Robin Kate Kelley, MD, Professor of Clinical Medicine at the University of California, San Francisco, was invited to discuss the results of LEAP-002.1 She said the main takeaway is that lenvatinib monotherapy is active as a preferred first-line agent for fit patients who have contraindications to first-line immune checkpoint inhibitor–based combinations. Dr. Kelley put the results in context with other studies in advanced liver cancer and shared some thoughts as to why the study did not meet its primary endpoints.
Systemic therapy options for advanced stages of hepatocellular carcinoma have expanded rapidly in the past 5 years, Dr. Kelley noted, with multiple new regimens improving survival. The agents now available for advanced hepatocellular carcinoma include tyrosine kinase inhibitors, antibodies against vascular endothelial growth factor receptor (VEGFR), immune checkpoint inhibitors, and combinations of these drugs. In 2020, the IMbrave150 study of the checkpoint inhibitor atezolizumab and the anti-VEGF agent bevacizumab demonstrated improved overall survival over sorafenib and was approved by the U.S. Food and Drug Administration as first-line therapy2; in 2022, the HIMALAYA study of dual checkpoint blockade with durvalumab and tremelimumab also demonstrated improvement in overall survival over sorafenib and is pending regulatory approval.3 In the COSMIC-312 trial, atezolizumab plus the tyrosine kinase inhibitor cabozantinib improved progression-free survival but not overall survival.4 Ongoing studies are aiming to boost immune responses by combining other antiangiogenic agents with checkpoint inhibitors, she said.
Robin Kate Kelley, MD
Departing from this onward progress is the LEAP-002 trial, which found no significant difference in overall or progression-free survival by adding pembrolizumab to lenvatinib. Numerical improvements in progression-free and overall survival were, however, observed at landmark timepoints, and response rates were increased over lenvatinib plus placebo.
“Lenvatinib plus placebo showed a median overall survival of 19 months, which is the longest control outcome for a randomized trial in advanced hepatocellular carcinoma to date,” Dr. Kelley emphasized.
She noted that the grade 3 or 4 treatment-related adverse event rate of 61.5% is somewhat higher than the 43% observed with the checkpoint inhibitor plus antiangiogenic regimen in IMbrave150. Otherwise, however, there were no unexpected signals, and the steroid requirement was as expected from pembrolizumab monotherapy.
Possible Reasons for LEAP-002’s Negative Findings
Dr. Kelley proposed several factors that potentially contributed to the trial’s negative findings. Of note, based on results from the previous REFLECT trial,5 the power calculations assumed the control arm would have a median progression-free survival of 7.3 months and an overall survival of 14.5 months, but single-agent lenvatinib greatly outperformed expectations, achieving a median progression-free survival of 8.1 months and a median overall survival of 19.0 months. In another study presented at the European Society for Medical Oncology (ESMO) Congress 2022,6 camrelizumab plus rivoceranib improved overall survival over sorafenib, demonstrating a median overall survival of 22.1 months—just 1 month longer than that achieved with lenvatinib plus pembrolizumab.
“The question on all our minds is, would LEAP-002 have been a positive study if sorafenib had been the control arm? Scientifically speaking, lenvatinib plus placebo was certainly the optimal control arm, but it is a very active control,” she pointed out.
Other potential factors might be the stringent eligibility for enrollment, which could have enriched for lower-risk patients and resulted in a reduction in effect size; the improvements in prognosis of advanced hepatocellular carcinoma in general, thanks to better supportive care and the impact of subsequent posttrial treatments; and the higher proportion of patients with nonviral etiology in LEAP-002, which has shown association with a lack of survival benefit from immune checkpoint inhibitor–based treatments in some studies.
A key question is whether proportions of Asian and hepatitis B–positive and/or nonviral patients drive study outcomes in checkpoint inhibitor–based therapies for advanced hepatocellular carcinoma, she posed. Finally, she added, the optimal antiangiogenic and kinase inhibitor partners for immune checkpoint inhibitors remain unclear.
What Next?
“This is a negative study. There is no current role for lenvatinib plus pembrolizumab in first-line therapy algorithms,” Dr. Kelley concluded. “However, I would say the landmark overall and progression-free survival rates require longer follow-up, noting there is increasing separation of the curves over time that could be signaling a proportion of patients with prolonged immune responses in the combination arm. The robust objective response rate and progression-free survival with this combination merit ongoing evaluation in early- or intermediate-stage disease. The shorter half-life of lenvatinib vs bevacizumab may be advantageous when we think about pairing it with liver-directed or any other locoregional therapies, and the washout windows are minimized.”
The phase III LEAP-012 trial comparing lenvatinib plus pembrolizumab in addition to transarterial chemoembolization (TACE) vs placebo plus TACE is underway in patients with no portal vein thrombosis who have tumors confined to the liver and are not amenable to curative treatment.
DISCLOSURE: Dr. Kelley reported personal financial relationships with Exact Sciences, Genentech/Roche, Gilead Sciences, and Ipsen.
REFERENCES
1. Finn RS, Kudo M, Merle P, et al: Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line therapy for advanced hepatocellular carcinoma. ESMO Congress 2022. Abstract LBA34. Presented September 10, 2022.
2. Cheng AL, Qin S, Ikeda M, et al: Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 76:862-873, 2022.
3. Abou-Alfa GK, Chan SL, Kudo M, et al: Phase 3 randomized, open-label, multicenter study of tremelimumab and durvalumab as first-line therapy in patients with unresectable hepatocellular carcinoma: HIMALAYA. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 379. Presented January 21, 2022.
4. Kelley RK, Rimassa L, Cheng AL, et al: Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 23:995-1008, 2022.
5. 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 391:1163-1173, 2018.
6. Qin S, Chan LS, Gu S, et al: Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma: A randomized, phase III trial. ESMO Congress 2022. Abstract LBA35. Presented September 10, 2022.
