Genentech Reports Positive Phase III Krascendo 1 Results Demonstrating Divarasib Improves Survival in Previously Treated KRAS G12C Non-Small Cell Lung Cancer
Genentech, a member of the Roche Group, has announced positive topline results from its pivotal Phase III Krascendo 1 clinical trial evaluating the investigational next-generation KRAS G12C inhibitor divarasib in patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC). The study demonstrated that divarasib outperformed currently approved first-generation KRAS G12C inhibitors, achieving statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS), while maintaining a safety profile consistent with earlier clinical studies.
The findings represent a significant milestone in the development of targeted therapies for one of the most common molecular subtypes of lung cancer. According to Genentech, the results support the potential for divarasib to become a new standard treatment option for patients whose disease has progressed after previous therapy.
Phase III Trial Meets Primary and Key Secondary Endpoints
The global Phase III Krascendo 1 study directly compared divarasib with the currently approved KRAS G12C inhibitors sotorasib and adagrasib in patients with previously treated KRAS G12C-mutated NSCLC. Unlike earlier studies that compared investigational therapies with chemotherapy or placebo, Krascendo 1 was designed as a head-to-head evaluation against existing targeted treatments, providing a direct assessment of the clinical benefits offered by a next-generation KRAS inhibitor.
The trial successfully met both its primary endpoint and its key secondary endpoint. Patients treated with divarasib experienced significantly longer progression-free survival, indicating that the therapy was more effective at delaying disease progression than the currently available first-generation KRAS G12C inhibitors.
In addition to delaying disease progression, divarasib also demonstrated a statistically significant improvement in overall survival, showing that patients receiving the investigational therapy lived longer than those treated with existing targeted therapies. Achieving improvements in both progression-free survival and overall survival is considered particularly meaningful in oncology, as it demonstrates benefits in controlling disease while also extending patients’ lives.
Genentech noted that these results reinforce the therapeutic potential of divarasib as an important advancement in precision medicine for lung cancer.
Favorable Safety Profile Consistent with Earlier Studies
Beyond demonstrating superior efficacy, divarasib maintained a favorable safety profile throughout the Phase III trial.
According to the company, no new safety concerns were identified during the study, and the adverse events observed were consistent with previous clinical experience involving divarasib.
The most commonly reported treatment-related adverse events were manageable and reversible, supporting the overall tolerability of the therapy. Maintaining a predictable safety profile while improving clinical outcomes is considered an important factor when evaluating potential new standards of care, particularly for patients who may require long-term treatment.
The consistency of the safety findings across clinical studies also strengthens confidence in the drug’s overall benefit-risk profile as regulatory submissions move forward.
Addressing an Important Unmet Need in Lung Cancer
Non-small cell lung cancer remains the most common form of lung cancer worldwide, accounting for approximately 85% of all lung cancer diagnoses. Despite substantial advances in targeted therapies over the past decade, many patients continue to experience disease progression following initial treatment, highlighting the need for more effective therapeutic options.
Among NSCLC patients, mutations affecting the KRAS gene represent one of the most frequently observed genetic alterations. Historically, KRAS mutations were considered particularly difficult to target therapeutically, earning the reputation of being “undruggable” for many years.
Recent scientific breakthroughs have changed that landscape with the introduction of the first generation of KRAS G12C inhibitors. However, while these therapies marked a major advance, many patients eventually develop resistance or experience disease progression, creating demand for newer treatments capable of delivering deeper and more durable responses.
Divarasib has been designed as a next-generation KRAS G12C inhibitor intended to overcome some of the limitations associated with earlier therapies while providing improved clinical outcomes.
Understanding the KRAS G12C Mutation
The KRAS G12C mutation represents one of the most common KRAS alterations found in patients with non-small cell lung cancer.
Approximately 14% of NSCLC patients carry this specific genetic mutation, making it one of the largest biomarker-defined patient populations within lung cancer.
The mutation causes continuous activation of cellular signaling pathways that promote uncontrolled tumor growth and cancer cell survival. Patients whose tumors harbor KRAS G12C mutations often face aggressive disease and generally have poorer clinical outcomes compared with some other molecular subtypes.
The development of therapies specifically targeting KRAS G12C has therefore become an important focus within precision oncology, offering treatment options tailored to the molecular characteristics of an individual’s cancer.
Potential to Establish a New Standard of Care
Commenting on the study results, Levi Garraway, M.D., Ph.D., Chief Medical Officer and Head of Global Product Development at Genentech, emphasized the significance of the findings.
He stated that the superior survival demonstrated in the head-to-head comparison confirms divarasib’s potential to improve outcomes for patients with KRAS G12C-mutated non-small cell lung cancer. According to Garraway, the Phase III results support the possibility that divarasib could become the new standard of care for patients who have previously received treatment for this genetically defined subtype of lung cancer.
The direct comparison with currently approved KRAS G12C inhibitors provides particularly compelling evidence because it evaluates divarasib against therapies already used in routine clinical practice rather than against chemotherapy alone.
Broad Clinical Development Program Continues
The Krascendo 1 trial represents one component of Genentech’s broader global development strategy for divarasib.
The company is conducting an extensive Phase III clinical program evaluating the investigational therapy across multiple treatment settings and stages of non-small cell lung cancer.
Current studies are examining divarasib both as a standalone monotherapy and in chemotherapy-free combination regimens designed to further improve treatment outcomes while potentially reducing toxicity associated with conventional chemotherapy.
Researchers are also investigating the therapy across different lines of treatment, including earlier stages of disease, with the goal of determining where divarasib may provide the greatest clinical benefit.
This comprehensive development strategy reflects the growing importance of biomarker-driven therapies in modern oncology, where treatment decisions are increasingly guided by the specific genetic characteristics of individual tumors.
Regulatory Recognition Supports Development
The progress of divarasib has already been recognized by U.S. regulators through several important designations.
In 2022, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to divarasib, recognizing its potential to offer substantial improvement over existing therapies for patients with KRAS G12C-mutated lung cancer.
More recently, in 2026, the FDA also awarded Orphan Drug Designation for the treatment of KRAS G12C non-small cell lung cancer. This designation is intended to encourage the development of therapies for rare diseases or distinct patient populations by providing regulatory incentives that can help accelerate drug development.
These regulatory milestones underscore the significant unmet medical need that remains for patients with KRAS G12C-positive NSCLC and support ongoing efforts to bring innovative targeted therapies to clinical practice.
Next Steps Toward Regulatory Approval
Following the successful completion of the Phase III Krascendo 1 study, Genentech plans to present the full clinical results at an upcoming international medical congress, where oncology specialists will have the opportunity to review the detailed efficacy and safety data.
The company also intends to submit the study findings to regulatory authorities around the world as part of applications seeking approval for divarasib in previously treated KRAS G12C-mutated non-small cell lung cancer.
If approved, divarasib could provide physicians with a next-generation targeted therapy capable of delivering improved survival outcomes for patients whose disease has progressed after earlier treatment.
Advancing Precision Oncology
The positive Krascendo 1 results further reinforce the growing impact of precision oncology, where treatments are developed to target the unique molecular drivers of individual cancers rather than relying solely on traditional chemotherapy.
For patients with KRAS G12C-mutated NSCLC, the emergence of increasingly effective targeted therapies represents an important evolution in treatment options. The superior progression-free and overall survival observed with divarasib compared with currently approved KRAS G12C inhibitors suggests that next-generation drug design may continue to improve outcomes even within established classes of targeted therapies.
As Genentech advances regulatory submissions and continues its extensive Phase III clinical development program, divarasib has the potential to become a significant new therapeutic option that further expands personalized treatment strategies for patients living with KRAS G12C-positive non-small cell lung cancer.
About the Krascendo 1 study
The Krascendo 1 study [NCT06497556] is the only global head-to-head study evaluating a Kirsten rat sarcoma virus (KRAS) G12C inhibitor in direct comparison with first generation KRAS G12C inhibitors. This Phase III, randomized, open-label, multicenter study evaluates the efficacy and safety of divarasib monotherapy versus sotorasib or adagrasib in people with previously treated KRAS G12C-mutant advanced or metastatic non-small cell lung cancer. The study includes 338 adults, randomized to receive either divarasib (once daily) or, either sotorasib (once daily) or adagrasib (twice daily). The primary endpoint is blinded independent central review (BICR)-assessed progression-free survival. Secondary endpoint measures include overall survival, confirmed objective response, duration of response, as well as other efficacy and safety measures.
About divarasib
Divarasib is an investigational, next-generation, oral, KRAS G12C inhibitor. It has shown greater potency and selectivity in preclinical studies compared with first generation KRAS G12C-targeting treatments, sotorasib and adagrasib. Divarasib is designed to selectively bind to the KRAS G12C protein, locking the protein in an inactive (“off”) state, thereby turning off its tumor-driving signaling.
About KRAS G12C non-small cell lung cancer
Despite advances in treatment, lung cancer remains the leading cause of cancer-related deaths worldwide, surpassing the combined mortality rates of breast, prostate, and stomach cancers. Each year, it claims the lives of 1.8 million people, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. KRAS is one of the most frequently mutated genes in lung cancer, occurring in approximately 25% of newly diagnosed lung cancers. The G12C mutation is one of the most common KRAS mutations, found in approximately 14% of NSCLC cases.
The KRAS gene produces the KRAS protein, which acts as a cellular control switch, cycling between an active (“on”) and inactive (“off”) state to regulate cell growth and proliferation, making it a critical target for new therapeutic strategies. The G12C mutation locks the KRAS protein in its active (“on”) state, leading to continuous, unregulated signaling for cell growth, driving tumor proliferation.
About Genentech in Lung Cancer
With a 30-year legacy across oncology, Genentech has been driving innovations in small cell and non-small cell lung cancers that have shaped the treatment paradigm for people living with lung cancer. We are leveraging precision medicine to tackle some of the hardest-to-treat diseases, driven by our passion to deliver functional, real-world care. We are committed to ensuring that innovative solutions reach patients wherever they receive their care, working in lockstep with the community to deliver on our goal to improve outcomes for as many people affected by lung cancer as possible.
About Genentech
Founded 50 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.
