ECOG Performance Status Influences Adagrasib Efficacy and Survival in KRAS G12C+ NSCLC

Adagrasib, a second-generation KRAS G12C inhibitor, has demonstrated a 31% confirmed objective response rate (cORR) in elderly patients with an ECOG performance status (PS) of 0 or 1. However, updated results from the ETOP ADEPPT trial (NCT05673187) reveal that patients with an ECOG PS of 2 experience limited clinical activity, emphasizing the role of performance status as a determinant of therapeutic success.¹

ETOP ADEPPT Trial Design and Patient Stratification

The international, multicenter study evaluated adagrasib (600 mg orally twice daily) in two distinct cohorts of patients with pretreated, KRAS G12C–mutant metastatic NSCLC:

• Cohort A: Patients ≥70 years old with an ECOG PS of 0 or 1.
• Cohort B: Patients of any age with an ECOG PS of 2.

At the data cutoff, the median age was 76 years in cohort A and 64 in cohort B. Most patients had previously received platinum-based chemotherapy or immune checkpoint inhibition.

Clinical Outcomes by Performance Status

The primary end point was the cORR at 12 weeks. Cohort A met the study’s success criterion, while cohort B did not reach the primary efficacy threshold.

The primary end point was the cORR at 12 weeks, which the study defined as a success if the rate reached at least 15%. Cohort A met this criterion with a cORR of 31% (95% CI, 16%-50%), including one complete response and nine partial responses. In contrast, cohort B saw a cORR of 18% (95% CI, 7%-35%), with all six responders achieving partial responses.

Survival outcomes also diverged significantly between the groups; cohort A reached a median progression-free survival (PFS) of 7.6 months and a median overall survival (OS) of 9.5 months, while cohort B saw a median PFS of only 2.7 months and a median OS of 4.3 months.

Despite the limited survival extension in the PS 2 cohort, these patients achieved a "median important difference" in quality of life (QOL) scores by 12 weeks, which was sustained through 15 weeks. In cohort A, the QOL benefit was more modest and achieved later, at the 30-week mark.

Safety Profile and Treatment Tolerability

Any-grade adverse effects (AEs) occurred in all patients across both cohorts. However, the severity and management of these events differed by performance status.

Treatment-Related Adverse Events

Grade 3 or higher treatment-related adverse events (TRAEs) were more prevalent in the ECOG PS 2 population (62%) compared with the elderly PS 0 to1 population (41%). Discontinuation due to TRAEs occurred in 19% of cohort A and 26% of cohort B.

The most frequent toxicities requiring nursing assessment and intervention included:

• Gastrointestinal: Diarrhea (59% in A; 47% in B), nausea, and vomiting.
• Constitutional: Fatigue (38% in A; 24% in B) and anorexia.
• Laboratory Abnormalities: Increased AST/ALT, increased creatinine, and increased gamma-glutamyl transferase (GGT).

Treatment interruptions were common, occurring in 63% of cohort A and 59% of cohort B, while dose reductions were utilized more frequently in the elderly cohort (47% vs 32%).

ADEPPT Trial Impact on Nursing Practice

The ADEPPT trial results suggest that for patients with a KRAS G12C mutation, age, specifically at 70 years or older, is not a barrier to achieving a durable response with adagrasib, provided the patient maintains a PS of 0 or 1. For those with a PS of 2, the clinical impact shifts from survival extension toward QOL stabilization.

Monitoring is necessary for high rates of gastrointestinal toxicity and laboratory elevations, which frequently necessitate treatment interruptions or dose modifications to maintain patient adherence and QOL.

References

1. Naidoo J, Lindsay C, Vervita K, et al. Phase II ETOP ADEPPT trial: adagrasib in patients with KRASG12C-mutant NSCLC who are elderly or have poor performance status - final results. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 5MO.
2. Adagrasib in patients with KRASG12C-mutant NSCLC who are elderly or have poor performance status (ADEPPT). ClinicalTrials.gov. Updated January 21, 2026. Accessed March 26, 2026. https://clinicaltrials.gov/study/NCT05673187