Hepatocellular carcinoma (HCC) is a malignancy characterized by high lethality and limited treatment options.1 Curative approaches, such as liver resection, ablation, or transplantation, can only be offered to patients diagnosed with early-stage disease.2 3 The majority of cases are diagnosed with intermediate or advanced Barcelona Clinic Liver Cancer (BCLC) HCC, for which loco-regional and systemic therapies are standard of care and treatment intent is palliative.4–6 The provision of systemic treatment has traditionally been complicated by the intrinsic chemoresistance of HCC7 and the presence of concomitant liver dysfunction,8 factors that have contributed to late-stage attrition in drug development. Current options for patients not suitable for transplantation, resection, or loco-regional therapies include the multitargeted tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib,9 10 both approved as frontline therapy for advanced HCC, followed by second-line options such as regorafenib, cabozantinib,11 12 and ramucirumab.13 Despite the rapid expansion of treatment options, achievement of long-term survivorship in patients with advanced HCC is limited by the occurrence of therapeutic resistance.14

The significant role of innate and adaptive immunity in influencing the pathogenesis and progression of HCC has made it an appealing target for antibody therapy against immune coinhibitory signals in the tumor microenvironment.15–17 Monoclonal antibodies against programmed cell death protein 1 (PD-1) or its ligand 1 (PD-L1) have recently become standard of care for a widening range of malignancies, including non-small cell lung cancer, melanoma, urothelial, renal cell cancers and many others.18 Therapeutic blockade of PD-1 or PD-L1 enhances the effector function of tumor-specific CD8 T-cells to drive tumor rejection.19 In HCC, the expression of PD-1/PD-L1 is associated with increased risk of recurrence and shortened survival rates,20 21 suggesting a rationale for inhibition.15

Evidence to support nivolumab use in HCC stems from CheckMate-040,22 a single-arm, open-label phase I/II study that has provided evidence of safety and antitumor efficacy in advanced disease. Although statistical significance was not achieved for the primary endpoint of overall survival (OS) in CheckMate-459, the follow-on phase III study of nivolumab versus sorafenib as first-line treatment in advanced HCC,23 nivolumab appears to benefit a proportion of patients, especially in the context of a radiological response—particularly if complete remission is achieved. In absence of predictive biomarkers of benefit to PD-1 monotherapy, the demonstration of radiological evidence of antitumor efficacy in approximately 20% of patients with unselected HCC, together with a favorable safety profile, led nivolumab to be the first PD-1 inhibitor to receive conditional approval by the US Food and Drug Administration (FDA) in 2017 for the treatment of patients with unresectable HCC and Child-Pugh (CP) A class after prior TKI exposure.

Post-registration studies to confirm safety and efficacy of nivolumab therapy in advanced HCC are lacking. “Real world” studies represent an invaluable source of confirmation to level I evidence and are increasingly recommended by regulatory authorities to ensure novel therapies are demonstrated to be deliverable in routine practice, outside stringent criteria dictated by trial protocols. Obtaining a reliable portrait of the prescribing strategies and clinical outcomes surrounding nivolumab therapy is a point of greater consequence given the competing indication for molecularly targeted therapies with regorafenib, cabozantinib, and ramucirumab in previously treated advanced HCC,24 where dual inhibition of PD-1 and cytotoxic T cell antigen-4 (CTLA-4) with ipilimumab and nivolumab has recently been approved as second-line immunotherapeutic option.25 In addition, the failure to demonstrate a significant survival benefit for PD-1-targeted monotherapy as a first and second-line systemic therapy options,23 26 jointly with demonstration of synergistic efficacy by combination of atezolizumab and bevacizumab in patients with treatment-naïve unresectable HCC27 urges clinicians and researchers to rethink the therapeutic landscape of HCC in routine practice.

To address the current gap in knowledge, we conducted a retrospective multicenter study to document safety and efficacy of nivolumab monotherapy in a large, international cohort of patients treated outside clinical studies, with the attempt of establishing basic information on patient outcomes and prognostic outlook that can be used as a point of reference for future clinical studies.

The rising incidence and high mortality from HCC make this oncological diagnosis an area of high unmet need. Immune-based therapies targeting the PD-1 axis have shown initial evidence of oncological efficacy in HCC and a favorable therapeutic index. While it is undoubted that a fraction of patients will derive durable benefit from PD-1 inhibitors, deciphering the clinical value of PD-1 monotherapy has been challenging in clinical studies because of the lack of predictive markers and the influence of post-progression therapy on OS.23 26 In a rapidly evolving therapeutic landscape, where the atezolizumab/bevacizumab combination has demonstrated superiority to sorafenib in treatment-naïve patients27 and combination therapy with pembrolizumab and lenvatinib is showing promise,28 post-registration evidence of safety and efficacy of nivolumab in advanced HCC is needed to appreciate the clinical role of this therapeutic option outside clinical trials.

Capitalizing on an international collaborative network of investigators involved in the multidisciplinary management of HCC, we report the results of the largest real-world dataset to include patients who received nivolumab outside common clinical trial eligibility criteria including 32.2% with CP-B functional class and 44.2% outside second-line prescribing.

In our study, we reproduce the antitumor efficacy of nivolumab with ORR of 22.4% and DCR of 52.1%, estimates that are comparable to those reported in the dose expansion cohort of CheckMate-040 (ORR 20%, DCR 58%),22 as well as in a smaller retrospective study by Scheiner et al (ORR 15%, DCR 44%).29 When accounting for the heterogeneity in treatment line and liver functional reserve described in our cohort, the reported mOS of 12.2 months of our study appears consistent with that of sorafenib-experienced trial participants (13.2 months)22 and compares positively with first-line nivolumab experience in CheckMate-459 (mOS 16.4 months)23 and observational evidence (Scheiner et al, mOS 9.0).29

We have demonstrated that patients achieving a radiologically measurable tumor response are the ones with longer OS following nivolumab therapy, with greatest benefit observed in patients with a documented CR, whose median OS was in excess of 30 months. In absence of molecular predictors, achievement of radiological response following nivolumab can help clinicians to identify patients who are likely to derive long-term benefit from single-agent anti-PD-1 therapy. To our knowledge, this is the first observational study to validate such important prognostic role in patients treated with PD-1 inhibitors outside clinical trials: previous studies were underpowered to evaluate this aspect, having accrued no complete responders29 or having included patients treated with immunotherapy combinations.30

In this study, responses to nivolumab were consistent across patients’ subgroups, being independent of viral etiology, baseline BCLC stage and CP class. However, the OS of patients classifying within CP-B class was 9 months shorter than CP-A (median: 7.3 months vs 16.3 months), underscoring the prognostic impact of liver functional reserve prior to immunotherapy.

CP-B patients derive small benefit from sorafenib31 and more advanced liver dysfunction is postulated to gear the liver microenvironment towards more profound immune-suppression,32 implying reduced responsiveness to ICI. In contrast to this hypothesis, our data suggest equal probability of response to PD-1 inhibitors and acceptable safety in CP-B patients, in keeping with published evidence from smaller studies.33

While requiring prospective confirmation, our results stand as a valuable point of reference for future prospective evaluation of nivolumab in CP-B patients. Preliminary data from cohort 5 of CheckMate-040, which is currently exploring efficacy and safety of nivolumab in a restricted group of CP B7-8 patients without encephalopathy or ascites,34 reassuringly confirm our findings with a median OS of 7.6 months and a comparable ORR, DCR and proportion of trAEs.

Our study is also the first to document outcomes of a subset of patients who received nivolumab as off-label therapy for HCC beyond FDA-approved second-line use. Recommendation for nivolumab therapy in these patients followed individualized discussion within the treating multidisciplinary team and agreement of funding within respective treating institutions. The accrual of a wide proportion of patients treated with nivolumab from first to fourth line allowed us to perform a detailed analysis of its efficacy across line of therapy including first-line use, where median OS of 16.3 months overlays with CheckMate-459 data.23 Despite comparable ORR and DCR, we found that earlier provision of immunotherapy was associated with improved OS and PFS compared with later-line use. While of interest, these results are not meant to inform changes in practice, especially after the documented failure of nivolumab to improve OS in first-line advanced HCC.23 Despite equal proportion of post-progression therapy, patients receiving nivolumab as first-line systemic therapy in our study had shorter interval from original HCC diagnosis, a key factor to explain the significantly longer OS and PFS in this group compared with more heavily pretreated patients.

Perhaps unsurprisingly, we found a higher degree of heterogeneity in the assessment of PFS (median 10.1 months) which is closer to the estimate of 9.0 months published in CheckMate-04022 compared with CheckMate-459 (3.7 months)23 and the Scheiner study (4.3 months).29 Differences in PFS between observational versus interventional studies are not uncommon and attributable not only to patient heterogeneity but also to inherent differences in investigator-based versus central assessment of progression as well as in the variable frequency of re-staging that is typical of routine practice. In our study, we lack assessment of response by immune-related RECIST criteria which, unlike investigator-led adjudication of progression outcomes on the basis of RECIST version 1.1 criteria, would have facilitated identification of pseudo-progression events in our patient cohort.35

In addition to efficacy estimates, our study provides important confirmatory evidence of the safety of nivolumab in routine practice. We observed no unexpected safety signals from routine nivolumab use nor treatment-related deaths. The overall trAE rate of 26.6% and grade >3 trAE rate of 6.4% compare favorably with the proportion of grade >3 trAE observed in CheckMate-040 (19.0%),22 CheckMate-459 (22%),23 and Scheiner et al (15%).29 The rate of discontinuation due to unacceptable toxicity was also low and comparable to previous studies. Importantly, we documented no significant differences in trAE rates between CP class A and B. This is reassuring given concerns raised by a retrospective case series (n=18) that reported an all-grade trAE rate of 94% and a rate of grade ≥3 trAE of 28% in CP-B patients receiving nivolumab.33

The retrospective nature of our work stands as an important limitation of our study. However, the geographic diversity of our cohort, with patients from the USA, Europe, and Asia, significantly expands on previous studies of real-world cohorts from Germany, Austria (n=34)29 and the USA (n=18).33 The demographics of our cohort were comparable with previous studies with regards to commonly reported parameters, including age, etiology of liver disease and stage.22 23 29

Our cohort size (n=233) positively compares to that of phase II (n=214) and III (n=371) studies in this indication,22 23 with the important distinctive feature of having included patients subgroups for whom little prospective data on safety and efficacy exist (ie, CP-B or heavily pretreated patients).

Our study confirms that PD-1-targeted immunotherapy with nivolumab is a deliverable treatment option in a real-world patient cohort including patients with varying degrees of liver dysfunction and prior-treatment. Measures of efficacy and safety of nivolumab therapy were comparable to clinical trial data and longer survival was observed in patients achieving radiological response to treatment.

As combination immunotherapy expands across the treatment landscape of advanced HCC,27 28 the favorable response and toxicity observed in CP-B patients supports the case to investigate the use of nivolumab in this treatment-deprived patient population who is currently ineligible to molecularly targeted therapies and might be more at risk of vascular events from combination of ICI with anti-angiogenics.