As clinical data on RAS inhibitor combinations continue to evolve, the question of whether these agents will move into the first-line setting by 2026 was a central topic at the conclusion of the session titled Targeted Therapies: KRAS, BRAF, SHP2, SOS1 during the 2026 Targeted Therapies of Lung Cancer (TTLC) conference in Huntington Beach, California.
Ferdinandos Skoulidis, MD, PhD, MRCP, from the University of Texas MD Anderson Cancer Center, and Marina C. Garassino, MD, from the University of Chicago, aimed to answer this question during a TTLC debate.
Taking the position that KRAS inhibitors will be available for first-line treatment by 2026, Dr. Skoulidis began by outlining the biological rationale for combining these agents with PD-(L)1 inhibitors, particularly in immunogenic, T-cell-inflamed tumors.
After laying the groundwork, he addressed what he framed as a key question: What about the clinical data? Dr. Skoulidis presented three clinical examples supporting the combination of KRAS inhibitors with immune checkpoint inhibitors (ICIs) in the first-line setting, focusing primarily on KRAS G12C inhibitors plus pembrolizumab for patients with PD-L1 tumor proportion scores (TPS) of 50% or higher.
For his first example, he referenced data evaluating olomorasib plus pembrolizumab in previously untreated patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC) and a PD-L1 TPS of 50% or higher. The combination demonstrated an objective response rate (ORR) of 78%, which he noted was nearly double the response rate observed with pembrolizumab monotherapy in this population.
He also highlighted findings with calderasib (MK-1084) in the same patient group, which showed an 88% confirmed ORR, with a median duration of response (DOR) that had not yet been reached. Additionally, adagrasib in combination with pembrolizumab demonstrated a median progression-free survival (PFS) of 27.7 months in this population.
Turning to safety, Dr. Skoulidis cited data from LOXO-RAS-20001, SUNRAY-01, KRYSTAL-7, and KANDLELIT-001, stating that the combinations were generally well tolerated. He acknowledged “one concern with high-grade transaminitis,” adding that the elevations were asymptomatic, reversible, monitorable, and manageable with dose holds and steroids.
Addressing the regulatory timeline, Dr. Skoulidis reiterated the central question of the debate: Will these inhibitors receive approval in 2026?
“They will unequivocally be approved,” he said. “But will they be approved in 2026 or not? Well, I want you to focus on the date September 4, 2025.” On that date, Eli Lilly’s olomorasib received breakthrough therapy designation (BTD) from the US Food and Drug Administration (FDA) in combination with pembrolizumab for patients with KRAS G12C-mutant advanced NSCLC and a PD-L1 TPS greater than 50%.
He pointed to previous intervals between BTD and accelerated approval (AA) for other agents, citing sotorasib at 6 months and zongertinib at 8 months. Based on that precedent, he argued there is “considerable room” for AA of pembrolizumab plus olomorasib as first-line therapy by late 2026.
Taking the opposing view, Dr. Garassino argued that RAS inhibitors are unlikely to reach the first-line setting by 2026, opening her remarks by consulting ChatGPT. When asked to estimate the likelihood that olomorasib, adagrasib, or calderasib would receive first-line approval by 2026, the artificial intelligence (AI) platform suggested a probability of only 10%–20%.
Dr. Garassino then reviewed the available evidence. She revisited data from CodeBreaK 200 and KRYSTAL-12, noting that although both studies demonstrated improvements in PFS, they failed to show a clear overall survival (OS) benefit. She also emphasized that phase III data remain lacking for many of the KRAS inhibitor combinations, despite reports of prolonged PFS in earlier-phase studies.
“We need to have the results of the phase III trial, and SUNRAY-01 is still enrolling,” Dr. Garassino said. “At best, we will complete enrollment by the end of the year. Then we have to clean the data and analyze the results. I would guess that we will not arrive by 2026.”
She also directly challenged Dr. Skoulidis’ interpretation of the data, referencing a recently launched phase III trial that does not include KRAS inhibitors in the frontline regimen.
“He’s lying,” Dr. Garassino said, arguing that the trial design itself reflects continued reliance on immunotherapy-based combinations in patients with KRAS-mutant disease. “In November 2025, he launched this large phase III trial. Can you see the KRAS inhibitors? No, because he believes in the combination of immunotherapy and dual immunotherapy.”
She maintained that first-line adoption of KRAS inhibitors by 2026 remains unlikely, emphasizing the need for mature phase III data and the time required for regulatory review. “Keep calm and carry on researching,” Dr. Garassino concluded.
Following the debate, the session chairs asked the audience to applaud the side they believed won. A noticeably louder response supported Dr. Garassino’s position that RAS inhibitors are unlikely to enter the first-line setting by 2026.
