Lenvatinib as a Therapeutic Option in Unresectable Metastatic Pheochromocytoma and Paragangliomas

Lauren Hassan Nelson; Harry Fuentes-Bayne; Jun Yin; Erik Asmus; Mabel Ryder; John C. Morris; Crystal R. Hilger; Keith C. Bible; Ashish V. Chintakuntlawar; Sarika N. Rao

Disclosures

J Endo Soc. 2022;6(5) 

In This Article

Discussion

Pheochromocytomas and paragangliomas are highly vascular tumors and their growth is promoted by this increased blood supply. For focal disease, treatment options include surgery, ablation, and radiation; however, the treatment for inoperable, multisite disease remains a challenge, especially given the rarity of this neuroendocrine malignancy. Systemic options have included nuclear medicine–based therapies, such as 131I-MIBG (Azedra) and 177Lu-DOTATATE, although time to maximal response may be delayed after initial treatment or reduced number and degree of PR.[7,25]

Cytotoxic chemotherapeutic options have traditionally involved cyclophosphamide, vincristine, and dacarbazine. This combination has shown an ORR of 57% to 100%[8–10,26] and 72% to 79% of patients among 2 studies experienced a complete or partial biochemical response.[8,9] Response duration was 1 to 2 years, although patients experienced hematologic, neurologic, and gastrointestinal side effects.[8–10]

MKIs also remain as an effective treatment strategy against several malignancies as they targets angiogenesis. In mPPGL, there is a significantly higher expression of VEGF, which accounts for the tumor's high vascularity and subsequent growth.[11] Given the high expression of VEGF in mPPGL and its role in tumor growth, MKIs have been a viable option to treat these tumors.

The MKI lenvatinib broadly inhibits various receptor targets both on the tumor as well as its vascular supply. Among these targets include VEGF, fibroblast growth factor, and platelet-derived growth factor receptors, which are regulators of angiogenesis, as well as RET and KIT, which are directly expressed on tumors. Through these mechanisms, lenvatinib has been effective in treating other malignancies. Our study has also shown promising outcomes, including a prolonged median PFS of 14.7 months as well as an ORR of 63% among those with measurable disease. Although head-to-head comparison between lenvatinib, sunitinib, or pazopanib could not be achieved due to differences in study design, ORR and PFS may be higher in the lenvatinib-treated population.

In a retrospective analysis of 17 patients who received sunitinib, median PFS was 4.1 months and ORR was 57% (8 of the 14 assessable patients); progressive disease occurred in 6 patients. There was also some improvement in other clinical parameters, including overall blood pressure, and it was noted that patients with an SDHB mutation saw a benefit.[20] Sunitinib was also evaluated in a phase II open label trial, where 23 of the evaluable patients had a median PFS of 13.4 (95% CI, 5.3–24.6) months; the ORR was 13%. Similar to our study, the OS end point was not reached.[22] Currently, a multicenter randomized controlled phase II study assessing efficacy of sunitinib on PFS of mPPGL is underway (NCT01371201), in which preliminary results have shown a median PFS of 8.9 months (95% CI, 5.5–12.7) in the sunitinib group vs 3.6 months (95% CI, 3.1–6.1) in the placebo group.[27] Pazopanib was also assessed in a phase II open label prospective trial; however, due to poor accrual rate, the study was discontinued. Of the 6 enrolled and evaluable patients, median PFS was 6.5 months and OS was 14.8 months, suggesting some clinical efficacy; however, only 1 patient experienced a PR.[21]

Hypertension remains the most common side effect of all MKIs, particularly for lenvatinib as it inhibits multiple sites of angiogenesis, and this a potential limiting factor when treating secretory mPPGL. While hypertension may be more challenging to manage at the initiation of drug therapy, as time passes and if disease and biochemical regression occur, then the number of antihypertensive medications needed should decline. Therefore, it is important that all patients have well-controlled blood pressure prior to initiating an MKI and patients need close follow-up throughout their treatment course. Additional AEs, such as hematologic and gastrointestinal, and other generalized symptoms, such as fatigue and weight loss, are shared by all MKIs.

The study was limited by its combination of prospective and retrospective cohorts and sample size. We also did not have data on pre- and post-therapy biochemical levels, that is, metanephrines/normetanephrines in all of the patients; hence, these could not be used as a surrogate tumor marker for response in our cohort. Additional data, such as tracking quality of life before and during lenvatinib therapy are lacking. We were unable to conclude whether exposure to a prior MKI impacted response in our population due to small sample size. However, in other tumor populations, lenvatinib continued to show activity in spite of prior exposure to other VEGF inhibitors.[28,29]

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