A Role for Neoadjuvant Immunotherapy in Liver Cancer?

Neoadjuvant immunotherapy appears to be feasible, safe, and active in patients with hepatocellular carcinoma (HCC), according to results from two small studies.

In the first study, perioperative nivolumab (Opdivo) with or without ipilimumab (Yervoy) induced major pathological responses in nearly a third of patients who underwent surgery, reported Ahmed Omar Kaseb, MD, of MD Anderson Cancer Center in Houston, and colleagues.

While in the second study, investigators led by Thomas U. Marron, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City, found that a short course of neoadjuvant cemiplimab (Libtayo) led to significant tumor necrosis in 20% of patients with resectable HCC, with every patient able to go on to surgery.

The phase II trials were published in Lancet Gastroenterology & Hepatology.

“Both studies provide somehow consistent results in terms of safety, efficacy, and tissue analyses,” wrote Nicola Personeni, MD, and Lorenza Rimassa, MD, both of Humanitas University in Milan, Italy, in a commentary accompanying the studies. “Taken together, they suggest an acceptable safety profile of both therapies, since none of the patients enrolled had surgery cancelled due to adverse events [AEs], while a minimal fraction did not undergo surgery because of disease progression.”

Personeni and Rimassa added that the results support further avenues of investigation into the use of neoadjuvant immunotherapy for HCC that “consider the most appropriate combinations of agents, the optimal therapy duration, and tailoring of subsequent postoperative therapy on the basis of risk factor stratification.”

Neoadjuvant Nivolumab Alone or Plus Ipilimumab

While surgical resection of early-stage HCC is standard practice, recurrence rates are high, and “immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma,” Kaseb’s group wrote.

They conducted a single-center, open-label trial in which 27 patients with resectable HCC were randomly assigned 1:1 to 6 weeks of preoperative nivolumab alone (n=13) or with ipilimumab (n=14), followed by surgery and subsequent adjuvant checkpoint inhibition for up to 2 years. The primary endpoint of the study was safety, while secondary endpoints included overall response rate (ORR), time to progression, and progression-free survival (PFS).

Grade 3/4 AEs were higher with nivolumab plus ipilimumab than with nivolumab alone (43% vs 23%). The most common treatment-related AEs of any grade were increased alanine aminotransferase (50% vs 23%, respectively) and aspartate aminotransferase (50% vs 23%). No patient in either group had surgery delayed due to grade 3 or worse AEs, though seven had surgery cancelled for other reasons.

The ORR was 23% for the nivolumab monotherapy group while no patients responded to the combination.

Of the 20 patients who underwent surgery, six (30%) had a major pathological response (≥70% necrosis in the resected tumor area), including three of 9 (33%) with nivolumab and three of 11 (27%) with nivolumab/ipilimumab. Two patients had a complete pathological response with nivolumab, as did three patients with the combination.

“Notably, the six patients who had a major pathological response with neoadjuvant immune checkpoint therapy did not have recurrence after a median follow-up of 26.8 months; by contrast, seven of 14 patients who did not have a major pathological response developed recurrence,” the authors wrote.

Estimated median PFS was 9.4 months with nivolumab alone and 19.53 months with the combination, with 2-year PFS rates of 42% and 26%, respectively.

“Our findings provide the first evidence that neoadjuvant immune checkpoint therapy is safe in patients with resectable hepatocellular carcinoma,” wrote Kaseb and his colleagues. “Preliminary activity results suggest that patients treated with neoadjuvant immune checkpoint therapy can achieve a major pathological response with longer recurrence-free survival.”

Neoadjuvant Cemiplimab

Marron and colleagues enrolled 21 patients with resectable hepatocellular carcinoma (stage Ib-IIIb) who received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection.

The primary endpoint was significant tumor necrosis on pathological examination (>70% necrosis of the resected tumor). Secondary endpoints included ORR and safety.

Of the 20 patients that were evaluable after surgery, four had significant tumor necrosis (20%), three of which had complete necrosis (15%). Overall, about a third of patients had 50% or greater tumor necrosis, and about two-thirds had less than 50% necrosis.

“This finding is in line with the response rates of neoadjuvant PD-1 blockade observed in other trials of different tumor types and correlates well with the findings of Kaseb and colleagues’ study,” Marron and coauthors observed.

ORR on imaging was 15% (three partial responses), while all other patients maintained stable disease.

Twenty of the 21 patients in the study (95%) had AEs of any grade during the neoadjuvant treatment period, the most common of which were increased aspartate aminotransferase, increased blood creatine phosphokinase, constipation, and fatigue. A third of patients experienced grade 3 AEs, while no grade 4/5 AEs were observed.