Faculty Collaboration Database

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study. Genome Med 2021 Oct 04;13(1):155

Date

10/06/2021

Pubmed ID

34607609

Pubmed Central ID

PMC8491393

DOI

10.1186/s13073-021-00969-w

Scopus ID

2-s2.0-85116352781 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

BACKGROUND: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study.

METHODS: A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS).

RESULTS: Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R² = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups.

CONCLUSIONS: Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies.

TRIAL REGISTRATION: I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.

Author List

Sicklick JK, Kato S, Okamura R, Patel H, Nikanjam M, Fanta PT, Hahn ME, De P, Williams C, Guido J, Solomon BM, McKay RR, Krie A, Boles SG, Ross JS, Lee JJ, Leyland-Jones B, Lippman SM, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Combined Modality Therapy
Female
Genomics
Humans
Male
Middle Aged
Molecular Targeted Therapy
Neoplasms
Prospective Studies
Young Adult