Optimizing treatment outcomes for a patient with rapidly progressing HCC using a PD-1 inhibitor
Presentation and management
The patient was a 65-year-old male, a chronic smoker and an alcoholic. He was a hepatitis B virus (HBV) carrier and has not received treatment for his infection. He was first diagnosed with advanced hepatocellular carcinoma (HCC) in mainland China in 2017, which was deemed curable and resectable. In May 2017, the patient underwent hepatectomy, followed by transarterial chemoembolization (TACE) plus sorafenib treatment in China. One month later, the disease recurred with multiple lesions in the remaining lobe, and radiofrequency ablation (RFA) was performed for the accessible tumours. After RFA, the patient’s alpha-fetoprotein (AFP) level was about 1,000 ng/mL.
In late June 2017, the patient presented to our clinic with a viable tumour detected by radiological imaging, along with a very substantial increase in AFP level (>30,000 ng/mL). (Figure 1A) At that time, he was asymptomatic and able to carry out normal activities (Karnofsky grade, 90). Since the disease was progressing rapidly despite surgery, TACE and sorafenib treatment, and given the patient’s Child-Pugh class B liver disease with mild ascites, he was switched to immunotherapy with nivolumab.
Following treatment with nivolumab, the patient’s AFP level decreased dramatically to about 10,000 ng/mL and his condition became stable. He tolerated nivolumab well, with no immune-related adverse events (IRAEs) reported. After about 6 months of treatment, radiologic findings showed partial response. (Figure 1B)
In May 2018, after almost 1 year of nivolumab treatment, the disease progressed; the patient’s AFP level had increased to 27,000 ng/mL and he was commenced on a multikinase inhibitor. While the treatment stabilized his condition, the disease progressed again after several months. Subsequently, he was put on various multikinase inhibitors and VEGF inhibitors in different regimens. While each regimen provided some clinical response initially, his disease eventually progressed again. When the patient was last seen in July 2019, he was still on treatment with a multikinase inhibitor. He currently resides in mainland China and is no longer fit to travel to our clinic for regular disease monitoring.
HCC is a heterogeneous disease in terms of aetiology, clinical presentation and management approaches. The majority of patients are diagnosed at an advanced stage and not many are eligible for curative therapies.1 Systemic treatment has become the last resort for patients with advanced HCC when locoregional therapies, such as RFA and TACE, are insufficient.1 At present, multikinase inhibitors are the preferred first-line systemic treatment for advanced HCC.2 Immune checkpoint inhibitor (ICI) nivolumab is currently recommended for patients who have been previously treated with sorafenib.2
Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that blocks programmed death-1 (PD-1).3 It has demonstrated safety and efficacy in terms of long-term survival and objective responses in sorafenib-experienced patients with advanced HCC in the CheckMate 040 trial.3,4
CheckMate 040 is an ongoing, prospective, noncomparative, open-label, phase I/II trial involving patients with advanced HCC. The trial comprises a dose-escalation phase and a dose-expansion phase. In the dose-expansion phase (n=214), patients were divided into four cohorts: sorafenib-untreated or sorafenib-intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV-infected or HBV-infected.4 In this phase, nivolumab was given at a dose of 3 mg/kg every 2 weeks, which, along 240 mg every 2 weeks, is one of the two currently recommended doses of nivolumab for second-line treatment of HCC.
While follow-up is still ongoing, 202 of 262 patients (70 percent) have completed treatment. The objective response rate (ORR) was 20 percent in the dose-expansion phase, which was substantially higher than the historic response rates with first-line sorafenib (2–3 percent) and second-line regorafenib (7 percent) attained in previous studies.5-7 Nivolumab also demonstrated durable responses (median duration of response, 17 months), which other therapies for advanced HCC could not offer.4
Nivolumab treatment elicited durable responses (median duration of response, 19.4 months and 9.7 months) with similar long-term survival outcomes (median overall survival [OS], 15.1 months and 14.9 months) in the intent-to-treat (ITT) population (n=182) and in Asian patients (n=85). After a median follow-up of more than 30 months, subanalysis of CheckMate 040 showed ORRs of 14 percent and 15 percent in the ITT and Asian populations, respectively,. Similarly, disease control rates were comparable between the ITT and Asian populations (55 percent and 49 percent), while the 24-month OS rates were 33.6 percent and 34.6 percent, respectively. The frequency of any-grade treatment-related adverse events (TRAEs) was comparable between the Asian cohort and ITT population (74 percent and 79 percent, respectively). The frequency of grade 3/4 TRAEs was similarly comparable between the Asian cohort (16 percent) and ITT population (19 percent).8
Patients with Child-Pugh class B liver function, such as ours, have a poorer prognosis and a historical OS with sorafenib of approximately 3–5 months.9,10 The median OS for the Child-Pugh class B sorafenib-treated cohort (n=24) of the CheckMate 040 trial was 7.4 months (95 percent confidence interval, 2.3 to 12.1), while these patients’ ORR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was 12.5 percent (n=3).11 This response rate was comparable to the 14.3 percent ORR achieved by Child-Pugh class A patients who progressed on or were intolerant to sorafenib in the same trial.3 In an earlier CheckMate 040 analysis, which reported an ORR of 10.2 percent (n=5) among Child-Pugh class B patients, four of the five responders improved from Child-Pugh class B status at baseline to Child-Pugh class A5 or A6 and maintained this improvement for ≥6 months.12
Nivolumab is generally well tolerated, with a favourable safety profile demonstrated in a series of CheckMate trials, including long-term follow-up data.13 The most frequently reported adverse events (AEs) were fatigue, decreased appetite, nausea and asthenia, most of which were low-grade events.14 Indeed, our patient tolerated nivolumab treatment well and experienced no IRAEs.
In summary, this case demonstrates the safety and efficacy of second-line nivolumab therapy in a patient with rapidly progressing HCC following locoregional treatment and first-line sorafenib. Although HCC will inevitably progress regardless of initial treatment response, using nivolumab in earlier lines of treatment may result in better outcomes for patients with a heavy disease burden.