Real-life Experience of Rare Hepatoid Adenocarcinomas of the Lung: A Large Retrospective French Cohort.

Background: Hepatoid adenocarcinoma of the lung (HAL) is a rare subtype of lung cancer exhibiting common histological features with hepatocellular carcinomas (HCC). Therapeutic landscape is currently similar to lung adenocarcinoma standards. We report here the largest descriptive cohort of HAL with focus on (chemo)immunotherapy (chemo)IO) efficacy.

Methods: In this single-center retrospective observational study, we selected all consecutive cases of HAL patients from January 2013 to December 2022. Eligible patients had primary lung tumor with positive immunohistochemical hepatocyte marker. HCC was eliminated with liver imaging. We provide a descriptive analysis of HAL population and describe our therapeutic experience.

Results: A total of 23 patients were included. Main characteristics at diagnosis were: median age of 64.5 years [41-81], 78.3% of males, with 79% of PS 0-1. All patients had smoking history, with 8 active smokers. Majority of HAL (73.9%) originated from the upper lobes and 69.5% affected the right lung. Twenty-two patients (95.6%) had stage IV disease. Median number of metastatic sites was 2 with a maximum of 6 metastatic sites; most common metastatic sites were the bone (39.1%) and the brain (30.4%). PD-L1 status was < 1% (n = 11), 1-49% (n = 3), ≥ 50% (n = 5), unknown (n = 4). Ten (43.5%) patients harbored KRAS mutation: G12C (n = 6), G60D (n = 1), G12V (n = 1), G12F (n = 1), G13C (n = 1). Median overall survival (mOS) since diagnosis achieved 6.4 months (95% CI, 3.7-9.6). Early exclusive palliative care concerned 7 patients. Seven patients received first-line chemoIO. Best overall response was: partial response (n = 3), stable disease (n = 2), progressive disease (n = 1), not evaluable (n = 1). One patient treated with first-line pembrolizumab achieved stable disease. Median progression free survival of first line (chemo)IO was estimated at 4.5 months (95% CI, 2.3-5.4), objective response rate was 37.5%, and disease control rate was 75%. Five patients received second-line IO but experienced early progressive disease. Two patients received a KRAS inhibitor as third-line treatment, but no response was observed.

Conclusion: Our results highlighted that HAL patients were more frequently male and heavy smokers. HALs most often originate from the right upper lobe, with an overrepresentation of KRAS mutations and an aggressive, metastatic profile, which accounted for the poor mOS of 6.4 months. Patients may benefit from upfront (chemo)IO, but further studies were warranted to confirm it.