Budigalimab Plus ABBV-151 Demonstrates Variable Activity Across Locally Advanced or Metastatic Solid Tumors

The addition of budigalimab to ABBV-151 was well tolerated and significantly enhanced responses in patients with locally advanced or metastatic solid tumors, according to findings from a phase 1 trial (NCT03821935) presented at the 2022 SITC Annual Meeting.

The objective response rate (ORR) was 10% (95% CI, 5.7%-15.5%) in the overall population (n = 163). The ORR was 0% with ABBV-151 in dose-escalation and 12% with the combination.

The ORR was 16% (95% CI, 6.2%-32.0%) in the patients with urothelial cancer that was relapsed/refractory to PD-1 inhibition. The ORRs were 33% (95% CI, 9.9%-65.1%), 0%, and 8% (95% CI, 1.0%-26.0%) in the patients with PD-1–naïve hepatocellular carcinoma (HCC), pancreatic cancer, and microsatellite stable colorectal cancer (MSS-CRC), respectively.

“ABBV-151 [with or without] budigalimab showed a manageable safety profile and dose-proportional pharmacokinetics in patients with advanced solid tumors. ABBV-151 combined with budigalimab demonstrates durable antitumor activity in heavily pretreated patients,” the study authors wrote in the poster.

Glycoprotein-A repetitions predominant (GARP) is expressed on regulatory T cells and modulates the immunosuppressive cytokine TGFβ1.

ABBV-151 is a first-in-class monoclonal antibody that binds to the GARP-TGFβ1 complex, preventing the release of active TGFβ1.

In preclinical models, inhibiting GARP-TGFβ1 and PD-1 enhanced antitumor activity compared with PD-1 inhibition alone. As such, adding ABBV-151 to the anti–PD-1 antibody budigalimab may enhance antitumor activity by dampening the immunosuppressive effects of TGFβ1.

The first-in-human, open-label, multicenter study consisted of a dose-escalation phase by Bayesian optimal interval design (part 1) and a dose-expansion phase (part 2).

Part 1 enrolled approximately 57 patients with locally advanced or metastatic solid tumors that are refractory or intolerant to all available treatments. In the monotherapy arm, patients received intravenous (IV) ABBV-151 every 2 weeks at 1 of 7 doses: 3 mg (n = 1), 10 mg (n = 1), 30 mg (n = 3), 100 mg (n = 3), 300 mg (n = 3), 1000 mg (n = 4), and 1500 mg (n = 8). In the combination arm, patients received the same schedule of ABBV-151 plus 500 mg of IV budigalimab every 4 weeks at 1 of 6 doses: 10 mg (n = 4), 30 mg (n = 8), 100 mg (n = 3), 300 mg (n = 4), 1000 mg (n = 4), and 1500 mg (n = 11).

Part 2 enrolled between 138 and 191 patients with urothelial cancer (n = 23-46), non–small cell lung cancer (NSCLC; n = 23), and head and neck squamous cell carcinoma (HNSCC; n = 23) that is relapsed or refractory to PD-1 inhibition; or HCC (n = 23), MSS-CRC (n = 23), and pancreatic cancer (n = 23-30) naïve to PD-1 inhibition. These patients will receive 1500 mg of IV ABBV-151 every 2 weeks plus 500 mg of IV budigalimab every 4 weeks.

In addition, patients with HCC and pancreatic cancer must have progressed on 1 prior line of systemic therapy, patients with urothelial cancer must have progressed after platinum-based chemotherapy. Patients with MSS-CRC must have received 1 or 2 prior chemotherapy regimens and refused or are ineligible for other approved treatments.

Regarding overall patient characteristics, the median age was 63 years (range, 20-85), and most patients were male (n = 96; 59%). The median number of prior lines of therapy was 2 (range, 0-10), and most patients did not receive prior PD-(L)1 inhibition (n = 99; 61%). The median number of doses of ABBV-151 was 4 (range, 1-48).

Safety and efficacy served as co-primary end points of the trial. Safety included the evaluation of adverse effects (AEs) and serious AEs, laboratory parameters, vital signs, electrocardiogram results, pharmacokinetic measurements of both regimens, and antidrug antibodies. 

Efficacy was measured by objective response per RECIST v1.1 criteria, progression-free survival, and duration of response.  

Regarding safety, the maximum-tolerated dose was not reached. The maximum administered dose of 1500 mg of ABBV-151 was selected as the dose for the expansion phase.

Any-grade treatment-emergent AEs occurred in 98% of patients (n = 160), and AEs that may have been related to ABBV-151 or budigalimab occurred in 61% (n = 99) and 56% (n = 79) of patients, respectively. Pruritus was the most frequent event in all cases occurring in 31%, 23%, and 27% of patients, respectively.

Overall, 17% (n = 28) of patients experienced a grade 3 or greater AE related to either study drug. There were no grade 5 events. Serious AEs (SAEs) occurred in 56% (n = 91) of patients overall, and 10% (n = 17) were deemed potentially related to either treatment. The 3 cases of grade 4 treatment-related SAEs included myasthenia in a patient with pancreatic cancer and diabetic ketoacidosis and toxic epidermal necrolysis in two patients with HCC.

Treatment-related AEs leading to treatment discontinuation occurred in 12% (n = 19) of patients. The most common reasons for discontinuation were pruritus, rash, and maculopapular rash (2% each).

In February 2022, investigators paused the HCC cohort because of significant safety concerns resulting from grade 3/4 drug-related AEs in 7 of 12 patients. Although an ad-hoc independent data monitoring committee did not recommend the discontinuation of the HCC cohort, investigators ultimately dissolved the cohort following a paradigm change in the studied indication.

Reference

1. Tolcher A, Roda-Perez D, He K, et al. Safety, efficacy, and pharmacokinetic results from a phase I first-in-human study of ABBV-151 with or without anti-PD1 mAb (budigalimab) in patients with locally advanced or metastatic solid tumors. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 770.