Tivozanib/Durvalumab Combo Demonstrates Early Efficacy, Tolerability in Advanced HCC

The combination of tivozanib (Fotivda) and durvalumab (Imfinzi) showcased early efficacy with a manageable safety profile in patients with previously untreated advanced hepatocellular carcinoma (HCC), according to data from the phase 1b/2 DEDUCTIVE trial (NCT03970616).¹

Results from the study, which were presented during the 2022 Gastrointestinal Cancers Symposium, revealed that among 18 evaluable patients, tivozanib plus durvalumab elicited an overall response rate (ORR) of 27.8%, a median progression-free survival (PFS) of 7.3 months (95% CI, 1.8–not evaluable [NE]), and a median overall survival (OS) of 13.4 months (95% CI, 8.2-NR).

“In terms of safety and tolerability, we saw that the combination was well tolerated,” lead study author Renuka V. Iyer, MD, of Roswell Park Comprehensive Cancer Center, said in a poster presentation on the data. “There were a number of adverse effects [AEs], but grade 3 AEs that were treatment related were few.”

In those with advanced HCC, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) has improved outcomes compared with sorafenib (Nexavar). This doublet has been found to lead to a median PFS of 6.8 months (95% CI, 5.7-8.3) and a 12-month OS rate of 67.2% (95% CI, 61.3%-73.1%). Serious toxicities were reported in 38% of patients.²

Tivozanib and durvalumab have both previously displayed activity as monotherapies in HCC. Tivozanib, a potent and selective VEGFR 1, 2, and 3 TKI, has been shown to reduce the production of regulatory T cells to potentially enable immune-mediated responses. The PD-L1 antibody, durvalumab, blocks the interaction between PD-L1 and PD-1, which encourages the proliferation of cytotoxic T cells.

Investigators hypothesized that the selectivity and favorable tolerability of tivozanib may allow it to be leveraged as part of a novel combination with an immune checkpoint inhibitor, which could result in even better safety and efficacy outcomes in those with HCC.

The purpose of the open-label, multicenter, phase 1b/2 study was to examine the safety and efficacy of tivozanib in combination with durvalumab; the trial is comprised of 2 cohorts. Results from cohort A, which included patients with previously untreated HCC, were presented during the meeting. Cohort B, which will examine the doublet in patients with HCC who were pretreated with bevacizumab and atezolizumab, is still enrolling.

Cohort A enrolled patients with histologically and/or cytologically confirmed advanced HCC who were previously untreated. Patients were required to be at least 18 years of age with measurable or evaluable disease, an ECOG performance status of 0 or 1, and Child-Pugh Class A disease. Patients with co-infection of hepatitis B and C virus or significant organ dysfunction, were excluded.

Patients with previously untreated HCC who were enrolled to cohort A (n = 20) received oral tivozanib at 0.89 mg once daily for 21 days on and 7 days off, plus intravenous durvalumab at 1500 mg every 4 weeks. Patients underwent CT scan or MRI assessments every 8 weeks. Treatment was continued until disease progression or unacceptable toxicity. Those in cohort B (n = 20) will be given the same dose and schedule of the combination.

The primary end point of the study was safety and tolerability. The secondary end points included PFS, OS, and ORR.

Among the patients enrolled to cohort A (n = 20), the median age was 68.5 years (range, 40-82), 85% were male, and 65% were White. Furthermore, 60% had an ECOG performance status of 1, and the median baseline body mass index was 27.2 (range, 21.8-37.9).

Additional data showed that the 5 patients who responded to the combination all experienced partial responses to treatment; this translated to a rate of 27.8%. Moreover, 40% of patients had stable disease, and 27.8% experienced disease progression. The disease control rate was 67.8%, and the median duration of response was NE (95% CI, 2.6-NE). The OS rate at 1 year was 76% with the combination.

Regarding safety, 80% of all patients in cohort A experienced a treatment-related AE (TRAE) of any grade; 15% had a TRAE that was grade 3 to 5 in severity. Furthermore, 95% of patients had a treatment-emergent AE (TEAE) of any grade, and 55% experienced a TEAE that was grade 3, 4, or 5 in severity. Specifically, 1 patient had a grade 4 TEAE, and 1 patient had a grade 5 TEAE, both in the form of hepatic encephalopathy. One patient died from a TEAE.

Notably, no grade 4 or 5 TRAEs were observed. Of the 3 patients who experienced a grade 3 TRAE, 2 had hypertension and 1 had gastrointestinal hemorrhage. The most common TRAEs of any grade that were experienced with the combination included hypertension (35%), fatigue (20%), diarrhea (20%), nausea (20%), hypothyroidism (20%), elevated liver function tests (20%), dysphonia (15%), arthralgia (10%), and palmar-plantar erythrodysesthesia (10%).

References

1. Iyer RV, Li D, Dayani F, et al. A phase 1b/2 study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (DEDUCTIVE): efficacy results in previously untreated patients. J Clin Oncol. 2022;40(suppl 4):462. doi:10.1200/JCO.2022.40.4_suppl.462
2. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745