Addition of Pembrolizumab to Lenvatinib for HCC Elicits Similar Scores in LEAP-002

Josep Llovet, MD

A follow-up analysis of the phase 3 LEAP-002 study (NCT03713593) in patients with advanced hepatocellular carcinoma (HCC) showed similar health-related quality of life scores for patients given the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) or lenvatinib and placebo, according to data presented at the 2023 Gastrointestinal Cancers Symposium.¹

Patients receiving lenvatinib plus pembrolizumab reported, at baseline, a mean EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health score/quality of life score of 71.59 and, at week 27, a score of 66.77, resulting in a least square mean (LSM) change of -8.13 (95% CI, -10.38 to -5.87). For patients receiving placebo in addition to lenvatinib, the mean baseline score was 72.43, and the mean score at week 27 was 66.60, yielding a LSM change of -8.58 (95% CI, -10.83 to -6.33). Across the total study population, the difference in LSM change from baseline to week 27 was 0.45 (95% CI, -2.53-3.44).

Further, patients receiving lenvatinib plus pembrolizumab reported a mean baseline EuroQol 5-dimension, 5-level (EQ-5D-5L) visual analog scale (VAS) score of 76.82 and a score of 72.61 at week 27, resulting in a LSM change of -6.92 (95% CI, -8.82 to -5.03). For patients receiving placebo in addition to lenvatinib, the mean baseline score was 76.10, and the mean score at week 27 was 71.93, yielding a LSM change of -7.53 (95% CI, -9.43 to -5.64). Across the total study population, the difference in LSM change from baseline to week 27 was 0.61 (95% CI, -1.98-3.20).

“Adding pembrolizumab to lenvatinib, the current standard of care, showed similar HRQOL to lenvatinib plus placebo in the first-line treatment of patients with advanced HCC,” Josep Llovet, MD, director of the Liver Cancer Program and full professor of medicine, at the Tisch Cancer Institute in New York, New York, and co-investigators wrote in the poster.

The LEAP-002 study evaluated the efficacy of the immunotherapy in combination with lenvatinib against placebo plus lenvatinib in patients with advanced HCC. Lenvatinib alone is the current standard of care. Top-line results from this trial showed that the adverse event profiles with the combination were consistent with the known profiles for the agents alone in the treatment of advanced HCC.^2-4

Of note, although first-line lenvatinib plus pembrolizumab demonstrated numerical improvements in both progression-free survival (PFS) and overall survival (OS), in LEAP-002, the combination did not meet the pre-specified statistical significance criteria for these domains.2 Nevertheless, investigators stated that the HRQOL analysis warrants further investigation into immunotherapy’s role in HCC.

“Combined with efficacy and safety results from the LEAP-002 study, these findings support continued development of lenvatinib plus pembrolizumab in HCC,” study authors wrote.

Key eligibility criteria for the LEAP trial included an HCC diagnosis, a Barcelona clinic liver classification of stage C or B—not amenable to or refractory to locoregional therapy and not amenable to curative therapy, a Child-Pugh liver class A, measurable disease per RECIST v1.1 by BIR, an ECOG performance status of 0 or 1, no main portal vein invasion, and an esophagogastroduodenoscopy within 3 months of randomization. Patients could not have received prior systemic therapy for advanced disease.

Following enrollment, eligible participants (n = 794) were randomly assigned 1:1 to receive either lenvatinib at a dosage of 8 mg (if their body weight was 60 kg or less) or 12 mg (if their body weight was at least 60 kg) by mouth every day, along with intravenous (IV) pembrolizumab at 200 mg every 3 weeks (n = 395), or lenvatinib, at the same doing regimen, along with placebo IV every 3 weeks. Treatment continued until a maximum of 35 cycles, or until disease progression, unacceptable toxicity, or study discontinuation. Patients were allowed to continue receiving lenvatinib if they discontinued treatment with pembrolizumab.

The dual primary end points were OS and PFS, per RECIST v1.1 by blinded independent central review. Secondary end points included overall response rate, duration of response, disease control rate, time to progression, along with safety and tolerability. The results were stratified by the following factors: geographic region (Asia without Japan vs Japan and the rest of the world). Macroscopic portal vein invasion and/or extrahepatic spread, a-fetoprotein level (less than vs more than 400 ng/mL) and ECOG performance status (0 vs 1).

Investigators used the EORTC QLQ-C30, EORTC Quality of Life Questionnaire HCC 18-question module (EORTC QLQ-HCC18), and EQ-5D-5L. These were administered electronically at baseline, every 3 weeks until week 27, and every 6 weeks thereafter for up to 1 year or end of treatment, at discontinuation, and at the 30-day posttreatments safety follow-up visit.

Key HRQOL end points include the time point for mean change from baseline analysis based on blinded data review; changes from baseline to week 27 in EORTC QLQ-C30 global health status/quality of life (GHS/QOL) and functional and symptoms domain scored; change from baseline to week 27 in EORTC QLQ-HCC18 scores; TTD in EORTC QLQ-C30 GHS/QOL, physical functioning, and role functioning domains, and TTD in EORTC QLQ-HCC18 abdominal swelling fatigue, and pain domains, along with the change form baseline to week 27 for health utilities based on EQ-5D-5L visual analog score (VAS). The median follow-up time was 33 months.

In an estimate of time to deterioration (TTD) analysis of EORTC QLQ-C30 global health score/fatigue, the percentage of 44.5% (n = 171) in the pembrolizumab arm and 54.0% (n = 203) with placebo. The TTD between these 2 arms was 11.47 (95% CI, 5.59- not reached [NR]) vs 4.34 (95% CI, 3.45-5.52). The hazard ratio was 0.80 (95% CI, 0.65-0.98).

In an analysis of physical functioning, the percentage of patients who experienced an event was 48.7% (n = 187) with pembrolizumab vs 46.0% (n = 173) in the placebo arm. The median TTD between the 2 arms was 5.65 (95% CI, 4.34-10.42) vs 9.07 (95% CI, 6.21-NR). The hazard ratio for physical functioning was 1.14 (95% CI, 0.93-1.41).

Across role functioning domains, the percentage of patients who experienced an event was 51.0% (n = 196) with pembrolizumab vs 53.5% (n = 201) in the placebo arm. The median TTD between the 2 arms was 4.90 (95% CI, 3.48-6.44) vs 5.06 (95% CI, 4.17-6.41). The hazard ratio for role functioning domains was 0.98 (95% CI, 0.81-1.20).

Moreover, according to Kaplan-Meier estimations of TTD in the QLQ-HCC18, the percentage of patients who experienced adnominal swelling events in the pembrolizumab arm was 25% (n = 95. The TTD was NR (95% CI, NR-NR). In the placebo arm, the percentage was 22.6% (n = 83), and the TTD was also NR (95% CI, NR-NR). The hazard ratio for abdominal swelling was 1.19 (95% CI, 0.89-1.60).

In an analysis of fatigue, the percentage of patients who experienced an event was 57.6% (n = 216) versus 59.9% (n = 220). The median TTD between the pembrolizumab and placebo arms was 2.89 months (95% CI, 2.17-4.76) vs 2.79 (95% CI, 2.10-3.58. The hazard ratio for pain was 0.98 (95% CI, 0.81-1.19).

Moreover, in the pain domain, the percentage of patients who experienced a deterioration event was 42.9% (n = 161) vs 46.0% (n = 169). The median TTD between the pembrolizumab and placebo arms was 9.63 (95% CI, 6.21-NR) vs 7.85 (95% CI, 4.96-NR). The hazard ratio for pain was 0.93 (95% CI, 0.75-1.16).

References

1. LLovet J, Kudo M, Meyer MT, et al. Health-related quality of life impact of lenvatinib plus pembrolizumab versus lenvatinib plus placebo as first-line therapy for advanced hepatocellular carcinoma: phase 3 LEAP-002 study. J Clin Oncol. 2023;41(suppl 4):506. doi: 10.1200/JCO.2023.41.3_suppl.506

2. Finn RS, Kudeo M, Merle P, et al. Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33(suppl 7): S808-S869.doi:10.1016/annonc/annonc1089

3. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960-2970. doi:10.1200/JCO.20.00808

4. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1