The final analysis of the phase 3 LEAP-002 study did not demonstrate an overall survival (OS) benefit of the addition of pembrolizumab to first-line lenvatinib in patients with advanced hepatocellular carcinoma (HCC). However, the study supports the potential usefulness of lenvatinib as a standard first-line treatment for advanced HCC.
Systemic therapy options for advanced stages of HCC have rapidly expanded in the past years. The REFLECT trial (NCT01761266) demonstrated lenvatinib in first-line to be non-inferior to sorafenib regarding OS . In a phase 1 study, lenvatinib plus pembrolizumab demonstrated promising anti-tumour activity as first-line therapy in unresectable HCC . The current global, randomised, double-blind, phase 3 LEAP-002 trial (NCT03713593), presented by Prof. Richard Finn (David Geffen School of Medicine, CA, USA) evaluated the efficacy of lenvatinib plus pembrolizumab versus lenvatinib plus placebo as first-line therapy for advanced HCC .
The trial randomised 794 patients with advanced HCC, Child-Pugh class A, and without prior systemic treatment 1:1 to lenvatinib plus pembrolizumab or lenvatinib plus placebo. The dual primary endpoints were progression-free survival (PFS) and OS. Pre-specified efficacy boundaries were one-sided P=0.002 for PFS at the interim analysis (pre-specified final PFS analysis) and 0.0185 for OS at the final analysis.
Median OS in patients treated with lenvatinib plus pembrolizumab was 21.2 months (comparable to the phase 1 study) versus 19.0 months in patients with monotherapy lenvatinib (HR 0.840; P=0.0227). This difference was not statistically significant according to the pre-specified efficacy boundaries.
The median PFS at the time of the final analysis was 8.2 versus 8.1 months (HR 0.834). At 24 months, 16.7% of participants treated with lenvatinib plus pembrolizumab were progression-free versus 9.3% of patients treated with lenvatinib plus placebo. The disease control rate was 81.3% in the lenvatinib plus pembrolizumab arm (26.1% objective response rate [ORR]) versus 78.4% (17.5% ORR) in the lenvatinib plus placebo arm. The duration of response was 16.6 and 10.4 months, respectively.
Overall, 44.1% of patients treated with lenvatinib plus pembrolizumab received subsequent systemic anti-cancer treatment (34.9% tyrosine kinase inhibitor, 14.4% immunotherapy, 3.5% chemotherapy). Of all patients treated with lenvatinib plus placebo, 52.1% received subsequent systemic therapy (40.1% tyrosine kinase inhibitor, 22.8% immunotherapy, 3.3% chemotherapy).
Based on these results, Prof. Finn concluded that “this study does not meet its pre-specified statistical significance for OS and PFS. Nonetheless, median OS in the lenvatinib monotherapy arm was longer than what was observed in REFLECT (14.5 months), which supports its role as a standard first-line treatment for advanced HCC.”
- Kudo M, et al. Lancet 2018;391(10126):1163–1173.
- Finn RS, et al. J Clin Oncol. 2020;38(26):2960–2970.
- Finn RS, 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). Abstract LBA34, ESMO Congress 2022, 09–13 September, Paris, France.
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Table of Contents: ESMO 2022
Letter from the Editor
High pathological responses to neoadjuvant immune checkpoint inhibition in locally advanced dMMR colon cancer
Fruquintinib: a potential new treatment for patients with refractory mCRC
Second-line avelumab is effective in patients with MSI-H/dMMR mCRC
Upper Gastrointestinal Cancer
Deep learning models predict the risk of relapse and the mutational profile in GIST
Addition of pembrolizumab to lenvatinib does not improve OS in advanced HCC
New, highly selective inhibitor of FGFR2 driver alterations and resistance mutations
Chemo-immunotherapy in gastric cancer is more effective when administered in parallel
Tumour infiltrating lymphocytes identify patients with immunogenic triple-negative breast cancer
OS benefit of abemaciclib in HR-positive/HER2-negative advanced breast cancer not (yet) statistically significant
OS benefit of sacituzumab govitecan in pre-treated HR-positive/HER2-negative metastatic breast cancer
A pathway from air pollution to lung cancer in non-smokers identified
Selective KRASG12C inhibitor sotorasib demonstrates superior PFS and ORR compared to docetaxel in previously treated patients with NSCLC
Promising clinical activity of tepotinib plus osimertinib in NSCLC with MET amplification after progression on first-line osimertinib
High pathological responses in borderline resectable NSCLC patients after induction with dual immunotherapy and concurrent chemoradiotherapy
Treatment with tumour-infiltrating lymphocytes for advanced melanoma outperforms ipilimumab
Neoadjuvant pembrolizumab outperforms adjuvant pembrolizumab in resectable stage III–IV melanomas
Survival-benefit of neoadjuvant T-VEC maintained over 5 years of follow-up
Baseline ctDNA predicts survival in resected stage III–IV melanoma
Genitourinary Cancer – Prostate Cancer
Overall survival benefit of abiraterone in mHSPC is maintained for 7 years
Limited benefit of adding long-term ADT to post-operative radiotherapy in prostate cancer
Intensified ADT benefits biochemical progression-free survival in biochemically relapsed prostate cancer
Genitourinary Cancer – Non-Prostate Cancer
Adjuvant nivolumab plus ipilimumab does not improve survival in patients with localised RCC at high risk of relapse after nephrectomy
Triple therapy improves progression-free survival in patients with advanced RCC versus dual therapy
Adjuvant atezolizumab does not improve outcomes for patients with RCC and increased risk of recurrence
OS benefit for advanced ovarian cancer patients treated with maintenance olaparib
Maintenance tegafur-uracil does not improve survival in locally advanced cervical cancer
Head and Neck Cancer
Adding first-line pembrolizumab to CRT in locally advanced HNSCC does not significantly prolong survival or event-free survival
5-FU-free chemotherapy combination as an alternative for first-line treatment of recurrent or metastatic HNSCC
Epstein Barr virus-specific autologous cytotoxic T lymphocytes do not improve survival in nasopharyngeal carcinoma