Old, New, Borrowed, and Blue: Clinical Trial Results Highlight Therapeutic Approaches for Non-small Cell Lung Cancer

May 16, 2025 by

Like a wedding dress tailored to fit a blushing bride, some therapies are designed to match a patient’s particular cancer drivers. And just how one style or size of wedding dress doesn’t work for every bride, the same treatment doesn’t work for every patient with non-small cell lung cancer (NSCLC). 

NSCLC can be driven by mutations in a variety of different genes, some of which can be targeted by antibodies, small molecules, or other treatments that have been approved by the U.S. Food and Drug Administration (FDA). But with 226,650 cases of lung cancer expected to be diagnosed in the United States in 2025—the majority of which will be NSCLC—researchers are developing new drugs to target additional drivers and to improve upon existing therapies. 

The AACR Annual Meeting 2025, held in Chicago April 25-30, featured an impressive slate of clinical trial presentations showcasing new therapies for NSCLC. Across the clinical trials program, there was “something old, something new, something borrowed, and something blue,” as researchers covered new and improved therapeutics for old targets, therapies aimed at new drug targets, and strategies “borrowed” from other cancers. There was also a trial that might have made some researchers feel blue. 

Old Targets: EGFR and ROS1 

The epidermal growth factor receptor (EGFR) and ROS1 are established targets for NSCLC, with the first EGFR inhibitor approved in 2003 and the first ROS1 inhibitor approved in 2011. Presentations at the Annual Meeting examined new ways to inhibit these old targets to overcome some of the limitations of existing drugs. 

The FDA has approved a total of seven EGFR-targeted therapies for NSCLC, but many patients with EGFR-mutated NSCLC do not respond to these therapies or develop resistance. Therefore, researchers continue to design new treatments that improve upon old designs in order to help more patients. 

Enter aumolertinib, an EGFR-targeted therapy approved in China for the first-line treatment of patients with locally advanced or metastatic NSCLC that harbors an exon 19 deletion or L858R mutation in EGFR. At the AACR Annual Meeting, researchers presented data from two phase III clinical trials testing aumolertinib in new treatment settings. 

Shun Lu, MD, PhD, provided updates on several clinical trials for potential new lung cancer treatments at the AACR Annual Meeting 2025.

Aumolertinib is currently approved in China as a monotherapy, and researchers in the AENEAS2 trial evaluated whether the addition of chemotherapy could improve outcomes compared with aumolertinib alone. Researchers enrolled 624 patients with treatment-naïve, locally advanced or metastatic NSCLC that harbored an EGFR exon 19 deletion or L858R mutation, according to Shun Lu, MD, PhD, from Shanghai Chest Hospital, who presented the study. Patients were randomly assigned to receive aumolertinib alone or in combination with chemotherapy. 

The median progression-free survival was 28.9 months in the combination arm and 18.9 months in the monotherapy arm, and the overall survival was immature at the time of analysis. The rate of severe (grade 3 or higher) adverse events was higher in the combination arm—75.7% versus 23.7% in the monotherapy arm—but Lu considered the side effect profile tolerable, even in the combination arm. 

“Aumolertinib combined with platinum-pemetrexed has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival,” said Lu. “Aumolertinib plus chemotherapy offers a new first-line treatment option for patients with locally advanced or metastatic EGFR-mutated NSCLC.” 

In the phase III ARTS trial, presented by Ying Cheng, MD, from Jilin Cancer Hospital in China, researchers evaluated the efficacy of aumolertinib after surgery for patients with resectable disease. The researchers enrolled 214 patients and randomly assigned them to receive aumolertinib or a placebo following complete resection of the tumor. Some patients had also received chemotherapy after surgery. 

After two years of treatment, 11.8% of patients treated with aumolertinib had experienced a recurrence compared with 59.4% of patients treated with placebo. 

While small molecule inhibitors have largely dominated the field of EGFR-targeted therapies, researchers are also approaching the problem from a different angle. Lu also presented results from a first-in-human, phase I clinical trial of SYS6010, an antibody-drug conjugate (ADC) that targets EGFR regardless of the type of driver mutation. The trial included 232 patients, 137 of whom had NSCLC, who were intolerant to, did not respond to, or relapsed following treatment with a standard-of-care therapy. 

The objective response rate was 32.8% in the overall population and 50% among patients with NSCLC. Notably, among 10 patients with NSCLC who were previously treated with small molecule inhibitors targeting EGFR, nine experienced an objective response, and all 10 experienced disease control. 

Hongyun Zhao, PhD, shared results from a trial examining a novel ROS1 inhibitor to treat non-small cell lung cancer.

Beyond the EGFR pathway, researchers are also working to improve options for targeting ROS1, because some NSCLCs can evade inhibition via the G2032R mutation. Another challenge of existing ROS1 inhibitors is their suboptimal ability to cross the blood-brain barrier, which can limit efficacy against brain metastases, according to Hongyun Zhao, PhD, from the Sun Yat-sen University Cancer Center in China. 

The novel ROS1 inhibitor JYP0322 was designed to cross the blood-brain barrier and to overcome the ROS1 G2032R resistance mutation. In a phase I clinical trial, Zhao and colleagues tested the safety and efficacy of JYP0322 in 81 patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.  

Among patients who had previously received other ROS1 inhibitors, 57.4% experienced an objective response. The patients who had not been previously treated with ROS1 inhibitors had an objective response rate of 78.9%. 

Patients with brain metastases had an intracranial objective response rate of 42.9% and an intracranial disease control rate of 73.5%. Zhao noted that the observed concentration of JYP0322 in the intracranial space was higher than that reported in trials of other ROS1 inhibitors. 

“Based on this, we think JYP0322 may have significant potential in treating ROS1-fusion NSCLC with brain metastasis,” Zhao said. 

A New Target for Lung Cancer Treatment: KRAS G12D 

Perhaps the poster child for drugging the undruggable, KRAS made headlines in 2021 when the first KRAS-targeted therapy, sotorasib (Lumakras), was approved by the FDA for certain patients with NSCLC. Sotorasib and its close cousin adagrasib (Krazati) both target the KRAS G12C mutation, which is present in 35% to 40% of NSCLC cases. 

Researchers are now expanding their sights beyond G12C to other KRAS mutations. KRAS G12D, the most common KRAS mutation in human cancer, has become a popular subject of efforts to expand KRAS targeting. 

At the AACR Annual Meeting 2025, Kathryn C. Arbour, MD, offered findings from a trial evaluating the KRAS G12D inhibitor zoldonrasib.

Zoldonrasib is a KRAS G12D inhibitor that, unlike currently approved KRAS G12C inhibitors that lock mutated KRAS in an inactive conformation, targets the active conformation of KRAS. This may delay or prevent resistance because the cell cannot circumvent the blockade by boosting upstream signaling, explained Kathryn C. Arbour, MD, from Memorial Sloan Kettering Cancer Center. 

Arbour and colleagues conducted a phase I clinical trial assessing the safety and efficacy of zoldonrasib in patients with KRAS G12D-mutated solid tumors who have received at least one previous line of treatment. The efficacy analysis included 18 patients with NSCLC who, at the time of data cut off, had been enrolled for at least eight weeks. The objective response rate of these patients was 61%, and the disease control rate was 89%. 

No grade 4 or 5 treatment-related adverse events were observed. Among patients treated at the recommended phase II dose of 1,200 mg daily, one patient discontinued treatment, four patients reduced their dose, and eight patients had dose interruptions due to treatment-related side effects. However, Arbour explained that while toxicities such as rash, mucositis, and transaminitis have been observed with other RAS-targeted therapies, these side effects were not observed during treatment with zoldonrasib. 

“Zoldonrasib has demonstrated encouraging preliminary antitumor activity in patients with non-small cell lung cancer harboring a KRAS G12D mutation,” Arbour said. “Preliminary safety and antitumor activity support the continued development of zoldonrasib as monotherapy, and it’s also being explored in combination with other therapies.” 

A Borrowed Target: HER2 

Like KRAS G12C inhibitors, which have since been approved for colorectal cancer after first being approved for NSCLC, many targeted therapies that prove effective in one tumor type can be applied to others. 

A prominent example is the human epidermal growth factor receptor 2 (HER2), for which FDA-approved inhibitors have existed since 1998 for use in breast cancer. Nevertheless, no targeted therapies effective in HER2-mutated lung cancer were approved until 2022. The ADC trastuzumab deruxtecan (T-DXd; Enhertu) remains the only FDA-approved HER2-targeted therapy for this patient population. 

John V. Heymach, MD, PhD, shared results on using zongertinib as a treatment for non-small cell lung cancer.

However, T-DXd is not effective in all patients, must be delivered intravenously, and may cause significant side effects. Oral small molecule inhibitors of HER2, such as lapatinib and neratinib (Nerlynx), have been approved by the FDA for HER2-overexpressing breast cancer, but these inhibitors are not as effective against HER2-mutated cancers and can also cause side effects related to cross-targeting of EGFR, explained John V. Heymach, MD, PhD, from The University of Texas MD Anderson Cancer Center. 

“There remains a clear unmet need for a potent tyrosine kinase inhibitor that selectively inhibits HER2 while sparing these EGFR-related toxicities,” said Heymach, who is a member of the AACR Lung Cancer Task Force. 

Heymach and colleagues tested a novel HER2 small-molecule inhibitor, zongertinib, in patients with HER2-mutated NSCLC that had been previously treated with at least one prior line of therapy in the first-in-human phase I Beamion LUNG-1 clinical trial. Their primary analysis cohort consisted of 75 patients whose tumors harbored mutations in the tyrosine kinase domain of HER2. Among these patients, 71% had an objective response to zongertinib with a median response duration of 14.1 months, and 17% of patients experienced grade 3 or higher adverse events.  

Heymach and colleagues also assessed outcomes in an exploratory cohort of patients whose tumors had HER2 mutations outside the tyrosine kinase domain and in another cohort of patients who previously received a HER2-targeted ADC. The objective response rates in these cohorts were 30% and 48%, respectively. 

Heymach also praised the limited toxicity of zongertinib. “Zongertinib demonstrated a very favorable safety profile, with little or no significant rash, diarrhea, or pneumonitis—toxicities that were observed in prior therapies,” he said in a press release. 

Meanwhile, other researchers have been building new HER2-targeted ADCs. Lu, who presented the EGFR-targeted ADC, also presented updated data from a phase I/II study of SHR-A1811, a HER2-targeted ADC with a similar design to T-DXd. Lu and colleagues enrolled and treated 94 patients with HER2-mutated NSCLC who were previously treated with chemotherapy and PD-1/PD-L1 inhibitors. 

The overall response rate was 74.5%, with responses lasting a median of 9.8 months, and the 12-month overall survival rate was 88.2%. 

Feeling Blue About TIGIT 

Negative data from the phase III SKYSCRAPER-01 clinical trial had the potential to leave researchers feeling blue about targeting the immune checkpoint TIGIT in NSCLC, but presenter Solange Peters, MD, PhD, from Lausanne University Hospital in Switzerland, remained hopeful. Peters is also a member of the AACR Lung Cancer Task Force. 

Solange Peters, MD, PhD, presenting clinical trial results at the AACR Annual Meeting 2025.

Despite the field’s success at targeting other immune checkpoints, including CTLA-4 and the PD-1/PD-L1 axis, drugs targeting TIGIT have yet to garner FDA approval. Promising results from the phase II CITYSCAPE trial testing the TIGIT inhibitor tiragolumab in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) as first-line treatment spurred SKYSCRAPER-01, in which researchers enrolled patients with previously untreated locally advanced or metastatic NSCLC expressing high levels of PD-L1. Patients were randomly assigned (1:1) to receive tiragolumab plus atezolizumab or placebo plus atezolizumab. 

The efficacy-evaluable population consisted of 266 patients in the tiragolumab arm and 268 patients in the placebo arm. The median progression-free survival and median overall survival were 7 months and 23.1 months, respectively, in the tiragolumab arm and 5.6 months and 16.9 months, respectively, in the placebo arm. Neither difference was statistically significant. Further, more overall adverse events and more adverse events leading to treatment discontinuation were observed in the tiragolumab arm. 

Nevertheless, the observed numerical differences, combined with tiragolumab’s success in the phase II trial, gave Peters hope that refining the patient population in future trials may help researchers establish a group of patients for whom TIGIT-targeted therapy is effective. 

“I’m convinced that further data … are needed to identify the patient population who potentially could benefit from combining an anti-PD-1 or anti-PD-L1 strategy with the inhibition of the TIGIT pathway,” she concluded. 

The AACR Career Development Awards in Lung Cancer Research were established to encourage and support early-career investigators in this field. The deadline for 2025 applications, which are open to institutions worldwide, is May 29.