TY - JOUR
T1 - Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study
AU - Sicklick, Jason K.
AU - Kato, Shumei
AU - Okamura, Ryosuke
AU - Patel, Hitendra
AU - Nikanjam, Mina
AU - Fanta, Paul T.
AU - Hahn, Michael E.
AU - De, Pradip
AU - Williams, Casey
AU - Guido, Jessica
AU - Solomon, Benjamin M.
AU - McKay, Rana R.
AU - Krie, Amy
AU - Boles, Sarah G.
AU - Ross, Jeffrey S.
AU - Lee, J. Jack
AU - Leyland-Jones, Brian
AU - Lippman, Scott M.
AU - Kurzrock, Razelle
N1 - Funding Information:
This work was funded in part by Foundation Medicine, the Joan and Irwin Jacobs Fund (RK), Jon Strong (JKS, PTF), and NIH P30 CA023100 (JKS, SL, RK). We appreciate funding support from NIH R01 CA226803 (JKS) and FDA R01 FD006334 (JKS).
Funding Information:
This work was supported in part by Foundation Medicine Inc. We thank Ruth Japtok, Shukurat Sulaiman, and Ceonne Kim for their critical role in clinical trial and data management, Leticia Marquez for medication acquisition, and, most importantly, the patients and their families.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Clinical trial
KW - Genomics
KW - Immunotherapy
KW - Personalized
KW - Precision
KW - Targeted
UR - http://www.scopus.com/inward/record.url?scp=85116352781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116352781&partnerID=8YFLogxK
U2 - 10.1186/s13073-021-00969-w
DO - 10.1186/s13073-021-00969-w
M3 - Article
C2 - 34607609
AN - SCOPUS:85116352781
SN - 1756-994X
VL - 13
JO - Genome medicine
JF - Genome medicine
IS - 1
M1 - 155
ER -