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. 2023 Sep 1;41(25):4097-4106.
doi: 10.1200/JCO.23.00434. Epub 2023 Apr 26.

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation

Tanios S Bekaii-Saab  1 , Rona Yaeger  2 , Alexander I Spira  3   4   5 , Meredith S Pelster  6 , Joshua K Sabari  7 , Navid Hafez  8 , Minal Barve  9 , Karen Velastegui  10 , Xiaohong Yan  10 , Aditya Shetty  10 , Hirak Der-Torossian  10 , Shubham Pant  11
Affiliations

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation

Tanios S Bekaii-Saab et al. J Clin Oncol. .

Abstract

Purpose: Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation.

Methods: In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety.

Results: As of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients.

Conclusion: Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRASG12C-mutated solid tumors.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Patient disposition. aOne patient with appendiceal cancer was enrolled at the point of data cutoff (October 1, 2022) but had not been treated at this time. BICR, blinded independent central review.
FIG 2.
FIG 2.
Efficacy outcomes for patients with evaluable disease by BICR. (A) Waterfall plot of best percentage tumor change from baseline (n = 54). (B) Swimmer plot showing individual duration of treatment, response, and clinical outcome at data cutoff (n = 54). (C) Kaplan-Meier graphical representation of duration of response. (D) Kaplan-Meier graphical representation of PFS. Data as of October 1, 2022 (median follow-up, 16.8 months). BICR, blinded independent central review; DOR, duration of response; PDAC, pancreatic ductal adenocarcinoma; PFS, progression-free survival.
FIG A1.
FIG A1.
Waterfall plot of maximum percentage tumor change from baseline in patients with (A) PDAC and (B) BTC cancers. BTC, biliary tract cancer; PDAC, pancreatic ductal adenocarcinoma.
FIG A2.
FIG A2.
OS in patients with KRASG12C-mutated solid tumorsa (N = 64). Data as of October 1, 2022 (median follow-up, 16.8 months). aExcluding non–small-cell lung cancer and colorectal cancer. OS, overall survival.
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