Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial
Abstract
Background Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).
Methods This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level −1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).
https://jitc.bmj.com/content/8/2/e001561
Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial
Re: Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial
Discussion
In this phase Ib/II trial, we found that the 6-month PFSR was 48% according to RECIST and independent central review. This outcome widely exceeds the 15% considered promising in the statistical assumption of this trial. This threshold was based on the European Organisation for Research and Treatment of Cancer (EORTC) recommendation cut-off for activity, in terms of 6-month PFSR, in second line drugs of advanced STS.22 This indicator was chosen considering that a valuable immunotherapy should induce durable disease control; accordingly, 3-month PFSR would not be useful enough in detecting the potential added value of immunomodulation in sarcoma. The scheme was in general manageable even when it required transient dose interruptions in up to 59% of patients. Neutropenia, which could be related to FLT3 inhibition by sunitinib,23 was found at a higher proportion than sarcoma trials with anti-PD-1 alone19 or sunitinib alone.24 The difference with the latter could be explained by the shorter use of sunitinib due to earlier progression in the monotherapy trial.
The mOS of 24 months is worth mentioning; phase III trials showing significant benefits of some active drugs in STS second line reported mOS ranging from 12.5 to 13.5 months.25–27 It will be important to analyze postprotocol therapies and microenvironment transformation after the immunomodulatory treatment since the clinical impact of the sunitinib and nivolumab scheme could also have an influence on subsequent postprotocol therapies. We have analyzed the potential bias of selecting some more indolent histologies or those histologies more sensitive to antiangiogenics as the reason for this prolonged survival, but we did not find significant differences in survival between groups.
The 6-month PFSR of 48% and the mOS of 24 months showed in our trial favorably compare with the activity reported with anti-PD-1 or sunitinib in monotherapy in previous STS trials. The SARC028 study reported 32% and 11.4 months for 6-month PFSR and mOS, respectively, in 42 patients with STS treated with pembrolizumab.19 Nevertheless, the SARC028 study selected the four more frequent histotypes for the STS cohort, making comparison with our study difficult since only synovial sarcoma and UPS were common histologies in both trials. The Alliance-091401 trial reported 15% and 10.7 months, respectively, for the same indicators in 43 patients with STS treated in the monotherapy arm with nivolumab.17 Another study was prematurely closed, with 12 patients with uterine leiomyosarcoma treated with nivolumab, after observing an mPFS of 1.8 months at the interim analysis and with no patient free of progression at 6 months.18 Sunitinib was also trialed as monotherapy in a phase II study of 50 patients with STS, reporting a 6-month PFSR of 22% with an mPFS of 1.8 months, while OS data were not provided.24 Of note, the GMI in our study is comparable with those reported with active chemotherapy in second line,28 and the median elapsed time of 1.17 months between previous progression and enrollment reinforces the outcome in terms of PFS. Furthermore, the GMI in the subset of subtypes with higher potential sensitivity to antiangiogenics was even better. A limitation of this study is inherent to design assumption: it is not possible to distinguish separately the efficacy of antiangiogenic or anti-PD-1. The differences detected between immunomodulation with combination approach and monotherapy underline the feature that STS exhibits, in general, a cold immune microenvironment. In line with this, a combined immunotherapy approach tried to convert a cold into inflamed microenvironment in sarcomas. Thus, the combination arm of Alliance-091401 addressed a double immune-checkpoint inhibition with nivolumab plus ipilimumab. Patients in the combination arm had a 6-month PFSR of 28% and a mOS of 14.3 months, all the efficacy indicators being superior to monotherapy arm. The lower 6-month PFSR and the shorter OS in the combination arm in comparison with our trial could be explained, at least partially, by the restriction in the number of ipilimumab cycles (four at maximum).17 Conceptually similar to our study, the administration of antiangiogenic plus anti-PD-1 agents was explored in a single-center phase II trial with axitinib plus pembrolizumab . The 6-month PFSR was 46.9% and the mOS was 18.7 months, which were both closely similar to our study. A substantially different aspect was based on the proportion of ASPS; while in the axitinib-pembrolizumab 36% of the patients had this subtype, in our trial only 7% had this diagnosis. Thus, for the non-ASPS cases of that trial, the mPFS was 3 months, the 6-month PFSR was 38.1%, the mOS was 13.1 months, while no patient survived beyond 2 years. All these parameters seemed to be worse than ours, although limited by indirect comparisons. The indolence and special sensitivity of this subtype to both antiangiogenic and immunomodulation could have influenced the survival results. In our series, four of seven accrued patients with ASPS (considering both phases) had partial response (57%), whereas in a randomized phase II trial exploring cediranib versus placebo in ASPS the authors reported responses in 6 of 31 (19%) patients.29 In fact, excluding ASPS from the analysis of PFS due to its inherent indolence, we were not able to find statistical differences between potential antiangiogenic sensitive subtypes and others. In other words, ASPS cases could represent bias for the main endpoint of 6-month PFSR. Intriguingly, ASPS does not exhibit some features of the classic immune sensitive microenvironment; thus, the proportion of tumor infiltrating lymphocytes, or specifically CD8+ or FOXP3+ subpopulations, per cubic millimeter is lower in ASPS than in non-translocation-related sarcomas.30 Additionally, TMB is lower in ASPS compared with other sarcomas, such as synovial sarcoma or Ewing sarcoma. The activity of anti-PD-1 in ASPS has been related with molecular mismatch-repair deficiency signature, even in the absence of high TMB, but a broader number of cases to confirm this point will be required.31
The proportion of responding patients, 13% in phase II or 21% joining STS evaluable patients from phase Ib and II of our trial, is similar to the 18% reported with pembrolizumab in the SARC028 study. This could be explained by STS heterogeneity, even within specific subtype; for instance, from seven evaluable patients with UPS in our phase II, only two had stabilization and five had progressive disease, with an mPFS of 1.8 months. By contrast, in the SARC028 study, from nine patients with UPS, four responded, three were stable and two progressed, with an mPFS of 7 months. This emphasizes the concept of the relevance of the microenvironment in the immunomodulation results in sarcoma. A potential molecular prognostic signature with impact on survival has been proposed in our exploratory translational research. Of note, inflammatory processes were associated with better survival, whereas metabolic processes were linked to worse outcome. The role of metabolism in tumor immune evasion has been previously described.32 33 Also, the significant prognostic value of PDGFD or IL16 overexpression in longer survival, shown in online supplemental results, is a finding that deserves to be further explored.
Based on the findings of this study, six subtypes of sarcoma were selected for a multicohort phase II trial, which has been recently activated, with the same regimen. In the translational research, only 28 samples were used for transcriptomics, which is a limitation of this study. However, a broad comprehensive analysis of the immune populations within the tumor and their association with gene signatures and clinical outcomes is currently ongoing and expected to be published as a separate correlative study. Sunitinib inhibits several tyrosine kinase receptors (TKR), including angiogenic (eg, Vascular Endothelial Growth Factor Receptor (VEGFR) types 1 and 2, and PDGFR-α and PDGFR-β), pro-oncogenic (eg, fms like tyrosine kinase 3 (FLT3), rearranged during transfection (RET), and KIT) or immune-related pathways (eg, Colony stimulating factor 1 receptor (CSF1R)). Although the main hypothesis of this study is to convert the sarcoma cold microenvironment into an inflamed one, by inhibiting immunosuppression driven by angiogenesis, we cannot discard the potential added value of targeting other TKRs. In fact, it seems that CSF1 expression has been described as an adaptive mechanism of resistance to anti-PD-1 inhibition in melanoma, while the combination of anti-CSF1R and anti-PD-1 inhibitions was demonstrated to be active in BRAFV600E-driven, transplant mouse melanomas. The efficacy of this combination was dependent on the elimination of tumor-associated macrophages (TAMs).34 Likewise, it has been reported that the combination of CSF1R inhibitor with anti-PD-L1/PD-1 axis blockage is also highly active in hepatocellular carcinoma mouse models, increasing intratumoral CD8+ T cells infiltrate and reducing TAMs.35 Translational and preclinical studies will also address the potential role of targeting these TKRs for anti-PD-1/PD-L1 axis inhibition efficacy in STS.
In conclusion, our study supports the idea that the PD-1/PD-L1 axis inhibition per se is not enough in the context of STS. Combination strategies promoting inflamed microenvironment resulted in a higher efficacy in this setting. Targeting new immune-checkpoint inhibitors and selecting histological subtypes could also be advantageous in future trials. Correlative studies searching predictive signatures will allow a better selection of patients for immunotherapy.
Asps and mismatched repair defiencey-
https://cureasps.org/forum/viewtopic.php?p=15229#p15229
In this phase Ib/II trial, we found that the 6-month PFSR was 48% according to RECIST and independent central review. This outcome widely exceeds the 15% considered promising in the statistical assumption of this trial. This threshold was based on the European Organisation for Research and Treatment of Cancer (EORTC) recommendation cut-off for activity, in terms of 6-month PFSR, in second line drugs of advanced STS.22 This indicator was chosen considering that a valuable immunotherapy should induce durable disease control; accordingly, 3-month PFSR would not be useful enough in detecting the potential added value of immunomodulation in sarcoma. The scheme was in general manageable even when it required transient dose interruptions in up to 59% of patients. Neutropenia, which could be related to FLT3 inhibition by sunitinib,23 was found at a higher proportion than sarcoma trials with anti-PD-1 alone19 or sunitinib alone.24 The difference with the latter could be explained by the shorter use of sunitinib due to earlier progression in the monotherapy trial.
The mOS of 24 months is worth mentioning; phase III trials showing significant benefits of some active drugs in STS second line reported mOS ranging from 12.5 to 13.5 months.25–27 It will be important to analyze postprotocol therapies and microenvironment transformation after the immunomodulatory treatment since the clinical impact of the sunitinib and nivolumab scheme could also have an influence on subsequent postprotocol therapies. We have analyzed the potential bias of selecting some more indolent histologies or those histologies more sensitive to antiangiogenics as the reason for this prolonged survival, but we did not find significant differences in survival between groups.
The 6-month PFSR of 48% and the mOS of 24 months showed in our trial favorably compare with the activity reported with anti-PD-1 or sunitinib in monotherapy in previous STS trials. The SARC028 study reported 32% and 11.4 months for 6-month PFSR and mOS, respectively, in 42 patients with STS treated with pembrolizumab.19 Nevertheless, the SARC028 study selected the four more frequent histotypes for the STS cohort, making comparison with our study difficult since only synovial sarcoma and UPS were common histologies in both trials. The Alliance-091401 trial reported 15% and 10.7 months, respectively, for the same indicators in 43 patients with STS treated in the monotherapy arm with nivolumab.17 Another study was prematurely closed, with 12 patients with uterine leiomyosarcoma treated with nivolumab, after observing an mPFS of 1.8 months at the interim analysis and with no patient free of progression at 6 months.18 Sunitinib was also trialed as monotherapy in a phase II study of 50 patients with STS, reporting a 6-month PFSR of 22% with an mPFS of 1.8 months, while OS data were not provided.24 Of note, the GMI in our study is comparable with those reported with active chemotherapy in second line,28 and the median elapsed time of 1.17 months between previous progression and enrollment reinforces the outcome in terms of PFS. Furthermore, the GMI in the subset of subtypes with higher potential sensitivity to antiangiogenics was even better. A limitation of this study is inherent to design assumption: it is not possible to distinguish separately the efficacy of antiangiogenic or anti-PD-1. The differences detected between immunomodulation with combination approach and monotherapy underline the feature that STS exhibits, in general, a cold immune microenvironment. In line with this, a combined immunotherapy approach tried to convert a cold into inflamed microenvironment in sarcomas. Thus, the combination arm of Alliance-091401 addressed a double immune-checkpoint inhibition with nivolumab plus ipilimumab. Patients in the combination arm had a 6-month PFSR of 28% and a mOS of 14.3 months, all the efficacy indicators being superior to monotherapy arm. The lower 6-month PFSR and the shorter OS in the combination arm in comparison with our trial could be explained, at least partially, by the restriction in the number of ipilimumab cycles (four at maximum).17 Conceptually similar to our study, the administration of antiangiogenic plus anti-PD-1 agents was explored in a single-center phase II trial with axitinib plus pembrolizumab . The 6-month PFSR was 46.9% and the mOS was 18.7 months, which were both closely similar to our study. A substantially different aspect was based on the proportion of ASPS; while in the axitinib-pembrolizumab 36% of the patients had this subtype, in our trial only 7% had this diagnosis. Thus, for the non-ASPS cases of that trial, the mPFS was 3 months, the 6-month PFSR was 38.1%, the mOS was 13.1 months, while no patient survived beyond 2 years. All these parameters seemed to be worse than ours, although limited by indirect comparisons. The indolence and special sensitivity of this subtype to both antiangiogenic and immunomodulation could have influenced the survival results. In our series, four of seven accrued patients with ASPS (considering both phases) had partial response (57%), whereas in a randomized phase II trial exploring cediranib versus placebo in ASPS the authors reported responses in 6 of 31 (19%) patients.29 In fact, excluding ASPS from the analysis of PFS due to its inherent indolence, we were not able to find statistical differences between potential antiangiogenic sensitive subtypes and others. In other words, ASPS cases could represent bias for the main endpoint of 6-month PFSR. Intriguingly, ASPS does not exhibit some features of the classic immune sensitive microenvironment; thus, the proportion of tumor infiltrating lymphocytes, or specifically CD8+ or FOXP3+ subpopulations, per cubic millimeter is lower in ASPS than in non-translocation-related sarcomas.30 Additionally, TMB is lower in ASPS compared with other sarcomas, such as synovial sarcoma or Ewing sarcoma. The activity of anti-PD-1 in ASPS has been related with molecular mismatch-repair deficiency signature, even in the absence of high TMB, but a broader number of cases to confirm this point will be required.31
The proportion of responding patients, 13% in phase II or 21% joining STS evaluable patients from phase Ib and II of our trial, is similar to the 18% reported with pembrolizumab in the SARC028 study. This could be explained by STS heterogeneity, even within specific subtype; for instance, from seven evaluable patients with UPS in our phase II, only two had stabilization and five had progressive disease, with an mPFS of 1.8 months. By contrast, in the SARC028 study, from nine patients with UPS, four responded, three were stable and two progressed, with an mPFS of 7 months. This emphasizes the concept of the relevance of the microenvironment in the immunomodulation results in sarcoma. A potential molecular prognostic signature with impact on survival has been proposed in our exploratory translational research. Of note, inflammatory processes were associated with better survival, whereas metabolic processes were linked to worse outcome. The role of metabolism in tumor immune evasion has been previously described.32 33 Also, the significant prognostic value of PDGFD or IL16 overexpression in longer survival, shown in online supplemental results, is a finding that deserves to be further explored.
Based on the findings of this study, six subtypes of sarcoma were selected for a multicohort phase II trial, which has been recently activated, with the same regimen. In the translational research, only 28 samples were used for transcriptomics, which is a limitation of this study. However, a broad comprehensive analysis of the immune populations within the tumor and their association with gene signatures and clinical outcomes is currently ongoing and expected to be published as a separate correlative study. Sunitinib inhibits several tyrosine kinase receptors (TKR), including angiogenic (eg, Vascular Endothelial Growth Factor Receptor (VEGFR) types 1 and 2, and PDGFR-α and PDGFR-β), pro-oncogenic (eg, fms like tyrosine kinase 3 (FLT3), rearranged during transfection (RET), and KIT) or immune-related pathways (eg, Colony stimulating factor 1 receptor (CSF1R)). Although the main hypothesis of this study is to convert the sarcoma cold microenvironment into an inflamed one, by inhibiting immunosuppression driven by angiogenesis, we cannot discard the potential added value of targeting other TKRs. In fact, it seems that CSF1 expression has been described as an adaptive mechanism of resistance to anti-PD-1 inhibition in melanoma, while the combination of anti-CSF1R and anti-PD-1 inhibitions was demonstrated to be active in BRAFV600E-driven, transplant mouse melanomas. The efficacy of this combination was dependent on the elimination of tumor-associated macrophages (TAMs).34 Likewise, it has been reported that the combination of CSF1R inhibitor with anti-PD-L1/PD-1 axis blockage is also highly active in hepatocellular carcinoma mouse models, increasing intratumoral CD8+ T cells infiltrate and reducing TAMs.35 Translational and preclinical studies will also address the potential role of targeting these TKRs for anti-PD-1/PD-L1 axis inhibition efficacy in STS.
In conclusion, our study supports the idea that the PD-1/PD-L1 axis inhibition per se is not enough in the context of STS. Combination strategies promoting inflamed microenvironment resulted in a higher efficacy in this setting. Targeting new immune-checkpoint inhibitors and selecting histological subtypes could also be advantageous in future trials. Correlative studies searching predictive signatures will allow a better selection of patients for immunotherapy.
Asps and mismatched repair defiencey-
https://cureasps.org/forum/viewtopic.php?p=15229#p15229
Debbie