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Expert Investigators Highlight Cross-Cancer Updates for Fellows From the 2025 AACR Annual Meeting

Oncology Fellows, Vol. 17/No. 2, Volume 17, Issue 2

Experts in the fields of lung, head and neck, HER2+ breast, and hematologic cancers discuss notable updates for fellows from the 2025 AACR Annual Meeting.

AACR Annual Meeting |   Image Credit: © catalin - stock.adobe.com

AACR Annual Meeting |

Image Credit: © catalin - stock.adobe.com

During the 2025 American Association for Cancer Research (AACR) Annual Meeting, investigators gathered in Chicago, Illinois, to share their most recent findings, which included data from patients with lung and head and neck cancers, as well as novel combination regimens in breast cancer and acute myeloid leukemia (AML).

“There’s a lot going on. AACR is comprehensive, and we’re talking about not just the basic science or clinical research, but also a lot of other aspects of oncology care,” Herbert H. F. Loong, MBBS, PDipMDPath, MRCP, FRCP Edin, FHKCP, FHKAM (Medicine), FASCO, of The Chinese University of Hong Kong, said in an interview with Oncology Fellows.

“What I like about going to AACR is getting to hear things that I wouldn’t think about normally, as well as learning from experts about things that are immediately relevant to my work,” Erica Maria Pimenta, MD, PhD, a postdoctoral research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts, added in an interview with Oncology Fellows.

In this article, we recap the most exciting data from the meeting that oncology fellows should know and their potential effect on clinical practice. Our coverage also features commentary from on-site interviews with the expert investigators who participated in the studies, as well as quotes from the data presentations.

Emerging TKIs Make a Splash in Lung Cancer

During the AACR Annual Meeting, investigators presented data from multiple notable studies exploring the use of oral tyrosine kinase inhibitors (TKIs) in patients with non–small cell lung cancer (NSCLC). In the phase 3 ARTS trial (NCT04687241), the third-generation EGFR TKI aumolertinib (Ameile) was compared with placebo as adjuvant treatment following complete tumor resection in patients with stage II to IIIB NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.1 The primary end point of the study was disease-free survival (DFS) per blinded independent central review (BICR).

At a median follow-up of 27.6 months, patients who received aumolertinib (n = 106) achieved a median DFS that was not reached (NR; 95% CI, 29.1-not applicable) vs 19.4 months (95% CI, 11.2-26.2) among patients who received placebo (n = 104; HR, 0.166; 95% CI, 0.094-0.294; P < .0001). The 24-month DFS rates were 88.2% and 40.6%, respectively.

“Aumolertinib was tolerable, suggesting this strategy is suitable for long-term administration as adjuvant therapy,” lead study author Ying Cheng, MD, director of the Jilin Lung Cancer Diagnosis and Treatment Centre in Changchun, China, said during a presentation of the data. “[Aumolertinib] offers a practicechanging option for this defined population.”

The phase 1b Beamion LUNG-1 trial (NCT04886804) evaluated the HER2-selective TKI zongertinib (BI 1810631) in patients with HER2-altered solid tumors, including NSCLC.2 The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. Secondary end points included duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR).

“To date, we haven’t been able to [develop] a successful HER2-targeted oral TKI for patients [with NSCLC],” John V. Heymach, MD, PhD, chair of the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Oncology Fellows. “Right now, the only option is fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], which is a HER2[-targeted] antibody- drug conjugate [ADC]. Having an oral option that’s hopefully more effective would be a huge advance for these patients.”

Findings presented by Heymach during the meeting demonstrated that patients with pretreated NSCLC with tyrosine kinase domain (TKD) mutations in HER2 (n = 75) achieved an ORR of 71% (95% CI, 60%-80%), including a complete response (CR) rate of 7%. The DCR was 96%. The median DOR was 14.1 months (95% CI, 6.9-not evaluable [NE]), and the median PFS was 12.4 months (95% CI, 8.2-NE).

In patients with non-TKD HER2-mutated NSCLC (n = 20), the ORR was 30% (95% CI, 15%-52%) and the DCR was 65% (95% CI, 43%-82%). These respective rates were 48% (95% CI, 32%-65%), with a 3% CR rate, and 97% (95% CI, 84%-99%), respectively, among patients with NSCLC with HER2 TKD mutations who previously received a HER2-directed ADC (n = 31).

“[Zongertinib] is under priority review for potential FDA approval, and we’ll hear [the result] of that [in the third quarter of 2025] based on the Prescription Drug User Fee Act action date,” Heymach said. “Moving forward, the randomized phase 3 Beamion LUNG-2 trial [NCT06151574] is examining the agent in the first-line setting to see if it can [outperform] chemotherapy, which is still the standard first-line treatment. If so, this would become the [standard] first-line agent for this space.”

Perioperative Pembrolizumab Bests SOC in Head and Neck Cancers

In the phase 3 KEYNOTE-689 study (NCT03765918), perioperative treatment with pembrolizumab (Keytruda) plus standard-of-care (SOC) therapy was compared with SOC adjuvant radiotherapy with or without cisplatin in patients with stage III or IVA, locally advanced head and neck squamous cell carcinoma (HNSCC).3 The primary end point was event-free survival (EFS) per RECIST 1.1 criteria per BICR. Secondary end points included major pathological response (mPR), overall survival (OS), and safety.

“[KEYNOTE-689] employed a novel clinical trial design looking at patients who received immunotherapy before and after surgery,” Ravindra Uppaluri, MD, PhD, the first author of the study, said in an interview with Oncology Fellows. “The premise is that there is a priming of the immune system with all the tumor and lymph nodes intact before surgery, which activates the immune system. Then, giving additional immunotherapy afterward maintains that and helps mop up any minimal residual disease in the adjuvant setting.”

Uppaluri is the director of head and neck surgical oncology at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, as well as an associate professor of surgery at Harvard Medical School, in Boston, Massachusetts.

At the July 25, 2024, data cutoff, findings from the first interim analysis of KEYNOTE-689 demonstrated that patients in the pembrolizumab arm (n = 363) achieved a median EFS of 51.8 months (95% CI, 37.5-NR) compared with 30.4 months (95% CI, 21.8-50.1) in the SOC arm (n = 351; HR, 0.73; 95% CI, 0.58-0.92; P = .0041). The EFS benefi t with perioperative pembrolizumab was also observed among patients with a PD-L1 combined positive score (CPS) of at least 10; the median EFS was 59.7 months (95% CI, 41.1-NR) vs 26.9 months (95% CI, 18.3-51.5) in the investigational (n = 234) and SOC (n = 231) arms, respectively (HR, 0.66; 95% CI, 0.49-0.88; P = .0022). Patients with a PD-L1 CPS of at least 1 in the pembrolizumab (n = 347) and SOC (n = 335) arms achieved a median EFS of 59.7 months (95% CI, 37.9-NR) vs 29.6 (95% CI, 19.5-41.9), respectively (HR, 0.70; 95% CI, 0.55- 0.89; P = .0014).

Additional data showed that the median OS among patients with a PD-L1 CPS of at least 10 was NR (95% CI, NR-NR) vs 61.8 months (95% CI, 49.2-NR) in the investigational and SOC arms, respectively (HR, 0.72; 95% CI, 0.52- 0.98; P = .02). The mPR rates in the overall population were 9.4% (95% CI, 6.6%-12.8%) and 0.0% (95% CI, 0.0%-1.0%), respectively, for an estimated difference of 9.3% (95% CI, 6.7%-12.8%; P < .00001).

“The OS data are not statistically significant at this first interim analysis. Additional follow-up is ongoing, [and] we expect that to change [because] the curves are already separating,” Uppaluri said. “The main conclusion is that we believe neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab concurrent with and after postoperative chemoradiation represents a new SOC in the treatment of patients with resectable [HNSCC].”

Relatlimab Plus Nivolumab and Azacitidine ± Venetoclax Displays Early Efficacy in Frontline AML

The phase 2 AARON trial (NCT04913922) examined the LAG-3 inhibitor relatlimab in combination with nivolumab (Opdualag) and azacitidine with or without venetoclax (Venclexta) in patients with adverse-risk AML who were not fit for intensive chemotherapy.4

Findings from an interim analysis of AARON showed that evaluable patients who received the combination (n = 10) achieved a complete remission rate of 80%, including 1 patient with a blast response; no patients with relapsed/refractory disease (n = 12) achieved a response. The median time to progression in patients with relapsed/refractory AML was 2.3 months and was NR among patients who were treated in the first line. At a median follow-up of 6.8 months, the median OS was 3.5 months and 8.3 months, respectively.

“Despite sufficient safety of the treatment, [the] enrollment of [patients with] relapsed/refractory AML has been stopped due to moderate activity in that cohort,” study authors wrote in a poster presentation of the data. “[However, azacitidine/venetoclax] plus LAG-3/PD-1 inhibition was safe in [patients with] adverse-risk frontline AML [who were] not fit for intensive chemotherapy and showed promising [early] efficacy.”

Runimotamab Shows Potential as a Combination Component in HER2+ Breast Cancer

Runimotamab, a T-cell–engaging bispecific antibody, was evaluated in combination with trastuzumab (Herceptin) in patients with HER2- expressing breast cancer in a phase 1 study (NCT03448042).5 The trial included patients with breast cancer who experienced disease progression following standard treatments with an ECOG performance status of 0 or 1.

“Runimotamab monotherapy was limited by its tolerability and we saw no antitumor activity,” Shanu Modi, MD, attending physician at Memorial Sloan Kettering Cancer Center, New York, New York, said during a presentation of the data. “[However], when combined with trastuzumab, we observed improved tolerability, decreased frequency of cytokine release syndrome [CRS], and a manageable safety profile.”

The study included patients who were heavily pretreated; the median number of prior lines of therapy in phase 1a was 7, and it was 8 in phase 1b. Despite this, the confirmed ORR across all doses of runimotamab plus trastuzumab was 19% (n = 10/53). Additionally, patients treated with runimotamab at the 20-mg and 60-mg dose level in combination with trastuzumab (n = 23) achieved a confirmed ORR of 30%.

In terms of safety, 2 dose-limiting toxicities occurred with the combination: one instance each of grade 3 rash and pneumonitis. CRS or infusion-related reactions occurred in 31% of patients. Investigators selected 20 mg/60 mg as the recommended dose of runimotamab for expansion.

“As we look to future combination strategies, adding a checkpoint inhibitor or a co-stimulatory agent may further enhance the potential antitumor activity of runimotamab and trastuzumab,” Modi concluded.

References

  1. Cheng Y, Zhang X, Wu L, et al. Aumolertinib as adjuvant therapy in patients with stage II-IIIB EGFR-mutated NSCLC after complete tumor resection: a randomized, double-blind, placebo-controlled, phase 3 trial (ARTS). Cancer Res. 2025;85(suppl 2):CT126. doi:10.1158/1538-7445. AM2025-CT126
  2. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Presented at: 2025 American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT050.
  3. Uppaluri R, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Presented at: 2025 American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT001.
  4. Buecklein V, Magno G, Rausch C, et al. AARON: an ongoing open-label phase I/II study of relatlimab (anti-LAG-3) with nivolumab (anti-PD-1) in combination with azacitidine ± venetoclax for the treatment of patients with relapsed/refractory and non-fit patients with newly diagnosed acute myeloid leukemia - interim analysis. Cancer Res. 2025;85(suppl 2):CT225. doi:10.1158/1538-7445.AM2025-CT225
  5. Modi S, Yap TA, Tan TJ, et al. Phase 1a/b study of runimotamab, a HER2 x CD3 T cell-engaging bispecific antibody, administered as a single agent and in combination with trastuzumab in patients with HER2- expressing breast cancer (BC). Cancer Res. 2025;85(suppl 2):CT204. doi:10.1158/1538-7445.AM2025-CT204

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