Due to the insidious nature of liver cancer, most patients are diagnosed in the advanced stages, losing the opportunity for curative surgery and facing a poor prognosis. In recent years, non-surgical local treatments and systemic drug therapies have rapidly developed, leading to more effective treatment options and raising hope for the transformation (from initially unresectable liver cancer to resectable) and long-term survival of patients with intermediate to advanced liver cancer. At the 2023 Annual Meeting of the European Society for Medical Oncology (ESMO), a prospective, non-randomized, open-label Phase II extension study [1] conducted by Professor Shichun Lu ‘s team at the People’s Liberation Army General Hospital in China reported that the combination of lenvatinib and sintilimab can achieve a 51% successful transformation rate in unresectable hepatocellular carcinoma (HCC) patients and significantly improve the long-term survival of successfully transformed patients.
Introduction
Research Methods
Inclusion criteria:
1. Age 18-75 years
2. Pathologically and/or radiologically diagnosed HCC with at least one measurable lesion (mRECIST criteria)
3. Presence of one or more of the following factors: invasion of the main portal vein or inferior vena cava, extrahepatic metastases, inadequate surgical margins, insufficient remaining liver volume after hepatectomy.
Transformation success criteria:
1. Child-Pugh score <7
2. ECOG score ≤1
3. No extrahepatic lesions, or extrahepatic lesions deemed non-active by a multidisciplinary team (MDT) before surgery
4. Major vessel invasion can be R0 resected, and vascular structure can be reconstructed
5. Sufficient remaining liver volume after hepatectomy
6. Adequate surgical margins
Patients in the study received sintilimab (200 mg, intravenous injection every three weeks) in combination with lenvatinib (12 mg/day for weight ≥60 kg, 8 mg/day for weight <60 kg, oral, once daily). After meeting the transformation success criteria, patients underwent surgical resection and postoperative adjuvant therapy. The postoperative adjuvant therapy plan was determined based on the postoperative pathology results. In cases of complete remission (pCR) in the pathology results, sintilimab monotherapy was continued for 6 months; otherwise, the initial combination therapy was continued for 12 months.
The primary endpoints of the study were transformation rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety, among others.
Figure 1. Study Design
Results
As of April 10, 2023, a total of 137 patients were screened, and 100 were included in the study. Among the 100 patients, 26 had extrahepatic metastases, and 58 had major vessel invasion. The results showed that based on mRECIST criteria, the ORR was 54%, and the disease control rate (DCR) was 77%. The radiology-based transformation success rate was 51%, with 47 patients (47%) undergoing surgical resection. All surgeries achieved R0 resection of both the tumor and portal vein tumor thrombus/extrahepatic metastases, with no Clavien-Dindo III or higher complications or postoperative deaths.
At a median follow-up of 17 months, the median OS for all patients was 25 months, with a 3-year survival rate of 31.9%. The median OS for the transformation resection group and the non-transformation resection group was not reached and 15 months, with 3-year survival rates of 55.6% and 11.3%, respectively. The median recurrence-free survival (RFS) for the transformation resection group was 25 months, and the median PFS for the non-transformation resection group was 7 months. Patients with pathological disease progression (pPD) had a worse prognosis.
Figure 2. Overall Survival Curves for Transformed Resection and Non-Transformed Resection Patients (Left) and Recurrence-Free Survival Curve for Transformed Resection Patients (Right)
In terms of safety, 83% of patients experienced treatment-related adverse events (TRAE), of which 28 cases (28%) were classified as grade 3 TRAE.
Research Conclusion
The combination of lenvatinib and zidiximab is a safe, effective, reasonable, and promising treatment regimen for the transformation of unresectable hepatocellular carcinoma in the middle to late stages.
Researchers’ Comments
The exploration of conversion therapy has a history, from localized treatment-based case reports to current systemic conversion therapy based on immunotherapy, and this has provided new hope for curative treatment for patients with intermediate to advanced unresectable hepatocellular carcinoma. We have observed encouraging objective response rates (ORR) in patients with unresectable HCC treated with anti-angiogenesis drugs, such as lenvatinib in combination with nivolumab and pembrolizumab, achieving ORRs of 54.2% and 36.0%, respectively. Early small-sample retrospective conversion therapy studies have suggested higher conversion rates to surgical resection with higher ORRs. However, overall, there is a lack of prospective, large-sample, high-level evidence for the conversion therapy studies with immune checkpoint inhibitors (ICIs).
In this context, our team has been committed to the prospective exploration of conversion therapy in intermediate to advanced unresectable hepatocellular carcinoma based on ICIs. The data from the extension cohort of 100 patients in this study were reported at the ESMO conference. When compared with our previous data on 56 patients from a Phase II study published in the Journal for ImmunoTherapy of Cancer, the uniformity of the treatment plan, extended follow-up time, and increased sample size all help maintain overall stability in both ORR and transformation success rates. Moreover, OS data consistently reflect the long-term survival benefits brought about by conversion surgery. This further confirms the value of immune checkpoint inhibitors in conversion therapy for intermediate to advanced liver cancer, providing reliable data for further exploration. The study is ongoing, and with longer follow-up time and more patients enrolled, we hope to accumulate more robust data to contribute to the development of conversion therapy for intermediate to advanced liver cancer and improve the long-term survival of these patients.
References
1. Lu, S. et al. 946P Sintilimab plus lenvatinib as conversion therapy in patients with unresectable hepatocellular carcinoma: A prospective, non-randomized, open-label, phase II, expansion cohort study. Annals of Oncology, Vol. 34, Supplement, S594–S595.
2. Kudo M, Ikeda M, Motomura K, et al. A phase IB study of Lenvatinib (Len) plus Nivolumab (Niv) in patients (Pts) with Unresectable hepatocellular carcinoma (Uhcc): study 117. JCO2020;38(4_suppl):513.
3. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. Journal of Clinical Oncology 2020;38:2960–2970.
4. Zhang W, Tong S, Hu B, et al. Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial. J Immunother Cancer. 2023;11
(9):e007366. doi:10.1136/jitc-2023-007366.
Professor Shichun Lu
Chief Physician, Professor, Ph.D., Doctoral Supervisor
Recipient of the State Council Special Allowance Expert
Currently, he serves as the Academic Director of the Hepatobiliary and Pancreatic Surgery Department at the People’s Liberation Army General Hospital.
Chairman of the Hepatobiliary and Pancreatic Disease Prevention and Control Professional Committee of the Chinese Preventive Medicine Association.
Member of the Ninth Committee of the Organ Transplantation Branch of the Chinese Medical Association.
Deputy Chairman of the Organ Transplantation Branch of the Beijing Medical Association.
Executive Committee Member of the Military Organ Transplantation Professional Committee.
Deputy Editor-in-Chief of the Chinese Journal of Hepatobiliary Surgery.
Editorial board member for the Chinese Journal of Surgery, Chinese Journal of Organ Transplantation, and Chinese Journal of Hepatic Disease.
