duration of response (DoR, the time from first recorded complete or partial response to disease progression or death), progression-free survival (PFS, the time from the first dose of study medication to radiographic disease progression or death), OS (the time from the first dose of study medication to death due to any cause), the probability of 9/12/18-month OS, and safety. An exploratory endpoint included the correlation between PD-L1 expression and efficacy.

Statistical analysis

This was a single arm study with two cohorts. For the first-line cohort: assuming an observed proportion of patients with ORR was 30%, a sample size of 56 patients would ensure that the distance from the observed proportion to the limit of a 95% CI was 12%. For the second-line cohort: based on the ORR of standard second-line regimens being no more than 10%, at least a 25% of ORR for the treatment was expected to be achieved. A sample size of 64 patients would ensure at least 90% power to detect that the lower boundary of 95% CI of ORR would be greater than 10%. If a 20% dropout rate was considered, 80 patients would be enrolled in this cohort. The sample size was enlarged to evaluate the efficacy and safety in a larger size of population in support of the potential China National Medical Products Administration New Drug Application submission.

The full analysis set, which was defined as all patients who were enrolled and received at least one dose of study treatment, was the primary analysis set for the efficacy analysis. The safety set included all patients who received at least one dose of study treatment and had safety data recorded after the dose. The ORR and DCR were calculated along with two-sided 95% CIs calculated using the Clopper–Pearson method. The OS, PFS, and DoR were evaluated using the Kaplan–Meier method. The median OS was estimated, and the corresponding 95% CIs were calculated using the Brookmeyer and Crowley method. The probabilities of 9/12/18-month OS were also calculated using the Kaplan–Meier method, and the corresponding 95% CIs were calculated using log–log transformation according to normal distribution approximation with back transformation to CIs on the untransformed scale. All statistical analyses were performed using SAS v9.4.

Between March 13, 2018 and January 03, 2019, a total of 190 eligible patients were enrolled and received a combination treatment of camrelizumab and apatinib, and included 70 patients in the first-line treatment cohort and 120 patients in the second-line treatment cohort, which comprised the efficacy and safety analysis population (Fig. 1). The demographics and disease characteristics at baseline are shown in Table 1. In the second-line cohort, the median time on treatment for the previous targeted therapy was 6.3 months [interquartile range (IQR) 4.1–13.0], and median time between suspension of targeted therapy and randomization was 0.8 months (IQR 0.6–1.6).

Figure 1.

Trial profile. The three deaths in first-line cohort included one pneumonitis, one disease progression, and one multiple organ dysfunction syndrome. The six deaths in the second-line cohort included one sudden cardiac death, one esophageal varices hemorrhage, one disease progression, two multiple organ dysfunction syndromes, and one death of unknown cause.

Figure 1.

Trial profile. The three deaths in first-line cohort included one pneumonitis, one disease progression, and one multiple organ dysfunction syndrome. The six deaths in the second-line cohort included one sudden cardiac death, one esophageal varices hemorrhage, one disease progression, two multiple organ dysfunction syndromes, and one death of unknown cause.

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Table 1.

Demographic and disease characteristics at baseline.

First-line (N = 70)Second-line (N = 120)
Age, years 
 Median (IQR) 53 (44–60) 51 (43–58) 
Gender 
 Male 63 (90.0) 106 (88.3) 
 Female 7 (10.0) 14 (11.7) 
ECOG performance status 
 0 46 (65.7) 68 (56.7) 
 1 24 (34.3) 52 (43.3) 
Child-Pugh score 
 A5 61 (87.1) 101 (84.2) 
 A6 9 (12.9) 19 (15.8) 
HBV infectiona 62 (88.6) 106 (88.3) 
HCV infection 1 (0.8) 
BCLC stage 
 B 12 (17.1) 22 (18.3) 
 C 58 (82.9) 98 (81.7) 
Extrahepatic metastases 48 (68.6) 91 (75.8) 
Macrovascular invasion 20 (28.6) 29 (24.2) 
α-fetoprotein concentration 
 <400 ng/mL 34 (48.6) 60 (50.0) 
 ≥400 ng/mL 35 (50.0) 58 (48.3) 
 Unknown 1 (1.4) 2 (1.7) 
Platelet count 
 <130 × 109/L 21 (30.0) 34 (28.3) 
 ≥130 × 109/L 49 (70.0) 86 (71.7) 
Bilirubin 
 ≤1 ULN 61 (87.1) 104 (86.7) 
 >1 ULN 9 (12.9) 16 (13.3) 
INR (×ULN), mean ± SD 1.1 ± 0.1 1.0 ± 0.1 
Previous local regional therapy 
 Surgery 47 (67.1) 100 (83.3) 
 Radiotherapyb 11 (15.7) 27 (22.5) 
 Interventional therapyc 44 (62.9) 93 (77.5) 
 Local ablation 21 (30.0) 43 (35.8) 
 Targeted therapyd 120 (100) 
  Sorafenib 112 (93.3) 
  Donafenib 8 (6.7) 
 Others 2 (2.9) 6 (5.0) 
First-line (N = 70)Second-line (N = 120)
Age, years 
 Median (IQR) 53 (44–60) 51 (43–58) 
Gender 
 Male 63 (90.0) 106 (88.3) 
 Female 7 (10.0) 14 (11.7) 
ECOG performance status 
 0 46 (65.7) 68 (56.7) 
 1 24 (34.3) 52 (43.3) 
Child-Pugh score 
 A5 61 (87.1) 101 (84.2) 
 A6 9 (12.9) 19 (15.8) 
HBV infectiona 62 (88.6) 106 (88.3) 
HCV infection 1 (0.8) 
BCLC stage 
 B 12 (17.1) 22 (18.3) 
 C 58 (82.9) 98 (81.7) 
Extrahepatic metastases 48 (68.6) 91 (75.8) 
Macrovascular invasion 20 (28.6) 29 (24.2) 
α-fetoprotein concentration 
 <400 ng/mL 34 (48.6) 60 (50.0) 
 ≥400 ng/mL 35 (50.0) 58 (48.3) 
 Unknown 1 (1.4) 2 (1.7) 
Platelet count 
 <130 × 109/L 21 (30.0) 34 (28.3) 
 ≥130 × 109/L 49 (70.0) 86 (71.7) 
Bilirubin 
 ≤1 ULN 61 (87.1) 104 (86.7) 
 >1 ULN 9 (12.9) 16 (13.3) 
INR (×ULN), mean ± SD 1.1 ± 0.1 1.0 ± 0.1 
Previous local regional therapy 
 Surgery 47 (67.1) 100 (83.3) 
 Radiotherapyb 11 (15.7) 27 (22.5) 
 Interventional therapyc 44 (62.9) 93 (77.5) 
 Local ablation 21 (30.0) 43 (35.8) 
 Targeted therapyd 120 (100) 
  Sorafenib 112 (93.3) 
  Donafenib 8 (6.7) 
 Others 2 (2.9) 6 (5.0) 

Note: Data are median (IQR) or N (%).

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio; ULN, upper limit of normal.

aHBV infection was defined as HBsAg+ and HBV DNA <2,000 IU/mL.

bPatients who had received radioactive seed implantation were excluded.

cIncluding transcatheter arterial chemoembolization, transcatheter arterial embolization, and hepatic arterial infusion chemotherapy.

d118 patients developed progressive disease and 2 patients were intolerant to previous targeted therapy.

As of January 10, 2020, the data cut-off date, the median follow-up was 16.7 months (IQR 11.1–18.2) and 14.0 months (IQR 9.6–17.0) in the first-line and second-line treatment cohort, respectively. Fourteen (20.0%) of the 70 patients in the first-line treatment cohort and 32 (26.7%) of the 120 patients in the second-line cohort were still under treatment. The primary reason for treatment discontinuation was disease progression for both cohorts (first-line, 54.3%, 38/70; second-line, 57.5%, 69/120). The median duration of camrelizumab treatment was 8.2 months (IQR 4.6–13.8) in the first-line cohort and 7.4 months (IQR 4.4–13.8) in the second-line cohort, and the median duration of apatinib treatment was 6.9 months (IQR 3.5–10.6) and 6.5 months (IQR 3.6–12.7), respectively. Thirty-one (44.3%) of 70 patients in the first-line cohort and 60 (50.0%) of 120 patients in the second-line cohort continued to receive other subsequent therapies after study treatment discontinuation, with targeted therapy being the most common treatment choice (Supplementary Table S2).

As of the data cut-off, the ORR assessed by IRC per RECIST v1.1 was 34.3% (24/70; 95% CI, 23.3–46.6) in the first-line treatment cohort (Table 2). In the second-line treatment cohort, the ORR assessed by the IRC as per RECIST v1.1 guidelines for the initially planned 80 patients was 23.8% (19/80; 95% CI, 14.9–34.6). After sample size enlargement to 120 patients, the ORR (22.5%; 27/120, 95% CI, 15.4–31.0) was similar to that of the initially planned patients, indicating the consistency of the evidence supporting the clinical significance of the efficacy of this drug combination (Table 2). Disease control assessed by the IRC as per RECIST v1.1 guidelines was reported in 54 (77.1%; 95% CI, 65.6–86.3) of the 70 patients in the first-line cohort and in 91 (75.8%; 95% CI, 67.2–83.2) of the 120 patients in the second-line cohort. The best changes from baseline in the sum of the longest target lesion diameter per patient are presented in Fig. 2, and the percentage changes in tumor lesion size from baseline over time are shown in Supplementary Fig. S1. Among the 24 patients and 27 patients achieving objective response in first-line and second-line treatment cohorts, respectively median time to response (TTR) was 1.9 months (IQR 1.8–3.7) and 1.9 months (IQR 1.8–3.7). The median DoR was 14.8 (95% CI, 5.5–not reached) in the first-line cohort and was not reached in the second-line cohort. Response was ongoing in 10 (41.7%) and 20 (74.1%) patients in each cohort as of the data cut-off date. Results of ORR, DCR, TTR, and DoR were assessed by both investigator review per RECIST v1.1 and IRC per mRECIST guidelines are presented in Table 2. ORRs were generally consistent across all subgroups analyzed (Supplementary Fig. S2; Supplementary Table S3), except for those with a very small sample size, such as females and patients ages ≥65 years.

Table 2.

Tumor response.

IRC per RECIST v1.1Investigator review per RECIST v1.1IRC per mRECIST
First-line (N = 70)Second-line (N = 120)First-line (N = 70)Second-line (N = 120)First-line (N = 70)Second-line (N = 120)
Best overall response 
 Complete response 1 (1.4) 2 (1.7) 1 (0.8) 6 (8.6) 2 (1.7) 
 Partial response 23 (32.9) 25 (20.8) 24 (34.3) 32 (26.7) 26 (37.1) 28 (23.3) 
 Stable disease 30 (42.9) 64 (53.3) 32 (45.7) 58 (48.3) 23 (32.9) 61 (50.8) 
 Progressive disease 13 (18.6) 26 (21.7) 11 (15.7) 26 (21.7) 12 (17.1) 26 (21.7) 
 Not evaluable 3 (4.3) 3 (2.5) 3 (4.3) 3 (2.5) 3 (4.3) 3 (2.5) 
Objective response 24 (34.3%, 23.3–46.6) 27 (22.5%, 15.4–31.0) 24 (34.3%, 23.3–46.6) 33 (27.5%, 19.7–36.4) 32 (45.7%, 33.7–58.1) 30 (25.0%, 17.5–33.7) 
Disease control 54 (77.1%, 65.6–86.3) 91 (75.8%, 67.2–83.2) 56 (80.0%, 68.7–88.6) 91 (75.8%, 67.2–83.2) 55 (78.6%, 67.1–87.5) 91 (75.8%, 67.2–83.2) 
Median time to response, months (IQR) 1.9 (1.8–3.7) 1.9 (1.8–3.7) 2.9 (1.8–5.5) 1.9 (1.8–3.7) 1.9 (1.8–2.5) 1.8 (1.8–3.5) 
Median duration of response, months (95% CI) 14.8 (5.5–NR) NR 9.2 (4.7–NR) NR (12.9–NR) NR (5.8–NR) NR 
Number of ongoing responses 10 (41.7) 20 (74.1) 11 (45.8) 21 (63.6) 13 (40.6) 19 (63.3) 
IRC per RECIST v1.1Investigator review per RECIST v1.1IRC per mRECIST
First-line (N = 70)Second-line (N = 120)First-line (N = 70)Second-line (N = 120)First-line (N = 70)Second-line (N = 120)
Best overall response 
 Complete response 1 (1.4) 2 (1.7) 1 (0.8) 6 (8.6) 2 (1.7) 
 Partial response 23 (32.9) 25 (20.8) 24 (34.3) 32 (26.7) 26 (37.1) 28 (23.3) 
 Stable disease 30 (42.9) 64 (53.3) 32 (45.7) 58 (48.3) 23 (32.9) 61 (50.8) 
 Progressive disease 13 (18.6) 26 (21.7) 11 (15.7) 26 (21.7) 12 (17.1) 26 (21.7) 
 Not evaluable 3 (4.3) 3 (2.5) 3 (4.3) 3 (2.5) 3 (4.3) 3 (2.5) 
Objective response 24 (34.3%, 23.3–46.6) 27 (22.5%, 15.4–31.0) 24 (34.3%, 23.3–46.6) 33 (27.5%, 19.7–36.4) 32 (45.7%, 33.7–58.1) 30 (25.0%, 17.5–33.7) 
Disease control 54 (77.1%, 65.6–86.3) 91 (75.8%, 67.2–83.2) 56 (80.0%, 68.7–88.6) 91 (75.8%, 67.2–83.2) 55 (78.6%, 67.1–87.5) 91 (75.8%, 67.2–83.2) 
Median time to response, months (IQR) 1.9 (1.8–3.7) 1.9 (1.8–3.7) 2.9 (1.8–5.5) 1.9 (1.8–3.7) 1.9 (1.8–2.5) 1.8 (1.8–3.5) 
Median duration of response, months (95% CI) 14.8 (5.5–NR) NR 9.2 (4.7–NR) NR (12.9–NR) NR (5.8–NR) NR 
Number of ongoing responses 10 (41.7) 20 (74.1) 11 (45.8) 21 (63.6) 13 (40.6) 19 (63.3) 

Note: Data are N (%), N (%, 95% CI), or months (95% CI), unless otherwise indicated.

Abbreviations: IRC, independent review committee; NR, not reached.

Figure 2.

The best change from baseline in sum of the longest target lesion diameter per patient in the first-line cohort (A) and the second-line cohort (B). Patients who were still under study treatment are marked by a star. The ratios of tumor shrinkage or enlargement in the y-axis are the best change from the baseline in the sum of the longest target lesion diameter, and different color codes (CR, PR, SD, PD, and NE) indicate overall response. CR and PR indicate confirmed CR and confirmed PR. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable.

Figure 2.

The best change from baseline in sum of the longest target lesion diameter per patient in the first-line cohort (A) and the second-line cohort (B). Patients who were still under study treatment are marked by a star. The ratios of tumor shrinkage or enlargement in the y-axis are the best change from the baseline in the sum of the longest target lesion diameter, and different color codes (CR, PR, SD, PD, and NE) indicate overall response. CR and PR indicate confirmed CR and confirmed PR. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable.

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On the basis of the IRC assessment per RECIST v1.1 guidelines, 49 (70.0%) of 70 patients in the first-line treatment cohort and 82 (68.3%) of 120 patients in the second-line cohort experienced disease progression or death as of the data cut-off date. The median PFS was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively (Fig. 3A and B; Supplementary Fig. S3). A total of 29 (41.4%) deaths occurred in the first-line cohort and 47 (39.2%) deaths occurred in the second-line cohort. The median OS was immature (Fig. 3C and D). The Kaplan–Meier estimated 9-month OS rates were 86.7% (95% CI, 76.0–92.8) and 79.1% (95% CI, 70.7–85.4), the 12-month OS rates were 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), and the 18-month OS rates were 58.1% (95% CI, 45.4–68.9) and 56.5% (95% CI, 45.7–66.0), respectively, for the first-line and second-line cohorts. The different median OS in the second-line patients with baseline AFP <400 ng/mL and ≥400 ng/mL indicated the potential value of AFP level for survival prediction (Supplementary Fig. S4). For patients that achieved a complete/partial response, stable disease, or progressive disease, the probabilities of 12-month survival were similar between the first-line and second-line treatment cohorts (Fig. 3E and F). In addition, the best overall response was positively correlated with OS, indicating that high DCR might be a potential predictor of long-term survival.

Figure 3.

Kaplan–Meier plots of PFS and OS. A and B, PFS in first-line cohort (A) and second-line cohort (B) assessed by the IRC as per RECIST v1.1 guidelines. OS in first-line cohort (C) and second-line cohort (D). OS in patients with best overall response of CR/PR, SD, and PD in the first-line cohort (E) and the second-line cohort (F). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Figure 3.

Kaplan–Meier plots of PFS and OS. A and B, PFS in first-line cohort (A) and second-line cohort (B) assessed by the IRC as per RECIST v1.1 guidelines. OS in first-line cohort (C) and second-line cohort (D). OS in patients with best overall response of CR/PR, SD, and PD in the first-line cohort (E) and the second-line cohort (F). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

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In the exploratory analysis, 54 (28.4%) of the 190 patients had tumor tissue samples available for baseline PD-L1 expression levels evaluation; 22 (40.7%, 22/54) patients demonstrated PD-L1 TPS ≥1% (Supplementary Table S4). Both the ORR and PFS events were similar between patients with PD-L1 TPS ≥1% and <1% (Supplementary Table S5).

Safety profiles were similar between patients in the first-line and second-line cohort (Table 3; Supplementary Table S6). In total, 189 (99.5%) of the 190 patients who received camrelizumab in combination with apatinib had at least one treatment-related AE (TRAE). The most common TRAEs of any grade were hypertension (72.6%), increased aspartate aminotransferase (63.2%), proteinuria (61.6%), and hyperbilirubinemia (61.6%). Grade 3 or greater TRAEs were reported in 147 (77.4%) of the 190 patients, with the most common adverse events being hypertension (34.2%), increased gamma-glutamyltransferase (11.6%), and neutropenia (11.1%). Twenty-three (12.1%) of 190 patients discontinued camrelizumab combined with apatinib because of TRAEs. Treatment interruption or modification due to TRAEs was reported in 137 (72.1%) patients. Serious TRAEs occurred in 55 (28.9%) patients. Deaths related to study drugs were reported for 2 (1.1%) patients, including one hepatic failure and one pneumonitis.

Table 3.

Treatment-related adverse events.

First-line cohort (N = 70)Second-line cohort (N = 120)Total (N = 190)
Any 69 (98.6) 120 (100.0) 189 (99.5) 
 Grade 3–5 55 (78.6) 92 (76.7) 147 (77.4) 
 Led to treatment interruption or dose modification 54 (77.1) 83 (69.2) 137 (72.1) 
 Camrelizumab interruption 39 (55.7) 57 (47.5) 96 (50.5) 
 Apatinib interruption/dose modification 58 (82.9) 90 (75.0) 148 (77.9) 
 Led to treatment discontinuation 12 (17.1) 11 (9.2) 23 (12.1) 
 Camrelizumab discontinuation 2 (2.9) 4 (3.3) 6 (3.2) 
 Apatinib discontinuation 11 (15.7) 10 (8.3) 21 (11.1) 
 Serious TRAEs 23 (32.9) 32 (26.7) 55 (28.9) 
 Led to death 1 (1.4) 1 (0.8) 2 (1.1) 
TRAEs Any grade Grade 3–5 Any grade Grade 3–5 Any grade Grade 3–5 
 Hypertensiona 51 (72.9) 28 (40.0) 87 (72.5) 37 (30.8) 138 (72.6) 65 (34.2) 
 Aspartate aminotransferase increased 48 (68.6) 7 (10.0) 72 (60.0) 13 (10.8) 120 (63.2) 20 (10.5) 
 Proteinuriaa 45 (64.3) 5 (7.1) 72 (60.0) 8 (6.7) 117 (61.6) 13 (6.8) 
 Hyperbilirubinemiaa 47 (67.1) 10 (14.3) 70 (58.3) 10 (8.3) 117 (61.6) 20 (10.5) 
 Thrombocytopeniaa 45 (64.3) 7 (10.0) 69 (57.5) 12 (10.0) 114 (60.0) 19 (10.0) 
 Hand–foot syndrome 31 (44.3) 6 (8.6) 77 (64.2) 11 (9.2) 108 (56.8) 17 (8.9) 
 Alanine aminotransferase increased 47 (67.1) 6 (8.6) 53 (44.2) 8 (6.7) 100 (52.6) 14 (7.4) 
 Leukopeniaa 33 (47.1) 4 (5.7) 62 (51.7) 4 (3.3) 95 (50.0) 8 (4.2) 
 Neutropeniaa 30 (42.9) 8 (11.4) 56 (46.7) 13 (10.8) 86 (45.3) 21 (11.1) 
 Astheniaa 31 (44.3) 34 (28.3) 65 (34.2) 
 Diarrheaa 21 (30.0) 3 (4.3) 41 (34.2) 1 (0.8) 62 (32.6) 4 (2.1) 
 Reactive cutaneous capillary endothelial proliferation 19 (27.1) 37 (30.8) 1 (0.8) 56 (29.5) 1 (0.5) 
 Rasha 25 (35.7) 1 (1.4) 30 (25.0) 55 (28.9) 1 (0.5) 
 Abdominal paina 19 (27.1) 1 (1.4) 32 (26.7) 2 (1.7) 51 (26.8) 3 (1.6) 
 Hypothyroidisma 18 (25.7) 29 (24.2) 47 (24.7) 
 Hematuriaa 17 (24.3) 29 (24.2) 1 (0.8) 46 (24.2) 1 (0.5) 
 Hypoalbuminemiaa 19 (27.1) 24 (20.0) 43 (22.6) 
 Gamma-glutamyltransferase increased 21 (30.0) 13 (18.6) 19 (15.8) 9 (7.5) 40 (21.1) 22 (11.6) 
 Decreased appetitea 18 (25.7) 22 (18.3) 40 (21.1) 
 Anemiaa 15 (21.4) 1 (1.4) 23 (19.2) 1 (0.8) 38 (20.0) 2 (1.1) 
 Hepatic function abnormala 11 (15.7) 7 (10.0) 14 (11.7) 10 (8.3) 25 (13.2) 17 (8.9) 
 Lymphopeniaa 13 (18.6) 5 (7.1) 12 (10.0) 2 (1.7) 25 (13.2) 7 (3.7) 
 Hypokalemiaa 5 (7.1) 4 (5.7) 7 (5.8) 1 (0.8) 12 (6.3) 5 (2.6) 
 Hypophosphatemia 3 (4.3) 2 (2.9) 4 (3.3) 2 (1.7) 7 (3.7) 4 (2.1) 
 Hepatotoxicitya 1 (1.4) 1 (1.4) 5 (4.2) 5 (4.2) 6 (3.2) 6 (3.2) 
First-line cohort (N = 70)Second-line cohort (N = 120)Total (N = 190)
Any 69 (98.6) 120 (100.0) 189 (99.5) 
 Grade 3–5 55 (78.6) 92 (76.7) 147 (77.4) 
 Led to treatment interruption or dose modification 54 (77.1) 83 (69.2) 137 (72.1) 
 Camrelizumab interruption 39 (55.7) 57 (47.5) 96 (50.5) 
 Apatinib interruption/dose modification 58 (82.9) 90 (75.0) 148 (77.9) 
 Led to treatment discontinuation 12 (17.1) 11 (9.2) 23 (12.1) 
 Camrelizumab discontinuation 2 (2.9) 4 (3.3) 6 (3.2) 
 Apatinib discontinuation 11 (15.7) 10 (8.3) 21 (11.1) 
 Serious TRAEs 23 (32.9) 32 (26.7) 55 (28.9) 
 Led to death 1 (1.4) 1 (0.8) 2 (1.1) 
TRAEs Any grade Grade 3–5 Any grade Grade 3–5 Any grade Grade 3–5 
 Hypertensiona 51 (72.9) 28 (40.0) 87 (72.5) 37 (30.8) 138 (72.6) 65 (34.2) 
 Aspartate aminotransferase increased 48 (68.6) 7 (10.0) 72 (60.0) 13 (10.8) 120 (63.2) 20 (10.5) 
 Proteinuriaa 45 (64.3) 5 (7.1) 72 (60.0) 8 (6.7) 117 (61.6) 13 (6.8) 
 Hyperbilirubinemiaa 47 (67.1) 10 (14.3) 70 (58.3) 10 (8.3) 117 (61.6) 20 (10.5) 
 Thrombocytopeniaa 45 (64.3) 7 (10.0) 69 (57.5) 12 (10.0) 114 (60.0) 19 (10.0) 
 Hand–foot syndrome 31 (44.3) 6 (8.6) 77 (64.2) 11 (9.2) 108 (56.8) 17 (8.9) 
 Alanine aminotransferase increased 47 (67.1) 6 (8.6) 53 (44.2) 8 (6.7) 100 (52.6) 14 (7.4) 
 Leukopeniaa 33 (47.1) 4 (5.7) 62 (51.7) 4 (3.3) 95 (50.0) 8 (4.2) 
 Neutropeniaa 30 (42.9) 8 (11.4) 56 (46.7) 13 (10.8) 86 (45.3) 21 (11.1) 
 Astheniaa 31 (44.3) 34 (28.3) 65 (34.2) 
 Diarrheaa 21 (30.0) 3 (4.3) 41 (34.2) 1 (0.8) 62 (32.6) 4 (2.1) 
 Reactive cutaneous capillary endothelial proliferation 19 (27.1) 37 (30.8) 1 (0.8) 56 (29.5) 1 (0.5) 
 Rasha 25 (35.7) 1 (1.4) 30 (25.0) 55 (28.9) 1 (0.5) 
 Abdominal paina 19 (27.1) 1 (1.4) 32 (26.7) 2 (1.7) 51 (26.8) 3 (1.6) 
 Hypothyroidisma 18 (25.7) 29 (24.2) 47 (24.7) 
 Hematuriaa 17 (24.3) 29 (24.2) 1 (0.8) 46 (24.2) 1 (0.5) 
 Hypoalbuminemiaa 19 (27.1) 24 (20.0) 43 (22.6) 
 Gamma-glutamyltransferase increased 21 (30.0) 13 (18.6) 19 (15.8) 9 (7.5) 40 (21.1) 22 (11.6) 
 Decreased appetitea 18 (25.7) 22 (18.3) 40 (21.1) 
 Anemiaa 15 (21.4) 1 (1.4) 23 (19.2) 1 (0.8) 38 (20.0) 2 (1.1) 
 Hepatic function abnormala 11 (15.7) 7 (10.0) 14 (11.7) 10 (8.3) 25 (13.2) 17 (8.9) 
 Lymphopeniaa 13 (18.6) 5 (7.1) 12 (10.0) 2 (1.7) 25 (13.2) 7 (3.7) 
 Hypokalemiaa 5 (7.1) 4 (5.7) 7 (5.8) 1 (0.8) 12 (6.3) 5 (2.6) 
 Hypophosphatemia 3 (4.3) 2 (2.9) 4 (3.3) 2 (1.7) 7 (3.7) 4 (2.1) 
 Hepatotoxicitya 1 (1.4) 1 (1.4) 5 (4.2) 5 (4.2) 6 (3.2) 6 (3.2) 

Note: Data are N (%). TRAEs of any grade occurring in ≥20% of total patients are listed; grade 3–5 TRAEs occurring in ≥2% of total patients are listed.

Abbreviation: TRAE, treatment-related adverse events.

aTRAE cluster consisting of several preferred terms (Supplementary Table S4).

Fifty-three (27.9%) of the 190 patients experienced irAEs, with the most common being hypothyroidism (16, 8.4%), rash (7, 3.7%), and hyperglycemia (6, 3.2%; Supplementary Table S7). Grade ≥3 irAEs occurred in 14 (7.4%) patients (Supplementary Table S8).

The efficacy of monotherapy (targeted therapy or immunotherapy) in advanced HCC is limited and FDA-approved first-line combination therapies are only available in a few regions of the world, thus alternative therapies are needed. On the basis of our phase I study, we conducted this phase II study reported herein and showed that combination of camrelizumab and apatinib achieved potent efficacy in terms of ORR, DoR, and OS in advanced HCC both in the first-line and second-line settings. The safety was manageable. To our knowledge, this trial is the largest study conducted in a population having a high proportion of HBV infection to assess efficacy and safety of camrelizumab plus apatinib in advanced HCC. In addition, this was the first reported combination strategy of anti-PD-1/PD-L1 antibody and an antiangiogenic agent for HCC as the second-line treatment.

This study met its primary endpoint in both the first-line and second-line cohorts. The efficacy of camrelizumab plus apatinib in the first-line cohort was comparable with that of pembrolizumab plus lenvatinib as well as atezolizumab plus bevacizumab (the first-line standard therapy approved by FDA; refs. 13, 14). Efficacy of this combination strategy in the second-line cohort was also in line with the FDA-approved second-line combination strategy, nivolumab plus ipilimumab (an anti-CTLA-4 antibody; ref. 17). Cross-trial comparisons should be interpreted with caution due to the different patient populations included. However, our data suggested that camrelizumab combined with apatinib might be an efficacious treatment option for advanced HCC both in the first-line and second-line settings.

Subgroup analyses of ORRs were generally consistent with those in the overall study population, in both cohorts. Higher ORRs were observed in the subgroup of females and in patients ages ≥65 years, but this result might have resulted from a bias introduced by the small sample size in these subgroups. For sorafenib-intolerant patients enrolled in the second-line cohort, additional inclusion criteria (such as Child-Pugh score A and laboratory examinations) were required. Therefore, the proportion of patients we enrolled who were intolerant to sorafenib did not actually reflect the proportion of first-line sorafenib intolerance observed in clinical practice or the proportion of sorafenib withdrawn due to adverse events.

We observed a clear discrepancy of IRC-assessed ORRs per mRECIST guidelines (P = 0.003, Pearson χ2 test) between the first-line and second-line cohorts, but no significant differences in IRC-assessed ORRs per RECIST (P = 0.08) or investigator-assessed ORRs per RECIST guidelines (P = 0.32) between the first-line and second-line cohorts existed. This result may be attributed to the smaller sample size of the first-line cohort. Another possible reason is that the antiangiogenic effect of apatinib as second-line therapy may be affected by the first-line sorafenib treatment history, because more than 98% of patients had progressed on sorafenib.

The safety profile showed no unexpected or new toxic effects relative to single-agent camrelizumab or apatinib (18, 19). Pneumotoxicity (lung infection and pneumonitis) and reactive cutaneous capillary endothelial proliferation (RCCEP, an immune response of skin capillary endothelial cells) were likely associated with camrelizumab (19, 20), while the occurrence of hand–foot syndrome, hypertension, proteinuria, and neutropenia (no febrile neutropenia occurred) were likely associated with apatinib (18). We observed that the incidence of hand–foot syndrome at grade 3 or greater was lower that of apatinib monotherapy (18), which might be attributable to the two-thirds dose reduction of apatinib in this combination in our study. Occurrence of other TRAEs, including fatigue, increased alanine aminotransferase, increased aspartate aminotransferase, hyperbilirubinemia, and laboratory abnormalities, might be associated with the combination treatment.

Upper gastrointestinal bleeding commonly occurred in patients with HCC. In the IMbrave 150 trial (13), the incidence of upper gastrointestinal bleeding observed in the atezolizumab–bevacizumab group was 7% because bleeding is a known AE to bevacizumab. In our study, upper gastrointestinal hemorrhage was only reported in 3 (1.6%) patients, including 1 (1.4%) patient in the first-line cohort and 2 (1.7%) patients in the second-line cohort, and none was considered treatment related. We found the incidence of increased aspartate aminotransferase was high, and this might have resulted from a higher proportion of patients with HBV infection included in this study. In the 147 (77.4%) patients with TRAEs of grade ≥3, 65 (34.2%) patients had grade ≥3 hypertension, and no grade 4 or 5 hypertension was reported. Hypertension can be controlled by antihypertensive drugs, and usually does not lead to hospitalization or become life threatening. Together with the low incidences of irAE (27.9%), our data suggested that the combination of camrelizumab and apatinib was tolerable and had a manageable safety profile.

Notably, RCCEP, which is a common skin toxicity caused by camrelizumab, was reduced remarkably in this study when compared with camrelizumab monotherapy (29.5% vs. 66.8%; ref. 19), suggesting that the VEGFA/VEGFR-2 signaling pathway may be involved in the pathogenesis of RCCEP. We speculate that the balance between an angiogenesis enhancer and inhibitor could be disrupted by the camrelizumab-induced reactivation of the immune response, which leads to the excessive proliferation of capillary endothelial cells.

This trial had several limitations. First, there was no control group and 88.4% of the patients were HBV-infected which might affect the generalizability of the results to the broader population. The randomized, open-label, international, multicenter, phase III trial (NCT03764293, launched at 2018) evaluating the efficacy and safety of camrelizumab plus apatinib versus sorafenib as first-line therapy in patients with advanced HCC may address these concerns. Second, only 54 patients had tumor tissue available to be tested for baseline PD-L1 expression levels; thus, the predictive value of PD-L1 status for treatment efficacy could not be clearly defined. Further evaluation of PD-L1 as biomarker for predicting efficacy is warranted in a larger cohort. Third, this study is also limited by the lack of quality-of-life data, which can provide evidence of the impact of this combination strategy on functioning and symptoms of advanced HCC.

In conclusion, this phase II study demonstrated that camrelizumab in combination with apatinib displayed high ORR, durable response, long survival, as well as a manageable safety profile in advanced HCC with a high proportion of HBV infection. This study indicated that this combination strategy might be suitable as a novel treatment option in the first-line or second-line setting for this patient population.

X. Zhang, S. Wang, and Q. Wang are employees of Jiangsu Hengrui Medicine Co., Ltd. No disclosures were reported by the other authors.

J. Xu: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, methodology, writing-original draft, project administration, writing-review and editing. J. Shen: Data curation, supervision, investigation, methodology, writing-review and editing. S. Gu: Data curation, supervision, investigation, methodology, writing-review and editing. Y. Zhang: Data curation, supervision, investigation, methodology, writing-review and editing. L. Wu: Data curation, supervision, investigation, methodology, writing-review and editing. J. Wu: Data curation, supervision, investigation, methodology, writing-review and editing. G. Shao: Data curation, supervision, investigation, methodology, writing-review and editing. Y. Zhang: Data curation, supervision, investigation, methodology, writing-review and editing. L. Xu: Data curation, supervision, investigation, methodology, writing-review and editing. T. Yin: Data curation, supervision, investigation, methodology, writing-review and editing. J. Liu: Data curation, supervision, investigation, methodology, writing-review and editing. Z. Ren: Data curation, supervision, investigation, methodology, writing-review and editing. J. Xiong: Data curation, supervision, investigation, methodology, writing-review and editing. X. Mao: Data curation, supervision, investigation, methodology, writing-review and editing. L. Zhang: Data curation, supervision, investigation, methodology, writing-review and editing. J. Yang: Data curation, supervision, investigation, methodology, writing-review and editing. L. Li: Data curation, supervision, investigation, methodology, writing-review and editing. X. Chen: Data curation, supervision, investigation, methodology, writing-review and editing. Z. Wang: Data curation, supervision, investigation, methodology, writing-review and editing. K. Gu: Data curation, supervision, investigation, methodology, writing-review and editing. X. Chen: Data curation, supervision, investigation, methodology, writing-review and editing. Z. Pan: Data curation, supervision, investigation, methodology, writing-review and editing. K. Ma: Data curation, supervision, investigation, methodology, writing-review and editing. X. Zhou: Data curation, supervision, investigation, methodology, writing-review and editing. Z. Yu: Data curation, supervision, investigation, methodology, writing-review and editing. E. Li: Data curation, supervision, investigation, methodology, writing-review and editing. G. Yin: Data curation, supervision, investigation, methodology, writing-review and editing. X. Zhang: Software, formal analysis, methodology, writing-review and editing. S. Wang: Data curation, supervision, methodology, project administration, writing-review and editing. Q. Wang: Conceptualization, data curation, supervision, investigation, methodology, project administration, writing-review and editing.

This work was supported by Jiangsu Hengrui Medicine Co., Ltd. We thank all the patients participating in this trial and the clinical study site investigators. Medical writing for this article was provided by Tengfei Zhang, PhD (Medical Writer at Hengrui) according to Good Publication Practice Guidelines.

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.

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