ESMO 2026: Key KRAS Inhibitor Takeaways for Oncology Nurses

Divarasib extended both progression-free survival (PFS) and overall survival (OS) compared with the approved KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati) in previously treated non–small cell lung cancer (NSCLC), according to phase 3 Krascendo 1 data presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, and published simultaneously in The New England Journal of Medicine.^1-3

Other ESMO data addressed first-line KRAS G12C combinations, RAS subgroups in pancreatic cancer, and KRAS G12D inhibition.

How did divarasib compare with sotorasib and adagrasib?

Krascendo 1 (NCT06497556) randomly assigned 338 patients with previously treated KRAS G12C–mutant NSCLC to the investigational oral KRAS G12C inhibitor divarasib (n = 167) or to sotorasib or adagrasib (n = 171); 91% of control patients received sotorasib.^1,4 After a median follow-up of 14.3 months:⁴

• Median PFS: 9.8 vs 5.7 months (HR, 0.58; 95% CI, 0.44-0.76; P < .001).¹
• Median OS: 17.7 vs 12.0 months (HR, 0.56; 95% CI, 0.41-0.78; P < .001).¹
• Confirmed objective response rate: 58% vs 32%.¹

"For patients with KRAS G12C-mutant lung cancer, extending survival while delaying cancer progression are the outcomes that matter most," said study lead author Ferdinandos Skoulidis, MD, PhD, professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, in a news release.²

Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 24.6% of patients receiving divarasib vs 34.5% of controls, and 4.8% vs 11.7% discontinued because of TRAEs.⁴ Hepatotoxicity was lower with divarasib (grade 3-4 alkaline phosphatase increase, 0.6% vs 4.1%), but gastrointestinal toxicity was higher (grade 3-4 diarrhea, 9.0% vs 2.9%).⁴ Benjamin Besse, MD, PhD, of Gustave Roussy in Villejuif, France, noted in ESMO commentary that "divarasib may be more 'immunotherapy friendly' than sotorasib."⁴

What did olomorasib show in first-line KRAS G12C NSCLC?

Olomorasib, an investigational oral KRAS G12C inhibitor, was evaluated with pembrolizumab (Keytruda) in the phase 1/2 LOXO-RAS-20001 study and the safety lead-in of the phase 3 SUNRAY-01 trial (NCT06119581).⁵

With pembrolizumab alone (n = 85), the 18-month PFS rate was 55%; median PFS was not reached.⁵

With pembrolizumab plus pemetrexed and platinum chemotherapy (n = 77), the objective response rate was 62% and median PFS was 11.6 months (95% CI, 9.5-21.5).⁵

"Responses lasting a median of more than a year in patients across all PD-L1 tumor expression levels . . . is the type of progress we want to see in the first-line setting," said presenting author Marcelo V. Negrao, MD, of MD Anderson, in a news release.⁵

The most common grade 3 or higher TRAEs with the doublet were increased alanine aminotransferase (15.3%), increased aspartate aminotransferase (12.9%), and diarrhea (8.2%); no grade 5 TRAEs occurred in either cohort, and no prophylactic medications were required.⁵

What did a new RASolute 302 analysis show in pancreatic cancer?

Daraxonrasib (Rasonque), the RAS(ON) inhibitor the FDA approved in August 2026 for previously treated metastatic pancreatic adenocarcinoma, extended median OS to 13.2 vs 6.7 months with chemotherapy in the phase 3 RASolute 302 trial (NCT06625320).^6,7 A new analysis presented at ESMO found that survival consistently favored daraxonrasib across RAS mutation subgroups, including patients without an identified RAS mutation; some subgroups were small.⁶

"In this analysis, we demonstrate that depending on the individual mutation, daraxonrasib may have a different response," said Zev Wainberg, MD, MSc, professor of medicine at the UCLA Health Jonsson Comprehensive Cancer Center, in a news release.⁶

What is next for KRAS G12D inhibition?

In a phase 1 study (NCT06179160), the investigational KRAS G12D inhibitor INCB161734 was combined with chemotherapy in 54 patients with KRAS G12D–mutant metastatic pancreatic ductal adenocarcinoma. The objective response rate, including confirmed and pending responses, was 89% with modified FOLFIRINOX and 69% with gemcitabine plus nab-paclitaxel.⁸ Diarrhea (65%-68%) and nausea (64%-65%) were among the most common TRAEs; these were mostly grade 1 or 2 in severity.⁸

What are the key takeaways for oncology nurses?

• Prepare patients for diarrhea; grade 3-4 diarrhea was more frequent with divarasib than with control, and diarrhea was common with INCB161734.4,8
• Monitor liver function tests, particularly when a KRAS G12C inhibitor is combined with pembrolizumab.⁵
• Confirm RAS mutation status and allele; benefit may differ by mutation.⁶
• For patients receiving daraxonrasib, continue the prophylaxis and dose-hold strategies used since approval.⁹

References

1. Roche's divarasib demonstrated best-in-class efficacy, advancing the standard of care in previously treated KRAS G12C-mutated lung cancer. News release. Roche. October 25, 2026. Accessed October 26, 2026. https://www.roche.com/media/releases/med-cor-2026-10-25

2. ESMO 2026: new targeted therapy improved survival for patients with KRAS-mutated lung cancer. News release. The University of Texas MD Anderson Cancer Center. October 25, 2026. Accessed October 26, 2026. https://www.mdanderson.org/newsroom/research-newsroom/esmo-2026--new-targeted-therapy-improved-survival-for-patients-with-KRAS-mutated-lung-cancer.h00-159859290.html

3. Skoulidis F, et al. Krascendo 1: efficacy and safety of divarasib vs sotorasib or adagrasib in previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC. N Engl J Med. Published online October 25, 2026. doi:10.1056/NEJMoa2605703

4. Divarasib outperforms approved KRAS G12C inhibitors in NSCLC. European Society for Medical Oncology. October 25, 2026. Accessed October 26, 2026. https://www.esmo.org/insights-by-esmo/all-news/divarasib-outperforms-approved-kras-g12c-inhibitors-in-nsclc

5. New data on Lilly's investigational treatment olomorasib at ESMO 2026 show durable first-line activity in KRAS G12C-mutant non-small cell lung cancer. News release. Eli Lilly and Company. October 25, 2026. Accessed October 26, 2026. https://www.prnewswire.com/news-releases/new-data-on-lillys-investigational-treatment-olomorasib-at-esmo-2026-show-durable-first-line-activity-in-kras-g12c-mutant-non-small-cell-lung-cancer-302918479.html

6. ESMO: new analysis reinforces survival benefits of targeted therapy for advanced pancreatic cancer. News release. UCLA Health. October 23, 2026. Accessed October 26, 2026. https://www.uclahealth.org/news/release/esmo-new-analysis-reinforces-survival-benefits-targeted

7. ONN Staff. FDA approves daraxonrasib for metastatic pancreatic adenocarcinoma. Oncology Nursing News. August 26, 2026. Accessed October 26, 2026. https://www.oncnursingnews.com/view/fda-approves-daraxonrasib-for-metastatic-pancreatic-adenocarcinoma

8. Incyte highlights new data advancing its gastrointestinal cancer portfolio at ESMO 2026. News release. Incyte. October 26, 2026. Accessed October 26, 2026. https://www.businesswire.com/news/home/20261026987057/en/Incyte-Highlights-New-Data-Advancing-its-Gastrointestinal-Cancer-Portfolio-at-ESMO-2026

9. Biese A. Daraxonrasib approved: what oncology nurses must know about Rasonque. Oncology Nursing News. August 27, 2026. Accessed October 26, 2026. https://www.oncnursingnews.com/view/daraxonrasib-approved-what-oncology-nurses-must-know-about-rasonque