Letter to the Editor: Immune Checkpoint Inhibitors in Alveolar Soft Part Sarcoma: New Standard of Care?
Posted: Fri Jun 24, 2022 4:53 am
Letter to the Editor: Immune Checkpoint Inhibitors in Alveolar Soft Part Sarcoma: New Standard of Care?
Dear Editor,
Alveolar Soft Part Sarcoma (ASPS) is a rare soft tissue tumor commonly seen in adolescents and young adults with a female preponderance.1 Although it is an indolent disease, metastasis to lung, bone, and brain are seen in advanced disease with poor long-term outcomes (5 years overall survival of 20%).2 There is emerging evidence that immunotherapy targeting PD1-PDL1 pathway is effective in ASPS and may provide durable responses.3–5 We present first such case from India where sustained response with nivolumab was obtained in a patient with refractory ASPS previously treated with two tyrosine kinase inhibitors.
A 22-year-old lady presented with right-sided gluteal swelling for 3 months. Magnetic resonance imaging of gluteal region showed a well-defined heterogenous space occupying lesion 10.5 × 6.3 × 6.7 cm in the right gluteus maximus infiltrating underlying fatty tissue. Positron emission tomography-computed tomography (PET-CT) showed the primary mass lesion with multiple lung nodules largest 1.3 × 1.3 cm in left lung lower lobe (Fig. 1a). Biopsy from the primary lesion showed features of ASPS with immunohistochemistry (IHC) positive for CD10, CD68, TFE-3, INI, and negative for CK, vimentin, S100, and HMB-45. After progression on sunitinib and crizotinib, she was started on nivolumab 240 mg every 2 weeks. PET-CT showed good partial response after 6 cycles (Fig. 1b) with near complete response after 18 cycles suggesting durable response to nivolumab [total progression-free survival on nivolumab 12 months so far (Fig. 1c)]. PDL-1 IHC on biopsy was negative.
FIG. 1.
In the earliest report on efficacy of immunotherapy in ASPS, Groisberg et al. reported partial response with anti-PD-1 immunotherapy in two patients with heavily pretreated ASPS and the response was durable.3 In a phase II trial of combination of axitinib plus pembrolizumab in advanced sarcomas, best response was seen in 12 ASPS patients with 54.5% patients having a partial response. This benefit was independent of PDL1 status or tumor infiltrating lymphocytes reiterating that patient selection should not be based on these criteria.4 A study presented at CTOS 2018 tested single agent atezolizumab in ASPS. Out of 22 patients enrolled, 42% had a partial response.5 Median time to response was five cycles. Response did not correlate with tumor mutational burden (TMB). Median time on treatment was 11 cycles (range 1–25).
ASPS are cold tumors with low TMB and low PD-L1 expression. The most plausible hypothesis for effectiveness of immunotherapy in ASPS is creation of a neoantigen by unique X:17(p11;q25) ASPSCR1-TFE3 fusion that may be immunogenic. Second, TFE3 has been shown to upregulate the transforming growth factor-beta pathway, which in turn can stimulate production of Trigs from activated CD4 cells through increased FoXp3 expression. TFE3 may also play a role in C40L expression, which may be critical for development of T cells, B cells, and antigen-presenting cells.3,4
Owing to higher response rates and sustained responses (partial responses as compared with stable disease with tyrosine kinase inhibitors), immunotherapy has the potential to replace tyrosine kinase inhibitors as first-line therapy of ASPS. However, better biomarkers are required to select patients to maximize benefit in this rare subgroup of patients.
https://www.liebertpub.com/doi/full/10. ... .2020.0167
https://cureasps.org/forum/viewtopic.ph ... ors#p14040
https://cureasps.org/forum/viewtopic.php?p=377#p377
Dear Editor,
Alveolar Soft Part Sarcoma (ASPS) is a rare soft tissue tumor commonly seen in adolescents and young adults with a female preponderance.1 Although it is an indolent disease, metastasis to lung, bone, and brain are seen in advanced disease with poor long-term outcomes (5 years overall survival of 20%).2 There is emerging evidence that immunotherapy targeting PD1-PDL1 pathway is effective in ASPS and may provide durable responses.3–5 We present first such case from India where sustained response with nivolumab was obtained in a patient with refractory ASPS previously treated with two tyrosine kinase inhibitors.
A 22-year-old lady presented with right-sided gluteal swelling for 3 months. Magnetic resonance imaging of gluteal region showed a well-defined heterogenous space occupying lesion 10.5 × 6.3 × 6.7 cm in the right gluteus maximus infiltrating underlying fatty tissue. Positron emission tomography-computed tomography (PET-CT) showed the primary mass lesion with multiple lung nodules largest 1.3 × 1.3 cm in left lung lower lobe (Fig. 1a). Biopsy from the primary lesion showed features of ASPS with immunohistochemistry (IHC) positive for CD10, CD68, TFE-3, INI, and negative for CK, vimentin, S100, and HMB-45. After progression on sunitinib and crizotinib, she was started on nivolumab 240 mg every 2 weeks. PET-CT showed good partial response after 6 cycles (Fig. 1b) with near complete response after 18 cycles suggesting durable response to nivolumab [total progression-free survival on nivolumab 12 months so far (Fig. 1c)]. PDL-1 IHC on biopsy was negative.
FIG. 1.
In the earliest report on efficacy of immunotherapy in ASPS, Groisberg et al. reported partial response with anti-PD-1 immunotherapy in two patients with heavily pretreated ASPS and the response was durable.3 In a phase II trial of combination of axitinib plus pembrolizumab in advanced sarcomas, best response was seen in 12 ASPS patients with 54.5% patients having a partial response. This benefit was independent of PDL1 status or tumor infiltrating lymphocytes reiterating that patient selection should not be based on these criteria.4 A study presented at CTOS 2018 tested single agent atezolizumab in ASPS. Out of 22 patients enrolled, 42% had a partial response.5 Median time to response was five cycles. Response did not correlate with tumor mutational burden (TMB). Median time on treatment was 11 cycles (range 1–25).
ASPS are cold tumors with low TMB and low PD-L1 expression. The most plausible hypothesis for effectiveness of immunotherapy in ASPS is creation of a neoantigen by unique X:17(p11;q25) ASPSCR1-TFE3 fusion that may be immunogenic. Second, TFE3 has been shown to upregulate the transforming growth factor-beta pathway, which in turn can stimulate production of Trigs from activated CD4 cells through increased FoXp3 expression. TFE3 may also play a role in C40L expression, which may be critical for development of T cells, B cells, and antigen-presenting cells.3,4
Owing to higher response rates and sustained responses (partial responses as compared with stable disease with tyrosine kinase inhibitors), immunotherapy has the potential to replace tyrosine kinase inhibitors as first-line therapy of ASPS. However, better biomarkers are required to select patients to maximize benefit in this rare subgroup of patients.
https://www.liebertpub.com/doi/full/10. ... .2020.0167
Describes a tumor that is not likely to trigger a strong immune response. Cold tumors tend to be surrounded by cells that are able to suppress the immune response and keep T cells (a type of immune cell) from attacking the tumor cells and killing them. Cold tumors usually do not respond to immunotherapy.
https://www.cancer.gov/publications/dic ... cold-tumor
Tumor mutational burden (TMB) refers to the number of somatic gene mutations present in a tumor, which varies across different cancer types. 1. It is hypothesized that these tumor mutations can result in proteins expressed by tumor cells that are recognized by the immune system, called neoantigens.
https://www.cancertherapyadvisor.com/ho ... formation/
https://cureasps.org/forum/viewtopic.ph ... ors#p14040
https://cureasps.org/forum/viewtopic.php?p=377#p377