Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative

Abstract

Purpose: We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations.

Patient and methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy.

Results: Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P < 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).

Conclusion: Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials.

Figure 1

CONSORT diagram.

Figure 2

A, proportions of molecular aberrations (N = 1,144). Bars indicate proportions of patients whose tumors had a molecular aberration (number of patients with aberration/number of patients tested). Asterisk indicates patients with medullary thyroid cancer analyzed for RET mutation. B, molecular aberrations by tumor type (N = 1,144). Bars indicate percentages of patients whose tumors had genetic aberrations by type of cancer (number of patients with molecular aberrations/number of patients analyzed for the specific aberration).

Figure 3

A, best response by RECIST of 175 patients with one molecular aberration treated with matched therapy: changes from baseline in tumor measurements (waterfall plot). Patients with new lesions and/or clinical progression were illustrated as 20% progression (≥20% increase indicates progression; >30% decrease indicates partial response). B, best response by RECIST of 116 patients with 1 molecular aberration treated without molecular matching: changes from baseline in tumor measurements (waterfall plot; ≥20% increase indicates progression; ≥30% decrease indicates partial response). C, TTF of patients with 1 molecular aberration [matched targeted therapy: n = 175, median TTF = 5.2 months (95% CI, 4.3–6.2); therapy without matching: n = 116, median TTF = 2.2 months (95% CI, 2.0–2.7; P < 0.0001)]. D, survival of patients with 1 molecular aberration [matched targeted therapy: n = 175, median survival = 13.4 months (95% CI, 9.5–18.5); therapy without matching: n = 116, median survival = 9.0 months (95% CI, 5.9–11.7; P = 0.017)]. E, TTF of 175 patients with 1 molecular aberration treated with matched therapy (median, 5.2 months; 95% CI, 4.3–6.2) versus prior therapy (median, 3.1 months; 95% CI, 2.8–4.0; P < 0.0001). F, TTF of 116 patients with 1 molecular aberration treated with nonmatched therapy (median, 2.2 months; 95% CI, 2.0–2.7) versus prior therapy (median, 2.8 months; 95% CI, 2.2–3.2; P = 0.35).