A Multicenter Phase II Study of Second‐Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First‐Line Sorafenib Monotherapy

Abstract

Lessons Learned

• For patients with advanced hepatocellular carcinoma after failure of first‐line sorafenib monotherapy, second‐line axitinib provides modest efficacy with tolerable toxicity.

• The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers.

Background

Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second‐line axitinib for advanced HCC.

Methods

Patients with advanced HCC and Child‐Pugh A liver function, experiencing progression on first‐line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control.

Results

From April 2011 to March 2016, 45 patients were enrolled. Thirty‐seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression‐free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment‐related adverse events were compatible with previous reports of axitinib.

Conclusion

Second‐line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first‐line sorafenib monotherapy.

Discussion

In this study, we found that axitinib is well tolerated and provides modest activity for patients with advanced HCC following failure of front‐line sorafenib monotherapy. The response rate was 6.7%, and the disease control rate was 62.2% according to RECIST 1.1 (Fig. 1), which fulfilled the original goal to improve disease control rate to more than 40%. The median PFS and OS were 2.2 months and 10.1 months (Fig. 2), respectively. Treatment‐related adverse events of axitinib were compatible with previous reports 1, 2.

Figure 1.

Waterfall plots of objective tumor response by RECIST 1.1. The disease control rate and objective response rate were 62.2% and 6.7%, respectively.Abbreviations: PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2.

Kaplan‐Meier plots of PFS and OS. The median PFS was 2.2 months (95% confidence interval: 0.2–4.2 months), and the median OS was 10.1 months (95% confidence interval: 3.6–16.6 months).Abbreviations: OS, overall survival; PFS, progression‐free survival.

In separate phase II trials, McNamara et al. and Kang et al. demonstrated the acceptable efficacy and toxicities of axitinib for patients with advanced HCC following prior antiangiogenic therapy 1, 2. With the more stringent eligibility criteria in our study (all patients should have experienced first‐line sorafenib monotherapy), the response rate and PFS appeared lower than those observed in the above‐mentioned axitinib trials. Nevertheless, the OS observed was similar among all of the studies. For patients who achieved disease control in our study (62.2% of patients), the time to tumor progression ranged from 1.8 to 27.0 months (median 3.1 months, SD 5.76 months), suggesting that a proportion of patients with HCC may benefit from axitinib treatment and that the heterogeneity of patient cohorts may account for the different efficacy results among these three clinical trials. Development of reliable biomarkers to identify patients most likely to benefit from axitinib treatment is thus critical.

The association between treatment‐related adverse events and clinical efficacy is an extensively studied and debated issue. Most such association was found in drug‐induced dermatologic adverse events and hypertension 3, 4, 5, 6, 7, 8, 9. However, we should be cautious in interpreting this type of association because of the observer bias commonly seen when the adverse events and treatment efficacy are observed in nonblinded, nonrandomized trials 10. Besides, most of the association came from either post hoc subgroup analysis of clinical trials or retrospective review. Furthermore, dose escalation to induce the desired adverse events of the targeted agents did not appear to enhance the therapeutic efficacy 11, 12. The hypothesis of treatment‐related adverse events as a pharmacodynamic indicator and an efficacy predictor must be tested in prospective trials with prespecified comparison and ideally other pharmacokinetic and pharmacodynamic correlation.

In conclusion, we found that second‐line axitinib was a safe treatment with modest activity for patients with advanced HCC after failure of first‐line sorafenib monotherapy. Optimal patient selection with the aid of predictive biomarkers may be important for further clinical development of axitinib‐based therapies.

Trial Information

Disease	Hepatocellular carcinoma
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	1 prior regimen
Type of Study	Phase II, single arm
Primary Endpoint	Disease control rate
Secondary Endpoint	Overall response rate
Secondary Endpoint	Progression‐free survival
Secondary Endpoint	Overall survival
Secondary Endpoint	Safety
Additional Details of Endpoints or Study Design
Patient eligibility: The major eligibility criteria included (a) histological or clinical diagnosis of HCC according to American Association for the Study of Liver Diseases criteria 19; (b) documented progression on or intolerance to first‐line sorafenib monotherapy for advanced HCC; (c) age ≥ 18 years; (d) Eastern Cooperative Oncology Group performance status 0 or 1; (e) Child‐Pugh liver function classification A; (f) white blood count ≥3,000/uL; platelet count ≥75,000/uL; and (g) at least one measurable lesion according to RECIST 1.1.
Treatment and disease assessment: Patients received axitinib, 5 mg orally twice daily in the fasting status, until objective disease progression, development of unacceptable toxicity, or voluntary discontinuation. Patients may continue the study treatment after documented disease progression if there is sufficient evidence of clinical benefit. Patients experiencing grade 3 or greater drug reaction (Common Terminology Criteria for Adverse Events [CTCAE] version 3) received dose reduction (level − 1, 3 mg twice daily; level − 2, 2 mg twice daily). Patients with no CTCAE grade 2 or greater adverse events related to axitinib after 2 consecutive weeks of treatment might receive axitinib dose escalation (level + 1, 7 mg twice daily; level + 2, 10 mg twice daily). Tumor response was assessed by computed tomography or magnetic resonance imaging after 4 weeks and 8 weeks of treatment and every 8 weeks thereafter until objective disease progression.
Statistical analysis: The primary endpoint was rate of disease control, defined as complete or partial response, or stable disease according to RECIST 1.1 that lasts for at least 8 weeks without progression of tumor‐related symptoms. The secondary endpoints included objective response rate, PFS, and OS. PFS was defined as the duration from the date of the first dose of axitinib to the date of documented disease progression or death of any cause. OS was defined as the duration from the date of the first dose of axitinib to the date of death of any cause. Axitinib was considered noneffective if the disease control rate was 20% or lower and was worthy of further study if the disease control rate was 40% or higher. With type 1 and type 2 errors of 0.05 and 0.1, respectively, this design should accrue 24 and 21 patients at the first and second stages. If five or fewer patients with disease control were observed at the first stage, then the study was planned to be terminated. All enrolled patients were included in the analysis of treatment efficacy and safety.
Ethics: The study (www.clinicaltrials.gov NCT01273662) was approved by the institutional research ethical committees of the participating hospitals. All procedures performed in this trial were in accordance with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all patients included in this study.
Investigator's Analysis	Active but results overtaken by other developments

Drug Information

Drug 1
Generic/Working Name	Axitinib
Trade Name	Inlyta
Company Name	Pfizer Pharmaceutical Co., Ltd.
Drug Type	Small molecule
Drug Class	Angiogenesis ‐ VEGF
Dose	5 mg per flat dose
Route	p.o.
Schedule of Administration	5 mg orally twice daily with dose adjustments based on tolerability

Patient Characteristics

Number of Patients, Male	38
Number of Patients, Female	7
Stage	Barcelona Clinic Liver Cancer Stage B‐3 Stage C‐42
Age	Median (range): 56 (32–76) years
Number of Prior Systemic Therapies	Median: 1 (only prior sorafenib monotherapy allowed)
Performance Status: ECOG	0 — 18 1 — 27 2 — 0 3 — 0 Unknown — 0
Other	Complete details of patient characteristics are shown in Table 1.

Table 1.

Patient characteristics

Characteristics	Patients, n	%
Total	45	100
Median age (range), years	56 (32–76)
Male gender	38	84
Etiology
Hepatitis B	37	82
Hepatitis C	6	13
ECOG PS
0	18	40
1	27	60
AFP >400 ng/mL	22	49
Liver cirrhosis	34	76
Vascular invasion	25	56
Extrahepatic spread	35	78
BCLC stage
B	3	7
C	42	93
CLIP score
0	3	7
1	11	24
2	17	38
3	11	24
4	3	7
Prior therapy
Surgery	22	49
Ablation	16	36
TACE	39	87
Sorafenib	45	100

Abbreviations: AFP, α‐fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG, Eastern Cooperative Oncology Group; PS, performance status; TACE, transarterial chemoembolization.

Primary Assessment Method

Title	Disease control rate
Number of Patients Enrolled	45
Number of Patients Evaluable for Toxicity	45
Number of Patients Evaluated for Efficacy	44
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 3 (6.7%)
Response Assessment SD	n = 25 (55.6%)
Response Assessment PD	n = 16 (35.6%)
Response Assessment OTHER	n = 1 (2.2%)
(Median) Duration Assessments PFS	2.2 months, CI: 0.2–4.2
(Median) Duration Assessments OS	10.1 months, CI: 3.6–16.6
(Median) Duration Assessments Duration of Treatment	2.3 months

Adverse Events

All Cycles
Name	NC/NA	1	2	3	4	5	All grades
Fatigue	40%	27%	22%	11%	0%	0%	60%
Anorexia	43%	29%	24%	4%	0%	0%	57%
Hypertension	44%	7%	47%	2%	0%	0%	56%
Rash: hand‐foot skin reaction	51%	16%	22%	11%	0%	0%	49%
Diarrhea	55%	18%	16%	11%	0%	0%	45%
Weight loss	74%	20%	4%	2%	0%	0%	26%
Rash: acne/acneiform	76%	13%	9%	2%	0%	0%	24%
Vomiting	78%	13%	9%	0%	0%	0%	22%
Mucositis/stomatitis (clinical exam)	80%	4%	16%	0%	0%	0%	20%
Constipation	85%	11%	4%	0%	0%	0%	15%
Dyspnea (shortness of breath)	89%	11%	0%	0%	0%	0%	11%
Nausea	87%	9%	4%	0%	0%	0%	13%
AST, SGOT	51%	9%	18%	20%	2%	0%	49%
ALT, SGPT	51%	20%	11%	11%	7%	0%	49%
Bilirubin (hyperbilirubinemia)	62%	9%	11%	9%	9%	0%	38%
Proteinuria	73%	20%	7%	0%	0%	0%	27%
Leukocytes (total WBC)	87%	4%	9%	0%	0%	0%	13%
Hemoglobin	89%	0%	9%	2%	0%	0%	11%

Common treatment‐related adverse events and laboratory abnormalities; only adverse events occurring in more than 10% (all grades) of patients or with a severity of grade ≥ 3 are listed.
Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; NC/NA, no change from baseline/no adverse event; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; WBC, white blood cell.

Assessment, Analysis, and Discussion

Completion	Study completed
Investigator's Assessment	Active but results overtaken by other developments

As the second‐line treatment for advanced hepatocellular carcinoma (HCC), regorafenib (RESORCE trial) and cabozantinib (CELESTIAL trial) demonstrated the capability to prolong overall survival (OS) in placebo‐controlled phase III studies 13, 14. Median OS reached 10.6 months and 10.2 months for regorafenib and cabozantinib, respectively. Consistent with these reports, the median OS for patients receiving second‐line axitinib was 10.1 months in the current study. However, the progression‐free survival (PFS) found in this study (2.1 months) or in the RESORCE trial (3.1 months) was apparently shorter than the PFS in the CELESTIAL trial (5.1 months) 13, 14. Beyond multikinase inhibitory activity, regorafenib has been demonstrated to inhibit the growth and metastasis of colon cancer through its interaction with the tumor microenvironment 15; such immune modulatory effects may contribute to the prolonged OS for patients receiving second‐line regorafenib. Similarly, axitinib was proved to exert anticancer effects in melanoma 16 and glioblastoma 17 through facilitating antitumor immunity. Therefore, axitinib may provide additional OS benefit for patients with HCC through undefined immune‐modulatory effects.

The results of clinical trials using axitinib as salvage therapy for advanced HCC demonstrated that the heterogeneity of patients may have a significant impact on therapeutic efficacy. A major challenge in developing antiangiogenic therapy is a lack of useful predictive biomarkers 18. Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) is a sensitive method to detect the changes in tumor blood flow and vascular permeability 19. We have previously shown that DCE‐MRI was capable to predict therapeutic efficacy in patients with HCC receiving various antiangiogenic targeted therapy 20, 21, 22. In addition, the changes in tumor density measured by the modified RECIST (mRECIST) may also reflect the changes in tumor perfusion after antiangiogenic therapy and correlate with efficacy of antiangiogenic agents in HCC 23, 24. We therefore hypothesize that vascular response detected by DCE‐MRI or mRECIST may help identify patients with HCC who may benefit from antiangiogenic therapy. We plan to analyze the imaging data from patients treated with antiangiogenic agents in different clinical trials.

In recent years, the focus of developing new systemic therapy for HCC has shifted from targeted therapy to immunotherapy, particularly the immune checkpoint inhibitors targeting the programmed cell death‐1 (PD‐1) pathway. Although the anti‐PD‐1 agents nivolumab and pembrolizumab demonstrated an objective response rate of 15%–20% in patients with advanced HCC 25, 26, randomized trials did not demonstrate statistically significant improvement in OS in either first‐line (nivolumab vs. sorafenib) 27 or second‐line (pembrolizumab vs. placebo) 28 settings. Combination of anti‐PD‐1 therapy with antiangiogenic therapy has shown promising efficacy in patients with advanced renal cell carcinoma 29 as well as HCC 30. The future role of axitinib in this type of combination therapy and the relevant predictive biomarkers remain to be explored 31.

Disclosures

Ann‐Lii Cheng: Bayer‐Schering Pharma, Novartis, Merck Serono, Eisai, Merck Sharp & Dohme (I.A.) Corp., ONXEO, Bayer HealthCare Pharmaceuticals Inc., Bristol‐Myers Squibb Company, and Ono Pharmaceutical Co., Ltd. (C/A), Bayer‐Schering Pharma (SAB); Chiun Hsu: BMS/ONO, Roche, Ipsen (H), AstraZeneca, Bayer, BMS/ONO, Eisai, Eli Lilly, Ipsen, Merck Serono, MSD, Novartis, Roche, TTY Biopharm, Celgene (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board