86MO - Personalized molecularly matched therapies for carcinomas of unknown primary is associated with improved outcomes

Background

Carcinoma of unknown primary (CUP) is a rare cancer diagnosis of exclusion. Because of the paucity of CUP cases and the ill-defined treatment guidelines, patients have poor prognoses. In efforts to improve patient outcomes, the efficacy of a personalized genomic matched N-of-One approach including tailored combination therapies was investigated.

Methods

Overall, 97 tumors had next-generation sequencing (NGS) of tissue (N=74) and/or cell-free DNA (cfDNA) (N=72). Immune biomarkers including PD-L1 immunohistochemistry, microsatellite instability (MSI) status, and tumor mutation burden (TMB) were also evaluated. Matching Score (MS) (the number of targeted deleterious genomic alterations divided by the total number of deleterious alterations) was assessed for patients.

Results

Overall, 59 of 97 patients (60.8%) were women; median age at diagnosis was 63 years (range, 21-95). The median number of alterations for 74 patients with tissue NGS was 4 (range, 0-25); most commonly altered genes were TP53, 55.4% (41/74); CDKN2A, 24.3%; and KRAS, 20.3%. The median number of alterations for 72 patients with cfDNA was 2 (range, 0-9); most common altered genes were TP53, 61.1% (44/72); KRAS, 22.2%; and PIK3CA, 16.7%. Overall, 30.9% of 55 patients tested for PD-L1 were positive (defined as ≥1% on tumor [n = 16] or tumor-infiltrating lymphocytes [n = 1]); 9.4% (6/64) of tumors had high TMB (≥20 mutations/mb), while 3.6% (2/55) were MSI-High. Clinical outcomes for 62 patients were evaluable. Comparing patients with high degrees of matching of alterations to therapies (MS≥50%; n=15) versus low MS (<50%;n=47, including 25 with no matched therapy), median progression-free survival was 10.4 vs. 2.8 months (95% CI 0.11-0.64; HR 0.27; P=0.002); median overall survival, 15.8 vs. 6.9 months (95% CI 0.17-1.16; HR 0.45; P=0.09). The disease control rate (stable disease ≥6 months plus partial or complete response) was significantly higher in the high vs. low MS group (71% vs. 24%; P=0.003).

Conclusions

Among patients with CUP, personalized combination treatments with high degrees of molecular matching to genomic alterations (MS≥50%) were associated with improved outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Joan and Irwin Jacobs Fund and NIH P30 CA023100.

Disclosure

S. Kato: Advisory/Consultancy: Foundation Medicine. J. Sicklick: Research grant/Funding (institution): Novartis Pharmaceuticals; Research grant/Funding (institution): Amgen Pharmaceuticals; Research grant/Funding (institution): Foundation Medicine; Advisory/Consultancy: Grand Rounds; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Deciphera; Advisory/Consultancy: Roche. R. Kurzrock: Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Serono; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Sequenom; Research grant/Funding (institution): Foundation Medicine; Research grant/Funding (institution): Grifols; Research grant/Funding (institution): Guardant; Advisory/Consultancy: Loxo; Advisory/Consultancy: X Biotech; Advisory/Consultancy: NeoMed; Advisory/Consultancy: Actuate Therapeutics; Speaker Bureau/Expert testimony: Roche; Leadership role, Shareholder/Stockholder/Stock options: IDby DNA; Leadership role, Shareholder/Stockholder/Stock options: Curematch Inc. All other authors have declared no conflicts of interest.