Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Sai-Hong Ignatius Ou; Misako Nagasaka; Danielle Brazel; Yujie Hou; Viola W Zhu

doi:10.1016/j.tranon.2021.101191

Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Transl Oncol. 2021 Nov;14(11):101191. doi: 10.1016/j.tranon.2021.101191. Epub 2021 Aug 5.

Authors

Sai-Hong Ignatius Ou¹, Misako Nagasaka², Danielle Brazel³, Yujie Hou⁴, Viola W Zhu⁵

Affiliations

¹ University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States; Chao Family Comprehensive Cancer Center, Orange, California, United States. Electronic address: siou@hs.uci.edu.
² University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States; Chao Family Comprehensive Cancer Center, Orange, California, United States; St. Marianna University, School of Medicine, Kawasaki, Japan.
³ University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States.
⁴ Samuel Curtis Johnson Graduate School of Management, Cornell University, Ithaca, New York, United States.
⁵ University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States; Chao Family Comprehensive Cancer Center, Orange, California, United States.

Abstract

Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all "single mutant active" with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of "single mutant active" ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) "double mutant active" ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities ("singe mutant active" versus "double mutant active") rather than the loosely-defined "generational" (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.

Keywords: 4th-generation ALK TKI; ALK+ NSCLC; Anaplastic lymphoma kinase tyrosine kinase inhibitors; NVL-655; TPX-0131; “Double mutant active”; “Single mutant active”.