Durable remission of metastatic myxoid liposarcoma following the cautious addition of pembrolizumab to ongoing pazopanib treatment: A case report

Abstract

Responses to conventional treatments, like chemotherapy and targeted agents, are generally infrequent, and of brief duration in patients with metastatic soft tissue sarcomas. We present a case of metastatic myxoid liposarcoma that achieved biopsy-proven complete remission with minimal toxicity following the addition of pembrolizumab to pazopanib as fourth-line treatment. This regimen resulted in significant tumor regression following just five doses. After 15 doses of pembrolizumab, radiographs demonstrated an ongoing response, with stable residual lesions, and a biopsy of a sacral lesion confirmed a pathologic complete remission. The patient subsequently discontinued all therapies and remains in an ongoing unmaintained remission. The combination of pembrolizumab and pazopanib demonstrated unexpected clinical benefit with minimal toxicity, suggesting that it may be worthy of further investigation in myxoid liposarcoma and possibly other histologic subtypes of STS.

Introduction

Soft tissue sarcomas (STS) represent a rare group of mesenchymal malignancies that includes more than 50 histological subtypes, each with unique histopathological characteristics.^1–3 Localized STS are primarily managed with surgical resection. ¹ Adjuvant radiotherapy or systemic therapy may be considered for high-risk tumors or following suboptimal resections.^1–3 Despite these treatments, over 25% of patients with large, high-grade sarcomas will eventually develop distant metastasis, resulting in a poor prognosis.^4,5 While systemic chemotherapy remains the standard of care for metastatic sarcomas, first-line chemotherapy produces only a modest response rate characterized by rare complete remissions with a relatively short response duration.^6,7 Targeted agents such as pazopanib have also shown only modest effectiveness in reducing the growth of metastatic sarcoma.^8,9 Therefore, more effective treatment options for metastatic sarcomas are a crucial need.

The discovery of immune checkpoint inhibitors (ICI) targeting CTLA-4, PD-1, and PD-L1 has revolutionized cancer management, significantly improving patient outcomes in many epithelial cancers. ¹⁰ However, the incorporation of ICI treatment remains a challenge in STS management, since these tumors are immunologically quiescent, with a low tumor mutational burden (TMB) and an immunosuppressive tumor microenvironment. ¹¹

We present a case of heavily pretreated metastatic myxoid liposarcoma that underwent a biopsy-proven pathologic remission following the addition of pembrolizumab to pazopanib treatment.

Case description

A 32-year-old woman presented with a mass in her left thigh in 2016 with complaints of increasing discomfort and pain spanning 5 months. Magnetic resonance imaging (MRI) of the femur revealed an 11 x 5.5 x 3.7 cm lobulated heterogeneous mass between the vastus intermedius muscle and the femoral shaft. A subsequent positron emission tomography/computerized tomography scan (PET/CT) confirmed uptake in the thigh with no additional disease visualized. A core-needle biopsy was suspicious for sarcoma. The mass was resected, confirming a myxoid liposarcoma with 3 mitoses/HPF. Genomic testing identified a FUS-DDIT3 fusion (variant 1). Due to narrow surgical margins, postoperative adjuvant radiation was administered.

The patient remained in remission for two years when subcutaneous nodules were noted in the sternal notch and the right abdominal wall. Biopsies of these nodules showed metastatic myxoid liposarcoma. The patient also had pain in the T10-11 vertebral area with leg weakness due to a vertebral metastasis. The patient underwent laminectomy followed by spinal irradiation.

In 9/2018, the patient began systemic therapy with liposomal doxorubicin with olaratumab (an anti-PDGFRα monoclonal antibody). The patient received 8 cycles over the span of 6 months. A follow up CT scan of chest, abdomen and pelvis showed progression of disease with increase in the right parasternal mass and a subcutaneous mass. The patient was then treated with pazopanib 800mg/d, starting in May 2019, without significant toxicity. After 4 months, a CT scan showed only a 20% reduction in the tumor size.

The patient continued pazopanib therapy for 15 months with stable disease. Treatment was complicated by hypothyroidism. However, by March 2021, she developed a sudden increase in the left buttock pain radiating down her left leg. An MRI of the pelvis showed a new sacral metastasis. Radiation therapy was administered to the pelvic mass, leading to significant pain relief. Following radiation, trabectidin was started. Unfortunately, the patient developed rapid cancer progression after just 2 doses. She developed a new scapular metastasis with significant growth of existing sacral and subcutaneous lesions (Figure 1 Panel A,B). A core needle biopsy of a chest wall lesion demonstrated metastatic myxoid liposarcoma (Figure 2 Panel A, B).

Figure 1.

Matched CT images of sites of selected metastatic lesions before and after 5 months of pazopanib plus pembrolizumab therapy. (Panel A) A sternal metastasis is shown pretreatment, (Panel B) A large right flank subcutaneous lesion is shown prior to treatment. (Panel C) The radiographic complete response of the sternal lesion is shown. (Panel D) A radiographic partial response of the right flank lesion after 5 months of therapy is shown.

Figure 2.

(Panel A) Histologic evaluation of chest wall lesion pre- and post-treatment. Pretreatment core needle biopsy (H&E, 200×) shows a moderately cellular neoplasm composed of uniform round to oval cells with small nucleoli. (Panel B) A higher power view (H&E, 400×) demonstrated finely granular chromatin, and moderate eosinophilic cytoplasm in a prominent myxoid stroma. Scattered delicate capillaries are seen. Findings are diagnostic of metastatic myxoid liposarcoma. (Panel C) Post-treatment core biopsy (H&E, 200×) reveals acellular fibrotic and myxoid stroma with scattered hemosiderin-laden macrophages and no residual viable tumor cells, consistent with complete pathologic response. (Panel D) The absence of viable tumor cells was confirmed on a higher magnification view (H&E, 400×).

After a discussion of potential salvage chemotherapy options, a decision was made to restart pazopanib due to the previous long period of stable disease, with the cautious addition of pembrolizumab (200mg i.v. every 3 weeks) in July 2021. There was no apparent toxicity. This combination showed initial improvement of subcutaneous lesions after just two doses of pembrolizumab. Further remarkable improvement at all the tumor sites was seen on follow-up CT scans after 5 doses of pembrolizumab (Figure 1 Panel C,D). Another PET/CT performed after 8 doses of pembrolizumab further demonstrated improvement in all metastatic lesions. A total of 19 doses of pembrolizumab in combination with daily pazopanib were administered over a span of 16 months. No apparent toxicity was noted. Due to persistent stable radiographic abnormalities in bone and subcutaneous metastases, a core-needle biopsy of a sacral lesion was performed (7/6/22). This biopsy revealed a pathologic complete remission with residual necrotic tumor (Figure 2 Panel C,D). Despite multiple discussions of elective treatment discontinuation, the patient requested to continue immunotherapy. Pembrolizumab was eventually held due to the development of a generalized maculopapular rash in December 2022. The rash was successfully treated with topical and oral steroids.

The patient was transiently lost to follow-up due to insurance changes, resulting in involuntary discontinuation of pembrolizumab. She continued pazopanib 800 mg/d monotherapy during this interval. Given the patient’s apparent pathologic complete remission and stable radiologic findings for nearly two years after initiation of pembrolizumab, a decision was made to gradually taper and discontinue pazopanib, ending in June 2024. The patient has remained in an ongoing complete remission since this time without further treatment (last follow-up December 2024). A schema of the treatment course with some interim tumor measurements is provided (Figure 3).

Figure 3.

Treatment timeline with index tumor measurements.

Discussion

Liposarcoma remains a devastating diagnosis. The incidence in the United States is approximately 1/100,000 individuals. ¹² This uncommon cancer represents approximately 12.8% of soft tissue malignancies. ¹² The de-differentiated and pleomorphic histologic subtypes appear to have a worse prognosis than other forms of liposarcoma. ¹³ Surgery with potential adjuvant radiotherapy is often successful in curing relatively small and localized tumors.^1–3 However, induction of durable responses continues to be a challenge in patients with bulky or metastatic disease. There is an unmet need for improvements in systemic treatment for locally advanced or metastatic STS. Over the last 40 years, there has been minimal, if any, improvement in survival of locally advanced or metastatic STS with single pharmacologic agents or combination chemotherapy regimens compared to doxorubicin treatment alone.^6,7,9

For example, in 2014, Judson et al. conducted a study involving 455 patients with STS, comparing the effects of doxorubicin alone to a combination of doxorubicin and ifosfamide. ⁶ This study found that median progression-free survival was longer in the combination group, at 7.4 months, compared to doxorubicin alone. Similarly, the overall response was also higher in the combination group (24%); Unfortunately, these improvements were accompanied by a significant increase in the incidence of treatment-related adverse events (grade 3 or higher). In addition, there was no difference in overall survival with doxorubicin plus ifosfamide treatment, compared to doxorubicin alone. ⁶ Thus, doxorubicin remains the initial standard treatment for metastatic STS, even though this agent has a low level of activity in liposarcoma treatment.

Another study enrolling 807 patients assessed the efficacy of the common first-line regimens in STS not suitable for surgery or radiation therapy. The regimens studied were doxorubicin alone (41%), doxorubicin plus ifosfamide (19%), docetaxel plus gemcitabine (9%), paclitaxel alone (4%) and ifosfamide (4%). The median overall survival reported was only 17.6 months. These authors concluded that newer therapies that improve OS in advanced sarcomas are needed desperately for treatment of advanced sarcomas. ¹⁴

More recently, several novel agents, including pazopanib, trabectedin, and eribulin, received regulatory approval for treatment of advanced sarcomas. These agents have demonstrated a modest improvement in the PFS and OS. As single agents, however, they rarely produce durable remissions. ¹⁵

In recent decades, the clinical use of immunotherapies with immune checkpoint inhibitors for various immuno-sensitive tumors (e.g. melanoma, non-small cell lung cancer) has expanded significantly, yielding promising outcomes. ¹⁶ In these cancers, expression of high levels of tumor mutational burden (TMB), significant infiltration with CD8+ lymphocytes, and elevated levels of programmed death ligand – 1 (PD-L1), correlate with an increased probability of response to ICI treatment. ¹⁷ In contrast, these favorable predictive markers are not present in most patients with STS. The largest case series on STS reported low TMB, low CD8+ lymphocyte infiltration, and low PD-L1 expression. ¹⁸

Multicenter studies have evaluated the effectiveness of ICI treatment in patients with locally advanced or metastatic STS. The SARC028 trial demonstrated the modest effectiveness of the PD-1 antibody pembrolizumab in certain forms of STS (leiomyosarcomas, liposarcomas, and undifferentiated pleomorphic sarcomas).^19,20 The overall objective response rate (ORR) in STS was found to be 18%. ²⁰ Only one complete response was reported.

The Alliance A091401 trial tested single-agent nivolumab or the combination of ipilimumab with nivolumab in patients with GI stromal tumors (GIST), de-differentiated liposarcoma and undifferentiated pleomorphic sarcoma. ²¹ Myxoid liposarcoma was not specifically included or reported among the evaluated cohorts. This study showed minimal effectiveness of either regimen in GIST. While single agent nivolumab had minimal activity, the combination regimen produced 16.6% complete remissions in de-differentiated liposarcoma and undifferentiated pleomorphic sarcoma. In that study, the liposarcoma cohort primarily consisted of dedifferentiated liposarcoma, and myxoid liposarcoma was not specifically represented or reported as a distinct subgroup.Some of these responses proved durable with 15-24 month follow-up. The clinical evidence supporting immunotherapy-based strategies in myxoid liposarcoma subtype remains extremely limited. The durable response observed in our patient therefore adds to the sparse literature suggesting that selected patients with myxoid liposarcoma may derive meaningful benefit from combined VEGFR inhibition and immune checkpoint blockade.

Combinations of agents targeting the vascular endothelial growth factor receptor (VEGFR) pathway plus ICI showed encouraging early clinical response rates in STS.^18,22–24 A more extensive experience with similar combinations exists in renal cell carcinoma patients. There are very few publications related to the specific combination of pazopanib with pembrolizumab. This may be because a phase 1 trial of this combination in RCC reported a 60% clinical benefit rate, but 80-90% of patients required dose interruption due to toxicity (usually hepatic enzyme elevations). ²⁵ A cohort with a run-in period on pazopanib, similar to the treatment of our patient, resulted in only a 24% incidence of treatment interruption. To our knowledge, this observation was not pursued further due to development of other less toxic combinations of targeted agents and PD-1 antibodies.

In the CheckMate 016 study evaluating nivolumab in combination with pazopanib or sunitinib in advanced RCC, ²⁶ the nivolumab–pazopanib arm was associated with substantial toxicity, particularly hepatotoxicity, which ultimately limited further development of this regimen. Grade 3–4 adverse events occurred in the majority of patients, with elevations in hepatic transaminases representing the most common severe toxicity, frequently necessitating treatment interruption or discontinuation. ²⁶ Thus these regimens have not yet been further tested in sarcoma patients.

A prior case report by Arora et al. described the use of the therapeutic combination—pazopanib with pembrolizumab—in a patient with metastatic undifferentiated pleomorphic sarcoma (UPS) who had progressed after multiple prior lines of therapy. ²⁴ In that report, the addition of pembrolizumab to ongoing pazopanib resulted in a marked radiologic response with sustained disease control. The combination therapy was generally well tolerated, with manageable immune-related adverse events. While UPS is typically considered a more immunogenic sarcoma subtype with greater immune cell infiltration than many other STS histologies, myxoid liposarcoma is generally characterized by a relatively immunologically quiescent tumor microenvironment. Despite these biologic differences, both this case and our own demonstrated sustained clinical benefit from combined VEGFR inhibition and PD-1 blockade. ²⁴

Notably, the present case differs from the UPS report in several important aspects. First, the histologic subtype in our patient was myxoid liposarcoma, which has been rarely represented in immunotherapy studies and is not typically considered among the more immune-responsive sarcoma subtypes. Second, our patient achieved a biopsy-confirmed pathologic complete remission, whereas the UPS case reported a durable radiographic response without pathologic confirmation. Third, the toxicity profile in our patient was minimal, consisting only of a delayed maculopapular rash responsive to corticosteroids, with no clinically significant hepatotoxicity or other grade ≥3 adverse events during therapy. Collectively, comparison of these two reports suggests that the combination of pazopanib and pembrolizumab may have activity across multiple soft tissue sarcoma subtypes and supports the hypothesis that VEGFR blockade may enhance responsiveness to PD-1 inhibition in selected sarcoma patients, although larger prospective studies are needed to confirm this observation.

We report a durable complete remission in an extensively pretreated patient with metastatic myxoid liposarcoma. The addition of pembrolizumab to pazopanib treatment resulted in a biopsy-proven complete remission lasting >30 months with minimal toxicity. This remission is ongoing for >6 months after discontinuation of all therapy. Based on this experience, we believe further systematic testing of combinations of VEGFR inhibitors, like pazopanib in combination with ICI in myxoid liposarcoma (and perhaps other histologic STS variants), is warranted. Careful attention to immune-related adverse events, especially hepatic enzyme elevation, ²⁵ is essential, as there is a potential risk of increased toxicity from combination therapy.

Tumor responses following ICI therapy, with residual stable persistent post-treatment radiographic abnormalities remain difficult to interpret. These residual abnormalities could represent either viable tumor or residual scar tissue. In these situations, a biopsy is helpful to assess the degree of pathologic response. The appropriate duration of therapy in patients who achieve an apparent complete remission currently is uncertain and requires further evaluation.

In conclusion, we report a case of widely metastatic myxoid liposarcoma treated with pembrolizumab, added to pazopanib therapy as a fourth-line palliative treatment. The combination resulted in dramatic and unexpected tumor regression, and an eventual biopsy-proven complete remission. It is noteworthy that durable complete remissions in metastatic sarcoma patients are extremely uncommon, particularly after failures of multiple prior treatments. The combination of pazopanib and pembrolizumab was very well tolerated, with minimal toxicity (delayed onset of rash). This report should be considered hypothesis-generating and suggests a rationale for further testing of pazopanib with checkpoint inhibitors in additional patients with myxoid liposarcoma.

Conclusions

In patients with metastatic soft tissue sarcomas, responses to conventional treatments are generally infrequent and transient. We present a case of metastatic myxoid liposarcoma that achieved biopsy-proven complete remission with minimal toxicity following the addition of pembrolizumab to pazopanib as fourth-line treatment. This regimen resulted in significant tumor regression, and a biopsy confirmed pathologic remission. Treatment was subsequently electively discontinued, and the patient currently remains in an ongoing unmaintained remission. The combination of pembrolizumab and pazopanib demonstrated unexpected clinical activity with minimal toxicity. Thus, this regimen may be worth of further investigation in treatment-refractory myxoid liposarcoma.