Introduction
Patients and methods
Patients
Matched therapy
Analysis of molecular aberrations
Endpoints and statistical methods
Results
Patient characteristics
Characteristic | N (%) | Matched therapy (%) | Non-matched therapy (%) | p |
---|---|---|---|---|
N = 711 | N = 596 | |||
Age, years | .38 | |||
< 60 | 708 (54.2) | 393 (55.3) | 315 (52.9) | |
≥ 60 | 599 (45.8) | 318 (44.7) | 281 (47.1) | |
Sex | .67 | |||
Female | 802 (61.4) | 440 (61.9) | 362 (6.7) | |
Male | 505 (38.6) | 271 (38.1) | 234 (39.3) | |
Number of prior therapies | .41 | |||
≤ 3 | 637 (48.7) | 354 (49.8) | 283 (47.5) | |
> 3 | 670 (51.3) | 357 (5.2) | 313 (52.5) | |
Performance status | .27 | |||
0–1 | 1211 (92.7) | 664 (93.4) | 547 (91.8) | |
> 1 | 96 (7.3) | 47 (6.6) | 49 (8.2) | |
Platelet count, × 109/L | .815 | |||
≤ 440 | 1254 (95.9) | 683 (96.1) | 571 (95.8) | |
> 440 | 53 (4.1) | 28 (3.9) | 25 (4.2) | |
Number of metastatic sites | .61 | |||
0-2 | 867 (66.3) | 476 (66.9) | 391 (65.6) | |
> 2 | 440 (33.7) | 235 (33.1) | 205 (34.4) | |
Liver metastases | .03 | |||
No | 839 (64.2) | 475 (66.8) | 364 (61.1) | |
Yes | 468 (35.8) | 236 (33.2) | 232 (38.9) | |
Lactate dehydrogenase, IU/L | < .001 | |||
≤ 618 | 856 (65.5) | 499 (7.2) | 357 (59.9) | |
> 618 | 451 (34.5) | 212 (29.8) | 239 (4.1) | |
Albumin, g/dL | .16 | |||
< 3.5 | 1185 (9.7) | 652 (91.7) | 533 (89.4) | |
≥ 3.5 | 122 (9.3) | 59 (8.3) | 63 (1.6) | |
Tumor type | N/A* | |||
Breast | 177 (13.5) | 120 (16.9) | 57 (9.6) | |
Colorectal | 238 (18.2) | 90 (12.7) | 148 (24.8) | |
Endometrial | 55 (4.2) | 40 (5.6) | 15 (2.5) | |
Gastrointestinal, other | 79 (6.0) | 33 (4.6) | 46 (7.7) | |
Genitourinary, other | 35 (2.7) | 17 (2.4) | 18 (3.0) | |
Gynecological, other | 67 (5.1) | 35 (4.9) | 32 (5.4) | |
Head and neck | 69 (5.3) | 36 (5.1) | 33 (5.5) | |
Renal | 12 (.9) | 6 (.8) | 6 (.8) | |
Lung | 114 (8.7) | 71 (1.0) | 43 (7.2) | |
Melanoma | 155 (11.9) | 101 (14.2) | 54 (9.1) | |
Other | 55 (4.2) | 33 (4.6) | 22 (3.7) | |
Ovarian | 132 (1.1) | 59 (8.3) | 73 (12.3) | |
Pancreatic | 25 (1.9) | 7 (1.0) | 18 (3.0) | |
Sarcoma | 33 (2.5) | 19 (2.7) | 14 (2.4) | |
Thyroid | 61 (4.7) | 44 (6.2) | 17 (2.9) |
Treatment
Response to therapy
Clinical Benefit (CR + PR + SD ≥ 6 months), evaluable for response (N = 1256) | |||
Risk Factor (vs. other) | OR | 95% CI | p |
PI3K/AKT/mTOR alterations | .73 | .53–1.02 | .06 |
Liver metastases | .54 | .39–.76 | < .001 |
LDH > ULN | .61 | .43–.86 | .004 |
Performance status > 1 | .50 | .24–1.02 | .06 |
Albumin < ULN | .68 | .37–1.25 | .21 |
Type of therapy added | |||
Non-matched therapy | .67 | .49–.90 | .01 |
PI3K/AKT/mTOR alterations | .67 | .48–.94 | .02 |
Liver metastases | .55 | .39–.77 | < .001 |
LDH > ULN | .63 | .45–.89 | .01 |
Performance status > 1 | .51 | .25–1.05 | .07 |
Albumin < ULN | .69 | .97–1.27 | .23 |
Progression-Free Survival (n = 1307) | |||
Risk Factor (vs. other) | HR | 95% CI | p |
PI3K/AKT/mTOR alterations | 1.11 | .98–1.27 | .09 |
Liver metastases | 1.45 | 1.27–1.64 | < .001 |
LDH > ULN | 1.50 | 1.31–1.70 | < .001 |
Performance status > 1 | 1.57 | 1.24–1.99 | < .001 |
Albumin < ULN | 1.35 | 1.09–1.67 | .01 |
Platelets > ULN | 1.14 | .85–1.53 | .39 |
Age ≥ 60 years | .97 | .86–1.09 | .57 |
Type of therapy added | |||
Non-matched therapy | 1.39 | 1.23–1.58 | < .001 |
PI3K/AKT/mTOR alterations | 1.16 | 1.02–1.32 | .02 |
Liver metastases | 1.43 | 1.26–1.62 | < .001 |
LDH > ULN | 1.44 | 1.26–1.64 | < .001 |
Performance status > 1 | 1.54 | 1.22–1.95 | < .001 |
Albumin < ULN | 1.31 | 1.06–1.62 | .01 |
Platelet count > ULN | 1.09 | .81–1.46 | .59 |
Age ≥ 60 years | .95 | .84–1.07 | .37 |
Progression-free survival
Overall survival
Factors independently prognostic of shorter overall survival | HR | 95%CI | p value | |
Training patient set (n = 903) | ||||
Non-matched therapy | 1.20 | 1.04 | 1.38 | 0.01 |
Performance status > 1 | 2.52 | 1.94 | 3.28 | < 0.001 |
Liver metastases | 1.52 | 1.31 | 1.77 | < 0.001 |
LDH > ULN | 1.66 | 1.42 | 1.93 | < 0.001 |
PI3K/AKT/mTOR pathway alterations | 1.18 | 1.01 | 1.37 | 0.03 |
Validation patient set (n = 404) | ||||
Non-matched therapy | 1.59 | 1.29 | 1.96 | < 0.001 |
Performance status > 1 | 2.21 | 1.53 | 3.20 | < 0.001 |
Liver metastases | 1.35 | 1.07 | 1.69 | 0.01 |
LDH > ULN | 1.70 | 1.36 | 2.12 | < 0.001 |
PI3K/AKT/mTOR pathway alterations | 1.43 | 1.14 | 1.80 | 0.002 |
All patients (N = 1307) | ||||
Non-matched therapy | 1.32 | 1.17 | 1.48 | < 0.001 |
Performance status > 1 | 2.38 | 1.93 | 2.95 | < 0.001 |
Liver metastases | 1.44 | 1.28 | 1.63 | < 0.001 |
LDH > ULN | 1.66 | 1.46 | 1.88 | < 0.001 |
PI3K/AKT/mTOR pathway alterations | 1.25 | 1.10 | 1.42 | < 0.001 |
Scoring system for survival model | ||||
Factors | HR | Score | ||
Matched therapy | ||||
Yes | 1.00 | 0 | ||
No | 1.32 | 1 | ||
Performance status | ||||
0–1 | 1.00 | 0 | ||
2–3 | 2.38 | 2 | ||
Liver metastases | ||||
No | 1.00 | 0 | ||
Yes | 1.44 | 1 | ||
LDH > ULN | ||||
No | 1.00 | 0 | ||
Yes | 1.66 | 1 | ||
PI3K/AKT/mTOR pathway alterations | ||||
No | 1.00 | 0 | ||
Yes | 1.25 | 1 |
Independent prognostic factors and prognostic score
Discussion
Summary
Conclusions
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Analysis of our data demonstrated that in patients with metastatic cancer, matched targeted therapy is associated with superior rates of objective response, PFS, and long-term OS compared to non-matched therapy.
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This was the first large precision medicine study across tumor types in patients who were referred for phase I clinical trials, and consequently, it has the longest follow-up. The 3-year overall survival rate was 15% in the matched group compared to 7% in the non-matched group and the 10-year overall survival rates were 6% vs. 1%, respectively.
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Matched therapy was an independent factor predicting longer survival in multivariate analysis.
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PI3K/Akt/mTOR pathway abnormalities were associated with inferior outcomes compared to other alterations.
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Independent factors predicting shorter OS in multivariate analysis were used to develop a prognostic score to predict an individual patient’s risk of death. These factors were non-matched therapy, liver metastases, LDH greater than the upper limit of normal, and PI3k/AKT/mTOR pathway alterations (score of 1 each) and performance status greater than 1 (score of 2). This prognostic model that includes molecular pathway abnormalities can be used to predict the expected OS of individual patients who are being considered for clinical trials.
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Implementation of precision medicine will dramatically improve the outcomes of patients with cancer.