Adding axitinib to octreotide LAR does not significantly delay disease progression in patients with advanced extra-pancreatic neuroendocrine tumors

Treatment options for patients with advanced extra-pancreatic neuroendocrine tumors (NETs) are limited. Unfortunately, also the phase II/III AXINET trial, evaluating the addition of axitinib to the somatostatin analogue octreotide LAR, failed to alleviate the medical need in this setting. In fact, despite a higher response rate with this combination compared to octreotide LAR alone, the progression-free survival (PFS) was not significantly prolonged. Moreover, the addition of axitinib added substantial toxicity to the treatment regimen with half of the patients treated with the axitinib-octreotide combination experiencing grade 3/4 toxicity.

Introduction

Angiogenesis plays an important role in the development and progression of NETs, making anti-angiogenesis an attractive therapeutic strategy in this setting. Axitinib is a potent and selective VEGFR-1,2,3 inhibitor that has already proven anti-tumoral activity in other solid tumor types. In the phase II/III AXINET study, investigators assessed whether the addition of this anti-VEGFR agent to the somatostatin analogue octreotide LAR would provide a clinical benefit in patients with advanced G1 or G2 extra-pancreatic NETs.

To this end, 256 patients with a G1-G2 extra-pancreatic NET were randomized to receive either axitinib (5mg BID) plus octreotide LAR (30mg IM q4w), or octreotide LAR in combination with a matched placebo. In order to be eligible for the trial, patients had to have an ECOG performance status of 0-2 and they were allowed to be pretreated with 2 prior lines of systemic therapy (no prior chemotherapy).

Adding axitinib induces a higher response rate, but no significant PFS benefit

Overall, patient and disease characteristics were well-balanced between the two treatment arms, with the exception of a slightly higher proportion of G2 tumors in the axitinib arm (69.8% vs. 58.5%). The median age of patients in the study was 61 years, about 60% had a gastrointestinal primary tumor and 45% of them did not receive any prior systemic therapy. At the time of the analysis, treatment was ongoing in 18.3% and 20% of patients in the experimental and control arm, respectively. In the axitinib-octreotide arm, 45.2% stopped therapy due to disease progression while a quarter had to terminate their treatment for reasons of toxicity. In the control arm, the situation was different with disease progression being responsible for 63.8% of all treatment discontinuations and toxicity leading to a treatment stop in only 4.6% of patients.

While the 17.2 months median PFS (investigator assessed) seen with the axitinib-octreotide LAR combination was numerically longer than the 12.3 months median PFS in the control arm, this difference did not reach statistical significance (HR[95%CI]: 0.816[0.610-1.091]; p= 0.169). A subgroup analysis of these findings in function of the stratification factors (i.e. primary tumor location, time from diagnosis and Ki-67 index) suggested that the benefit of axitinib was particularly modest in patients with a time from diagnosis >12 months and in patients with a Ki-67 index of >5% (HR: 0.90 for both). In contrast, patients with G1 tumors seemed to derive a more pronounced benefit from the addition of axitinib to octreotide, with a significant improvement in the median PFS from 19.04 to 30.15 months (HR: 0.50). The overall response rate (ORR) in patients treated with the axitinib-octreotide combination was reported at 17.5%, which is significantly higher than the 3.8% ORR seen in the control arm. Overall, 69% of patients treated with axitinib-octreotide experienced some form of tumor shrinkage as compared to 44% in the control arm.

With respect to safety, the addition of axitinib resulted in a substantial increase in the rate of grade 3/4 adverse events from 14% in the control arm to 52% in the axitinib-octreotide arm. This difference was particularly pronounced when looking at the incidence of grade 3/4 diarrhea (13.6% vs. 1.5%) and grade 3/4 hypertension (20.8% vs. 6.5%).

Conclusion

The AXINET trial did not meet its primary endpoint as the addition of axitinib to octreotide LAR failed to result in a significant improvement in the PFS of patients with advanced G1-G2 extra-pancreatic NETs. Nevertheless, adding axitinib did result in a significant improvement in the ORR and induced a numerical 4-month prolongation in the median PFS. The safety profile of axitinib-octreotide was in line with what could have been expected from this combination, with half of the patients experiencing grade 3/4 adverse events. An independent radiological assessment of the PFS is currently ongoing and the results of this analysis will be presented at future meetings.

Reference

Garcia-Carbonero R, Benavent M, Fonseca PJ, et al. A phase II/III randomized double-blind study of octreotide acetate with axitinib versus octreotide acetate with placebo in patients with advanced G1-G2 NETs of non-pancreatic origin (AXINET trial-GETNE-1107). Presented at ASCO GI 2021, Abstract 360.