Oncotarget

Clinical Research Papers:

Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials

Rabih Said, Yang Ye, Gerald Steven Falchook, Filip Janku, Aung Naing, Ralph Zinner, George R. Blumenschein Jr, Siqing Fu, David S. Hong, Sarina Anne Piha-Paul, Jennifer J. Wheler, Razelle Kurzrock, Gary A. Palmer, Kenneth Aldape, Kenneth . R Hess and Apostolia Maria Tsimberidou _

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Oncotarget. 2014; 5:8937-8946. https://doi.org/10.18632/oncotarget.2339

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Abstract

Rabih Said1,2, Yang Ye1, Gerald Steven Falchook1, Filip Janku1, Aung Naing1, Ralph Zinner1, George R. Blumenschein Jr.3, Siqing Fu1, David S. Hong1, Sarina Anne Piha-Paul1, Jennifer J. Wheler1, Razelle Kurzrock4, Gary A. Palmer5, Kenneth Aldape6, Kenneth R. Hess7 and Apostolia Maria Tsimberidou1

1 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX

2 Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX

3 Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

4 Department of Internal Medicine, Moores Cancer Center - University of California San Diego, LaJolla, CA

5 Foundation Medicine, Inc., Cambridge, MA

6 Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX

7 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX

Correspondence:

Apostolia-Maria Tsimberidou, email:

Keywords: Personalized medicine, Phase I, Clinical trials, Targeted therapy, Molecular alterations

Received: June 09, 2014 Accepted: August 09, 2014 Published: August 10, 2014

Abstract

Background: KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.

Methods: Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.

Results: Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥ 6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).

Conclusions: MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.


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