Axitinib in Progressive Metastatic Pheochromocytoma and Paraganglioma: Results of a Phase II Study

Problem
Metastatic pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine malignancies with limited systemic treatment options. While approximately 15% to 30% of PPGL cases develop metastatic disease, which is the principal cause of mortality, therapeutic strategies have historically been constrained. Standard options include combination chemotherapy (CVD), radiopharmaceuticals (¹³¹I-MIBG, PRRT), and, more recently, the HIF-2α inhibitor belzutifan. However, not all tumors respond to these modalities, and durable responses are often uncommon. A significant biological rationale exists for targeting the vascular endothelial growth factor (VEGF) pathway, as many PPGLs, particularly those with SDHx mutations, exhibit a pseudohypoxia phenotype characterized by HIF stabilization and upregulated VEGF expression. While the randomized FIRSTMAPPP trial established the multitargeted tyrosine kinase inhibitor (TKI) sunitinib as an active treatment, there remains a need for additional agents with distinct kinase selectivity and potentially improved tolerability profiles to manage the specific challenges of this population, including underlying catecholamine excess and associated cardiovascular risks.

Methodology
This study was a prospective, open-label, single-arm, Phase II clinical trial (NCT03839498) designed to evaluate the efficacy and safety of axitinib, a potent and selective inhibitor of VEGFR-1, -2, and -3. The study enrolled 19 adults with histologically confirmed, progressive, metastatic, or unresectable PPGL. Eligibility criteria required measurable disease per RECIST version 1.1, an ECOG performance status of 0–2, and no prior treatment with a VEGF receptor TKI. Patients were excluded if they had uncontrolled cardiovascular disease or active infection.

Axitinib was administered orally at a starting dose of 5 mg twice daily in continuous 28-day cycles. The protocol allowed for stepwise dose escalation to 7 mg and 10 mg twice daily for patients tolerating the initial dose, and dose reductions to 3 mg or 2 mg for toxicity. Treatment continued until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Adverse events were graded according to NCI CTCAE version 4.0, with treatment-related events defined as those with an attribution score of 3 or higher.

Key Contributions
The study provides prospective clinical data on the use of a highly selective VEGFR inhibitor (axitinib) in a population of patients with progressive metastatic PPGL. It contributes detailed characterization of the safety profile of axitinib in this specific cohort, particularly regarding the management of hypertension in patients who may already suffer from catecholamine-induced hypertension. Furthermore, the study offers practical evidence on the feasibility of managing VEGF-pathway toxicities in PPGL patients through supportive care and protocol-directed dose modifications without permanent treatment discontinuation.

Results
Nineteen patients were enrolled, and 17 received at least one dose of axitinib, constituting the safety and efficacy populations.

• Efficacy: Six patients achieved a confirmed partial response, resulting in an objective response rate (ORR) of 35.3%. No complete responses were observed. The median duration of response was 7.4 months. For the entire population, the median progression-free survival (PFS) was 7.9 months (95% CI, 6.1–16.8 months), and the median overall survival (OS) was 29 months. One patient remained on treatment for over 70 cycles at the time of data cutoff.
• Safety: Hypertension was the most common treatment-related adverse event, occurring in 79% of patients. It was effectively managed with antihypertensive therapy and dose modifications. Other common adverse events included fatigue, diarrhea, oral mucositis, and palmar-plantar erythrodysesthesia. Grade ≥3 treatment-related events included anemia, oral mucositis, hypophosphatemia, duodenal hemorrhage, and decreased lymphocyte count. Crucially, no patient permanently discontinued treatment due to treatment-related toxicity. Two serious adverse events (Grade 3 anemia and Grade 3 vaginal hemorrhage) occurred but were managed successfully and were classified as unlikely related to axitinib.

Significance
The authors conclude that axitinib demonstrates clinically meaningful antitumor activity in patients with progressive metastatic PPGL. The observed efficacy, with an ORR of 35.3% and median PFS of 7.9 months, is comparable to results reported for other VEGF-targeted therapies, including sunitinib in the FIRSTMAPPP trial. The study establishes that the safety profile of axitinib in this population is consistent with known VEGF pathway inhibition effects and is manageable with standard supportive care and dose adjustments.

The paper asserts that these findings support axitinib as a potential treatment option for metastatic PPGL. It highlights that the ability to manage hypertension and other toxicities without permanent discontinuation is clinically relevant, particularly for a disease requiring prolonged therapy. The authors note that while the optimal sequencing of therapies (including belzutifan and other TKIs) remains undefined due to the lack of head-to-head trials, this study adds to the prospective evidence base supporting VEGF pathway inhibition as a rational therapeutic strategy for this rare malignancy. The study acknowledges limitations, including its small cohort size, single-arm design, and premature termination by the sponsor, which limit definitive comparative efficacy assessments.