Phase II Trial and Correlative Genomic Analysis of Everolimus Plus Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma.
Purpose The decreased effectiveness of single-agent targeted therapies in advanced non-clear cell renal cell carcinoma (ncRCC) compared with clear cell renal cell carcinoma (RCC) supports the study of combination regimens. We evaluated the efficacy of everolimus plus bevacizumab in patients with metastatic ncRCC. Patients and Methods In this single-center phase II trial, treatment-naive patients received everolimus 10 mg oral once per day plus bevacizumab 10 mg/kg intravenously every 2 weeks. The primary end point was progression-free survival (PFS) at 6 months. Correlative analyses explored candidate tissue biomarkers through next-generation sequencing. Results Thirty-five patients were enrolled with the following histologic subtypes: chromophobe (n = 5), papillary (n = 5), and medullary (n = 2) RCC and unclassified RCC (uRCC, n = 23). The majority of patients had papillary growth as a major component (n = 14). For 34 evaluable patients, median PFS, overall survival, and objective response rate (ORR) were 11.0 months, 18.5 months, and 29%, respectively. PFS varied by histology ( P < .001), and ORR was higher in patients with significant papillary (seven of 18) or chromophobe (two of five) elements than for others (one of 11). Presence of papillary features were associated with benefit, including uRCC, where it correlated with ORR (43% v 11%), median PFS (12.9 v 1.9 months), and overall survival (28.2 v 9.3 months; P < .001). Several genetic alterations seemed to segregate by histology. In particular, somatic mutations in ARID1A were seen in five of 14 patients with papillary features but not in other RCC variants. All five patients achieved treatment benefit. Conclusion The study suggests efficacy for this combination in patients with ncRCC characterized by papillary features. Distinct mutational profiles among ncRCCs vary according to specific histology.
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Martin H
MH
Voss
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Ana M
AM
Molina
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Ying-Bei
YB
Chen
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Kaitlin M
KM
Woo
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Joshua L
JL
Chaim
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Devyn T
DT
Coskey
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Almedina
A
Redzematovic
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Patricia
P
Wang
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
William
W
Lee
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
S Duygu
SD
Selcuklu
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Chung-Han
CH
Lee
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Michael F
MF
Berger
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Satish K
SK
Tickoo
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Victor E
VE
Reuter
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Sujata
S
Patil
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
James J
JJ
Hsieh
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Robert J
RJ
Motzer
Martin H. Voss, Ying-Bei Chen, Kaitlin M. Woo, Joshua L. Chaim, Devyn T. Coskey, Almedina Redzematovic, Patricia Wang, William Lee, S. Duygu Selcuklu, Chung-Han Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, Sujata Pati, James J. Hsieh, Robert J. Motzer, and Darren R. Feldman, Memorial Sloan Kettering Cancer Center; and Ana M. Molina, Weill Cornell Medical College, New York, NY.
Darren R
DR
Feldman
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D014408:Biomarkers, Tumor; D000068258:Bevacizumab; D000068338:Everolimus