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

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  1 , Misako Nagasaka  2 , Danielle Brazel  3 , Yujie Hou  4 , Viola W Zhu  5
Affiliations

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 et al. Transl Oncol. 2021 Nov.

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”.

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Conflict of interest statement

Sai-Hong Ignatius Ou was a member of the scientific advisory board (SAB) of Turning Point Therapeutics until April 2019 and has stock ownership in Turning Point Therapeutics, which is developing TPX-0131; is a member of the SAB of Elevation Oncology and has stock ownership in Elevation Oncology; has received speaker honoraria from AstraZeneca, Merck, Pfizer, Roche/Genentech, and Takeda/ARIAD; has received advisory fees from AstraZeneca, Pfizer, Roche-Foundation Medicine, Roche/Genentech, Spectrum, Daiichi Sankyo, Jassen/JNJ, and X-covery.; Misako Nagasaka serves on the advisory board for AstraZeneca, Caris Life Sciences, Daiichi-Sankyo, Takeda, Novartis, EMD Serono, Janssen, Lilly and Genentech. She is a speaker for Blueprint Medicines, has received study funding from Tempus and has received travel support from An Heart Therapeutics.; Danielle Brazel and Yujie Hou have nothing to declare; Viola W. Zhu is currently an employee of Nuvalent which is developing NVL-655; has received honoraria from AstraZeneca, Blueprint, Roche-Foundation Medicine, Roche/Genentech, Takeda, and Xcovery; and had stock ownership of Turning Point Therapeutics (until May 2020).

Figures

Image, graphical abstract
Graphical abstract
Fig. 1
Fig. 1
Schema on the timeline of US FDA approval of ALK TKIs.
Fig. 2
Fig. 2
(A) Conceptual first-line randomized phase 3 trial design of 4 G ALK TKIs. 4G: 4th-generation; BIRC: blinded independent review committee; ctDNA: circulating tumor DNA; mPFS: median progression-free survival. (B) Conceptual second-line randomized phase 3 trial design of 4 G ALK TKIs. Lorlatinib does not have FDA indication immediately post-1 L brigatinib or immediately post-1 L ensartinib. Given alectinib is the most widely used 1 L ALK TKI, the trial is designed for post-1 L alectinib. 1L: first-line; 4G: 4th-generation; BIRC: blinded independent review committee; ctDNA: circulating tumor DNA; mPFS: median progression-free survival. (C) Conceptual third-line randomized phase 3 trial design of 4 G ALK TKIs. 4G: 4th-generation; BIRC: blinded independent review committee; ctDNA: circulating tumor DNA; mPFS: median progression-free survival.
Fig. 2
Fig. 2
(A) Conceptual first-line randomized phase 3 trial design of 4 G ALK TKIs. 4G: 4th-generation; BIRC: blinded independent review committee; ctDNA: circulating tumor DNA; mPFS: median progression-free survival. (B) Conceptual second-line randomized phase 3 trial design of 4 G ALK TKIs. Lorlatinib does not have FDA indication immediately post-1 L brigatinib or immediately post-1 L ensartinib. Given alectinib is the most widely used 1 L ALK TKI, the trial is designed for post-1 L alectinib. 1L: first-line; 4G: 4th-generation; BIRC: blinded independent review committee; ctDNA: circulating tumor DNA; mPFS: median progression-free survival. (C) Conceptual third-line randomized phase 3 trial design of 4 G ALK TKIs. 4G: 4th-generation; BIRC: blinded independent review committee; ctDNA: circulating tumor DNA; mPFS: median progression-free survival.
Fig. 3
Fig. 3
(A) Current “functional” view of ALK TKIs showing one current concept of classifying ALK TKIs into 1st-generation, 2nd-generation and 3rd-generation ALK TKIs. (B) Future “functional” view of ALK TKIs showing one future concept of classifying ALK TKIs into “wildtype active”, ‘single mutant active”, and “double mutant active” ALK TKIs with the development of 4th-generation ALK TKIs.
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