Could Divarasib Challenge Existing KRAS G12C Inhibitors in Lung Cancer?

The treatment landscape for KRAS G12C-mutated non–small cell lung cancer (NSCLC) could be approaching a turning point as new phase 3 findings suggest that investigational divarasib (Genentech) may outperform currently approved targeted therapies. With detailed results from the Krascendo 1 trial (NCT06497556) scheduled for presentation at the 2026 European Society for Medical Oncology (ESMO) Congress, attention is shifting toward whether a next-generation inhibitor could change treatment selection for patients whose disease has progressed following prior systemic therapy.¹

Previously, the manufacturer announced that divarasib achieved statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared with sotorasib (Lumakras; Amgen) or adagrasib (Krazati; Bristol Myers Squibb). The findings represent an important development in a treatment setting where targeted options remain limited and resistance continues to complicate long-term disease control.²

A Direct Comparison With Established KRAS G12C Therapies

KRAS G12C mutations occur in approximately 14% of NSCLC cases, making this molecular alteration an established target for precision oncology. Sotorasib and adagrasib have expanded treatment options for patients with previously treated, locally advanced or metastatic disease, although both received accelerated FDA approval based on tumor response outcomes rather than demonstrated overall survival benefits.^2,3

Divarasib is an oral, highly selective KRAS G12C inhibitor designed to maintain the mutant protein in its inactive state, interrupting the signaling that drives tumor growth. Earlier clinical findings demonstrated encouraging antitumor activity, providing the rationale for a randomized comparison against approved agents.^2,4

Krascendo 1 enrolled 338 adults with previously treated KRAS G12C-mutated advanced or metastatic NSCLC. Participants were randomly assigned to receive once-daily divarasib or an approved KRAS G12C inhibitor, either once-daily sotorasib or twice-daily adagrasib. The primary end point was PFS assessed by blinded independent central review, with OS and objective response among the secondary outcomes.²

According to the initial announcement, divarasib met the primary end point and demonstrated a statistically significant OS benefit at an interim analysis. No new safety signals were identified, and reported treatment-related adverse events (AEs) were generally manageable and reversible.² However, the publicly announced findings have not yet provided the numerical survival differences or hazard ratios needed to fully assess the magnitude of benefit. These results are expected during the upcoming ESMO presentation.¹

What Earlier Clinical Findings Suggest

Long-term follow-up from a phase 1 study provides additional context for divarasib's potential. Among 63 evaluable patients with advanced KRAS G12C-positive NSCLC, the confirmed objective response rate was approximately 55.6%, with a median response duration of 18.0 months. Nearly half of the 65 patients who received treatment remained on divarasib after 1 year.⁴

Although these findings support further investigation, the single-arm design limits comparisons with established treatments. The randomized Krascendo 1 results will be particularly important for determining whether divarasib offers a clinically meaningful advantage within the same treatment setting.

Implications for Oncology Pharmacists

If subsequent regulatory review supports divarasib's clinical benefit, oncology pharmacists could face new considerations when selecting and managing KRAS G12C-directed treatment. Current therapies require careful monitoring for toxicities that can affect treatment continuity. Sotorasib carries warnings for hepatotoxicity and interstitial lung disease or pneumonitis, while adagrasib requires additional attention to QTc prolongation and clinically significant drug interactions.^3,5

The safety profile observed with divarasib will need to be evaluated alongside its survival findings. Differences in gastrointestinal tolerability, hepatic AEs, and treatment interruptions could influence whether patients can remain on therapy long enough to derive its clinical benefit.

Administration schedules may also factor into medication counseling. Divarasib was administered once per day in Krascendo 1, compared with twice-daily adagrasib. Although dosing frequency can affect treatment burden, adherence advantages cannot be assumed without supporting evidence.

Molecular testing will remain central to appropriate treatment selection. Pharmacists can help verify documented KRAS G12C mutation status while reviewing prior therapies and potential barriers to initiating targeted treatment.

Looking Ahead to ESMO 2026

The upcoming presentation on the Krascendo 1 data will provide a more complete picture of divarasib’s efficacy and safety compared with currently approved KRAS G12C inhibitors. Detailed survival outcomes and AE findings will be essential for determining how the investigational therapy might fit into clinical practice.

For oncology pharmacists, the question extends beyond whether divarasib produces superior results in a randomized trial. Its potential place in lung cancer care will depend on how those findings translate into treatment decisions and sustainable medication management. If the reported survival advantage is confirmed by the complete data and regulatory review, divarasib could represent a significant shift in the management of previously treated KRAS G12C-mutated NSCLC.

REFERENCES

1. Roche to present pivotal data at ESMO 2026, showcasing advances across its lung and breast cancer late-stage portfolio. Roche. October 19, 2026. Accessed October 20, 2026. https://www.roche.com/media/releases/med-cor-2026-10-19

2. Genentech's divarasib shows superiority in head-to-head phase III trial against approved KRAS G12C inhibitors in non-small cell lung cancer. Genentech. July 1, 2026. Accessed October 20, 2026. https://www.gene.com/media/press-releases/15131/2026-07-01/genentechs-divarasib-shows-superiority-i

3. LUMAKRAS (sotorasib) tablets, for oral use. Prescribing information. Amgen Inc. Revised January 2025. Accessed October 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214665s009lbl.pdf

4. Sacher AG, Miller WH Jr, Patel MR, et al. Single-Agent Divarasib in Patients With KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study. J Clin Oncol. 2025;43(30):3249-3253. doi:10.1200/JCO-25-00040

5. KRAZATI (adagrasib) tablets, for oral use. Prescribing information. Bristol Myers Squibb. Revised August 2026. Accessed October 20, 2026. https://packageinserts.bms.com/pi/pi_krazati.pdf