Evaluation of neratinib (N), pembrolizumab (P), everolimus (E), and nivolumab (V) in patients (pts) with fibrolamellar carcinoma (FLC).

Abstract

310 Background: FLC, a rare liver cancer of young adults, has no effective systemic therapies. Surgical resection is used extensively with non-curative intent. FLC is associated with a DNAJB1- PRKACA chimeric transcript that produces a fusion protein with retained kinase activity and increased expression of several oncogenic signaling pathways including, but not limited to, HER2 ( ERBB2). Methods: N (240 mg oral daily) was studied in FLC pts in the SUMMIT study (NCT01953926); and later under compassionate use for N-based combinations (combo): P (2 mg/kg q3w), E (7.5 mg daily), and V (240 mg q2w) in doublet or triplet regimens. Eligible pts: ≥12y; histologically confirmed FLC; adequate organ function; any number of prior therapies. Primary endpoint: objective response rate (ORR; RECIST v1.1). Secondary endpoints: duration of response; clinical benefit rate (CBR); safety (CTCAE v4.0); somatic and germline sequencing (MSK IMPACT). Results: As of 03-Sep-2020, 15 pretreated pts received N in SUMMIT (confirmed ORR 0%; CBR 13%). Efficacy data for 5 pts from SUMMIT and 2 more pts receiving combo under compassionate use (4 male, 3 female, median age 26 years, median 0 [range 0–4] prior systemic therapies) are in shown in the table. The most common adverse events (AE) with single-agent N (n = 5) were diarrhea (grade 1 80%; grade 2 20%) and nausea (grade 1 60%); other AEs were grade ≤1 in ≤20% of pts. Conclusions: N monotherapy had limited benefit as a single agent in FLC pts. Several case studies evaluating N-based combo with checkpoint inhibitors administered under compassionate use demonstrated that NP led to 1 PR, and the triplet of NPE to prolonged SD. These are case-limited observations but are critical and worth evaluating further in upcoming clinical trials given the continued lack of a standard of care therapy for pts with FLC. Clinical trial information: NCT01953926. [Table: see text]