Lenvatinib With Toripalimab and HAIC May Offer a New Frontline Option for Advanced HCC Treatment

Results from the phase 2 LTHAIC study (NCT04044313) showed that adding toripalimab and hepatic arterial infusion chemotherapy (HAIC) to lenvatinib (Lenvima) achieved robust and durable responses in patients with advanced hepatocellular carcinoma (HCC), according to a presentation given during the 2021 ASCO Annual Meeting.

Data from the trial indicate that patients who were treated with the combination regimen achieved a 6-month progression-free survival (PFS) rate of 80.6%, as well as a median PFS of 10.5 months (95% CI, 6.21-14.79), after a median follow up of 11.2 months. Patients also achieved an overall response rate (ORR) per RECIST criteria of 63.9% (95% CI, 40.9%-73.0%), and an ORR per modified RECIST criteria of 66.7% (95% CI, 43.3%-75.1%), compared to 67.6% and 70.6% in the per-protocol arm, respectively. Moreover, the median overall survival (OS) was not reached.

While combining systemic and locoregional therapies has been a promising treatment strategy for patients with advanced HCC, locoregional therapies have been largely ignored. As such, investigators sought to examine the safety and efficacy of lenvatinib with the recombinant humanized PD-1 monoclonal antibody toripalimab plus HAIC as a first-line therapy in this patient population.

The single-arm trial enrolled adult patients with treatment-naïve, advanced HCC who were aged 18 years or older. Patients needed to have an ECOG performance status of 0 to 2, with Child-Pugh class A liver function in order to be eligible to enroll.

Patients were treated with oral lenvatinib once daily at a dose of either 8 mg for bodyweight <60, or 12 mg for body weigh ≥60, for 3 to 7 days prior to initial treatment with HAIC in order to confirm tolerability. From there, patients were administered 21-day treatment cycles of lenvatinib on day 1 to day 21, as well as 240 mg of intravenous toripalimab on day 1, and HAIC with oxaliplatin (85 mg/m2), leucovorin (400 mg/m2), and 5-fluorouracil bolus (400 mg/m2) on days 1, and 5-fluorouracil infusion (2400 mg/m2) for 24 hours. Treatment continued until disease progression or unacceptable toxicity occurred.

The primary end point of the trial was PFS at 6 months, while key secondary end points included median OS and PFS, ORR, and adverse effects (AEs).

In total, 15 patients were excluded from the original 51 who were screened due to eligibility criteria (n = 9), withdrawal of consent (n = 4), or other reasons (n = 2). The trial enrolled 36 patients from August 2019 to May 2020, including 33 men, and 3 women who were a median of 49 years old. Twenty-four patients discontinued treatment at data cutoff. The most common reasons for treatment discontinuation included disease progression (n = 11), AEs (n = 6), withdrawal of consent (n = 3), and liver resection (n = 4). Seven patients continued to be treated with lenvatinib, and 5 continued treatment with the combination.

In total, 13.9% of patients in the intent-to-treat arm achieved a radiologic complete response (CR) per modified RECIST criteria vs 14.7% in the per-protocol population.

Additional data indicated that 63.9% of patients in the intent-to-treat by RECIST criteria population experienced a partial response (PR) and 25% had stable disease. In total, 52.8% of those in the modified RECIST group had a PR and 22.2% had stable disease. Both intent-to-treat groups had a disease control rate (DCR) of 88.9%., 5.6% developed progressive disease, and 5.6% were not able to be assessed.

Moreover, 67.6% of patients in the per-protocol population who were evaluated by RECIST criteria had a PR and 26.5% had stable disease. Those who were evaluated by modified RECIST criteria achieved a PR of 55.9%, and 23.5% had stable disease. In total, 5.9% of patients in both groups developed progressive disease, and both had a DCR of 94.1%, respectively.

Patients experienced a median duration of response of 12.1 months (95% CI, 4.52-19.69). Of the 8 patients who were successfully downstaged and converted to resectable disease, 1 underwent liver transplantation, and 4 underwent curative surgical resection. One patient achieved a pathologic CR.

Grade 3/4 treatment-related AEs (TRAEs) occurred in 72.2% of patients, the most common being thrombocytopenia (13.9%), elevated aspartate aminotransferase (AST; 13.9%), and hypertension (11.1%). Moreover, the most common any grade TRAEs were hypoalbuminemia (69.4%), elevated AST (66.7%), and elevated alanine aminotransferase (ALT; 58.3%). Common grade 1/2 TRAEs included hypoalbuminemia (69.4%), elevated AST (66.7%), and elevated ALT (58.3%). However, all AEs were expected and managed, with no treatment-related deaths occurring on the study.

_References

_{He M, Ming S, Lai Z, et al. A phase II trial of lenvatinib plus toripalimab and hepatic arterial infusion chemotherapy as a first-line treatment for advanced hepatocellular carcinoma (LTHAIC study). J Clin Oncol. 2021;39(suppl 15; abstr 4083). doi:10.1200/JCO.2021.39.15_suppl.4083}