Characterization of Patients with Poor- Risk Metastatic Renal Cell Carcinoma Hamieh L 1 *, McKay RR 1 *, Lin X 2, Simantov R 2, Choueiri TK 1 *Equal contributions 1 Dana-Farber Cancer Institute, Boston, USA 2 Pfizer Oncology, New York, USA
The study was supported by: Pfizer Disclosures Dana-Farber/Harvard Cancer Center Kidney SPORE Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research
Background Survival outcomes are heterogeneous across different subsets of metastatic renal cell carcinoma (mrcc) patients. Risk stratification models have been designed to characterize these differences: 1. Memorial Sloan Kettering Cancer Center (MSKCC) model 2. International Metastatic Database Consortium (IMDC) model 3. Prognostic criteria used by Hudes phase III Temsirolimus trial The purpose of our study is to characterize poor-risk mrcc patients defined by the three models in a large clinical trials database.
Methods Retrospective analysis of 4,736 mrcc patients treated on phase II/III clinical trials sponsored by Pfizer. Patients meeting criteria for poor-risk disease as defined by the three models were selected. OS and PFS were estimated using the Kaplan-Meier method and were assessed using multivariable Cox regression*: In the total cohort In patients remaining on therapy > 12 months ORR and AEs were evaluated. The concordance (c-) index for each of the models was determined to assess their prognostic performance. *Adjusted for baseline characteristics including age, sex, race, body mass index (BMI), histology, prior nephrectomy, prior therapy, sites of metastasis and the models prognostic factors.
Baseline Characteristics Total Cohort The majority of the patients were/had: Caucasian Males Older than 65 years Good performance status Clear-cell histology Lungs as the most common metastatic site IMDC, N(%) MSKCC, N(%) Hudes, N(%) Poor-risk patients 1145 (24) 904 (19) 1901 (40) Risk factors (min-max) 3 (3-6) 3 (3-6) 3 (3-5) KPS<80% 461 (40) 467 (52) 533 (28) > 3 metastases 570 (50) 499 (55) 938 (49) No prior Nephrectomy 233 (20) 197 (22) 527 (28) Dx to Rx <1 yr 988 (86) 852 (94) 1667 (88) LDH > 1.5 ULN 184 (16) 280 (31) 354 (19) Hemoglobin <LLN 1038 ( 91) 833 ( 92) 1673 ( 88) Neutrophils > ULN 455 (40) 223 (25) 413 (22) Platelets > ULN 594 ( 52) 355 ( 39) 590 ( 31) Calcium > 10mg/dl 596 (52) 536 (59) 732 (39) IMDC = International Metastatic Database Consortium; MSKCC = Memorial Sloan Kettering Cancer Center; KPS= Karnofsky Performance Status; Dx= Diagnosis; Rx = Treatment; LLN= Lower Limit of Normal; ULN = Upper Limit of Normal; LDH = Lactate Dehydrogenase
Outcomes Total Cohort Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 n Median, mo (95% CI) IMDC 1145 8.6 (7.9 9.5) Hudes 1901 10.6 (9.9 11.3) MSKCC 904 7.5 (6.9 8.2) Median OS (95% CI) (mos) Median PFS (95% CI) (mos) IMDC MSKCC Hudes 8.6 (7.9-9.5) 7.5 (6.9-8.2) 10.6 (9.9-11.3) 3.7 (3.4-3.9) 3.5 (2.9-3.7) 4.2 (3.9-4.6) ORR (%) 10.7 10.3 14.6 0.2 0.1 Grade 3 AEs (%) 81.2 81.9 76.7 0.0 0 10 20 30 40 50 60 Time (months) Overall Survival of poor-risk patients defined by the MSKCC, IMDC and Hudes prognostic models C-index (95% CI) 0.826 (0.796-0.855) 0.830 (0.800-0.858) 0.825 (0.795-0.854) OS = Overall Survival; CI= Confidence Interval; mos = months; PFS = Progression Free Survival; ORR = Overall Response Rate; AEs = Adverse Events.
Patients Remaining on Therapy > 12 Months Baseline characteristics are similar to the total cohort 1.0 0.9 0.8 IMDC MSKCC Hudes N (%) 117 (10) 85 (9) 257 (14) Survival Probability 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 n Median, mo (95% CI) IMDC 117 30.7 (28.4 NR) Hudes 257 35.2 (30.7 NR) MSKCC 85 29.8 (26.1 NR) 0 10 20 30 40 50 60 Time (months) Overall Survival of poor-risk patients, defined by the MSKCC, IMDC and Hudes prognostic models, on therapy > 12 months Median OS (95% CI) (mos) Median PFS (95% CI) (mos) 30.7 (28.4 NR) 17.1 (14.7 20.2) 29.8 (26.1-NR) 17.2 (14.8-20.2) OS = Overall Survival; CI= Confidence Interval; mos = months; NR= Not Reached; PFS = Progression Free Survival; ORR = Overall Response Rate. 35.2 (30.7 - NR) 18.3 (16.4-20.7) ORR (%) 42 45 53
Conclusions The models have equivalent prognostic performance in the era of targeted therapy. They should be further evaluated in the setting of newer treatment modalities. Poor-risk patients continue to have dismal outcomes, hence the dire need for alternative therapies in these patients. However, a subset of poor-risk patients derived prolonged clinical benefit. This subset needs to be further explored for the identification of predictive biomarkers.
Acknowledgements Kidney cancer patients and their families Pfizer Oncology Dana Farber Lank Center for Genitourinary Oncology Dana-Farber/Harvard Cancer Center Kidney Cancer Program