Targeting KRAS: Promising New Therapy for Hard-to-Treat Lung Cancer Subtype
For decades, KRAS was considered one of cancer’s most elusive targets. Although KRAS mutations drive many cancers, the gene’s structure made it extraordinarily hard to inhibit with drugs, earning it a reputation as “undruggable.”
Non-small cell lung cancer (NSCLC) became the proving ground for the first successful KRAS-targeted therapies with the FDA approval of sotorasib in 2021 and adagrasib in 2022. These drugs, developed to inhibit the KRAS G12C mutation, demonstrated that KRAS-driven cancers could, in fact, be treated with mutation-specific therapies. However, other KRAS mutations—including KRAS G12D—have remained without approved targeted options.
Now, a new investigational therapy designed to selectively target KRAS G12D is being evaluated in a global registrational clinical trial, with the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia serving as one of the major academic centers participating in the study.
Early clinical data highlight potential in a hard-to-treat subset
Early Phase 1 clinical data of the drug, zoldonrasib, was presented at the American Association for Cancer Research (AACR) Annual Meeting in 2024. In a cohort of 18 patients with KRAS G12D–mutant NSCLC, investigators reported a 61% objective response rate, defined as significant tumor shrinkage.
By comparison, standard-of-care therapies for this patient population typically achieve response rates of approximately 10–15%. While the cohort was small and the data preliminary, the magnitude of response represented a notable signal in a molecularly defined lung cancer subset with limited targeted options.
“This response rate compared with the standard of care is truly remarkable,” says Benjamin Herzberg, MD, a thoracic oncologist at Columbia and an investigator involved in the study. “For patients with this rare type of mutation, this therapy could be hugely beneficial.”
A registrational study underway
Building on these results, an international registrational study was initiated to further evaluate zoldonrasib in patients with KRAS G12D–mutant cancers, including NSCLC. The study is designed to confirm whether early tumor responses are reproducible in a larger patient population and to assess the durability of benefit over time. The trial is not randomized; all enrolled patients receive the investigational therapy.
HICCC enrolled its first patient in July 2025 – and the first patient treated on the study of all sites.
“It’s important to us to get promising clinical trials to patients as quickly as possible,” says Herzberg. “Our role is to help determine whether promising early results translate into meaningful, lasting benefit for patients.”
FDA Breakthrough Therapy Designation follows early momentum
In January 2026, zoldonrasib received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of KRAS G12D–mutant NSCLC. The designation is intended to accelerate the development and review of therapies for serious conditions when early clinical evidence suggests substantial improvement over available treatments.
Breakthrough Therapy Designation reflects the strength of early data and the significant unmet need in this subset of lung cancer and aims to expedite the widespread use of a promising therapy for patients who need it most. At present, there are no approved targeted therapies for KRAS G12D–mutant NSCLC.
“The designation underscores both the promise of the early data and the importance of the ongoing trial,” Herzberg said. “Confirmatory studies like this are essential for understanding who benefits, for how long, and how these therapies may ultimately fit into lung cancer care.”
Addressing an unmet need in lung cancer
Although KRAS G12D represents a relatively small fraction of lung cancers, it accounts for thousands of patients each year who currently lack mutation-specific treatment options. For patients at Columbia and beyond, the ongoing registrational study offers access to an investigational therapy designed specifically for this mutation, while contributing to the evidence needed to determine its future role in lung cancer treatment.
“As we learn more from this study, we hope to better define how targeted approaches like this can address unmet needs in lung cancer and other cancers,” says Herzberg.
