Phase 2 Study of Telisotuzumab Adizutecan in ctDNA-Positive CRC Could Expand Treatment Beyond Active Surveillance

In recent years, the presence of circulating tumor DNA (ctDNA) and the absence of radiographic evidence of disease have emerged as reliable biomarkers for molecular residual disease (MRD) and strong predictors of disease recurrence in colorectal cancer (CRC) and other malignancies.¹ Observational and prospective studies have shown that patients with ctDNA positivity are at particularly high risk of relapse, and longitudinal testing may further enhance sensitivity for detecting residual disease. According to Kanwal P.S. Raghav, MD, MBBS, these findings have prompted investigators to evaluate whether the MRD window may represent an opportunity to introduce curative therapies before radiographic recurrence occurs.

One such effort is a phase 2 clinical trial (NCT07023289) evaluating the MET-directed antibody-drug conjugate (ADC) telisotuzumab adizutecan (Temab-A; formerly ABBV-400) in patients with ctDNA-positive CRC following adjuvant therapy.² The investigational agent has demonstrated a manageable safety profile and preliminary antitumor activity in patients with advanced solid tumors, including CRC, supporting further exploration in earlier disease settings.

“This is a very exciting clinical trial,” Raghav explained in an interview with OncLive. “Although there have been other trials using escalation or de-escalation strategies with ctDNA, this is one of the trials showing novel interventions.”

Raghav is a professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine, associate vice president of the Department of Ambulatory Medical Operations, and executive medical director of the Department of Ambulatory Treatment Centers at The University of Texas MD Anderson Cancer Center in Houston.

What is the rationale for targeting c-MET in CRC?

The current standard-of-care (SOC) management approach for patients with ctDNA-positive status after definitive therapy involves surgical tumor removal followed by adjuvant therapy and active surveillance.¹ However, there are no approved therapies specific for c-MET–overexpressing tumors, a prevalent amplification that can promote tumor progression and metastasis.^2,3

“All of these clinical trials are being placed in a clinical setting where we have already used up our SOC treatments; despite that, we have MRD, even though we do not have any evidence on scans,” Raghav said. “Therefore, the SOC here is active surveillance.”

Temab-A is a MET-directed ADC composed of a validated antibody against the novel c-MET epitope conjugated to a topoisomerase I inhibitor payload.¹ Unlike c-MET–targeting tyrosine kinase inhibitors or monoclonal antibodies, the antitumor effect of telisotuzumab adizutecan does not rely on inhibition of c-MET signaling but instead uses the receptor as a delivery mechanism for the cytotoxic payload.

“MET is a protein found ubiquitously on all CRC cells, making it a very prevalent biomarker,” Raghav explained. “Using this protein as a homing beacon, we can deliver a cytotoxic chemotherapy payload directly into the cells.”

Early efficacy and safety data observed with the c-MET–targeted ADC have shown the potential to bring a c-MET–targeted agent into the CRC treatment landscape, and there is a particularly unique opportunity to leverage this agent in the postadjuvant setting to achieve a cure.^1,2

“The drug has already shown promising activity in stage IV disease and is currently being evaluated in larger, more definitive trials; however, bringing it into this setting makes sense because of the activity we are already seeing,” Raghav explained. “Additionally, we can utilize this window of opportunity when the disease volume is low to bring about cures in this setting.”

What early-phase evidence has supported the use of Temab-A in ctDNA-positive CRC?

In a first-in-human phase 1 study (NCT05029882), which enrolled patients with BRAF wild-type, microsatellite-stable (MSS) or mismatch repair–proficient (pMMR) CRC who experienced disease progression on prior therapies, Temab-A demonstrated antitumor activity across multiple dose levels.³

Among patients who received the 2.4-mg/kg dose (n = 40), the objective response rate (ORR) was 18% and the median progression-free survival (PFS) was 5.3 months (95% CI, 3.8-5.9). Patients treated at the 3.0-mg/kg dose level (n = 41) achieved an ORR of 24% and a median PFS of 4.1 months (95% CI, 2.6-6.7). At the 1.6-mg/kg dose (n = 32), the ORR was 6%, with a median PFS of 5.1 months (95% CI, 2.8-6.8).

Biomarker analyses suggested greater benefit among patients with higher levels of c-MET expression. In patients with at least 10% of tumor cells demonstrating immunohistochemistry 3+ staining intensity, treatment with Temab-A at doses of 2.4 mg/kg or greater resulted in an ORR of 37.5% and a median PFS of 5.4 months (95% CI, 2.7-6.9). Comparatively, patients without biomarkers treated at similar dose levels achieved an ORR of 14% and a median PFS of 4.5 months (95% CI, 3.8-5.9). Across all patients treated with doses of at least 2.4 mg/kg, the ORR was 20%, with a median PFS of 4.6 months (95% CI, 3.9-5.4).

Safety findings from the phase 1 trial indicated that hematologic treatment-emergent adverse effects (TEAEs) were dose dependent. Grade 3 or higher TEAEs occurred in 38%, 73%, and 88% of patients treated at the 1.6-mg/kg, 2.4-mg/kg, and 3.0-mg/kg dose levels, respectively. The most common grade 3 or higher hematologic TEAEs included anemia (13% vs 33% vs 54%), neutropenia (6% vs 20% vs 32%), and thrombocytopenia (0% vs 8% vs 17%).

Treatment discontinuation due to TEAEs occurred in 25 patients (20.5%), most frequently due to anemia (n = 4), pneumonitis (n = 3), and febrile neutropenia (n = 2). Among these cases, 13 discontinuations were considered related to Temab-A.

Raghav emphasized that tolerability considerations are particularly important in the MRD setting, although the high risk of recurrence in the ctDNA-positive population must also be considered when attempting a curative approach. “When you are in this post–definitive treatment setting and you have MRD but no radiographic evidence of disease, most patients are going to be asymptomatic,” he said. “Therefore, it is very important that the drugs we bring into this space have promising efficacy. We need to have a higher threshold in this space because the patients are truly asymptomatic. If we give them a lot of toxicity without affording them cures, that would not be a palatable situation.”

How is the current phase 2 trial of Temab-A vs SOC surveillance designed?

The global, open-label, randomized trial is enrolling patients 18 years or older with histologically or cytologically confirmed adenocarcinoma of the colon or rectum who have ctDNA-positive status following the end of adjuvant therapy and have no radiographic evidence of disease as confirmed by chest, abdominal, and pelvic CT scans and liver MRIs within 6 weeks prior to the first dose of Temab-A.²

Patients are required to have received 3 or more months of platinum-based doublet chemotherapy in the adjuvant setting, have surgical tumor material available for assessment of c-MET protein levels, have an ECOG performance status of 0 or 1 prior to the first dose, and have received post-R0 resection of the primary and metastatic tumors. Of note, curative-intent ablation for oligometastatic sites is permitted if these sites are determined to have been completely treated by ablation by investigators.

Key exclusion criteria include a history of clinically significant, intercurrent lung-specific illnesses; untreated brain or meningeal metastases or other malignancies; interstitial lung disease or pneumonitis; cardiac disease or any other clinically significant medical condition; other malignancies within 3 years prior to screening, excepting patients with a negligible risk of metastasis or death; and the presence of microsatellite instability or mismatch repair deficiency.

The study has a planned enrollment of approximately 140 patients. Eligible patients will be randomly assigned 1:1 to receive either Temab-A at 2.4 mg/kg intravenously every 3 weeks (n = 70) or active surveillance for 9 months (n = 70). ctDNA testing will be conducted on day 1 of cycles 2, 3, and 4; at 6 months; and then at 9 months. CT scans will be administered every other cycle. Follow-up will continue every 3 months for the first 2 years and every 6 months for the ensuing 3-year period.

Investigator-assessed disease-free survival serves as the trial’s primary end point. Key secondary end points include ctDNA clearance at 6 months, 12 months, and any time; overall survival; time from random assignment to ctDNA clearance; duration of ctDNA clearance; safety; and pharmacokinetics and immunogenicity.

“If the study is positive and meets its primary end point, it would be one of the earlier studies to establish a novel therapeutic in this space,” Raghav asserted. “For that ctDNA-positive population, we would definitely move toward using this drug in this setting.”

Looking ahead, Raghav noted that the integration of ctDNA-directed therapy could complement existing surveillance strategies in CRC by providing higher sensitivity for residual disease and a more real-time, dynamic measure of tumor burden.⁴

“How this would impact surveillance is a slightly complicated question, because it would still depend on how many patients are actually being cured of the disease,” he said. “However, I believe current surveillance strategies integrating ctDNA would still be required even after these novel therapeutics show an effect.”

What additional phase 2 evaluations are ongoing for Temab-A in CRC?

Temab-A is also being evaluated as part of several combination regimens in metastatic CRC.^5,6

The phase 2 AndroMETa-CRC-533 (NCT06820463) trial is currently evaluating the safety and efficacy of Temab-A in combination with SOC regimens for patients with pMMR metastatic CRC.⁵ This global, open-label, randomized study will enroll approximately 300 patients and includes 2 substudies. In substudy 1, patients must have a KRAS/NRAS-mutant primary tumor or right-sided KRAS/NRAS wild-type primary tumor. In substudy 2, eligible patients must have KRAS/NRAS/BRAF wild-type and left-sided primary tumors.

During the dose-expansion and -escalation phases, patients will receive Temab-A in combination with either FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) and bevacizumab (Avastin; substudy 1) or 5-FU, leucovorin, and panitumumab (Vectibix; substudy 2) across various doses.

An additional phase 2 trial (NCT06107413) is evaluating Temab-A concurrent with 5-FU, leucovorin, and bevacizumab in patients with previously treated metastatic CRC.⁶ The study, initiated in November 2023, enrolled 19 patients with metastatic BRAF V600 wild-type, MSS or pMMR CRC as of April 23, 2024.

In the safety lead-in portion, 30 patients receive the Temab-A combination at various dose levels. The second stage of the trial is a dose-optimization phase enrolling 176 patients across 4 investigational cohorts evaluating the regimen administered at low or high doses every 4 weeks or every 2 weeks. An additional SOC cohort comprises patients receiving leucovorin, 5-FU, and irinotecan plus bevacizumab administered every 2 weeks.

References

1. Nakamura Y, Watanabe J, Akazawa N, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med. 2024;30(11):3272-3283. doi:10.1038/s41591-024-03254-6
2. Raghav KPS, Bando H, Ke TW, et al. A phase 2 randomized study comparing telisotuzumab adizutecan monotherapy with standard of care in patients with post-adjuvant circulating tumor DNA-positive colorectal cancer. J Clin Oncol. 2026;44(suppl 2):TPS265. doi:10.1200/JCO.2026.44.2_suppl.TPS265
3. Sharma MR, Strickler JH, Sommerhalder D, et al. First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: results in colorectal cancer. J Clin Oncol. 2024;42(suppl 16):3515. doi:10.1200/JCO.2024.42.16_suppl.3515
4. Krell M, Llera B, Brown ZJ. Circulating tumor DNA and management of colorectal cancer. Cancers (Basel). 2023;16(1):21. doi:10.3390/cancers16010021
5. Shergill A, Cecchini M, Prager GW, et al. A phase 2 randomized study of telisotuzumab adizutecan (ABBV-400, Temab-A) in combination with standard of care (SOC) in patients with metastatic colorectal cancer. J Clin Oncol. 2026;44(suppl 2):TPS255. doi:10.1200/JCO.2026.44.2_suppl.TPS255
6. Raghav KPS, Hubert A, Fakih M, et al. Phase 2 randomized study evaluating safety, efficacy, and optimal dose of ABBV-400 in combination with fluorouracil, folinic acid, and bevacizumab in previously treated patients with metastatic colorectal cancer. J Clin Oncol. 2024;42(suppl 16):TPS3636. doi:10.1200/JCO.2024.42.16_suppl.TPS3636