To our knowledge, few prospective clinical trials have reported the safety and efficacy of combining anti-PD1 with SBRT for patients with uHCC. It should be noted that, as shown in Table 1, most patients enrolled in the study had advanced stage disease (95.2% BCLC-C), large tumor burden, high AFP values, and were refractory to multiple prior line therapies with dismal prognosis. The combination treatment was safe and well tolerated, and promising antitumor activity was observed. Combining anti-PD1 therapy with SBRT might be a potential strategy to efficiently treat patients with uHCC.

Qin et al. (2020) reported that Chinese patients with similar baseline demographic and clinical characteristics received camrelizumab treatment. The ORR was 14.7%, and the median PFS was 2.1 months [8]. Camrelizumab has shown remarkable antitumor activity in patients with uHCC. In our study, the ORR (52.7% vs. 14.7%) and PFS (5.8 vs 2.1 months) were much better. Furthermore, in our study, CR was observed in one patient (4.8%) according to RECIST v1.1 and in two patients (9.5%) according to mRECIST. Fourteen patients (66.7%) achieved disease control according to the RECIST v1.1 and mRECIST. Compared with camrelizumab alone, OS probability with the combination treatment was 85.7% vs. 74.4% at 6 months, 76.2% vs. 64.0% at 9 months, and 59.9% vs. 55.9% at 12 months, revealing the therapeutic efficacy of combining anti-PD1 with SBRT. It is worth noting that 10 patients (71.4%) with disease control as the best response received 5 cycles of camrelizumab and did not continue treatment, and 4 with ECOG PS 0–1 and without taboos after disease progression refused any subsequent treatment, which may be an important reason for the decline in the efficacy of combining anti-PD1 with SBRT for uHCC. The efficacy of radiotherapy for uHCC has improved significantly in recent years. Eleni Gkika. reported that the median OS in the treatment of uHCC was 9 months (95% CI 7.7–10.3) [23]. For BCLC-C patients in South Korea, the median OS in the RT group was significantly longer than that in the sorafenib group (7.6 vs 3.8 months, p < 0.001) [24]. In this study, the median OS was significantly longer than that observed with SBRT alone. The combination of anti-PD1 and SBRT achieved better antitumor effects than anti-PD1 or SBRT alone in uHCC patients. This is mainly attributed to the phenomenon that non-targeted distant tumors were downsized following RT, known as the “abscopal effect” [25]. RT can gradually cause immunogenic death, such as cell death, which effectively exposes tumor antigens and triggers an immune response throughout the course and several months after RT [26]. RT can reprogram the tumor microenvironment by inducing chemokines and promoting dendritic cell maturation involved in the recruitment of effector T cells. Antigen-educated T cells can home not only into the irradiated but also non-irradiated tumor deposits, and may cause tumor regression [27]. Adding RT to ICI increases the clinical benefit in non-irradiated tumor sites in patients with HCC [28].

Sorafenib is recommended as a first-line treatment for patients with uHCC. The median OS in the sorafenib group was only 6.5 months, and the ORR was only 3.3% in Asia–Pacific uHCC patients with 70.7% HBV infection [6]. In our study, all patients were from China, and 85.7% had a chronic HBV etiology, indicating that they were more prone to develop progressive disease and had poorer prognoses [29]. Other baseline demographic and clinical characteristics were similar. Their clinical outcomes were significantly better than those treated with sorafenib. The REFELECT study showed that lenvatinib was not inferior to sorafenib in untreated patients with uHCC. The ORR in the lenvatinib arm was 18.8% by RECIST v1.1, based on a masked independent imaging review, and that in the sorafenib arm was 6.5% [5]. Better ORR was observed in our study, although most patients were refractory to multiple prior line therapies with dismal prognosis and high rates of chronic HBV infection, meaning that they were more prone to develop progressive disease and had poorer prognoses than those with hepatitis c virus [29, 30]. Combining atezolizumab with bevacizumab improved the efficacy of systemic therapy for uHCC, and the patients had an ORR of 27.3% according to independent assessment with RECIST v1.1 in the IMbrave150 trial [31]. Combining anti-PD1 with SBRT achieved better ORR and similar survival probabilities at 6 months (85.7% vs. 84.8%) and 12 months (59.9% vs. 67.2%). It should be noted that the patients with BCLC-A and B accounted for 17% in the IMbrave150 trial, which is much higher than that in our study (4.8%), and a large proportion of patients without progressive disease failed to remain on camrelizumab. Meanwhile, treatment with atezolizumab plus bevacizumab was too expensive.

As up to 95.2% of patients in this study had BCLC-C, the subgroup data were analyzed. The median OS with BCLC-C was 17.4 months in this study and 5.6 months for the Asia–Pacific patients receiving sorafenib [6]. For the subgroup BCLC-C analysis, the REFELECT study showed the median OS was 11.8 months in the lenvatinib group and 10.3 months in the sorafenib group [5]. This study revealed that the combination of camrelizumab with SBRT showed promising antitumor activity in patients with BCLC-C HCC.

In this study, there were no new or unexpected toxicities resulting from the SBRT plus camrelizumab combination therapy. Grade 3 TRAEs occurred in five patients (23.8%), including two with decreased hemoglobin, one with decreased neutrophil count, one with increased γ-glutamyltransferase, and one with decreased platelet count. The safety of SBRT plus camrelizumab combination therapy in this population was consistent with that of camrelizumab or SBRT alone in previously reported studies [8, 12, 23]. The occurrence rate of grade ≥ 3 TRAEs was less than 57% in patients treated with lenvatinib and 49% in patients treated with sorafenib reported in REFLECT [5], and 56.5% in patients treated with atezolizumab plus bevacizumab reported in IMbrave150 [31]. Serious AEs were reported in two patients (9.5%), including one patient with non-treatment-related esophageal and gastric variceal bleeding. Considering that this patient had severe varicose esophagogastric fundus veins at enrollment, we believe that the serious AEs were not treatment-related side effects.

This study has several limitations. First, the small sample size and nature of this single-arm study were the main limitations. Therefore, the results presented herein should be regarded as preliminary, requiring a larger sample size and phase 3 clinical studies for confirmation. Second, as it was not mandatory for patients to provide tumor samples, the lack of samples for PD-1/PD-L1 detection could be considered a limitation. Third, the patients could not continue camrelizumab because they could not afford it. However, in this case, promising antitumor activity was observed.

In conclusion, the results of this study demonstrated an acceptable safety profile of combining camrelizumab with SBRT for patients with uHCC. Despite the small sample size, we observed preliminary antitumor activity, especially in BCLC-C HCC. Combination treatment has several advantages over other recommended treatments: it incurs less cost, produces less grade ≥ 3 TRAEs, and is easier to accomplish than other treatments while having similar or better antitumor activity. This study provides evidence for a new therapeutic method that combines camrelizumab with SBRT for the treatment of uHCC.