People with metastatic KRAS-mutated lung cancer are generally treated with the combination of chemotherapy and immune checkpoint inhibitors. But what happens when those treatments fail?

KRAS-targeted therapies have revolutionized lung cancer treatment, breaking new ground against genetic mutations once considered "undruggable." The FDA’s approval of sotorasib (Lumakras) in 2021 marked a pivotal moment, offering a viable option for people with KRAS G12C mutations. This milestone ushered in a new era of precision oncology, where drugs can target mutated genes while allowing the protein to continue functioning in normal tissues.

However, despite these advances, significant challenges remain. 

KRAS is the most common oncogene mutation, accounting for approximately 15% to 30% of all non-small cell lung cancer cases. The G12C mutation is the most prevalent variant, occurring in approximately 13% of all non-small cell lung cancer (NSCLC) patients. Each year, 50,000 people are diagnosed with new KRAS-driven lung cancer in the United States. 

Treatment resistance—both de novo and acquired—limits the long-term efficacy of these new drugs. Additionally, the current therapeutic arsenal primarily targets a narrow subset of KRAS mutations, with limited options for people with other alterations such as G12D, G12V, or Q61H.

That’s why ALCMI is committed to uncovering the mysteries of KRAS, and our current SPARK clinical trial is critical to our understanding of these mutations. This remote, decentralized study is evaluating which mutations develop in response to treatment with the new KRAS inhibitors and other treatments. 

"The SPARK trial is essential because cancer doesn't just fight back — it evolves to resist treatment,” said Terri Conneran, lung cancer survivor and founder of KRAS Kickers. “By identifying resistance early, this research helps patients stay one step ahead and keep KRAS Kicking toward better survivorship." 

Expanding Horizons in KRAS Therapies

The KRAS research landscape is evolving rapidly, offering hope that more comprehensive and durable treatment strategies are on the horizon. 

Several emerging approaches are pushing the boundaries of what’s possible:

• Pan-KRAS inhibitors aim to target multiple KRAS mutations simultaneously, addressing the molecular diversity that limits the reach of existing therapies. These agents could expand treatment options for patients beyond those with the G12C mutation.
• Allosteric modulators disrupt the function of KRAS proteins by binding to regulatory sites distinct from the active site. This novel mechanism may offer an effective alternative when conventional inhibitors fall short, especially in resistant disease.
• Gene-editing platforms, including CRISPR, are being explored as a way to directly correct or disrupt KRAS mutations at the genomic level. While still in preclinical stages, these technologies offer a bold vision for future curative strategies.

Overcoming Resistance Mechanisms

Resistance to KRAS inhibitors poses a formidable barrier to long-term success. Mechanisms of resistance can include bypass signaling, secondary mutations, or adaptive rewiring of downstream pathways.

Innovative strategies being explored include:

• Combination therapies that pair KRAS inhibitors with agents targeting downstream signaling effectors such as MEK, SHP2, or PI3K. These combinations aim to prevent or delay the development of resistance and may improve treatment outcomes.
• Biomarker-driven approaches, such as tracking co-occurring mutations like TP53, STK11, and KEAP1 or using circulating tumor DNA (ctDNA) for real-time monitoring, allow clinicians to anticipate resistance patterns and adapt therapy accordingly.

Broadening the KRAS Therapeutic Landscape

While the development of G12C inhibitors, such as sotorasib and adagrasib, has opened new doors, this mutation accounts for only about 13% of KRAS mutations in non-small cell lung cancer. Expanding the scope to target other prevalent variants, such as G12D, the most common KRAS mutation across all cancers, is a critical next step.

Early-stage agents targeting KRAS G12D, including MRTX1133 and other allele-specific inhibitors, have shown promising preclinical activity. Simultaneously, efforts to stratify patients based on KRAS mutation subtype and co-mutation status are laying the groundwork for more personalized and effective treatments.

Finding ways to combine KRAS inhibitors with immunotherapy is another active area of research, with the new G12C inhibitors olomosertinib and durvasilib currently enrolling patients in advanced-phase clinical trials. 

Biomarkers and the Rise of Personalized Medicine

As the field advances, the role of biomarkers in KRAS-mutant lung cancer is becoming increasingly indispensable. Co-mutations can influence both prognosis and therapeutic response. For instance, KRAS/STK11 co-mutations are often associated with resistance to immunotherapy, while KRAS/TP53 co-mutations may confer enhanced sensitivity.

Additionally, ctDNA and liquid biopsies are emerging as powerful tools for non-invasive mutation detection, monitoring minimal residual disease, and guiding adaptive treatment strategies.

KRAS-targeted therapies have provided an array of new options in lung cancer care, offering real hope to patients with previously untreatable mutations. But the journey is far from over. To overcome resistance and address underrepresented mutations, we must continue to invest in research, particularly in remote, decentralized studies that offer a powerful, efficient, and rapid way to break new ground.