Thousands of forward-looking research studies defined the 2025 American Association for Cancer Research (AACR) Annual Meeting. Here, aside from our fuller coverage of key presentations in The ASCO Post, we offer a snapshot of a few additional abstracts that may be of interest to cancer researchers and clinicians.
VICTORI Trial: Liquid Biopsy Informed by ctDNA Assay
The VICTORI study is an ongoing observational trial on circulating tumor DNA (ctDNA) detection in patients with colorectal cancer after surgery, using the tumor-informed, ultrasensitive NeXT Personal® assay, which is designed to detect low traces of measurable residual disease (MRD) down to 1 to 3 parts per million (ppm) of ctDNA.1 The current reporting describes an interim analysis of the study that enrolled 71 patients with cancer who had data available before surgery and for landmark assessments at 2, 4, 6, and 8 weeks after surgery.
The presurgical ctDNA detection rate was 94.3% for treatment-naive patients, with 40% in the ultrasensitive range (< 100 ppm). After surgery in the landmark window, ctDNA was detected in 42% of patients, with 87% of those with clinical recurrence showing positive results. The study found 100% concordance between ctDNA negativity and no recurrence, and the detection of ctDNA at any landmark window timepoint was associated with a poorer prognosis, according to Emma Titmuss, MSc, of BC Cancer in Vancouver, Canada.
“We were able to detect 100% of recurrences by ctDNA ahead of clinical recurrence, including all lung metastases, which really highlights the importance of using a highly sensitive ctDNA test,” Ms. Titmuss said.
The study further found that patients with ultrasensitive levels of detection (< 100 ppm) are at increased risk of recurrence vs those with no ctDNA detected, but these patients have a longer lead time between detection and clinical recurrence compared with those who have higher ctDNA levels (> 100 ppm). In the study, 64% of all detections in the landmark window were < 100 ppm.
Other key findings:
- Total cell-free DNA increases after surgery and remains elevated up to 4 weeks, which can dilute the ctDNA signal. This suggests that 4 weeks is the optimal time for assessing ctDNA.
- A total of 42% of patients were ctDNA-positive in at least one sample 2 to 8 weeks after surgery.
- Across the entire landmark window (weeks 2–8), 87% of patients with a clinical recurrence were ctDNA-positive.
- A total of 100% of recurrences were detected by ctDNA ahead of imaging.
- For 70% of patients, the earliest positive sample after surgery was in the ultrasensitive range (a median of 24 ppm).
- At 4 weeks after surgery, the median disease-free survival time was not reached in the ctDNA-negative group; it was approximately 10 months in the ctDNA-ultrasensitive group (< 100 ppm) and about 5 months in the ctDNA-high group (> 100 ppm). There have been no recurrences in patients who have been ctDNA-negative to date, Ms. Titmuss said.
Phase I Trial: KRAS G12D Inhibitor in NSCLC
Encouraging results were reported for a novel KRAS G12D inhibitor in patients with previously treated non–small cell lung cancer (NSCLC) by Kathryn C. Arbour, MD, of Memorial Sloan Kettering Cancer Center, New York.2 Zoldonrasib (RMC-9805) is an orally bioavailable, mutant-selective, covalent inhibitor of RAS (in its ‘on’ state) G12D.
As Dr. Arbour explained, there has been a large unmet need in RAS G12D–mutant cancers, as uncontrolled RAS(ON) signaling drives cells to an oncogenic state. Furthermore, RAS G12D–mutant cancers are fairly common, occurring in about 40% of pancreatic cancers, 15% of colorectal cancers, and 4% of NSCLCs. In NSCLC, these patients tend to be nonsmokers with lower tumor mutational burdens and PD-L1 status vs patients with non-GD12 KRAS-mutant tumors, making them more difficult to treat, she said.
In a phase I study, zoldonrasib monotherapy, in doses of 150 mg to 1,200 mg daily, were given to 211 patients (90 received 1,200 mg daily). Of them, 14% had NSCLC, 55% had pancreatic cancer, and 31% had other tumor types. The median number of prior therapies was two, and 61% had metastatic disease at diagnosis.
Dr. Arbour presented the findings for only the 18 patients with NSCLC receiving zoldonrasib at 1,200 mg/d for at least 8 weeks. In this cohort, the objective response rate was 61%, and the disease control rate was 89%. At a press briefing, Dr. Arbour said the response rate in the pancreatic cancer cohort, which was previously reported, was 30%, and the disease control rate was 80%.
The drug was reported to be well tolerated, with almost all treatment-related toxicities limited to grade 1. Five patients required dose reductions or interruptions, and one patient discontinued treatment because of toxicity.
Dose optimization and expansion are ongoing in patients with NSCLC and other solid tumors, with 1,200 mg daily identified as the candidate recommended phase II dose.
“The therapy certainly is promising as monotherapy, but it’s also being explored in combination with the multi-RAS inhibitor daraxonrasib (RMC-6236) as well as with standard-of-care regimens for NSCLC and gastrointestinal cancers, including chemotherapy and immunotherapy,” Dr. Arbour said. “Those studies will be very informative, as we think about how to translate these results into potentially even first-line regimens.”
Phase II Trial: Use of Topical Gel for Skin Toxicity From EGFR Inhibitors
A new topical BRAF inhibitor gel currently labeled LUT014 successfully reduced the severity of a painful acneiform rash, a common side effect of EGFR inhibitors, researchers at The University of Texas MD Anderson Cancer Center reported.3 In a phase II study, more than two-thirds of patients on the higher dose of LUT014 were considered successfully treated, said Anisha B. Patel, MD.
Roughly 75% of patients on monoclonal antibody EGFR inhibitors will experience skin toxicity or severe rash, often necessitating a reduction in treatment dose or complete discontinuation of therapy. “We’re really excited about this novel topical gel…. Better control of the rash can lead to better control of the cancer and a better chance at significantly improving outcomes,” Dr. Patel said. “LUT014 is the first treatment to target the mechanism of the rash without being absorbed in the bloodstream, allowing us to effectively treat this unfortunate side effect without compromising tumor treatment. We saw results within a week for many of the patients.”
The multicenter phase II trial enrolled 118 patients with colorectal cancer who had developed moderate to severe acneiform rashes while taking an EGFR inhibitor (cetuximab or panitumumab). Patients were randomly assigned to receive a 0.1% formulation of LUT014, a 0.03% formulation of LUT014, or a placebo gel for 28 days. Treatment success was defined as a reduction in rash severity of at least grade 1 or an improvement in at least five skin-specific quality-of-life criteria. Treatment success was significantly better in patients who received one of the LUT014 formulations: 69% with the 0.1% formulation and 47.5% with the 0.03% formulation vs 33% with the placebo gel, with better quality of life reported in the active treatment arms.
KEYLYNK-007 Trial: Combination of PARP and PD-1 Inhibition
A subset of patients with advanced cancer in the tumor-agnostic phase II KEYLYNK-007 trial responded well to the combination of the PARP inhibitor olaparib plus the PD-1 inhibitor pembrolizumab.4 That subset included patients with homologous recombination repair (HRR) mutations and/or homologous recombination deficiency (HRD)-positive tumors, especially those with BRCA1/2-mutated disease, according to Timothy A. Yap, MBBS, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
KEYLYNK-007 enrolled 332 patients with 30 different cancer types, according to three different genetic alteration groups defined in advance. Patients had advanced tumors and had disease progression after standard therapy.
At a median follow-up of 13.4 months, patients with BRCA1/2-mutated disease (n = 132) had an objective response rate of 27.3%, of which 8.3% were complete responses. The disease control rate was 64.4%, and the median duration of response was 19.1 months.
At a median follow-up of 10.4 months, patients with non–BRCA-mutated disease with an HRR gene mutation (n = 104) achieved a response rate of 11.5%, of which 1.9% were complete responses. The disease control rate was 67.3%, and the median duration of response was 8.3 months. At a median follow-up of 10.8 months, the response rate for the HRR wild-type, HRD-positive disease subset (n = 96) was 12.5%, with 5.2% complete responses, and the median duration of response of 11.5 months.
“To the best of our knowledge, this is the largest data set of molecularly selected patients with HRR [gene]–mutated or HRD-positive, tumor-agnostic, advanced tumors treated with the combination of a PARP inhibitor and an anti–PD-1 or –PD-L1 [agent],” Dr. Yap said during the presentation. “Early signals of durable antitumor efficacy were observed with this combination using molecularly selected strategies in multiple indications where olaparib and/or pembrolizumab are not currently approved.”
Median progression-free survival ranged from 3.7 to 4.4 months, depending on the molecular profile, with 12-month rates ranging from 9.3% to 31.6%. Median overall survival ranged from 10.8 to 14.0 months, with rates from 47.1% to 57.2%.
SKYSCRAPER-01: Tiragolumab Plus Atezolizumab in PD-L1–High NSCLC
The phase III SKYSCRAPER-01 trial, investigating the addition of the anti-TIGIT (T-cell immunoglobulin and ITIM domain) antibody tiragolumab to the monoclonal antibody atezolizumab in previously untreated patients with locally advanced or metastatic NSCLC and high PD-L1 expression, did not meet its primary endpoints of investigator-assessed progression-free survival and overall survival.5
“While statistical significance was not achieved, numerical improvements were observed in progression-free survival, overall survival, response rates, and duration of response with the combination, suggesting potential antitumor activity that warrants further investigation to identify specific patient populations who might benefit,” said lead study author Solange Peters, MD, PhD, Professor and Director of the Medical Oncology and Thoracic Malignancies Program at the University Hospital of Lausanne in Switzerland.
As Dr. Peters explained, atezolizumab monotherapy is a standard front-line option for this patient population. However, the majority eventually experience disease progression, driving interest in novel combinations like TIGIT inhibition to enhance immune response.
Building on promising phase II data that suggested improved outcomes with the combination, particularly in patients with high PD-L1 expression, SKYSCRAPER-01 aimed to confirm this benefit in a larger phase III setting. The trial randomly assigned patients to receive either tiragolumab plus atezolizumab or placebo plus atezolizumab. The primary analysis set focused on patients with high PD-L1 expression (Tumor Proportion Score ≥ 50%).
At the primary analysis for progression-free survival, a numerical improvement was observed with the combination (7.0 months) compared with atezolizumab alone (5.6 months), but this did not reach the prespecified threshold for statistical significance (hazard ratio [HR] = 0.78). Similarly, median overall survival showed a numerical difference favoring the combination vs atezolizumab alone (23.1 months vs 16.9 months), but this also did not achieve statistical significance (HR = 0.87).
Beyond the primary endpoints, the combination did show numerical improvements in objective response rate (45.8% vs 35.1%) and duration of response (18.0 months vs 14.6 months).
The safety profile was manageable, with a numerically higher incidence of all-grade and grade 3 or 4 adverse events, including immune-mediated events, with the addition of tiragolumab; this led to more treatment withdrawals compared with atezolizumab alone, but no new safety signals were identified, including no reported drug-related interstitial lung disease. Despite not achieving statistical significance for the primary endpoints, investigators noted that the consistent numerical improvements across efficacy measures suggest potential antitumor activity for the combination.
Further research is considered necessary to potentially identify specific subsets of patients with high PD-L1 NSCLC who might derive a clinically meaningful benefit from TIGIT inhibition in combination with PD-L1 blockade. Ongoing trials investigating other anti-TIGIT agents and combinations in NSCLC and other cancers are anticipated to provide further clarity on the role of TIGIT inhibition in cancer immunotherapy.
DISCLOSURE: Ms. Titmuss reported no conflicts of interest. Dr. Arbour has served as a paid consultant (advisory board member) for Revolution Medicines, Merck, BMS, Regeneron, Lilly, Novartis, AstraZeneca, Sanofi-Genzyme, and Amgen; has received travel support from Revolution Medicines and BMS; and has received institutional support from Revolution Medicines, Lilly, Genentech, Mirati Therapeutics, BMS, and Versatem related to clinical trial conduct. Dr. Patel has served as a consultant to Asymmetric Therapeutics, Deciphera Pharmaceuticals, Erasca, Janssen Scientific Affairs, Lutris Pharma, OnQuality Pharmaceuticals, Repare Therapeutics, and SynOx Therapeutics. Dr. Yap has served as a consultant to AbbVie, Acrivon, Adagene, Aineid Therapeutics, Almac, Alterome Therapeutics, Aduro, Amgen, Amphista, Artios, Astex, AstraZeneca, Atavistik, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, Bicycle, BioCity Pharma, Bloom Burton, Blueprint, Bluestar Bio, Boxer, BirdGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research Horizons, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clasp, Clovis, Cybrexa, Daiichi Sankyo, DAiNA, Dark Blue Therapeutics, Dawn Manco, Debiopharm, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Eikon, Elipses Pharma, EMD Serono, Entos, Flagship Pioneering, Forbion, FoRx Therapeutics AG, F-Ster, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, Greu Wolf Therapeutics, GSK, Guardant, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Insitut Gustave Roussy, Intellisphere, Janssen, Jazz Pharmaceuticals, Joint Scientific Committee for Phase I Trials in Hong Kong, Kyn, Kyowa Kirin, Lumanity, MEI Pharma, Mereo, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey Therapeutics, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Plexium, Prelude Therapeutics, Prolynx, Protai Bio, PSIM, Radiopharma Therapeutics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Stablix, Synnovation, Synthis Therapeutics, Tango TCG Crossover, TD2, Techspert.io, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Thryz Therapeutics, Tolremo, Tome, Trevarx Biomedical, Varian, Veeva, Versant, Viblioma, Vivace, Voronoi, Xinthera, Zai Labs, and ZielBio. Dr. Peters reported financial relationships with AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BerGenBio, BioNTech, Biocartis, BioInvent, Bicycle Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genmab, Genzyme, Gilead Sciences, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Merck Serono, Merck Sharp and Dohme, Merrimack, Mirati Therapeutics, Novartis, Novocure, Nuvation Bio, Nykode Therapeutics, Pharma Mar, Pfizer, Promontory Therapeutics, Qlucore, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Zymeworks.
REFERENCES
1. Titmuss E, Vasconcelos JPS, Navarro FCP, et al: Detection of post-surgical minimal residual disease in colorectal cancer: Preliminary results from the VICTORI study. 2025 AACR Annual Meeting. Abstract 3774. Presented April 28, 2025.
2. Arbour KC, Tawee T, Yaeger R, et al: Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12-D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer from a phase 1 study in advanced solid tumors. 2025 AACR Annual Meeting. Abstract CT019. Presented April 27, 2025.
3. Patel AB, Purim O, Wainberg ZA, et al: A double-blind placebo-controlled randomized phase 2 clinical trial to assess the efficacy of a topical BRAF inhibitor for acneiform rash toxicities from anti-EGFR therapies. 2025 AACR Annual Meeting. Abstract CT018. Presented April 27, 2025.
4. Yap TA, Shapira-Frommer R, Lugowska I, et al: KEYLYNK-007: Tumor agnostic trial of olaparib plus pembrolizumab in homologous recombination repair mutation- and homologous recombination deficiency-positive advanced cancers. 2025 AACR Annual Meeting. Abstract CT004. Presented April 27, 2025.
5. Peters S, Herbst R, Horinouchi H, et al: SKYSCRAPER-01: A phase III, randomized trial of tiragolumab + atezolizumab versus placebo + atezolizumab in patients with previously untreated PD-L1-high, locally advanced unresectable/metastatic NSCLC. 2025 AACR Annual Meeting. Abstract CT051. Presented April 28, 2025.
