zipalertinib (CLN-081)

P2/3, N=131, Recruiting, Taiho Oncology Inc.

P2, N=324, Recruiting, Taiho Oncology, Inc. | N=224 --> 324 | Trial completion date: Aug 2026 --> Dec 2028 | Trial primary completion date: Feb 2026 --> Aug 2028

P2, N=16, Not yet recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Dec 2029 --> Jun 2030 | Initiation date: Jan 2026 --> Jun 2027 | Trial primary completion date: Dec 2028 --> Jun 2029

The role and the integration of therapies targeting exon20ins or uncommon mutations into the first- and second-line treatment armamentarium for NSCLC patients is not yet fully established, and the therapeutic impact of monotherapies (e.g., sunvozertinib, firmonertinib) versus combinations with standard platinum-based chemotherapy (e.g., zipalertinib, amivantamab) currently still lacks robust evidence to further change the therapeutic landscape for these patients. Therefore, results from the ongoing trials are eagerly awaited and are expected to shed some light on these open questions.

P2, N=16, Not yet recruiting, Jonsson Comprehensive Cancer Center

P3, N=272, Recruiting, Taiho Oncology, Inc. | Trial completion date: Aug 2026 --> May 2027 | Trial primary completion date: Jul 2026 --> Oct 2026

In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. In comparison, in the previously published EXCLAIM trial (NCT02716116), mobocertinib demonstrates similar activities across both groups in tumor size reduction (-38.5% vs. -34.1%, p = 0.59) and PFS (12.0 vs. 13.0 months, p = 0.99). Therefore, EGFRex20ins location differentially impacts the sensitivity of TKIs.

P3, N=360, Recruiting, Taiho Oncology, Inc.

P2, N=220, Recruiting, Taiho Oncology, Inc. | N=160 --> 220

Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in patients with EGFR ex20ins-mutant NSCLC who received prior platinum-based chemotherapy with or without amivantamab.

For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI...For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib...In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib...Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in patients that were pretreated with crizotinib and an ORR of 38% in patients pretreated with repotrectinib. In this review, we will discuss the relevant study results presented at ESMO 2024 for these three genomic drivers and hypothesize on their respective place in the sequence of treatment options.

P1/2, N=284, Active, not recruiting, Cullinan Therapeutics Inc. | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Dec 2024 --> Jan 2026