Phase II Trial of nab-Sirolimus in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT): Long-Term Efficacy and Safety Update

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

nab-Sirolimus is approved in the United States for the treatment of metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa) on the basis of the primary analysis results of the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570). Results from the primary analysis were previously published; however, the median duration of response (mDOR) had not been reached at that time. Here, 3 years after the primary analysis, we report final efficacy and safety data (data cutoff: April 29, 2022). At study completion, the confirmed overall response rate (by independent radiologist review using RECIST v1.1) was 38.7% (95% CI, 21.8 to 57.8), with an additional converted confirmed complete response (n = 2). Median progression-free survival remained the same at 10.6 months (95% CI, 5.5 to 41.2). The mDOR was reached at 39.7 months (95% CI, 6.5 to not reached [NR]), and the median overall survival at completion was 53.1 months (95% CI, 22.2 to NR). The most common treatment-related adverse events (TRAEs) were stomatitis (82.4%) and fatigue and rash (each 61.8%). No new or unexpected adverse events occurred, and no grade ≥4 TRAEs were reported. These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

INTRODUCTION

Malignant perivascular epithelioid cell tumors (PEComas) are an ultrarare, aggressive soft tissue sarcoma in which cytotoxic chemotherapy regimens have shown modest benefit.¹ nab-Sirolimus is a nanoparticle, albumin-bound, intravenously administered mTOR inhibitor approved in the United States for the treatment of patients with locally advanced, unresectable, or metastatic malignant PEComas.² In the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570), the predefined primary analysis was conducted when all patients were treated for at least 6 months (data cutoff [DCO]: May 22, 2019). The confirmed overall response rate (ORR), as assessed by independent radiologists, was 38.7% (12 of 31 patients; 95% CI, 21.8 to 57.8), all partial responses.

At the 1.5-year follow-up after the primary analysis date (November 23, 2020; 2 years after the last patient started treatment), seven of 12 responders had ongoing treatment, and the median duration of response (DOR) had not been reached after a median follow-up for response of 2.5 years (DOR range, 5.6-47.2+ months).³ The median progression-free survival (PFS) was 10.6 months (95% CI, 5.5 months to not reached [NR]), and the median overall survival (OS) was 40.8 months (95% CI, 22.2 to NR). Most treatment-related adverse events (TRAEs) were grade 1 or 2 and were manageable for long-term treatment; no deaths related to nab-sirolimus occurred. Herein, we report the final analysis (DCO: April 29, 2022), including the median DOR, at 3.5 years after the last patient initiated treatment.

METHODS

AMPECT was an open-label, phase II, multicenter, registrational trial in adults (18 years and older). Trial design details and outcome measures have been previously published.³

Eligible patients had histologically confirmed diagnosis of malignant PEComa, an Eastern Cooperative Group performance status score of ≤1, locally advanced inoperable or metastatic disease, and no previous mTOR inhibitor use. Patients received nab-sirolimus 100 mg/m² by intravenous infusion once weekly for 2 weeks, on days 1 and 8, of a 21-day cycle until disease progression, unacceptable toxicity, patient preference, or transfer to commercially available drug after US Food and Drug Administration (FDA) approval. The primary end point was confirmed ORR by 6 months on the basis of independent radiographic review using RECIST v1.1. Secondary end points included DOR, PFS at 6 months, median PFS, median OS, and safety and tolerability. Exploratory end points included assessment of tumor biomarkers using next-generation sequencing and immunohistochemistry and their relationship to clinical outcomes.

The study was approved by independent institutional review boards of each participating site and was conducted in accordance with the ethics principles of the Declaration of Helsinki and with Good Clinical Practice guidelines defined by the International Conference on Harmonization. All patients provided written informed consent.

RESULTS

Baseline patient demographics and clinical characteristics are summarized in Table 1.

TABLE 1.

Baseline Patient Demographics and Clinical Characteristics

Parameter			All Treated Patients (N = 34)
Age, years, median (range)			60 (27-78)
≥65 years, No. (%)			15 (44.1)
Sex, female, No. (%)			28 (82.4)
Race, No. (%)
White			24 (70.6)
Black			3 (8.8)
Asian			3 (8.8)
Pacific Islander/Hawaiian			1 (2.9)
Other/unknown			1 (2.9)
Not reported			2 (5.9)
ECOG PS
0			26 (76.5)
1			8 (23.5)
Disease status, No. (%)
Metastatic			29 (85.3)
Locally advanced, inoperable			5 (14.7)
Previous systemic therapy for advanced PEComa, No. (%)a			4 (11.8)
Primary tumor location, No. (%)
Uterus			8 (23.5)
Pelvis, extrauterine			6 (17.6)
Retroperitoneum			6 (17.6)
Lung			4 (11.8)
Kidney			4 (11.8)
Aorta			1 (2.9)
Brain			1 (2.9)
Liver			1 (2.9)
Muscle			1 (2.9)
Ovary			1 (2.9)
Small bowel			1 (2.9)
Site of metastatic disease, No. (%)b
Lung, thoracicc			21 (72.4)
Abdomend			8 (27.6)
Pelvis			7 (24.1)
Liver			6 (20.7)
Colon			4 (13.8)
Retroperitoneum			3 (10.3)
Bone, unspecified			2 (6.9)
Spleen			2 (6.9)
Kidney			1 (3.4)
Ovary			1 (3.4)
No. of metastatic sites, No. (%)
1			11 (37.9)
2			9 (31.0)
3			7 (24.1)
>3			2 (6.9)

NOTE. Reused from the study by Wagner et al³ licensed under CC BY 4.0.

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PEComa, perivascular epithelioid cell tumor.

^a Includes systemic treatment for advanced disease (docetaxel, doxorubicin, gemcitabine, ifosfamide, and olaratumab; excludes neoadjuvant and adjuvant therapy).

^b n = 29.

^c Includes lymph nodes (hilar and precarinal).

^d Includes omentum, perigastric area, mesenteric root, peritoneum, and serosa.

Efficacy

In the final analysis, 3 of 34 patients were receiving treatment with nab-sirolimus. The mean treatment duration for all patients was 14.5 months (range, 0.3-65.2). Reasons for discontinuing treatment were disease progression (n = 20, 58.8%), withdrawal of consent (n = 6, 17.6%), adverse event (n = 2, 5.9%), and initiation of new cancer therapy, death, and other (no reason recorded; n = 1 each, 2.9%).

In the efficacy-evaluable population (n = 31), the primary end point of confirmed ORR by RECIST v1.1 remained at 38.7% (95% CI, 21.8 to 57.8; Table 2). By study completion, 2 of 31 (6.5%) patients achieved a confirmed complete response, both of which had a TSC2-inactivating alteration (one frameshift, one homozygous deletion), at 11 and 34 months from the start of therapy, despite having a dose reduction or interruption (Table 2). The median DOR was 39.7 months (95% CI, 6.5 to NR; Table 2, Fig 1A), ranging from 5.6 to 60.8 months. Stable disease was the best response in 16 (51.6%) patients and progressive disease in three (9.7%) patients (Table 2). Disease control rate remained at 71% (95% CI, 52.0 to 85.8; Table 2). The median PFS was 10.6 months (95% CI, 5.5 to 41.2; Table 2, Fig 1A), and the median OS was 53.1 months (95% CI, 22.2 to NR). Two patients initially ineligible for surgery of their locally advanced tumor subsequently had resection of disease after treatment with nab-sirolimus and remained in long-term survival follow-up for 3.5 years and 5.5 years.

TABLE 2.

Summary of Key Efficacy End Points in Final Analysis on the Basis of RECIST Assessments

Efficacy End Point	All Efficacy-Evaluable Patients (n = 31)	Patients With Alterations in TSC1 (n = 5)a	Patients With Alterations in TSC2 (n = 9)a
Overall response rate, No. (%)	12 (38.7)	—	—
95% CI	21.8 to 57.8	—	—
Best overall response (confirmed), No. (%)
Complete response	2 (6.5)	0	2 (22.2)
Partial response	10 (32.3)	1 (20.0)	6 (66.7)
Stable disease	16 (51.6)	3 (60.0)	1 (11.1)
Progressive disease	3 (9.7)	1 (20.0)	0
Disease control rate,b No. (%)	22 (71.0)	—	—
95% CI	52.0 to 85.8	—	—
Median DOR, months	39.7	5.6	51.7
95% CI	6.5 to NR	NE	6.5 to NR
Median PFS, months	10.6	5.5	53.1
95% CI	5.5 to 41.2	1.4 to NR	10.6 to NR
Median OS, monthsc	53.1	31.6	NR
95% CI	22.2 to NR	3.8 to NR	53.1 to NR

NOTE. Percentages are rounded and are based on the number of patients with positive, negative, or unevaluable biomarker status at screening.

Abbreviations: DOR, duration of response; NE, not evaluable; NR, not reached; OS, overall survival; PFS, progression-free survival.

^a Of the 25 patients with tissue sufficient for next-generation sequencing, 14 patients had inactivating alterations in TSC1 or TSC2.

^b Percentage of patients with a confirmed objective response or with stable disease of ≥12-week duration.

^c The median time from first dose to last contact during OS follow-up was 22.0 months (range, 1-66).

FIG 1.

Tumor responses to nab-sirolimus in patients with PEComa per RECIST v1.1. (A) Spider plot showing changes in the sum of target tumor measurements over time. Arrowheads indicate patients who were still on treatment at the time of the 3.5-year follow-up. (B) Waterfall plot of the best overall change from baseline in the sum of target tumor measurements, evaluated at the 3.5-year follow-up. PEComa, perivascular epithelioid cell tumor.

Observed outcomes from exploratory biomarker analyses of response were consistent with previously reported responses for patients with inactivating alterations in TSC1 (n = 5) or TSC2 (n = 9) and with expression of pS6, a downstream marker of mTOR activation (Table 2 and Fig 1B).

Safety

The safety-evaluable population consisted of 34 patients treated with at least one dose of nab-sirolimus. There was no change in the overall safety profile during long-term follow-up (Appendix Table A1, online only). The most common TRAEs were stomatitis (28 of 34 patients [82.4%]) and fatigue and rash (21 of 34 patients [61.8%] each). Of the 56 stomatitis events that occurred among 28 patients, 91.0% (51 of 56) resolved at the time of data cutoff. Stomatitis was most commonly managed with steroid mouthwash; 68% of all patients received stomatologic preparations (most frequently magic mouthwash, sucralfate, nystatin, and dexamethasone).

Overall, the median dose intensity was 60 mg/m²/week, representing 90% of the planned protocol maximum dose intensity of 66.6 mg/m²/week, with a dosing schedule of 100 mg/m² given once weekly for 2 weeks, on days 1 and 8, of a 21-day cycle. In the final analysis, 14 of 34 (41.2%) patients had at least one dose reduction (n = 13 because of TRAEs; n = 1 because of physician decision); 3 of the 14 patients received two dose reductions during the study, and most (76.5%) dose reductions occurred within the first 3 months of treatment (Appendix Fig A1). The most common TRAEs associated with dose reductions were pneumonitis (4 of 13 patients [31%]) and stomatitis (3 of 13 patients [23%]; Appendix Table A2). Of 22 noninfectious pneumonitis events that occurred in 7 of 34 (20.6%) patients, all were grade 1 or 2, 21 (95.5%) events were resolved, and no events led to treatment discontinuation.

Five of 14 patients with a dose reduction had a confirmed response either before (3 of 5 patients) or after (2 of 5 patients) their first dose reduction (Appendix Fig A1). All five responders maintained their response for 6.1-37.3 months after the first dose reduction (Appendix Fig A1). None of the 14 patients who received a dose reduction discontinued nab-sirolimus because of a TRAE. At study closure, no additional discontinuations because of TRAEs were reported, and no new treatment-related serious safety signals were identified.

DISCUSSION

This long-term follow-up analysis of nab-sirolimus for patients with malignant PEComa showed a clinically meaningful overall response rate, median duration of response of more than 3 years, and durable disease control and survival, reflecting the clinical benefit of nab-sirolimus in the treatment of this aggressive, ultrarare sarcoma. Although responses were most commonly seen in patients with tumors harboring TSC2 mutations, responses and prolonged disease control were also observed in patients with differing tumor genotypes, suggesting that mTOR inhibition is effective for a broader patient population with malignant PEComa. The sample size in this single-arm phase II study was too small to draw definitive conclusions about the exploratory analysis of tumor genotypes; however, preliminary efficacy signals observed among patients with tumors with select biomarkers warrant further evaluation.

There were no new safety signals at study closure, which reaffirms the manageable long-term safety profile of nab-sirolimus, consistent with the mTOR inhibitor class. Taken together, the durable clinical benefit and acceptable safety profile support the use of nab-sirolimus as the first FDA-approved therapy for patients with advanced malignant PEComa.²

APPENDIX

FIG A1.

Best overall response among patients with at least one dose reduction (n = 14). Best overall responses are based on independent radiologist review; however, treatment decisions were made by the treating investigator on the basis of radiology review and clinical symptoms. ^aThe patient had unconfirmed PR and discontinued therapy because of an AE without a confirmatory scan. AE, adverse event; PR, partial response.

TABLE A1.

Any-Grade TRAEs Occurring in ≥25% of Patients (N = 34)

TRAE	Any Grade, No. (%)	Grade 3, No. (%)a
Hematologic TRAEs
Anemiab	18 (52.9)	5 (14.7)
Thrombocytopeniab	12 (35.3)	1 (2.9)
Nonhematologic TRAEs
Stomatitisb	28 (82.4)	6 (17.6)
Fatigue	21 (61.8)	1 (2.9)
Rashb	21 (61.8)	0
Nausea	16 (47.1)	0
Diarrheab	14 (41.2)	1 (2.9)
Hyperglycemiab	14 (41.2)	3 (8.8)
Weight decreased	14 (41.2)	0
Hypertriglyceridemiab	12 (35.3)	1 (2.9)
Edemab	12 (35.3)	1 (2.9)
Appetite decreased	12 (35.3)	0
Hypercholesterolemiab	11 (32.4)	0
Headache	11 (32.4)	0
Dysgeusiab	10 (29.4)	0
Pruritus	9 (26.5)	0
ALT increasedb	9 (26.5)	1 (2.9)
Vomiting	9 (26.5)	1 (2.9)

Abbreviation: TRAE, treatment-related adverse event.

^a Additional grade 3 TRAEs reported in ≥1 patient were abdominal pain, AST increased, lymphopenia, pancytopenia (n = 1 each), and dehydration and hypokalemia (n = 2 each). No grade 4 or 5 TRAEs were reported.

^b Reported on the basis of groupings of preferred terms defined by standardized queries in the Medical Dictionary for Regulatory Activities v24.0.

TABLE A2.

Any-Grade TRAEs Leading to Dose Reduction

TRAE	Patient (N = 34), No. (%)
Any TRAE leading to dose reduction	13 (38.2)
Pneumonitis	4 (11.8)
Stomatitis	3 (8.8)
Abdominal pain	1 (2.9)
Acute coronary syndrome	1 (2.9)
Dehydration	1 (2.9)
Fatigue	1 (2.9)
Hyperglycemia	1 (2.9)
Increased ALT	1 (2.9)
Increased AST	1 (2.9)
Increased creatinine	1 (2.9)
Thrombocytopenia	1 (2.9)
Weight decreased	1 (2.9)

Abbreviation: TRAE, treatment-related adverse event.

DATA SHARING STATEMENT

The data used for the analyses in this manuscript are available on request from the corresponding author.

AUTHOR CONTRIBUTIONS

Conception and design: Andrew J. Wagner, Vinod Ravi, Kristen Ganjoo, Anita N. Schmid, Mark A. Dickson

Provision of study materials or patients: Andrew J. Wagner, Vinod Ravi, Richard F. Riedel, Kristen Ganjoo, Brian A. Van Tine, Rashmi Chugh, Lee Cranmer, Erlinda M. Gordon, Mark A. Dickson

Collection and assembly of data: Andrew J. Wagner, Vinod Ravi, Richard F. Riedel, Kristen Ganjoo, Brian A. Van Tine, Rashmi Chugh, Lee Cranmer, Jason L. Hornick, Heng Du, Anita N. Schmid, Mark A. Dickson, Li Ding, David J. Kwiatkowski

Data analysis and interpretation: Andrew J. Wagner, Vinod Ravi, Richard F. Riedel, Kristen Ganjoo, Brian A. Van Tine, Rashmi Chugh, Lee Cranmer, Erlinda M. Gordon, Jason L. Hornick, Li Ding, Anita N. Schmid, Willis H. Navarro, David J. Kwiatkowski, Mark A. Dickson, Li Ding

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Phase II Trial of nab-Sirolimus in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT): Long-Term Efficacy and Safety Update

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