Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma

Abstract

RET (rearranged during transfection) is a transmembrane receptor tyrosine kinase encoded by proto-oncogene RET (1) and is crucial for the development of the enteric nervous system and kidneys (2, 3). Mutations resulting in constitutively active RET are linked to the development of several cancers and are associated with tumor proliferation, invasion, and migration (4-6).

Pheochromocytoma is a very rare cancer with an annual incidence of approximately 500 to 1600 cases in the United States (7). Pheochromocytomas are neuroendocrine tumors deriving from chromaffin cells of the medulla of the adrenal glands. Germline mutations have been identified, most commonly seen in SDHB (9%), VHL (4%), and RET (6%) (8). The majority of pheochromocytomas occur sporadically. Somatic mutations in HRAS (10%), NF1 (9%), and RET (3%) can be identified in a minority of patients (8). These tumors are also observed in several familiar disorders including multiple endocrine neoplasia type 2 (MEN2), an autosomal dominant disorder that arises from germline activating RET mutations (9). Virtually all patients with MEN2 syndrome are at risk of developing medullary thyroid cancer (MTC), and approximately 50% of patients also develop pheochromocytoma (10), depending on the type of mutation (11). The overall likelihood of malignancy in MEN2-associated pheochromocytoma is lower compared with the sporadic incidence rate of pheochromocytoma.

The vast majority of pheochromocytomas are benign; however, 10% to 17% are metastatic, defined as the occurrence of chromaffin tumor cells in organs that are physiologically devoid of such cells. The 5-year survival rate of metastatic pheochromocytoma is estimated to be between 34% and 60% (12-14). Patients with pheochromocytoma present with a number of symptoms caused by the overproduction of catecholamines, including hypertension, headache, palpitation, and ephidrosis (15). Additional symptoms including constipation are a late sign of catecholamine excess in advanced cases (16).

Selpercatinib is a first-in-class highly selective and potent RET kinase inhibitor with central nervous system activity and is approved in multiple countries for the treatment of RET-activated lung or thyroid cancers (17, 18). Selpercatinib was also granted approval by the US Food and Drug Administration for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. In LIBRETTO-001 (NCT03157128), a global phase 1/2, multicohort clinical trial involving adolescent and adult patients with solid tumors harboring an activating RET alteration, selpercatinib efficacy was evaluated in 41 patients with tumors other than non–small cell lung cancer and thyroid cancer with somatic RET-fusion. The overall response rate was 44% with a median duration of response of 24.5 months (19). Tumor types with responses included pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The approval of the tumor agnostic indication underscores the importance of routine RET genomic testing and the clinical benefits of targeting RET alterations regardless of tumor type.

The first case of pheochromocytoma in which an oncogenic RET fusion was therapeutically targeted has been reported previously (20). A 66-year-old male with RET fusion-positive metastatic pheochromocytoma received selpercatinib as part of the expanded access program of LIBRETTO-201. After only 1 month of treatment, his bone pain improved, and he achieved a partial response following 12 weeks of treatment (20). This highlights the potential use of selpercatinib in other RET-activated cancers. This case series describes 6 patients with pheochromocytoma treated with selpercatinib in this trial.

Case Reports

This study received ethical/institutional review board approval and was conducted in accordance with the Declaration of Helsinki, and patients provided informed consent before enrollment.

Case 1

A 70-year-old man presented with metastatic pheochromocytoma approximately 41 years after bilateral adrenalectomy and subsequent diagnosis with MEN2A (thyroidectomy for MTC and confirmed germline RET-mutation C634F) (Table 1). Symptomatic recurrence occurred in the left adrenal bed, aortocaval nodes, and small pulmonary metastases. Resection was not performed because of the multifocal recurrence. Both plasma normetanephrine and metanephrine were elevated, serum calcitonin was detectable but relatively low at 1.7 pmol/L, and CEA was <1 µg/L, which together with avid MIBG uptake in metastatic lesions strongly suggested these to be from pheochromocytoma rather than MTC. Biopsy was not performed due to the risk of catecholamine crisis. The patient was treated with MIBG after initial diagnosis. Progressive metastatic disease was subsequently treated with ¹⁷⁷Lu-DOTATATE. After the development of severe hypertension and ileus, phenoxybenzamine and metoprolol were added. He presented with severe thoracic back pain associated with a destructive lesion in T6, resulting in treatment by external beam radiation therapy. Approximately 1 year after ¹⁷⁷Lu-DOTATATE, the patient had subsequent and progressive metastatic disease of an aortocaval mass, pancreatic mass, and multiple pulmonary lesions, and he commenced selpercatinib 160 mg twice per day. Selpercatinib treatment resulted in a confirmed partial response with 8.3 months duration by independent review committee (IRC) and stable disease per investigator assessment. Clinical response with reduction in thoracic back pain was notable within days of commencing treatment. Plasma normetanephrine decreased from >9.999 nmol/L to 1.190 nmol/L (normal range: <1.280 nmol/L), and metanephrine from 0.906 nmol/L to <0.050 nmol/L (normal range: <0.447 nmol/L). Within 3 months of starting RET-targeted treatment, the patient was able to discontinue alpha- and beta-blockers. The patient had progressive disease per investigator assessment after 13.8 months and per IRC after 19.4 months. After radiographic progression, the patient signed informed consent for treatment beyond progression and continued selpercatinib therapy. After approximately 18 months of treatment, he experienced grade 2 diarrhea and had a dose reduction to 80 mg twice daily. The patient received selpercatinib for a total of 37 months and discontinued due to further disease progression. He died 2 months after discontinuation from treatment.

Computerized tomography (CT) scan images of the patient's tumor at baseline and after 14 months of treatment with selpercatinib are included in Fig. 1.

Figure 1.

CT images at baseline and after 14 months of treatment with selpercatinib for case 1 and case 3. Case 4, CT images of the patient’s lungs at baseline and after 7 months of treatment with selpercatinib. For case 5, images at baseline and cycle 4 and cycle 25 of treatment with selpercatinib. All figures were provided by investigators.

Abbreviations: CT, computed tomography; PCC, pheochromocytoma; PR, partial response; SD, stable disease.

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Case 2

A 51-year-old woman with MEN2A and a history of MTC and pheochromocytoma underwent a thyroidectomy and adrenalectomy (Table 1). She developed metastatic pheochromocytoma, with multiple bone, omentum, lung, liver, and spleen metastases in 3 years. She was treated with multiple courses of radiation, additional resection, sunitinib, and subsequently temozolomide/capecitabine in the subsequent 5 years. She had a partial response with sunitinib but experienced further progressive disease. Biopsy of a bone lesion confirmed RET C618S somatic mutation and metastatic pheochromocytoma. The patient's CEA blood level was normal, and calcitonin IHC was negative in the metastatic tissues, suggesting a low likelihood that the relapse was of MTC origin. Secondary to her disease progression and uncontrolled bone pain, the patient was treated with selpercatinib 160 mg twice daily and experienced a partial response that lasted 3.8 months by both IRC and investigator assessment. She had progressive disease after 5.5 months. After radiographic progression, the patient signed informed consent for treatment beyond progression and continued selpercatinib therapy. She received a total of 9.4 months of treatment and discontinued due to further disease progression. She died 1 month after discontinuation from treatment due to disease progression.

Case 3

A 45-year-old woman was diagnosed with pheochromocytoma (Table 1). Hereditary Paraganglioma-Pheochromocytoma Panel plus Limited Evidence Genes were performed. Genomic results indicated no clear deleterious mutations in any of the 14 genes on this panel and ruled out the hereditary risk factor for this patient. Over the subsequent decade, she underwent a bilateral adrenalectomy because of localized recurrence, resection of recurrent tumor, and debulking of right retroperitoneal tumor. Her disease progressed slowly over the next 10 years. The biopsy report from the initial adrenalectomy specimen and the subsequent recurrent disease resected tumor sample confirmed pheochromocytoma. She underwent 2 cycles of cyclophosphamide/vincristine/dacarbazine chemotherapy without clinical benefit. She subsequently received 131-MIBG therapy with autologous stem cell rescue, without tumor shrinkage but with improvement in blood pressure, palpitations, and flushing. However, abdominal pain and constipation from the possible mass effect of the tumor remained persistent. Due to a somatic M918T RET-mutation noted with next-generation sequencing in a tumor sample, she began selpercatinib treatment 22 years after the initial diagnosis of pheochromocytoma, with resolution of abdominal pain and constipation and with marked improvement in plasma metanephrine levels. Her baseline plasma free metanephrine was >20 000 pg/mL (normal range: <57 pg/mL), and free normetanephrine was >20 000 pg/mL (normal range: <148 pg/mL). Metanephrine decreased to 6880 pg/mL and 3315 pg/mL at 6 months and 12 months posttreatment, respectively. Plasma normetanephrines remained elevated (>20 000 pg/mL). She developed treatment-related grade 3 palmar-plantar erthrodysaesthesia requiring serial dose reductions to 60 mg twice daily. Her best response on study treatment was stable disease by IRC and investigator assessment. The patient experienced progressive disease (small new bone lesion) after 22.0 months by investigator assessment and was assessed with ongoing stable disease by IRC with progression-free survival more than 56.3 months. She remained on treatment at 120 mg daily (40 mg morning and 80 mg afternoon) as of January 2023.

CT scan images of the patient's tumor at baseline and after 14 months of treatment with selpercatinib are included in Fig. 1.

Case 4

A 23-year-old man initially presented with acute back pain. Retroperitoneal hemorrhage was diagnosed; the patient had liver and pulmonary metastasis, in addition to the right-sided adrenal tumor, which was resected later (Table 1). Pheochromocytoma was diagnosed by immunohistochemistry with a Ki-67-index of 4.8%. Germline RET-sequencing revealed a mutation of C634R. Further workup revealed concomitant primary hyperparathyroidism but no evidence of medullary thyroid carcinoma with a normal calcitonin level. Postoperatively, chromogranin A, urinary normetanephrines, and metanephrines remained excessively elevated, and cross-sectional imaging revealed extensive metastatic disease. A biopsy by video-assisted thoracoscopy was performed, and metastatic pheochromocytoma was histologically confirmed. His disease was treated with ¹⁷⁷Lu-DOTATOC radiopeptide therapy 4 months after initial diagnosis, followed by cyclophosphamide, dacarbazine, and vincristine 3 months later. He began treatment with selpercatinib 10 months after initial diagnosis at 160 mg twice daily. His baseline Eastern Cooperative Oncology Group performance status was 1, with hypoxia due to pulmonary metastases and hypertension related to extremely high catecholamines. Treatment resulted in clinical improvement with marked response of chromogranin A. The lowest level of plasma metanephrine was reached after 4 weeks, from 1110 ng/L to 419 ng/L (normal range: <84 ng/L). Plasma normetanephrine decreased from 24 000 ng/L to 12 600 ng/L (normal range: <103.5 ng/L). The best radiographic response was stable disease, which lasted 9.4 months by IRC and investigator assessment. The patient continued on treatment until death due to progressive disease.

CT scan images of the patient’s lungs at baseline and after 7 months of treatment with selpercatinib are shown in Fig. 1.

Case 5

A 30-year-old woman presented with metastatic MTC with a left-sided adrenal heterogeneous mass consistent with pheochromocytoma (Table 1). The patient also had multiple lesions at liver, lymph nodes, and bone, which could be MTC disease-related metastasis. Germline testing of peripheral blood leukocytes subsequently confirmed RET-mutation C634R. Due to the extent of metastatic disease and progression within 3 months of initial diagnosis of her MTC, she began treatment with selpercatinib 160 mg twice daily for progressive MTC, and observation of the asymptomatic pheochromocytoma was recommended. She did not have any symptoms of pheochromocytoma prior to initiating selpercatinib; thus, given the extent of MTC metastases, she did not have any further evaluation of this left adrenal mass with MIBG or surgical resection prior to starting selpercatinib. At baseline, her pheochromocytoma on the left adrenal measured 2.0 × 1.6 cm. After 4 months of therapy, the pheochromocytoma measured 1.4 × 1.1 cm. It measured 1.1 × 0.9 cm after 17 months of therapy and 1 × 0.8 cm at the most recent imaging after 25 months of therapy (see Case 5 images in Fig. 1). This correlates with a partial response of 50% decrease from the baseline longest diameter of the adrenal mass. Treatment also resulted in a partial response of the MTC per IRC and investigator assessment. The duration of partial response was 19.6 months per IRC and 17.4 months per investigator assessment. Biochemically, her baseline plasma free metanephrine was 0.84 nmol/L (normal range: <0.50 nmol/L), and free normetanephrine was 1.2 nmol/L (normal range: <0.9 nmol/L), and these decreased to normal levels on repeat testing 8 months after starting therapy. Plasma metanephrines remained normal on subsequent testing. Throughout her treatment, she never developed any hypertension or symptoms of pheochromocytoma. The patient received a total of 28.4 months of selpercatinib treatment and died due to progression of MTC.

CT scan images of the patient's tumor at baseline and cycle 4 and cycle 25 of treatment with selpercatinib are included in Fig. 1.

Case 6

A 40-year-old woman had an initial diagnosis of MTC and pheochromocytoma (Table 1). Germline testing revealed a RET M918T mutation associated with MEN2B. She underwent a total thyroidectomy and radical neck dissections at that time. Bilateral adrenalectomy was performed 4 years later. She had persistent abdominal pain, nausea, vomiting, and constipation, with ulcerative colitis as an additional complicating factor. She developed progressive metastatic MTC 27 years after the initial diagnosis. The RET M918T mutation was confirmed by next-generation sequencing. Baseline 24-hour urine fractionated metanephrines and plasma metanephrine/normetanephrine were elevated. These elevated values after bilateral adrenalectomy implied residual and/or metastatic pheochromocytoma disease for this patient. Treatment commenced with selpercatinib 160 mg twice daily for MTC. Plasma metanephrine decreased from 0.840 nmol/L to <0.200 nmol/L and normetanephrine from 0.940 nmol/L to 0.430 nmol/L. She had a complete response for her pheochromocytoma and MTC disease per IRC and partial response per investigator assessment. The patient continues on study treatment with a duration of response of 45.4 months. Her 24-hour urine fractionated metanephrines remained suppressed as of January 2023.

Safety

Overall, the safety findings were generally consistent with the safety profile of selpercatinib. Serious adverse events are summarized in Table 1. Only 1 serious adverse event (Campylobacter gastroenteritis grade 3) was considered to be related to the study drug. Two patients required a dosage reduction (a grade 2 diarrhea and a grade 3 palmar-plantar erythrodysaesthesia).

Discussion

For patients with metastatic pheochromocytoma, targeted and effective treatment options are greatly needed. The lack of approved systemic therapies, with the exception of ¹³¹I-Iobenguane in the United States, has typically led to therapy being selected on the basis of practice and experience, with the management of pheochromocytoma largely determined by its biochemical phenotype (21).

Chemotherapy using cyclophosphamide/vincristine/dacarbazine has historically been the most common regimen to treat metastatic pheochromocytoma (22). More recently, several anti-angiogenic tyrosine kinase inhibitors have been examined in this disease, a particularly important therapeutic approach as many germline or somatic mutations associated with pheochromocytoma and paraganglioma predispose to angiogenesis (21, 23). Published data related to these rare tumor types are limited, and there is a need for a better understanding of the overall clinical and survival outcomes in patients with pheochromocytoma (24-26). FIRSTMAPPP, the first randomized study in patients with malignant pheochromocytoma and paraganglioma, recently demonstrated sunitinib prolongs progression-free survival. The study enrolled 78 patients during an 8-year period. The primary endpoint of progression-free survival at 12 months was met by 35.9% of patients receiving sunitinib treatment and 18.9% of patients receiving placebo. The median progression-free survival was 8.9 months vs 3.6 months in the sunitinib and placebo arms, respectively (27). Investigations of other multikinase inhibitors including cabozantinib (NCT02302833) and axitinib (NCT03839498) are ongoing.

This pheochromocytoma case series is the first report of the responses of patients with RET-mutant malignant pheochromocytoma treated with selpercatinib and adds to the diversity of RET-activated tumor types that may benefit from a selective RET inhibitor.

We describe the first 6 patients with RET-mutant pheochromocytoma treated with selpercatinib in the LIBRETTO-001 study. Of the first 4 patients, who had pheochromocytoma alone, 2 patients achieved a partial response and 2 had stable disease per IRC. Patients 5 and 6 had concomitant MTC and pheochromocytoma at study entry and achieved a partial response and complete response respectively (of both MTC and pheochromocytoma) per IRC. These 2 cases suggest that pheochromocytoma in patients with MEN2-syndrome and with advanced, progressive MTC can be safely and effectively treated with selpercatinib without hyperadrenergic issues.

Treatment duration ranged between 9.2 months to more than 56.4 months. As of January 2023, 2 patients remained on treatment; the other 4 patients discontinued from study treatment due to disease progression.

No new or unexpected safety findings were reported in these 6 patients. One of the striking aspects of case 1 was the rapid and sustained reduction in plasma metanephrines and cessation of alpha-blockers. None of the patients were reported developing hypertension related to selpercatinib.

Conclusion

Targeted and effective treatment options are needed for advanced metastatic or unresectable malignant pheochromocytoma. While the natural course of this disease may be markedly variable, genomic information should be considered for guiding treatment decisions. This case series demonstrates the benefit of selpercatinib in RET-activated pheochromocytoma and adds to the diversity of RET-activated tumor types that may benefit from a selective RET inhibitor.

Further patient follow-up is being conducted to better characterize selpercatinib as a treatment option for various solid tumor types that extends beyond non–small cell lung cancer and thyroid cancers.

Acknowledgments

We thank the clinical trial participants, without whom this work would not be possible. Medical writing support was provided by Eli Lilly and Company.

Funding

This work was supported by Eli Lilly and Company (no grant numbers apply).

Disclosures

B.D.-B. reports consulting fees from Eli Lilly and Company. B.K. reports grant support to her institution from Eisai, Merck, and Xencor. E.M. reports consulting fees from AbbVie Consulting, Eli Lilly and Company, Mirati Therapeutics, Janssen Scientific Affairs LCC, Sonofi, Bristol Myers Squibb, Daiichi Sankyo Co, Fusion Pharmaceuticals, Gilead, Iovance Biotherapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Merck & Co., Eli Lilly and Company, Takeda Pharmaceuticals U.S.A., Inc. M.H. reports grants or contracts from Eli Lilly and Company and Blueprint Medicines; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Blueprint Medicines; participation on a Data Safety Monitoring Board or Advisory Board for Blueprint Medicines, Exelixis, and Eli Lilly and Company; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for American Thyroid Association. L.J.W. reports consulting fees for Bayer, Blueprint Medicines, Coherus, Eisai, Exelixis, Ellipses, Illumina, Eli Lilly and Company, Merck, Nested, EMD Serono; participation on a Data Safety Monitoring Board or Advisory Board for PDS Biotechnology. J.W. is an employee and shareholder of Eli Lilly and Company. X.X. is an employee and shareholder of Eli Lilly and Company. R.C.-B. has no disclosures to report.

Data Availability

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org/ourmember/lilly/.

References