Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients

Introduction Combining lenvatinib with a programmed cell death protein-1 (PD-1) inhibitor has been explored for the treatment of un-resectable hepatocellular carcinoma (uHCC). This study aimed to investigate the real-world efficacy of and prognostic factors for survival associated with lenvatinib plus PD-1 inhibitor treatment in a large cohort of Asian uHCC patients even the global LEAP-002 study failed to achieve the primary endpoints. Methods Patients with uHCC treated with lenvatinib and PD-1 inhibitors were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and adverse events (AEs). Prognostic factors for survival were also analyzed. Results A total of 378 uHCC patients from two medical centers in China were assessed retrospectively. The median patient age was 55 years, and 86.5% of patients were male. Hepatitis B virus (HBV) infection (89.9%) was the dominant etiology of uHCC. The median OS was 17.8 (95% confidence interval (CI) 14.0–21.6) months. The median PFS was 6.9 (95% CI 6.0–7.9) months. The best ORR and disease control rate (DCR) were 19.6% and 73.5%, respectively. In multivariate analysis, Child‒Pugh grade, Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group performance status score, involved organs, tumor burden score, and combination with local therapy were independent prognostic factors for OS. A total of 100% and 57.9% of patients experienced all-grade and grade 3/4 treatment-emergent AEs, respectively. Conclusion This real-world study of lenvatinib plus PD-1 inhibitor treatment demonstrated long survival and considerable ORRs and DCRs in uHCC patients in China. The tolerability of combination therapy was acceptable but must be monitored closely. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-022-10480-y.

Recently, phase 1b studies of lenvatinib plus a PD-1 inhibitor (pembrolizumab or nivolumab) for the treatment of uHCC patients showed promising efficacy in European and American [15] and Japanese cohorts [16]. Additionally, the recent LEAP-002 study found that compared with lenvatinib, lenvatinib plus pembrolizumab did not significantly increase OS (21.2 vs. 19.0 months, HR = 0.840, p = 0.0227 > 0.0185) but did result in the longest OS in patients with uHCC [10]. In East Asia, especially China, where chronic hepatitis B virus (HBV) infection is an important etiological factor of HCC and where the disease is different from that in other countries [1,17], the efficacy of lenvatinib plus PD-1 inhibitor combination therapy is unclear.
Many PD-1 inhibitors for patients with uHCC are approved for use in China [18][19][20]. However, there is a lack of studies of large Chinese uHCC cohorts to evaluate this combination therapy. Moreover, it is unclear whether such patients could achieve better survival with lenvatinib plus PD-1 inhibitor combination therapy. Therefore, we designed this study to retrospectively observe the effect of lenvatinib plus PD-1 inhibitor combination therapy in a large uHCC cohort and explore the prognostic factors for survival associated with this treatment.

Study design and patients
We retrospectively collected data on consecutive patients with uHCC treated with lenvatinib plus PD-1 inhibitors from October 2017 to November 2021 at 2 tertiary care hospitals (Peking Union Medical College Hospital (PUMCH) and the Fifth Medical Center of the People's Liberation Army General Hospital (PLAGH)).
Patients were eligible for this study if they met the following criteria: patients were pathologically confirmed or confirmed by imaging to have HCC [21][22][23]; patients exhibited at least one measurable lesion per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines; patients exhibited uHCC, i.e., were not eligible for curative treatment; patients were at least 18 years old; patients had a Child-Pugh classification of A-B, and patients exhibited Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 0-2. The exclusion criteria included the presence of end-stage HCC; history of organ transplant; prior lenvatinib or PD-1 inhibitor treatment; and discontinued use of combination therapy after less than 2 cycles of treatment. We performed a simple comparison with our realworld cohorts and similar randomized controlled LEAP-002 study to show the similarity and difference in baseline characteristics and clinical outcomes, which may also highlight some important clinical prognostic factors for survival.
This study is registered as NCT03892577.

Treatment
Patients were treated with the de novo combination of lenvatinib and a PD-1 inhibitor. The dose of lenvatinib was dependent on patient weight (> = 60 kg: 12 mg; < 60 kg: 8 mg). For PD-1 inhibitors, pembrolizumab or nivolumab, and camrelizumab, sintilimab, toripalimab, or tislelizumab were allowed, and 200 mg (toripalimab: 240 mg), every three weeks, was administered intravenously. The choice of the type of PD-1 inhibitor in our study was a joint decision between physicians and patients in the real-world practice.

Endpoints and assessments
The primary endpoints were OS and progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and safety. OS was defined as the time elapsed from the start of combination therapy until death (all causes). Surviving patients were censored at the last follow-up date. Tumor response was evaluated by the RECIST v1.1 guidelines [24]. PFS was defined as the time elapsed from the start of combination therapy until the date of progression or death (all causes), whichever occurred first. Durable clinical benefit (DCB) was defined as complete response (CR), partial response (PR), or stable disease (SD) for ≥ 24 weeks [25], which was evaluated by professional radiologists at our centers who were blinded to the therapeutic outcomes and clinicopathological features. Grades of adverse events (AEs) were assessed by physical examination and laboratory and imaging tests performed at the time of treatment based on the National Cancer Institute's Common Toxicity Criteria (CTCAE) version 5.0. Management of AEs was according to the related guidelines [26,27] and the guidelines for administration of the drug.

Statistical analyses
Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate Cox proportional hazard regression models were used to estimate the possible risk factors influencing PFS and OS; the results are reported as hazard ratios (HRs) and 95% confidence intervals (CIs

Patient characteristics
A total of 598 patients with HCC from October 2017 to November 2021 were screened from two hospitals, and 220 patients were excluded. Then, a total of 378 consecutively eligible uHCC patients who were treated with lenvatinib plus PD-1 inhibitors were evaluated ( Fig. 1). Their baseline demographic and clinical characteristics are summarized in Table 1.
The median age of the 378 patients was 55 years, and the majority (86.5%) of patients were male. The percentages of patients with ECOG-PS values of 0, 1 and 2 were 43.7%, 43.4% and 13.0%, respectively. Chronic HBV infection (89.9%) was the dominant etiology of uHCC. At baseline, 198 (52.4%) patients exhibited macrovascular invasion (MVI) by the tumor, whereas 173 (45.8%) exhibited extra-hepatic spread (EHS) of the tumor. The tumor burden score (TBS) was calculated by the maximum tumor size and number of tumors in the liver [28,29]. Using the cutoff of 8 [28,29], 47.4% of patients were classified as the high TBS score group. Most uHCC patients were systemic therapy-naïve (82.0%). During treatment, 54.5% of patients also received local therapy (trans-arterial chemoembolization (TACE), radiofrequency ablation (RFA) or radiation therapy (RT)) before and after two months of the combination therapy. There were many kinds of PD-1 inhibitors used for our cohort. The proportions of patients treated with pembrolizumab, nivolumab, sintilimab, camrelizumab, toripalimab, and tislelizumab were 18.3%, 5.6%, 33.9%, 27.5%, 11.6%, and 3.2%, respectively. We found that the important characteristics (ECOG, BCLC stage, etc.) were similar in lenvatinib plus different PD-1 inhibitors groups (Table S1). Only a relatively higher proportion of patients with Child-Pugh B liver function (49/129, 38.3%) were observed in lenvatinib plus sintilimab subgroup.

Discussion
To our knowledge, this is the largest real-world study of the use of lenvatinib plus PD-1 inhibitors in 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 that Child-Pugh grade, BCLC stage, 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, reported that an ORR of 36.0% was reached in 100 uHCC patients treated with lenvatinib plus the PD-1 inhibitor pembrolizumab. Moreover, the median PFS and median OS were 8.6 months and 22.0 months, respectively [15]. However, the phage 3 LEAP-002 study found that compared with lenvatinib plus placebo in patients with uHCC, lenvatinib plus pembrolizumab did not significantly increase OS (21.2 vs. 19.0 months, HR 0.840, p = 0.0227 > 0.0185) [10]. The negative LEAP-002 study found that OS in the lenvatinib plus placebo arm (19.0 months) was longer than that in the lenvatinib arm (13.6 months) in the 2018 REFLECT study [4] due to higher rates (22.8%) and efficacy of sequential immunotherapy [10]. In our cohorts, 18.3% (69/378) of patients were treated with the same drug of lenvatinib plus pembrolizumab combination therapy as in the LEAP-002 study [10], but we did not find significant differences for lenvatinib plus other kinds of PD-1 inhibitor (p = 0.33) in our study. For lenvatinib plus sintilimab or camrelizumab, which is the most employed anti-PD-1 inhibitors in our study, some small cohorts found that the mPFS of this  [30][31][32], which is comparable with that reported in the mPFS in the LEAP-002 study (8.2 months) and our present study (6.9 months).
In the Keynote-524 study [15] and LEAP-002 study [10], patients were excluded if they had with Child-Pugh class B or C liver function, invasion at the main portal vein (Vp4), ECOG-PS with 2 scores, or received prior systemic therapy. However, in present real-world cohort, 22.5% patients were with Child-Pugh class B, and 13.0% patients were with ECOG-PS scores of 2, and 18.0% received prior systemic therapy. 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 we think 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 also be more realistic in real-world practice in Asian uHCC patients who have a high rate of HBV infection. We hope to get more details to compare our cohort with the LEAP-002 study when the LEAP-002 study was published "in extenso".
In clinical practice, the main concern is selecting patients who would benefit from the therapy [33]. 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 grades (B vs. A) had a shorter OS (HR = 1.675, p = 0.005) but not PFS (p > 0.05) in multivariate analysis. Many studies have found that the ECOG score and Child-Pugh grade are prognostic factors for patients with uHCC who were administered lenvatinib and/or PD-1 inhibitors [34][35][36]. Wu et al. found in multivariate analyses that the Child-Pugh class (Class B vs. A, HR = 2.646, p = 0.039) but not an ECOG score of ≥ 1 (HR = 1.889, p = 0.162) was a poor prognostic factor for survival in uHCC patients treated with lenvatinib plus pembrolizumab [35]. Choi et al. studied 203 Korean patients with uHCC treated with nivolumab and found that the Child-Pugh B group had a shorter mOS (2.8 vs. 10.7 months; HR = 2.10; p < 0.001) but not mPFS (HR = 1.17, p = 0.430) [37]. 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.
Tumor characteristics are very important for survival in patients with uHCC [38]. We found that the involved organs and TBS may influence PFS and OS. In a post-analysis of the REFLECT study of patients with uHCC treated with lenvatinib or sorafenib, the number of tumor sites at baseline was a very important prognostic factor (p < 0.001) for OS in multivariate analysis [39]. Moreover, we found that combination loco-regional 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 PD-1 inhibitor or lenvatinib monotherapy regimen could lead to a high response and long survival [9,[40][41][42][43][44].
The most frequent AEs were consistent with the use of lenvatinib monotherapy [4]. We think these common AEs may be related to the anti-vascular endothelial growth factor (VEGF) target mechanism [4,45]. 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%), diarrhea (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% of uHCC patients underwent all-grade treatment-related adverse events (TRAE) and grade 3-4 TRAEs [10], respectively, which is similar to our study. However, in our study, 24.9% of treatment discontinuation due to AEs may be higher than about 18.0% in the Keynote-524 study [15] and LEAP-002 study [10]. It may be related to follow-up closely and realworld setting-based practice. We think careful management and adjustment of the drug dose may be important to address AEs and may prolong the duration of treatment and survival [46]. Notably in our cohort, fatigue, decreased appetite, and gastrointestinal bleeding may need closer monitoring and good management. Meanwhile, 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 [47]. In real-world practice, doctors should be reminded to carefully monitor patients' safety due to patients' irregular visits and the influence of the coronavirus disease 19 (COVID- 19) pandemic. There are several limitations in our study. First, potential bias could not easily be avoided due to the nature of the retrospective design. Second, multiple kinds of PD-1 inhibitors were heterogeneous and some were off-label used in the study; 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.

Conclusions
In conclusion, a real-world study found that lenvatinib plus PD-1 inhibitors achieved long survival and considerable response in uHCC patients in China. The tolerability of combination therapy was acceptable but should be monitored closely in real-world practice.
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