To our knowledge, this is the largest real-world study of the use of lenvatinib plus PD-1 inhibitors for uHCC patients. We found that the median OS was 17.8 months and the median PFS was 6.9 months. The ORR and DCR were 19.6% and 73.5%, respectively. We also found Child-Pugh score, BCLC, ECOG, involved organs, TBS, and combination with local therapy were independent prognostic factors for OS.
Many other cohort studies have also reported the efficacy of lenvatinib plus PD-1 inhibitors in uHCC patients. The phase I Keynote-524 study, the most representative study, found that lenvatinib plus the PD-1 inhibitor pembrolizumab for 100 uHCC patients could reach an ORR of 36.0%. Moreover, the median PFS and median OS were 8.6 months and 22.0 months, respectively [15]. However phage 3 LEAP-002 study found lenvatinib plus pembrolizumab don’t significant increase OS (21.2 vs. 19.0 months, HR, 0.840, P = 0.0227 < 0.0185) than lenvatinib plus placebo in patients with uHCC [10]. The negative LEAP-002 study found that OS in the lenvatinib plus placebo arm (19.0 months) was longer than in the lenvatinib arm (13.6 months) in 2018 REFLECT study [4] due to higher rates (22.8%) and efficacy of sequential immunotherapy [10]. The efficacy of the combination therapy in our real-world cohort was lower than that achieved in the Keynote-524 study [15] and LEAP-002 [10] because important baseline characteristics (Child-Pugh score, BCLC stage, ECOG PS scores, MVI) were better in these two studies than in our present study. However such parameters may be also more realistic in real-world practice.
In clinical practice, the main concern is selecting patients who would benefit from the therapy[28]. We found that worse ECOG PS (1–2 vs. 0) was a negative prognostic factor for OS (HR = 2.209, p < 0.001) and PFS (HR = 1.832, p < 0.001). Patients with worse Child-Pugh scores (B vs. A) had shorter OS (HR = 1.675, P = 0.005) but not PFS (P > 0.05) in multivariate analysis. Many studies also found that ECOG and Child-Pugh scores were prognostic factors for patients with uHCC who were administered lenvatinib and/or PD-1 inhibitors [29–31]. Wu et al found in multivariate analyses that Child-Pugh class (Class B vs. A, HR = 2.646, P = 0.039) but not ECOG of ≥ 1 (HR = 1.889, P = 0.162) was a poor prognostic factor of survival for uHCC patients treated with lenvatinib plus pembrolizumab [30]. Choi et al studied 203 Korean patients with uHCC treated with nivolumab and found that the Child-Pugh B group had shorter mOS (2.8 vs. 10.7 months; HR = 2.10; p < 0.001) but not mPFS (HR = 1.17, P = 0.430) [32]. Patients with worse ECOG PS or worse liver function might benefit less from lenvatinib plus PD-1 inhibitors, so the application of drugs should be done with caution.
Tumour characteristics are very important for survival for patients with uHCC [33]. We found that the involved organs and TBS may influence PFS and OS. In a post-analysis of the REFLECT study for patients with uHCC treated with lenvatinib or sorafenib, the number of tumour sites at baseline was a very important prognostic factor (P < 0.001) for OS in multivariate analysis [34]. Moreover, we found that combination locoregional therapy was an independent factor for both better PFS and OS. This result was consistent with the results of previous studies that found that adding locoregional therapy to a lenvatinib plus a PD-1 inhibitor or lenvatinib monotherapy therapeutic regimen could lead to a high response and long survival [9, 35–39].
Regarding safety, ≥grade 3 TEAEs need to be closely monitored. In the Keynote-524 study, grade 3 TEAEs were hypertension (18%), increased AST levels (14%), increased lipase levels (11%), diarrhoea (7%), increased blood bilirubin levels (6% at level 3 and 2% at level 4), fatigue (6%), asthenia (6%), increased ALT levels (6%), decreased weight (5%) and proteinuria (5%) [15]. In the LEAP-002 study, 96.5% and 61.5% uHCC patients underwent all grade treatment-related adverse events [10], which is similar to our study. In our cohort, notably, fatigue, decreased appetite, and gastrointestinal bleeding may need closer monitoring and good management. Fatigue and decreased appetite may lead to low quality of life, while gastrointestinal bleeding is always life-threatening, especially in patients with chronic liver disease [40].
There are several limitations in our study. First, potential bias could not easily be avoided due to the nature of the retrospective design. Second, there are multiple kinds of PD-1 inhibitors that exhibit heterogeneous effects; however, we did not find a significant difference when comparing the use of other PD-1 inhibitors with the use of pembrolizumab. Third, our cohort was predominantly HBV-infected uHCC patients, and the applicability of these findings to non-HBV-infected uHCC patients remains to be further validated in real-world practice.