Lenvatinib Plus Pembrolizumab or Nivolumab Active in Intrahepatic Cholangiocarcinoma

Combining lenvatinib (Lenvima) with PD-1 inhibitors had promising efficacy in patients with advanced intrahepatic cholangiocarcinoma (ICC), according to preliminary data from a single-center study reported at the 2018 Gastrointestinal Cancers Symposium.

When lenvatinib was combined with either pembrolizumab (Keytruda) or nivolumab (Opdivo) in this setting in 14 patients who received prior anticancer therapy, median progression-free survival (PFS) was 5.0 months.

“We found that both pembrolizumab and nivolumab showed effective anticancer function when combined with lenvatinib,” lead author Jianzhen Lin, MD, and colleagues from the Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Beijing, China, concluded. Patients with both microsatellite instability-high (MSI) and microsatellite stable (MSS) tumors gained clinical benefit with the combinations. High tumor burden correlated with a better therapeutic response and a longer PFS.

ICC is typically diagnosed at an advanced stage that carries a poor prognosis. Lenvatinib is a multikinase inhibitor that targets VEGFR 1-3, FGFR 1-4, and other kinases.

Patients with advanced ICC, at least 1 measurable lesion by RECIST, and progressive disease after prior anticancer treatment were enrolled. Thirteen of the 14 patients had at least 2 prior lines of therapy. All were treated with lenvatinib at 10 mg/day orally plus either pembrolizumab at 200 mg IV every 3 weeks (n = 10), or nivolumab at 140 mg IV every 2 weeks (n = 4). Primary endpoints included PFS, objective response rate (ORR), and disease control rate (DCR), measured per RECIST v1.1.

Median patient age was 49 years, 50% of patients had ECOG performance status of 0 or 1 and 50% had ECOG performance status of 2 or 3, 79% had 1 positive lymphatic node, and 28% had an elevated serum bilirubin. Three (21%) patients had hepatitis B virus infection.

Targeted next-generation sequencing of 450 clinically actionable or cancer driver genes was performed in 10 patients to assess tumor mutation burden, microsatellite instability status, and genomic mutational landscape. Eleven (79%) patients had MSS and 1 (7%) had MSI-H tumors, with status unknown in the other 2 patients.

The ORR was 21.4%, consisting of 3 partial response (PRs). Eleven (79%) patients had stable disease, for a DCR of 93%. The clinical benefit rate (ORR + durable stable disease ≥ 5 months) was 64.3%.

Eleven of 14 patients had tumor shrinkage—8 of the 10 who received pembrolizumab and 3 of the 4 who received nivolumab. One responder had a 399 bp deletion on MLH1, and was identified as MSI-H. Two patients with a low tumor burden had tumor progression, including 1 with an FGFR2 rearrangement. One other patient with low tumor burden and FGFR2 rearrangement had tumor shrinkage of 27%.

The most common genomic alterations in the 10 sequenced tumors occurred in ARID1A, ATR, PIK3CA, and IDH1. Four patients had high tumor burden (<12 mut/Mb), all of whom responded to lenvatinib plus a PD-1 inhibitor, with 2 PRs. One patient with low tumor burden and FGFR2 mutation had a 27% decrease in target lesion size.

Lenvatinib plus a PD-1 inhibitor was well tolerated, even in this group of patients at a late clinical stage with poor liver function, the investigators noted. The most common adverse events were hypertension in 77%, an elevation in the level of aminotransferase (56%), and fatigue (49%). There were 3 grade 3 adverse events: 1 each of hypothyroidism, pleural effusion, and upper gastrointestinal hemorrhage. There were no grade 4 adverse events.

The findings support a clinical trial with a larger sample size to assess overall survival, according to Lin and co-authors.

Lin J, Wang A, Shi W, et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 500.

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