Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers

Abstract

Patients and MethodsPatients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS.ResultsFrom April 2014–October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84).ConclusionPatients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.

Potentially Actionable Targets: Evidence Standards for Credible Next Generation Sequencing Technology Assessment Claims

“…While broad brush claims for increased overall survival or progression free survival following application of NGS guidedinterventions are increasingly made, it is a moot point as to whether such claims are meaningful to reimbursers, let alone patients and treating physicians 9 . Given the experience in late stage cancer therapies including the impact of competing regimens on adverse effect profiles, the likelihood of adverse events and factors such as depression and anxiety on adherence and persistence, a case can be made that the quality of life and quality adjusted life years (QALYs) are more meaningful.…”

Precision medicine for hepatocelluar carcinoma using molecular pattern diagnostics: results from a preclinical pilot study

“…13 Precision oncology has been facilitated by the advent of next-generation sequencing, which enables particular molecular genetic profiles to be identified in the individual patient who may be targeted by precise, personalized therapy. Identified targets are then used to search databases for drugs that address these aberrantly expressed molecules and pathways using the bioinformatics pipeline.…”

Evaluating the Utility of a ‘N-of-1' Precision Cancer Medicine Strategy: The Case for ‘Time-to-Subsequent-Disease Progression'

“…In this search for novel but objectively valid assessment strategies, it is relevant to note the efforts of several groups who have proposed an approach that would permit observation of the natural history of the malignant disease process in an individual patient to serve as the ‘study control' in a subsequent evaluation of the clinical utility of the molecular-based ‘targeted' therapeutic against that individual patient's cancer [2,3,4]. …”

“…However, several retrospective studies examining the natural history of patients with ovarian cancer, or among individuals participating in early-phase clinical trials, have supported the hypothesis that the time-to-disease progression will remain relatively stable or shorten with subsequent treatment programs [5,6,7]. However, the critical exception to this observation would be when a new treatment regimen (e.g., standard-of-care agent or experimental drug delivered on a clinical trial) is shown to have a favorable impact on the course of the malignancy (e.g., second-line treatment with paclitaxel in ovarian cancer patients previously treated with a platinum agent and cyclophosphamide) [4]. …”

“…In fact, 41% of the treatments based on recommendations specifically ‘targeting' a molecular abnormality (employing next-generation sequencing) documented to be present within the tumor resulted in a PFS in a specific patient at least 30% longer than the PFS observed with the patient's prior antineoplastic regimen. Another recent single-institution study of patients with refractory cancers reported that 19 out of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥1.3 compared with 3 out of 57 (5.3%) treated with non-genomically-guided therapy (p < 0.0001) [4]. …”