Caroline Seymour

Tissue- and blood-based molecular analysis could help match patients with advanced hepatocellular carcinoma or hepatocholangiocarcinoma following disease progression on frontline atezolizumab and bevacizumab to targeted therapy or another TKI based on identified genomic alterations.

Hepatocellular Carcinoma

Tissue- and blood-based molecular analysis could help match patients with advanced hepatocellular carcinoma (HCC) or hepatocholangiocarcinoma (H-CCK) following disease progression on frontline atezolizumab (Tecentriq) and bevacizumab (Avastin) to targeted therapy or another TKI based on identified genomic alterations, according to retrospective findings from a single-center study presented at the 2023 International Liver Cancer Association Conference.

“Molecular-based guided therapy is feasible in patients with HCC/H-CCK progressing under atezolizumab/bevacizumab and may be useful in a subset of patients,” lead study author Wendy Limousin, of Cordeliers Research Center, Sorbonne Université, Paris, France, said in a presentation of the data.

Frontline treatment for patients with advanced HCC consists of a PD-L1–based combination regimens such as atezolizumab and bevacizumab or durvalumab (Imfinzi) and tremelimumab (Imjudo), after which TKIs such as sorafenib (Nexavar), regorafenib (Stivarga), lenvatinib (Lenvima), and cabozantinib (Cabometyx) are typically used. In patients with advanced H-CCK, no systemic therapy is approved for treatment; therefore, patients typically receive HCC or cholangiocarcinoma regimens.

Notably, HCC shares common molecular alterations to H-CCK and cholangiocarcinoma, including TP53, TERT promoter, AXIN1, KMT2D, IDH1, KRAS, BRAF, and FGFR2. As such, investigators evaluated potential second- and later-line targeted treatment regimens for these populations as part of the 2025 French Medicine Genomic Program, which is open to patients with rare tumors, cancers of unknown origin, and cancers that are refractory to systemic therapy.

To be eligible for inclusion in the single-center study in France, patients had to have HCC or H-CCK progressing on atezolizumab/bevacizumab, Child-Pugh A disease, an ECOG performance status of 0 or 1, and a frozen tumor sample for analysis.

Between 2020 and 2023, eligible patients received treatment with TKIs, during which time they underwent a molecular tumor board, oncogenetics consultation, and DNA/RNA sequencing with whole-genome sequencing on blood and tumor samples, along with whole-exome sequencing and RNA sequencing on tumor samples. After receiving the results, patients underwent a second molecular tumor board, where they were matched to an appropriate targeted therapy based on the tumor’s genomic alterations.

In total, 135 patients were treated with atezolizumab/bevacizumab between September 1, 2020, and January 30, 2023. One-hundred patients developed progressive disease, and 34 were deemed appropriate for second-line therapy. Of those patients, 20 underwent genomic analysis. Reasons for not undergoing genomic testing were follow-up in another hospital (n = 2), locoregional treatment (n = 2), severe malnutrition (n = 1), issue with medical insurance (n = 2), no frozen samples available (n = 4), and patient refusal (n = 3).

Of the 20 patients who underwent sequencing, most had HCC (80%) as opposed to H-CCK (20%). Most patients were male (70%), and they had a median age of 57.0 years (range, 43.5-70.2). Chronic alcohol intake and metabolic dysfunction-associated steatotic liver disease occurred in 25% and 20% of patients, respectively. Half of patients had cirrhosis, and hepatitis B and C virus was reported in 50% and 25% of patients, respectively. Most patients had received only 1 prior systemic therapy (60%), though 35% and 5% of patients had received 2 or 4 prior lines, respectively. Barcelona Clinic Liver Cancer (BCLC) stage C disease was most common, occurring in 85% of patients; 15% had BCLC stage B disease. Metastasis and tumor vascular invasion were documented in 70% and 45% of patients, respectively. Median serum alpha-fetoprotein level was 113.5 ug/l (range, 7.2-1097.8).

Genomic analysis was conducted on 19 biopsies and 1 surgical sample. Ten tumor samples were collected both prior to and after treatment with atezolizumab/bevacizumab. Median time from sample collection to results was 62 days (interquartile range [IQR], 50-88).

Nineteen of the 20 results (95%) were able to be analyzed. The median number of mutations found was 2.85 mut/mB (IQR, 2.38-3.65). The median of somatic nonsynonymous damaging single-nucleotide variant was 19.5 (IQR, 17-29). The mutational signature SBS24 (aflatoxin B1) was found in 5 patients, who were all born in Africa, and SBS22 (aristolochic acid) was found in 1 patient born in China. The median homologous recombination deficiency (HRD) score was 25 (IQR, 11-34), and one patient had a high HRD score of 88.

The most common somatic alterations in driver genes were TP53 (47.4%), RB1 (36.8%), TERT promoter (31.6%), CCND1 FGF19 amplification (21.0%), PTEN (20.0%), ALB (15.8%), CTNNB1 (15.8%), ARID1A (10.5%), CDKN2A (10.5%), PIK3CA (10.5%), TSC1 (10.5%), CDK4 (5.3%), CDKN2C (5.3%), MDM4 (5.3%), PALB2 (5.3%), TSC2 (5.3%), and VEGFA (5.3%).

Of the 19 patients with an evaluable sample, 70% (n = 14) harbored at least 1 actionable genomic alteration according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Nine (45%) of these patients were subsequently matched to a targeted therapy, most of whom had received prior TKI therapy (n = 7; 35%).

Responses were seen with everolimus (Afinitor; complete response, n = 1; progressive disease [PD], n = 2), trastuzumab (Herceptin) plus olaparib (Lynparza; stable disease, n = 1), trametinib (Mekinist; PD, n = 3), palbociclib (Ibrance; partial response, n = 1), and olaparib (PD, n = 1).

Notably, PR with palbociclib occurred in a patient with H-CCK with a CDK4 amplification, and CR occurred with everolimus in a patient with TSC2-mutant HCC.

However, given the limited number of patients, further validation studies will be required, Limousin concluded.

Reference

Limousin W, Laurent-Puig P, Ziol M, et al. Molecular-based targeted therapies in patients with hepatocellular carcinoma and hepato-cholangiocarcinoma refractory to atezolizumab-bevacizumab. Presented at: 2023 International Liver Cancer Association Conference; September 7-9, 2023; Amsterdam, Netherlands.