Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study

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.

Gaining Control of Combination Cancer Treatment Risk by Incorporating Cost and Value Data into the Drug Selection Process at the Point–of–Care

“…This study presupposes that the science supporting the clinical effectiveness of customized multidrug cancer therapies is proven. [1][2][3][4] and that the associated measurement tool is accurate in determining the degree to which a cancer therapy option addresses a patient's molecular cancer profile. [5][6][7] In choosing a study methodology, we considered the validity, appropriateness, infirmities and implications of many healthcare economic analysis instruments.…”

“…What Is The Current Knowledge On The Topic? ☑ The effectiveness of molecularly targeted multidrug therapies used to treat advanced cancer is well established; [1][2][3][4] that few clinicians are aware of the cost of the medications they prescribe, or which are more cost-effective, deliver a better return-on-investment or represent a financial value; 8 and, that it is intuitive to believe that a combination of multiple high-cost medications is more expensive than a single-drug or other standard therapy options.…”

“…OPDIVO ® (nivolumab) helps active T cells identify cancer cells that are hiding; YERVOY ® (ipilimumab) helps generate more active T cells to seek and destroy more cancer cells. The safety, efficacy and cost-effectiveness of combination multi-drug therapy is well documented [1][2][3][4] and, as such, they have become a cornerstone of cancer treatment.…”

“…What Question Did This Study Address? ☑ Although studies on the clinical impact of multidrug cancer treatments abound, [1][2][3][4] there are no examinations of the relative cost or value of combination therapies vs. that of traditional monotherapies, or how knowledge of how this data can be used in practice. A systematic method to calculate, evaluate and compare the relative cost of monotherapies, 2-and 3-drug combination cancer therapy options is presented for use by physicians, health systems and payers to better manage their oncology specialty pharmacy spend and drive better medical outcomes.…”

“…FDAapproved multidrug therapies to treat cancer date back to the 1990's. The safety, efficacy and cost-effectiveness of combination therapy is well documented [1][2][3][4] and, as such, they have become a cornerstone of cancer treatment.…”