Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson Precision Medicine Study

Abstract

Purpose: Genomic profiling is increasingly used in the management of cancer. We have previously reported preliminary results of our precision medicine program. Here, we present response and survival outcomes for 637 additional patients who were referred for phase I trials and were treated with matched targeted therapy (MTT) when available.

Patients and methods: Patients with advanced cancer who underwent tumor genomic analyses were treated with MTT when available.

Results: Overall, 1,179 (82.1%) of 1,436 patients had one or more alterations (median age, 59.7 years; men, 41.2%); 637 had one or more actionable aberrations and were treated with MTT (n = 390) or non-MTT (n = 247). Patients who were treated with MTT had higher rates of complete and partial response (11% v 5%; P = .0099), longer failure-free survival (FFS; 3.4 v 2.9 months; P = .0015), and longer overall survival (OS; 8.4 v 7.3 months; P = .041) than did unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders versus nonresponders was 7.6 versus 4.3 months (P < .001) and OS was 23.4 versus 8.5 months (P < .001), whereas for non-MTT patients (responders v nonresponders), FFS was 6.6 versus 4.1 months (P = .001) and OS was 15.2 versus 7.5 months (P = .43). Patients with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathway alterations matched to PI3K/Akt/mammalian target of rapamycin axis inhibitors alone demonstrated outcomes comparable to unmatched patients.

Conclusion: Our results support the use of genomic matching. Subset analyses indicate that matching patients who harbor a PI3K and mitogen-activated protein kinase pathway alteration to only a PI3K pathway inhibitor does not improve outcome. We have initiated IMPACT2, a randomized trial to compare treatment with and without genomic selection.

Fig 1.

Failure-free survival and overall survival in patient subgroups. Group 1: Matched targeted therapy (MTT) versus non-MTT. (A) Failure-free survival according to matched targeted therapy. (B) Overall survival according to matched targeted therapy. Group 2: MTT with TP53 (includes matching as previously published plus inclusion of anti–vascular endothelial growth factor [VEGF] therapy as targeted therapy against TP53) versus non-MTT. (C) Failure-free survival according to matched targeted therapy. (D) Overall survival according to matched targeted therapy. Group 3: MTT minus negative matches (includes patients who had matched targeted therapy, without considering TP53 mutations matched to VEGF/VEGF receptor [VEGFR] inhibitors and excluding the negative matches) versus non-MTT versus negative matches, with the latter defined as matched targeted therapy against an alteration in the PI3K axis in the presence of KRAS or BRAF or another MEK pathway mutation (the latter being a known resistance pathway) and no MEK/RAF inhibitors. (E) Failure-free survival. (F) Overall survival. Group 4: MTT with TP53 match minus negative matches (includes TP53 mutation matches to VEGF/VEGFR inhibitors but excludes negative matches) versus negative matches (see definition for group 3; Table 1) versus non-MTT. (G) Failure-free survival. (H) Overall survival. Group 5: Non-MTT (includes nontargeted therapy or targeted therapy against an alteration in the PI3K axis in the presence of KRAS or BRAF or other MEK pathway mutation and no MEK/RAF inhibitor) versus MTT (includes all other groups, including TP53 matches). (I) Group 5: failure-free survival. (J) Overall survival. HR, hazard ratio.

Fig 1.

Failure-free survival and overall survival in patient subgroups. Group 1: Matched targeted therapy (MTT) versus non-MTT. (A) Failure-free survival according to matched targeted therapy. (B) Overall survival according to matched targeted therapy. Group 2: MTT with TP53 (includes matching as previously published plus inclusion of anti–vascular endothelial growth factor [VEGF] therapy as targeted therapy against TP53) versus non-MTT. (C) Failure-free survival according to matched targeted therapy. (D) Overall survival according to matched targeted therapy. Group 3: MTT minus negative matches (includes patients who had matched targeted therapy, without considering TP53 mutations matched to VEGF/VEGF receptor [VEGFR] inhibitors and excluding the negative matches) versus non-MTT versus negative matches, with the latter defined as matched targeted therapy against an alteration in the PI3K axis in the presence of KRAS or BRAF or another MEK pathway mutation (the latter being a known resistance pathway) and no MEK/RAF inhibitors. (E) Failure-free survival. (F) Overall survival. Group 4: MTT with TP53 match minus negative matches (includes TP53 mutation matches to VEGF/VEGFR inhibitors but excludes negative matches) versus negative matches (see definition for group 3; Table 1) versus non-MTT. (G) Failure-free survival. (H) Overall survival. Group 5: Non-MTT (includes nontargeted therapy or targeted therapy against an alteration in the PI3K axis in the presence of KRAS or BRAF or other MEK pathway mutation and no MEK/RAF inhibitor) versus MTT (includes all other groups, including TP53 matches). (I) Group 5: failure-free survival. (J) Overall survival. HR, hazard ratio.

Fig 2.

Two-month landmark analyses. Group 1: Matched targeted therapy (MTT), as previously published. (A) Failure-free survival according to objective response (complete response [CR] + partial response [PR], yes) versus no response (No) in patients who received matched therapy (hazard ratio [HR], 0.49; 95% CI, 0.34 to 0.70; P < .001). (B) Failure-free survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.36; 95% CI, 0.18 to 0.70; P = .001). (C) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received matched therapy (HR, 0.49; 95% CI, 0.34 to 0.71; P < .001). (D) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.66; 95% CI, 0.35 to 1.25; P = .17). Group 2: MTT plus inclusion of anti–vascular endothelial growth factor (VEGF) therapy as targeted therapy against TP53. (E) Failure-free survival according to objective response (CR + PR, yes) versus no response (No) in patients who received matched therapy (HR, 0.50; 95% CI, 0.36 to 0.71; P < .001). (F) Failure-free survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.33; 95% CI, 0.16 to 0.71; P = .001). (G) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received matched therapy (HR, 0.49; 95% CI, 0.34 to 0.70; P < .001). (H) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.73; 95% CI, 0.36 to 1.49; P = .36).

Fig 2.

Two-month landmark analyses. Group 1: Matched targeted therapy (MTT), as previously published. (A) Failure-free survival according to objective response (complete response [CR] + partial response [PR], yes) versus no response (No) in patients who received matched therapy (hazard ratio [HR], 0.49; 95% CI, 0.34 to 0.70; P < .001). (B) Failure-free survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.36; 95% CI, 0.18 to 0.70; P = .001). (C) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received matched therapy (HR, 0.49; 95% CI, 0.34 to 0.71; P < .001). (D) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.66; 95% CI, 0.35 to 1.25; P = .17). Group 2: MTT plus inclusion of anti–vascular endothelial growth factor (VEGF) therapy as targeted therapy against TP53. (E) Failure-free survival according to objective response (CR + PR, yes) versus no response (No) in patients who received matched therapy (HR, 0.50; 95% CI, 0.36 to 0.71; P < .001). (F) Failure-free survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.33; 95% CI, 0.16 to 0.71; P = .001). (G) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received matched therapy (HR, 0.49; 95% CI, 0.34 to 0.70; P < .001). (H) Overall survival according to objective response (CR + PR, yes) versus no response (No) in patients who received nonmatched therapy (HR, 0.73; 95% CI, 0.36 to 1.49; P = .36).

Fig A1.

CONSORT diagram. The 257 patients who had no alterations were excluded from the analysis. Overall, 277 patients with molecular aberrations did not receive treatment by the time of this analysis for the following reasons: treated elsewhere (n = 118; 42.6%); worsening performance status (n = 39; 14.1%); received regional therapy (n = 31; 11.2%); ineligibility (n = 27; 9.7%); lost to follow-up (n = 23; 8.3%); declined investigational therapy (n = 15; 5.4%), insurance issues (n = 12; 4.3%); treated after the cutoff date of the data (n = 12; 4.3%).

Fig A2.

Numbers of patients with specific alterations. The following alterations were found in fewer than 10 patients: CCNE1 and CTNNB1 each in eight patients; CDH1, FGF3, MYST3, NFKBIA, and STK11 each in seven patients; ARID1A, FGF4, FGF19, HRAS, MLL2, and SOX2 each in six patients; AKT1, AKT3, CCND3, GNAS, IDH1, PIK3R1, RET, VHL, and ZNF703 each in five patients; BRCA2, CCND2, EMSY, FGFR2, FGFR3, KDM6A, MYCL1, and PDGFRA each in four patients; ATRX, FGF10, IRS2, LRP1B, MDM4, NF2, PTPRD, RICTOR, and TSC2 each in three patients; AR, ATR, AURKA, BAP1, BARD1, BCL2L2, CSF1R, EP300, ERBB2, ESR1, FANCA, FGF23, FLT4, GNAQ, GRIN2A, HGF, IKBKE, JAK2, JUN, MAP2K4, MLH1, MPL, MSH6, NKX2-1, NOTCH1, PALB2, PBRM1, PTCH1, SMAD2, and TSC1 each in two patients; and ABL1, AKT, AKT2, ALK, ARIDA, ARID2, ARFRP1, AURKB, BCORL1, BRIP1, CCDC6-RET, CDK6, CMARCB1, COX2, CREBBP, CRKL, DAXX, DNMT3A, DOT1L, EPHB1, ERBB3, ERBB4, ESR6, ESR13, ETV1, FAM123B, FANCC, FGF6, FLT1, FLT3, FOXL2, GATA3, IGF1R, IKZF1, JAK3, JAK2, MAP2K2, MAP3K1, MEN1, MSH2, YD88, PAX5, PDGFRB, PPP2R1A, PRKDC, PTPN11, RPTOR, STK11 loss, SMARCCB1, SMARCA4, SRC, TET2, TOP1, USP9X, WT1, XPO1, and ZNF217 each in one patient.

Fig A3.

(A) Landmark analysis of responders: Failure-free survival (hazard ratio [HR], 0.9; 95% CI, 0.4 to 1.9; P = .78. (B) Landmark analysis of responders: Overall survival (HR, 0.6; 95% CI, 0.3 to 1.2; P = .15. (C) Analysis excluding patients with estrogen receptor (ER)/progesterone receptor (PR) overexpression-based matching from the matched therapy group 1: Failure-free survival. (D) Analysis excluding patients with ER/PR overexpression-based matching from the matched therapy group 1: Overall survival. MTT, matched targeted therapy.