The ETOP ADEPPT trial met its primary end point with a 31% 12-week ORR with adagrasib in patients at least 70 years old with an ECOG PS of 0 or 1.
Treatment with adagrasib (Krazati) resulted in meaningful clinical benefit and manageable toxicities in elderly patients with pretreated non–small cell lung cancer (NSCLC) who displayed a KRAS G12C mutation and had an ECOG performance status (PS) of 0 or 1 (cohort A); however, the agent had limited activity in patients across all age groups with an ECOG PS of 2 (cohort B), according to updated data from the phase 2 ETOP ADEPPT trial (NCT05673187) presented during the
At a median follow-up of 16.8 months, 10 of the 32 patients in cohort A achieved a confirmed objective response (cOR) by 12 weeks, meeting the study’s main success criterion; this included 1 complete response and 9 partial responses (PRs). At a median follow-up of 18.5 months, only 6 patients in cohort B (n = 34) achieved a cOR; all were PRs. Of note, the primary hypothesis per cohort was a 12-week confirmed objective response rate (cORR) of at least 15% but no greater than 35%. cORRs were 31% (95% CI, 16%-50%) and 18% (95% CI, 7%-35%) in cohorts A and B, respectively.
There were 11 responses in cohort A and 13 in cohort B. The median duration of response was not reached vs 2.4 months in these respective cohorts.
“Unfortunately, adagrasib did not achieve the primary end point in the patients with an ECOG PS of 2 due to the overall limited clinical activity, although quality of life [QOL] improvements were observed,” lead study author Jarushka Naidoo, MBBCh, MHS, noted in her presentation.
Naidoo is a professor of medical oncology and consultant medical oncologist at the Beaumont RCSI Cancer Centre, Dublin, Ireland; an adjunct assistant professor of oncology at Johns Hopkins University, Baltimore, Maryland; and the National Lung Cancer Lead for Cancer Trials Ireland.
Adagrasib is a KRAS G12C inhibitor that has demonstrated clinical activity in patients with pretreated NSCLC and an ECOG PS of 0 or 1. However, a substantial proportion of patients with KRAS G12C–mutated NSCLC are older or have an ECOG PS of 2. The ETOP ADEPPT trial was therefore designed to evaluate the efficacy, toxicity, and impact on QOL of adagrasib in these underrepresented populations.
This international, single-arm, multicenter trial enrolled patients with histologically or cytologically confirmed stage IV NSCLC who displayed a KRAS G12C mutation and had previously received at least 1 line of platinum-based doublet chemotherapy and/or immune-checkpoint inhibition to treat their disease.1,2 Patients were also required to be at least 18 years of age with an ECOG PS of 2 (cohort B) or at least 70 years of age with an ECOG PS of 0 or 1 (cohort A). Eligible patients underwent a CT scan and brain MRI, completed a patient-reported outcome questionnaire, and had tissue and blood samples procured prior to enrollment and repeated at various time points throughout the treatment phase.1
All patients received 600 mg of oral adagrasib twice a day until disease progression or unacceptable toxicity.
The study’s primary end point was ORR by 12 weeks per RECIST 1.1 criteria. Secondary end points were durable clinical benefit, time to progression, progression-free survival (PFS), overall survival (OS), safety, and QOL.
The planned sample size for the study was 68 patients; 66 were enrolled onto the study by the database cutoff of July 28, 2025.
At this time, in cohort A, 12 patients were still on follow-up, and 6 were on long-term follow-up or had withdrawn from the study. In cohort B, 6 patients remained on follow-up, and 2 had withdrawn or were on long-term follow-up. All patients in both cohorts received 1 or more doses of the study drug and were included in the primary analysis and safety analysis.
At data cutoff, 7 patients in cohort A and 4 in cohort B were still on treatment. Patients in these respective cohorts discontinued treatment for the following reasons:
Regarding baseline characteristics, the median age of patients was 76 (range, 70-83) in cohort A and 64 (range, 49-70) in cohort B. Most patients in these respective cohorts were:
Brain metastases were not present in most patients (81%; 68%), although 3% of patients in cohort A were missing data. In cohort A, patients had either stage IVA (56%) or stage IVB (44%) disease. Twenty-five percent of patients had an ECOG PS of 0, and the remaining 75% had an ECOG PS of 1. In cohort B, 3%, 9%, and 88% of patients had stage IIIC, IVA, or IVB disease, respectively. All patients in this cohort had an ECOG PS of 2.
“Unfortunately, in [cohort B], with respect to survival, we see that the median PFS and OS were more favorable in the elderly cohort,” Naidoo reported.
Survival outcomes in cohort A were as follows:
Survival outcomes in cohort B were as follows:
Despite this, QOL improvements with adagrasib were observed in cohort B.
“We see that in [cohort B], the median important difference [in QOL] was achieved at 12 weeks and sustained at 15 weeks. However, the range of QOL was wide. In [cohort A], we see that overall, the QOL benefit was modest, but that this important difference was achieved at 30 weeks,” Naidoo detailed.
All patients in both cohorts experienced any-grade adverse effects (AEs). Serious AEs (SAEs) occurred in 59% and 50% of patients in cohorts A and B, respectively. Any treatment-related AEs (TRAEs) occurred in 88% and 94% of patients in these respective cohorts. This included grade 3 or higher TRAEs (cohort A = 41%; cohort B = 62%), as well as TRAEs leading to discontinuation (19%; 26%), treatment interruption (63%; 59%), dose reduction (47%; 32%), or death (0%; 3%). Any treatment-related SAEs occurred in 19% and 32% of patients, respectively.
The most frequent TRAEs across both cohorts were:
Disclosures: Dr Naidoo disclosed receipt of research funding from Amgen, Arcus Biosciences, AstraZeneca, Bristol Myers Squibb, Gilead, Roche/Genentech, Summit Therapeutics; serving on a consulting/advisory board for AbbVie, Amgen, Arcus Biosciences, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Elevation Oncology, Eli Lilly, Gilead, GSK Pharmaceuticals, Pfizer, Regeneron, Revolution Medicine, Roche/Genentech, Summit Therapeutics; Takeda, Zymeworks; serving on a steering committee for AstraZeneca, Bristol Myers Squibb, GSK Pharmaceuticals, Summit Therapeutics, Zymeworks; served on a data safety monitoring board for AstraZeneca, Bristol Myers Squibb, and Daiichi Sankyo; and received honoraria from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Roche/Genentech, and Regeneron.
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