Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract
Background
Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT®) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas.

https://www.ncbi.nlm.nih.gov/pmc/articl ... o=0.862069

Methods
We analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted.

Results
Among 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0–1 in 48 patients (96%); median number of prior therapies was 3 (0–12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9–3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%).

Discussion

Metastatic, relapsed and refractory sarcomas continue to have a grave prognosis. There is considerable enthusiasm for developmental therapeutics in sarcomas with recent approvals of pazopanib, eribulin, trabectedin and olaratumab with doxorubicin. There are multiple trials ongoing with the combinations of these agents [24–26]. The exceptional success of immunotherapy in other cancer types spurred us to examine our own records for potential responses to immunotherapy in sarcoma patients. As is frequently the case with sarcomas, our dataset is small and has many different sarcoma subtypes. Admittedly, this mix of low-grade and high-grade sarcomas makes comparison difficult. Complicating matters are the multiple different immunotherapies. Certain observationsemerge even in this heterogeneous group of sarcomas and therapies.

The most remarkable response was that of alveolar soft part sarcomas (ASPS) to immunotherapy. Even with a limited sample of four patients, half had a strong partial response bordering on complete response. The other two patients had stable disease. This is far outside the normal behavior for a biologically indolent but relentless tumor [27] and raises the question of mechanism. Is this a question of PD-L1 blockade and cytotoxic T-cell activation? We know that most tumors with FDA approved anti-PD-1 immunotherapy have response rates in the 10–20% range. This would imply that either our four patients are unusual responders such as those seen in prior interferon trials, or that other mechanisms exist. Tanaka et al. [28] created a mouse model of alveolar soft part sarcoma based on the characteristic ASPSCR1-TFE3 fusion protein. The model demonstrated a highly vascular tumor with genes expressed in transendothelial migration. This vascularity is key to the early metastatic potential of this tumor. Additionally, ASPS lines these new blood vessels with hemangiopericytes that prevent leakage of nutrients and oxygen out of the blood vessels. We know that chemokines and their ligands are often involved in vascular recognition and targeting of microvascular endothelial cells [29]. Perhaps chemokines play an important role in the action of immunotherapy in ASPS; our group is undertaking further studies to elucidate this mechanism. Alternatively, the TFE3 fusion may be immunogenic itself or act via TGF-β or CD40 ligand to stimulate T-cells and antigen presenting cells [30]. Others have reported that mismatch repair pathway aberrations may be responsible for ASPS response to immunotherapy [31].

Another interesting observationwas seen in the patients with stable disease. It is entirely possible that some of the patients simply had indolent disease, such as the GIST and well-differentiated liposarcoma. However, osteosarcoma, dedifferentiated liposarcoma, and leiomyosarcoma are generally not considered indolent diseases and their stabilization in response to immunotherapy may serve as an indication of activity. While next generation sequencing (NGS) data was not available for the liposarcoma or leiomyosarcoma patients, clinical grade NGS was performed on the osteosarcoma patient. This testing did not reveal a particularly high mutational load which is thought to increase response to immunotherapy. The response of the patients in our study along with recently reported abstracts of positive anti-PD-1 activity in diverse sarcomas suggests that earlier immunotherapy trials in sarcomas were not entirely correct in their negative experience. For example, a recently completed phase II trial of pembrolizumab showed activity in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma [32]. Another trial with advanced soft tissue sarcomas treated with pembrolizumab and metronomic cyclophosphamide yielded only one responder out of 50 treated patients [33]. While immunotherapy in sarcomas has shown small promise, we can say that it is unlikely to be the success that it has been in melanoma and non-small cell lung cancer.

GIST is a tumor with great preclinical data for immunotherapy that did not materialize into results for patients. Patients were enrolled on a trial of imatinib and ipilimumab based on convincing pre-clinical rationale that showed imatinib reduced levels of indoleamine 2,3-dioxygenase (Ido). Ido is an immunosuppressive enzyme and inhibition of Ido led to regulatory T-cell destabilization, deactivation, and apoptosis. Treatment naïve mice with KIT mutant GIST treated with imatinib showed decreased regulatory T cell activity [34]. In the clinical trial testing this hypothesis, the combination of imatinib and ipilimumab did not translate into improved response rates for patients or even a signal of synergistic activity [35].

The tolerability of immunotherapy in sarcomas appears to be similar to other patients. Rash, fever, and fatigue were the most common adverse events. As with other experiences with immunotherapeutic agents, some unusual toxicities were observed necessitating discontinuation of drug and administration of steroids [36]. The Royal Marsden Hospital prognostic scoring system continues to be a valid predictor of survival in a phase 1 trial (Fig. 1) [37]. Our trial had substantially longer overall survival than has been reported in other phase 1 trials of sarcoma patients. Previous trial experiences by our own group as well as groups from the Royal Marsden Hospital and the European phase 1 database have reported consistent OS in the 7.6–9.8 month range with a PFS between 2.1 and 3.5 months [38, 39]. Our extended overall survival with immunotherapy of 13.4 months can be explained either by patient selection for more indolent tumors, since PFS was similar at 2.4 months. Alternatively, there may be some downstream effect of immunotherapy that goes beyond response rates to contribute to an improved overall survival.

It is notable to point out that we experienced one patient with hyper-progression upon initiation of checkpoint blockade (Fig. 3). Others have reported a similar disturbing phenomenon in as many as 9% of patients. This hyper-progression is unrelated to tumor type or burden of disease, but did portend a poor prognosis especially for elderly patients [40]. One group reported that in their experience mutations in MDM2/MDM4 and EGFR predisposed to a hyper-progressor phenotype [41]. Our patient proceeded to another clinical trial where he had continued progression. Ultimately he succumbed to his disease. This reminds us that while adverse events are manageable with immunotherapy there is much we still do not know about the mechanism of these drugs and their ultimate potential.