KRAS G12C mutations occur in 10% to 15% of non-small cell lung cancer (NSCLC) cases. However, a significant proportion of these patients 70 years old or older or have poor performance status. The phase II ETOP ADEPPT trial investigated the efficacy, safety, and impact on quality of life (QoL) associated with adagrasib in these two understudied patient populations.
Adagrasib, a second-generation KRAS G12C inhibitor, has previously demonstrated a progression-free survival (PFS) benefit compared to docetaxel in the phase III KRYSTAL-12 study.
In the ETOP ADEPPT trial, adagrasib was found to be effective and reasonably tolerable in fit, patients aged 70 years and older with KRAS G12C-mutated NSCLC. The trial also demonstrated encouraging QoL outcomes.
MB BCH, MHS
Jarushka Naidoo, MB BCH, MHS, presented the final results from the ETOP ADEPPT trial during the 2026 European Lung Cancer Congress in March in Copenhagen, Denmark. Dr. Naidoo is Professor of Medical Oncology and Consultant Medical Oncologist at Beaumont RCSI Cancer Center in Dublin, Ireland.
Study Background and Design
The primary endpoint was the confirmed objective response rate (ORR) at 12 weeks. PFS, overall survival (OS), safety, and QoL were secondary endpoints.
Eligible patients included those with pathologically confirmed NSCLC harboring a KRAS G12C mutation. Patients may have received one to two prior lines of systemic therapy, and could enroll in either:
- Cohort A: patients aged 70 or older with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–1
- Cohort B: patients aged 18 or older with an ECOG PS of 2
The study enrolled 66 patients: 32 in cohort A and 34 in cohort B. The median age of all enrolled patients was 70 years, regardless of cohort.
The majority of patients were male (66% in cohort A vs. 62% in cohort B), had a history or smoking or currently smoked (97% in both Cohorts A and B), and had adenocarcinoma histology (100% in Cohort A vs. 91% in Cohort B). Notably, twice as many patients enrolled in Cohort B had brain metastases (32%) compared to those in Cohort A (16%).
Patients were administered 600 mg of adagrasib twice daily until disease progression or unacceptable toxicity occurred. The median potential follow-up was 16.8 months for Cohort A and 18.5 months for Cohort B. At the time of data cut-off (July 28, 2025), 7 patients in Cohort A and 4 patients in Cohort B were still undergoing treatment.
Trial Results
The primary endpoint, defined as a minimum of 10 confirmed objective responses at 12 weeks, was met in Cohort A but not in Cohort B.
“In cohort A, 10 of the 32 patients enrolled achieved an objective response (one complete, nine partial), resulting in an ORR of 31%, thereby meeting the primary endpoint of the study,” Dr. Naidoo said. “Unfortunately, in cohort B, only 6 of the 34 enrolled achieved an objective response at 12 weeks, equating to an ORR of 18%, thus not meeting the study’s endpoint.”
“Median PFS and OS were more favorable in the elderly cohort (Cohort A), with a PFS of 7.6 months and an OS of 9.5 months, respectively, Dr. Naidoo noted. In the ECOG PS 2 cohort (Cohort B), the median PFS was 2.7 months, and the median OS was 4.3 months, respectively.”
QoL was assessed using the patient-reported measure NFLSI-17, an independently validated tool based on 17 lung cancer-specific symptoms and designed to help identify and manage the symptoms that have the greatest impact on QoL.
“We see that in the ECOG PS 2 cohort (Cohort B), the median important difference was achieved at 12 weeks and sustained at 15 weeks. However, the QoL range was wide,” Dr. Naidoo said. “In the cohort aged 70 and over (Cohort A), we see that the QoL benefit was modest overall, but this important difference was achieved at 30 weeks.”
In terms of safety, all patients in both cohorts experienced an adverse event (AE). Treatment-related adverse events (TRAEs) were observed in the majority of patients in both cohorts (88% in Cohort A vs. 94% in Cohort B). However, 41% of patients in Cohort A experienced a grade 3 or higher TRAE, compared to 62% in Cohort B.
Notably, 19% of patients in Cohort A and 26% of patients in Cohort B discontinued treatment due to TRAEs. One fatal TRAE was reported in Cohort B; no fatalities were observed in Cohort A.
The spectrum of toxicities was similar in both cohorts. The most common AEs included diarrhea, nausea, and vomiting.
