ABBV-400 Demonstrates Preliminary Efficacy, Safety in MSS/pMMR Advanced CRC

Manish Sharma, MD

ABBV-400, a novel c-Met–targeted antibody-drug conjugate, displayed preliminary antitumor activity and was tolerable in patients with BRAF wild-type, microsatellite stable (MSS)/mismatch repair–proficient (pMMR) advanced colorectal cancer (CRC) that progressed on prior therapy, according to data from a phase 1 trial (NCT05029882).¹

Findings presented at the 2024 ASCO Annual Meeting showed that all patients treated at any dose level (n = 122) experienced at least 1 any-grade treatment-emergent adverse effect (TEAE), and grade 3 or higher TEAEs occurred in 71% of patients. The rates of grade 3 or higher TEAEs increased with higher dose levels; these rates were 38% for those treated at 1.6 mg/kg (n = 32), 73% for patients treated at 2.4 mg/kg (n = 40), and 88% for those administered a dose of 3.0 mg/kg (n = 41).

The most common hematologic TEAEs included anemia (any-grade, 56%; grade ≥3, 35%), neutropenia (40%; 25%), and thrombocytopenia (25%; 13%). The most frequent non-hematologic TEAEs included nausea (any-grade, 57%; grade ≥3, 3%), fatigue (44%; 2%), and vomiting (39%; 4%). Any-grade unadjudicated interstitial lung disease/pneumonitis was reported in 9% of all patients, including 2% of patients who experienced grade 3 or higher events.

TEAEs led to treatment discontinuation in 20.5% of patients, with the most common being anemia (n = 4), pneumonitis (n = 3), and febrile neutropenia (n = 2). Eleven percent of patients discontinued therapy due to TEAEs related to ABBV-400.

Regarding efficacy, the objective response rate (ORR) among all patients was 16%, and the median duration of response was 5.5 months (95% CI, 4.1–not evaluable). The 12- and 24-week clinical benefit rates (CBR) were 50% and 29%, respectively.

“ABBV-400 at both 2.4 mg/kg and 3.0 mg/kg [once every 3 weeks] showed promising antitumor activity in CRC, with a tolerable and manageable safety profile,” lead study author Manish Sharma, MD, of START Midwest in Grand Rapids, Michigan, said in a presentation of the data.

ABBV-400 combines telisotuzumab—a c-Met–targeted antibody—with a topoisomerase 1 inhibitor payload. Overexpression of c-Met is common in a variety of advanced solid tumors, including CRC.

The first-in-human phase 1 study is investigating the safety and antitumor activity of ABBV-400 in patients with advanced solid tumors. Patients with CRC were required to have BRAF wild-type, MSS/pMMR disease that progressed on prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan. Prior treatment with anti–EGFR therapy, anti-VEGF therapy, and targeted therapy were required for applicable patients. Patients deemed ineligible for or intolerant to standard therapy were allowed to enroll, as were those who received prior treatment with trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga).^1,2

Patients with CRC were enrolled regardless of c-Met protein expression status. Twenty-nine patients with CRC were treated during dose escalation, which established the maximum tolerated dose at 3.0 mg/kg once every 3 weeks. During dose expansion, patients with CRC were randomly assigned to receive ABBV-400 at 1.6 mg/kg, 2.4 mg/kg, or 3.0 mg/kg once every 3 weeks for dose optimization and determining the recommended phase 2 dose (RP2D).¹

The trial’s primary end points were evaluating the safety, tolerability, and pharmacokinetics of ABBV-400 monotherapy; accessing preliminary antitumor activity, including ORR, CBR, DOR, progression-free survival (PFS), and overall survival; and determining the RP2D.

Among the 122 enrolled patients with CRC, the median age was 56 years (range, 24-81), 53% of patients were male, and 61% of patients were White. Patients had an ECOG performance status of 0 (42%) or 1 (58%). MET amplification was reported in 5% of patients, and MET was not amplified in 13% of patients; MET amplification status was unknown or not tested in 82% of patients.

Patients received a median of 4 prior lines of treatment (range, 1-12). All patients received prior chemotherapy, 92% previously received bevacizumab (Avastin), and 39% received prior anti-EGFR therapy.

At the data cutoff of January 2024, 15% of patients (n = 18) remained on treatment; 104 patients discontinued treatment, including 52 who were off the study. The median treatment duration was 4.1 months (range, 0.7-18), and Sharma noted that dose reductions and interruptions were more frequent at higher doses. Median relative dose intensity was 100% at 1.6 mg/kg, 96% at 2.4 mg/kg, and 87% at 3.0 mg/kg.

Additional efficacy data showed that patients treated at 1.6 mg/kg experienced an ORR and CBR of 6% and 75%, respectively. The median PFS in this patient population was 5.1 months (95% CI, 2.8-6.8). Those treated at 2.4 mg/kg achieved an ORR of 18% and a CBR of 78%, and the median PFS was 5.3 months (95% CI, 3.8-5.9). Patients given ABBV-400 at 3.0 mg/kg had an ORR of 24% and a CBR of 68%. The median PFS in this population was 4.1 months (95% CI, 2.6-6.7).

Expression of c-Met status was evaluated via immunohistochemistry, and findings showed that evaluable patients with at least 10% of tumor cells showing 3+ staining experienced an ORR of 37.5% compared with 14% for those with less than 10% of tumor cells showing 3+ staining. The median PFS for these subgroups was 5.4 months (95% CI, 2.7-6.9) and 4.5 months (95% CI, 3.8-5.9), respectively.

Additional safety data showed that other hematological TEAEs reported in all patients included febrile neutropenia (any-grade, 6%; grade ≥3, 6%), leukopenia (25%; 12%), and lymphopenia (11%; 9%). Other non-hematologic TEAEs included decreased appetite (any-grade, 29%; grade ≥3, 0%), myalgia (25%; 1%), and diarrhea (21%; 1%).

References

1. Sharma M, 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
2. Study to assess adverse events and change in disease activity in adult participants with advanced solid tumors receiving intravenous (IV) ABBV-400 as monotherapy and in combination with IV bevacizumab. ClinicalTrials.gov. Updated July 15, 2024. Accessed July 31, 2024. https://clinicaltrials.gov/study/NCT05029882