Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses

Abstract

Purpose: The purpose of this study was to confirm our previous results that targeted agents matched with tumor molecular alterations were associated with improved outcomes compared with nonmatched therapy in patients with advanced cancer.

Experimental design: Outcomes of patients who were referred for treatment on phase I clinical trials at The University of Texas MD Anderson Cancer Center (Houston, TX) from March 2011 to January 2012 were compared between those who had received targeted therapy and those for whom no targeted therapy was available. Two-month landmark analyses for overall and progression-free survival (PFS) combining previously published and validation cohort patient data were performed.

Results: In patients with one alteration, matched therapy (n = 143) compared with treatment without matching (n = 236) was associated with a higher objective response rate (12% vs. 5%; P < 0.0001), longer PFS (median, 3.9 vs. 2.2 months; P = 0.001), and longer survival (median, 11.4 vs. 8.6 months; P = 0.04). In multivariate analysis, matched therapy was an independent factor predicting response (P < 0.015) and PFS (P < 0.004). Two-month landmark analyses in the matched therapy group demonstrated that the median survival of responders was 30.5 months compared with 11.3 months for nonresponders (P = 0.01); and the median PFS was 38.7 months compared with 5.9 months, respectively (P < 0.0001). The respective values in the nonmatched therapy group were 9.8 and 9.4 months (P = 0.46) and 8.5 and 4.2 months (P = 0.18).

Conclusion: This validation analysis confirms our previous observations. In the matched therapy group, 2-month landmark analyses demonstrated that responders have longer survival and PFS than nonresponders.

Figure 1. Consort diagram

One hundred and fifty-five patients were excluded from the analyses of clinical outcomes (regional therapy, n=37; ineligible for study pariticipation, n=114; too early, n=1; toxicity, n=3).

Figure 2a

Proportions of specific molecular alterations (N=1,276). Bars indicate proportions of patients whose tumors had a molecular alteration (number of patients with alteration/number of patients tested).

Figure 2b

Molecular alterations by tumor type (N=1,276). Bars indicate percentages of patients whose tumors had genetic alterations by type of cancer (number of patients with molecular alterations/number of patients analyzed for the specific alteration)

Figure 2c

Best response by RECIST of 143 evaluable patients with 1 molecular alteration treated with matched therapy: changes from baseline in tumor measurements (waterfall plot). Patients with new lesions and/or clinical progression are shown as 20% progression (≥20% increase indicates progression; ≥30% decrease indicates partial remission).

Figure 2d

Best response by RECIST of 236 evaluable patients with 1 molecular alteration treated without molecular matching: changes from baseline in tumor measurements (waterfall plot) (≥20% increase indicates progression; ≥30% decrease indicates partial response).

Figure 2e

Progression-free survival of patients with 1 molecular alteration by type of therapy (matched vs. non-matched).

Figure 2f

Survival of patients with 1 molecular alteration by type of therapy (matched vs. non-matched).

Figure 3a

Two-month landmark analysis of survival for the matched therapy group.

Figure 3b

Two-month landmark analysis of survival for the non-matched group.

Figure 4a

Two-month landmark analysis of PFS for the matched therapy group.

Figure 4b

Two-month landmark analysis of PFS for the non-matched therapy group.