This article is part of the Research Topic Drug-Diagnostics Co-Development in Oncology


Front. Oncol., 01 April 2014 |

Will the requirement by the US FDA to simultaneously co-develop companion diagnostics (CDx) delay the approval of receptor tyrosine kinase inhibitors for RTK-rearranged (ROS1-, RET-, AXL-, PDGFR-α-, NTRK1-) non-small cell lung cancer globally?

imageSai-Hong Ignatius Ou1*, imageRoss A. Soo2, imageAkihito Kubo3, imageTomoya Kawaguchi4 and imageMyung-Ju Ahn5
  • 1Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA
  • 2National University Health System and Cancer Science Institute of Singapore, Singapore
  • 3Aichi Medical University School of Medicine, Nagakute, Japan
  • 4National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai City, Japan
  • 5Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

The discovery of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) in 2007 and the approval of crizotinib for the treatment of advanced ALK-rearranged NSCLC in 2011 represents a landmark in the development of targeted oncology therapy. The approval of crizotinib was accompanied simultaneously by the approval of the Vysis (Abbott Molecular) break-apart fluorescence in situ hybridization (FISH) test as the companion diagnostic (CDx) test to detect ALK rearrangement. Pfizer, the manufacturer of crizotinib, sponsored the screening of thousands of patients and the standardization of the ALK FISH test as part of the approval process for crizotinib, a first in class ALK inhibitor. Many pharmaceutical companies are now using the Food and Drug Administration (FDA)-approved ALK FISH assay to enroll patients onto trials for their own respective ALK inhibitors. In essence they are “piggybacking” on the FDA-approved ALK FISH assay without having to pay for the development of a CDx, nor screening for ALK-rearranged NSCLC patients in the protocols because screening for ALK rearrangement is now the standard of care in NSCLC after the approval of crizotinib. Since 2007, rearrangement in more receptor tyrosine kinases (RTKs) such as ROS1, RET, AXL, PDGFR-α, and NTRK1 have been discovered in NSCLC but the incidence of each subtype of RTK-rearranged NSCLC is quite rare. Crizotinib has now demonstrated significant clinical activity in ROS1-rearranged NSCLC patients. Whether crizotinib will gain official FDA approval for use in ROS1-rearranged NSCLC, on the other hand, remains unclear as there is no test for ROS1-rearrangement currently being developed to support US FDA approval as a CDx. This may be due in part to the fact that the full cost associated with the development of a pre-market approved-approved CDx must be borne by the company seeking the first drug approval in a new indication. Given the low incidence of ROS1-rearrangement in NSCLC, and the availability of crizotinib in most countries, a more cost-effective way is for crizotinib to gain compendium listing for ROS1-rearranged NSCLC in treatment guidelines. However, without a formal indication from the FDA, a drug cannot be marketed for off label use, it is unlikely that payers public or private will routinely pay for molecular testing for ROS1-rearrangement in NSCLC let alone reimburse off label use of crizotinib. Similarly, several marketed tyrosine kinase inhibitors (TKIs) in the US (sorafenib, sunitinib, vandetanib, cabozantinib, regorafenib) are potent RET inhibitors in vitro. It does not make sense for any one pharmaceutical company to shoulder the full cost of developing a particular CDx for RET-rearranged NSCLC where, once approved, it may be used by other pharmaceutical companies to gain addition labeling approval for their own RET inhibitors. Thus, the requirement by the US FDA that a specific CDx have to be co-developed and standardized for each of the molecular subtype of NSCLC as part of the drug approval process, while prudent, may have the un-intended consequence of deterring clinical development of these TKIs in these very rare molecular subsets of NSCLC. While we all march to the drumbeat of precision cancer medicine, the stringent requirement of co-development CDx for each molecular subtype of solid tumor may inadvertently make this goal substantially more difficult to achieve.

Keywords: companion diagnostics, ALK-rearranged NSCLC, ROS1-rearranged NSCLC, RET-rearranged NSCLC, fluorescence in situ hybridization, immunohistochemistry, next generation sequencing, reverse transcription-polymerase chain reaction

Citation: Ou S-HI, Soo RA, Kubo A, Kawaguchi T and Ahn M-J (2014) Will the requirement by the US FDA to simultaneously co-develop companion diagnostics (CDx) delay the approval of receptor tyrosine kinase inhibitors for RTK-rearranged (ROS1-, RET-, AXL-, PDGFR-α-, NTRK1-) non-small cell lung cancer globally? Front. Oncol. 4:58. doi: 10.3389/fonc.2014.00058

Received: 04 January 2014; Accepted: 11 March 2014;
Published online: 01 April 2014.

Edited by:

Jan Trøst Jørgensen, Dx-Rx Institute, Denmark

Reviewed by:

Brion William Murray, Pfizer Worldwide Research & Development, USA
Amit K. Tiwari, Tuskegee University, USA

Copyright: © 2014 Ou, Soo, Kubo, Kawaguchi and Ahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sai-Hong Ignatius Ou, Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, University of California Irvine School of Medicine, 101 City Drive, Building 56, RT81, Orange, CA 92868-3298, USA e-mail: