The first Clinical Trials Plenary at the AACR Annual Meeting 2026 was dedicated to “New Frontiers in Precision Oncology” and included updates on four experimental targeted therapies that are being assessed in early clinical trials. The session was co-chaired by Annual Meeting Clinical Trials Program Committee Cochair Jayesh Desai, MBBS, of Peter MacCallum Cancer Centre in Australia, and Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center.

After conquering KRAS as a druggable target, researchers are hard at work to maximize the potential of KRAS inhibition, tackling therapy resistance and expanding treatment to other KRAS mutant forms. Two presentations discussed investigational agents that may expand the potential of KRAS inhibition in lung cancer.

Byoung Chul Cho, MD, of Yonsei Cancer Center, Yonsei University College of Medicine in Korea, presented updated results from a phase I/II clinical trial of the next-generation KRAS-G12C inhibitor elisrasib, which was designed for faster and stronger target engagement, to afford sustained inhibition, Cho explained.

The analysis focused on patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease progressed on previous immunotherapy and/or chemotherapy or first-generation KRAS G12C inhibitor therapy.

In this population, elisrasib demonstrated a favorable safety and tolerability profile and led to clinical benefit. Among the KRAS G12C inhibitor-naïve cohort, treatment at the recommended dose of 600 mg resulted in overall response rate (ORR) and disease control rate (DCR) of 58.8% and 98.5%, respectively. Median progression-free survival (mPFS) was 12.2 months; median duration of response (mDoR) and overall survival (OS) rate at 12 months were 16.5 months and 72%, respectively.

The researchers observed significantly higher response rate and prolonged tumor responses than with first-generation KRAS G12C inhibitors, indicating that elisrasib’s molecular design may be translating into improved clinical outcomes for patients, said Cho.

Among patients who experienced disease progression on earlier KRAS G12C inhibitor therapy, ORR was 32.3%, and DCR was 83.9%. Further, mPFS, mDoR, and OS rate at 12 months were 8.1 months, 15.6 months, and 71%, respectively.

Tumor responses were also observed in patients with brain metastases, a difficult-to-treat population, and in patients with KRAS gene amplification whose disease progressed on first-generation inhibitors, indicating elisrasib’s effectiveness in this biomarker-defined group, said Cho.

“Based on these promising efficacy and safety data, elisrasib monotherapy received Breakthrough Therapy Designation and Fast Track designation in NSCLC,” Cho added.

The two KRAS inhibitors approved by the U.S. Food and Drug Administration for treatment of NSCLC specifically target the KRAS G12C mutation. Next presenter Jonathan W. Riess, MD, of UC Davis Comprehensive Cancer Center, pointed out that KRAS G12D-mutated cancers are common, especially in pancreatic, colorectal, and lung cancer, and represent an area of large unmet need.

Riess discussed results from a phase I trial of zoldonrasib, a next-generation G12D-selective tricomplex RAS(ON) inhibitor that targets the active, GTP-bound state of KRAS. It works by forming a ternary complex with KRAS and blocking downstream signaling.

In the most recent analysis of 27 trial participants with G12D-mutant NSCLC whose disease had progressed on prior chemotherapy and immunotherapy, zoldonrasib was safe and led to a confirmed objective response rate of 52% and a disease control rate of 93% with a mPFS of 11.1 months and an OS rate at 12 months of 73%.

KRAS G12D-mutant circulating tumor DNA (ctDNA) was detected in 15 patients before zoldonrasib treatment, and 87% of them had a marked reduction upon treatment.

“The preliminary safety and antitumor activity support the continuing development of zoldonrasib as a single agent and in combination with other therapies,” said Riess.

Timothy A. Yap, MBBS, PhD, of The University of Texas MD Anderson Cancer Center, discussed early data from an ongoing phase I trial of a first-in-class combination of the investigational agents zedoresertib, a WEE1 inhibitor, and lunresertib, a PKMYT1 inhibitor in 62 patients with heavily pretreated solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations.

Cancers with these alterations represent an area of unmet clinical need, said Yap. CCNE1 amplification and PPP2R1A inactivating mutations induce high replication stress; FBXW7 is a ubiquitin E3 ligase that proteolytically degrades cyclin E1, therefore FBXW7 inactivating mutations result in increased cyclin E1 and consequently in replication stress.

WEE1 and PKMYT1 maintain the G2/M checkpoint integrity in cells with high replication stress. They represent promising therapeutic targets based on synthetic lethality in tumors with genomic alterations in cell cycle control genes. Zedoresertib and lunresertib are being evaluated individually in phase I clinical trials and have demonstrated manageable safety profiles as monotherapies, said Yap.

In the combination trial, the safety profile was in line with that of either drug alone, and target engagement was achieved across multiple dose levels. Yap reported frequent and deep tumor shrinkage with the zedoresertib and lunresertib combination across multiple tumor types. Among patients with ovarian carcinoma, 80% showed tumor shrinkage, ORR was 37.5%, and DCR was 87.5%. Response rate was even higher in patients with CCNE1 amplification (60%). The molecular response rate was 47% in the total population and 67% in patients with ovarian cancer.

Yap added that based on these data, the zedoresertib and lunresertib combination has been granted U.S. Food and Drug Administration Fast Track designation in patients with ovarian cancer harboring CCNE1 amplification, FBXW7, or PPP2R1A deleterious mutations.

Afshin Dowlati, MD, of University Hospitals Seidman Cancer Center and Case Western Reserve University, concluded the session with a talk on the phase I study of CID-078, a novel cyclin A/B-RxL inhibitor that binds to a previously undruggable hydrophobic patch on cyclin A and cyclin B. This patch interacts with the RxL motif present on substrates of the cyclin/cyclin-dependent kinase complex.

The CDK-Rb-E2F pathway regulates cell-cycle progression. In cells with hyperactivated E2F, CID-078 treatment interferes with two essential steps of the cell cycle, causing replication stress and accumulation of DNA damage and then forcing tumor cells into mitosis, which eventually results in mitotic catastrophe and apoptosis.

The discovery and preclinical characterization of CID-078 were discussed during “New Drugs on the Horizon: Part 3.”

Dowlati reported safety, pharmacokinetic, and early antitumor activity observations from the trial, which included a very heavily pretreated population. Most treatment-related adverse events were low grade and manageable. “As investigators in this phase I study, we are excited to see proof-of-principle clinical activity during the escalation phase of the trial,” said Dowlati. He reviewed the case of a patient with stage 4 undifferentiated pleomorphic sarcoma and another with a stage 4 neuroendocrine tumor in the duodenum, both of which had received multiple prior lines of therapy and experienced a reduction in tumor size of more than 40% on CID-078 treatment.

The recording of the full session is available on demand for registered Annual Meeting attendees through October 2026 via the virtual meeting platform.

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