Much Ado about ASPS: The Rapidly Changing Treatment Paradigms of 2022

In this issue of Clinical Cancer Research, Nguyen and colleagues report activity and tolerability of the commonly used tyrosine kinase inhibitors (TKI) cediranib and sunitinib in a randomized phase II trial for patients with progressing advanced and/or metastatic alveolar soft part sarcoma (ASPS; ref. 1). Given the rarity of ASPS, making up less than 1% of all soft-tissue sarcomas, and most frequently occurring in children and young adults, the authors are to be congratulated for conducting a dedicated prospective randomized clinical trial. In this study, 34 patients with confirmed progressing ASPS within 3–6 months prior to therapy were randomized to either cediranib or sunitinib, with crossover permitted at disease progression. In 29 evaluable patients, responses were modest (6.7% for cediranib and 7.1% for sunitinib) and did not meet prespecific response endpoints; however, a substantial proportion of patients achieved stable disease (86.7% for cediranib and 78.6% for sunitinib). Importantly, the median progression-free survival (PFS) was not different between the arms, and 66.7% of patients who crossed over during the study achieved clinical benefit for both first- and second-line TKIs.

ASPS can have unpredictable biological behavior; historically, the 5-year survival for metastatic patients has been as low as 20% in some series (2). However, some patients exhibit a very slow and indolent course with frequent long-term stability of early metastatic disease, with a 5-year overall survival of 71.1% and a 10-year overall survival of 63.1% based on more recent retrospective Surveillance, Epidemiology, and End Results data (3). Other patients rapidly succumb to progressive, overwhelming disease behaving as a high-grade sarcoma.

ASPS was quickly recognized to be resistant to traditional cytotoxic chemotherapies; however, the development of TKIs has greatly impacted management of the disease, likely due to downstream targets of the pathognomonic fusions that drive ASPS (4, 5). Because of the rarity of the disease, most clinical evidence is extrapolated from retrospective case studies or relatively small prospective clinical trials (Table 1). The most data now exist for cediranib, a broad-spectrum TKI studied in multiple prospective clinical trials, with previous studies reporting response rates from 19% to 35% and a significant proportion of patients with disease control (6, 7). Sunitinib has not previously been studied prospectively for ASPS, but a retrospective case series suggested high response rates of over 50% and promising median PFS of 13 months (8). Promising activity has also observed with anlotinib/catequentinib, a similar broad-spectrum TKI which is approved for treatment of ASPS and other sarcomas in China, with an ongoing registration trial including an ASPS arm in the United States (NCT03016819). Patients with ASPS have also achieved modest benefit in studies of pazopanib and cabozantinib (9, 10). Overall, while response rates remain low with TKIs, many patients can achieve clinically meaningful disease control including some patients with long-term stable disease with acceptable toxicity.

Importantly, the Nguyen study is the first prospective study of sunitinib in ASPS, and compared with prior studies of cediranib, uniquely required enrollment of rapidly progressing ASPS within 3 to 6 months before study entry. This may explain the inferior outcomes relative to prior prospective and retrospective experience with these TKIs. However, some patients achieved remarkable and durable benefit, such as a patient who crossed over from sunitinib after progression and continued to receive 46 cycles of cediranib. In addition to providing prospective data for these agents, Nguyen and colleagues also explore the impact of serial use of TKIs, demonstrating that failure of one agent does not guarantee failure of another. Given the multitude of TKIs in development and use for sarcoma, questions emerge as to the optimal sequence and selection of TKI for use in patients with ASPS. VEGF has long been assumed to be the central driver of disease pathogenesis in this disease; however, narrow-spectrum TKIs such as axitinib, a pan VEGFR inhibitor, has not shown as much activity with the limitations of cross-trial comparisons (11). Thus, additional understanding of targets of importance in ASPS and how these match with various TKI spectrums may shed light on the differences observed in activity.

In the past 10 years, ASPS has also been shown to have high rates of response to immune checkpoint inhibitors against PD1 and CTLA4, again dramatically reshaping the potential treatment options and prognosis for patients. On December 9, 2022, the PD-L1 inhibitor atezolizumab received approval from the FDA, becoming the first FDA-approved agent for ASPS. This was based on the results of atezolizumab monotherapy in adult and pediatric patients, which produced an objective response rate of 24% and 67% of patients achieving response maintaining it for at least 6 months, and 42% for at least 12 months according to a news release from the FDA (12). Including the previously reported data for atezolimab, over 100 patients have now been studied in a variety of prospective clinical trials with various checkpoint inhibitors, with response rates ranging widely from 7% to 40% and PFS from 6 to 34 months (Table 2). The underlying mechanism of immunogenicity is still unclear in this disease, which has low tumor mutation burden. Despite this, checkpoint blockade has been included in the National Comprehensive Cancer Network guidelines for the disease based on the striking impact (13).

With the promising results of antiangiogenic therapy as well as immunotherapy, the question of combination therapy comes into play. On the basis of the immune-modulating effects of VEGF and related cofactors, combinations of antiangiogenic TKIs and immunotherapy have shown dramatic benefit for other cancers dependent on VEGF and angiogenesis such as renal cell carcinoma. For ASPS, axitinib plus pembrolizumab demonstrated promising responses for 11 evaluable patients with ASPS included in the study, with response rates of 54.5% and median PFS of 12.4 months (14). Anlotinib plus the PD-L1 inhibitor TQB2450 was also reported recently and included 12 patients with ASPS; the response rate was 75% with a median PFS of 23 months (15). Importantly, ongoing randomized clinical trials, including bevacizumab with or without atezolizumab (NCT03141684), cabozantinib with or without ipilimumab/nivolumab where ASPS is eligible (NCT04551430), and various anlotinib combination studies may also shed light on impact of dual therapy in this disease.

Overall, the proven efficacy of TKIs and immunotherapy brings hope for patients with ASPS, even though many questions remain unanswered. These include the optimal timing for use of these agents, including possible sequential or concurrent employment, as well as the mechanism of action against the tumor and likely reciprocal enhancement (Fig. 1). Specifically, no drug has shown clear superiority and the choice of what agent to use first is left to the judgment of the treating clinician and institutional experience. Is combination therapy of antiangiogenic agents and immunotherapy superior to sequential or alternating administration? And, based on kinome profile, which TKIs are more likely to be most effective and for which patients? The impact of antiangiogenic therapy on the immune system has been widely investigated in other cancer types, but in ASPS we still must determine how antiangiogenic agents may be improving therapeutic responsiveness to immunotherapy, perhaps by priming the tumor microenvironment through inhibition of VEGF-driven immunosuppression and promoting infiltration of existing T cells. In addition, Groisberg and colleagues reviewed a series of patients with ASPS treated with targeted therapies against the hepatocyte growth factor/c-Met signaling pathway, also a downstream target of the ASPS fusion protein and one that can be impacted by broad-spectrum TKIs including pazopanib (16). Given the complexity of this disease and its unpredictable course, better understanding of disease biology and identification of biomarkers that can help select the best candidates for the different emerging treatments is paramount. The inclusion of correlative studies in Nguyen's trial as well as the prior axitinib plus pembrolizumab trial aims to evaluate these questions. With the future of ASPS treatment continuing to evolve, Nguyen's trial offers a crucial contribution to the field and represents a benchmark study to continue refining the treatment of patients with progressing ASPS.

No disclosures were reported.