Advances in KRAS G12C-Mutated NSCLC: Key Insights from ELCC 2025

The European Lung Cancer Congress (ELCC 2025), hosted by ESMO, took place from March 26-29, 2025, in Paris and online via the LIVE Plus format. The event brought together experts to discuss groundbreaking advancements in lung cancer research and treatment, shaping the future of patient care.

Advances in KRAS G12C-Targeted Therapies

At ELCC 2025, promising new treatments for non-small cell lung cancer (NSCLC) were highlighted, particularly for patients with the KRAS G12C mutation. Studies presented at the congress evaluated the efficacy and safety of novel therapies, including adagrasib and fulzerasib, shedding light on potential breakthroughs in first-line and advanced-stage treatment strategies.

Figure from : ScienceDirect.com

KRYSTAL-7 Trial: Adagrasib Plus Pembrolizumab

Key Findings

According to updated data from the phase II KRYSTAL-7 trial, the combination of adagrasib plus pembrolizumab continued to show encouraging efficacy in the first-line treatment of 54 patients with advanced/metastatic KRASG12C-mutated NSCLC and PD-L1 ≥50%. The objective response rate (ORR) was 59%, with a median duration of response (DOR) of 26.3 months. With over 22 months of median follow-up, median progression-free survival (PFS) reached 27.7 months, and the 18-month overall survival (OS) rate stood at 62%.

Expert Insights

Dr. Adrianus Johannes De Langen from the Netherlands Cancer Institute noted that adagrasib plus pembrolizumab demonstrated a significant improvement in PFS compared to pembrolizumab monotherapy, which has a median PFS of around 10 months based on the KEYNOTE-024 trial. However, he also pointed out concerns regarding toxicity, as 68% of patients across the KRYSTAL-7 trial experienced grade ≥3 treatment-related adverse events (TRAEs). Despite this, the combination remains a compelling option as the study moves into its phase III evaluation.

KROCUS Trial: Fulzerasib Plus Cetuximab

Key Findings

Another major highlight at ELCC 2025 was the phase II KROCUS trial, which assessed the efficacy of fulzerasib in combination with cetuximab in 47 patients with previously untreated advanced KRAS G12C-mutated NSCLC. The trial reported an ORR of 80%, with 58% of patients experiencing at least a 50% reduction in tumor size. Median PFS was 12.5 months, and the median DOR had not yet been reached at a median follow-up of 12.8 months. The safety profile was notable, with only 14.9% of patients experiencing grade 3 TRAEs and no reported grade 4 or 5 events.

Expert Insights

Dr. De Langen commented on the promising efficacy of fulzerasib plus cetuximab, though he suggested that adding immunotherapy to this combination could further enhance long-term outcomes. A phase III trial is now being planned to compare fulzerasib plus cetuximab against pembrolizumab plus chemotherapy in untreated patients with KRAS G12C-mutated NSCLC and PD-L1 <50%.

Emerging Therapies: Daraxonrasib and Beyond

Beyond KRAS G12C-targeted therapies, ELCC 2025 also featured new data on daraxonrasib, a RAS(ON) multi-selective tri-complex inhibitor designed to target GTP-bound mutant and wild-type RAS.

Key Findings

In a phase I/Ib study involving previously treated patients with RAS-mutant NSCLC, daraxonrasib achieved an ORR of 38%, a median DOR of 15.5 months, and a median PFS of 9.8 months. While the treatment required dose modifications in 41% of patients, its overall safety profile was favorable, with no grade 4 or 5 TRAEs reported.

Future Directions in KRAS G12C Research

As Dr. De Langen highlighted, the treatment landscape for KRAS G12C-mutated NSCLC is evolving rapidly, with multiple first-line phase III trials currently underway.

Investigational Therapies

Investigational KRAS G12C inhibitors such as olomorasib, divarasib, and MK-1084 are among the next wave of potential breakthroughs, reflecting the increasing focus on targeted therapies to improve patient outcomes.

ESMO also shared key updates from ELCC 2025 on their LinkedIn post, featuring highlights from clinical trials on KRASG12C-mutated NSCLC, including the KRYSTAL-7, KROCUS, and daraxonrasib studies.

For more insights and key takeaways, explore OncoDaily’s featured highlights from ELCC 2025 Day 1, Day 2, Day 3 & Day 4.

by:-  Md Foorquan Hashmi, MD, Sr. Editor, OncoDaily: India Bueura