Sarcoma & GIST

The rarity and complexities of bone and soft tissue sarcomas pose a major challenge to effective treatment. Historically, there has been a blanket approach to treatment, but more recently that has begun to change thanks to genome profiling studies and novel clinical trial strategies. Here, we discuss the resulting enrichment of the therapeutic armamentarium with molecularly targeted and immune therapies.

A challenging tumor type

Sarcomas are a large group of histologically diverse cancers that arise in the mesenchymal cells. They can be broadly divided into bone and soft tissue sarcomas (STS) but are further subdivided according to the type of cell from which they derive; osteosarcomas in the bone, rhabdomyosarcomas in the skeletal muscle, liposarcomas in the fat tissues, leiomyosarcomas in the smooth muscle, and chondrosarcomas in the cartilaginous tissue, for example.

Each sarcoma subtype itself encompasses a range of different cancers with unique biology. Under the umbrella of liposarcoma, for example, are well/dedifferentiated liposarcomas and myxoid liposarcomas, which have very different pathologies and clinical courses.

As a whole, sarcomas are extremely rare tumors, accounting for less than 1% of all adult cancers, although they disproportionately affect children and young adults, with a prevalence closer to 15%.^1,2 Certain sarcoma subtypes are exceptionally rare, with only a few cases diagnosed worldwide each year, whereas liposarcomas are at the other end of the spectrum, comprising the most common form of STS (Figure 1).³

Magic bullet for GIST

Despite their clear heterogeneity and complexity, sarcomas have tended to be treated as a single entity. Chemotherapy has played a central role in the treatment of advanced sarcomas and continues to do so, with 2 newer drugs approved by the United States Food and Drug Administration (FDA) in the past several years.^6,7

The development of targeted therapy, on the other hand, for the most part proved unsuccessful. In general, studies examining the somatic mutation landscape in sarcomas found very few that were highly recurrent. The exception was gastrointestinal stromal tumors (GIST), which represent around 8% of STS.⁸ Frequent mutations in several highly targetable tyrosine kinases, notably KIT, which is mutated in around 85% of cases,⁹ and platelet-derived growth factor receptor alpha (PDGFRα) were identified in these tumors.¹⁰This prompted the development of tyrosine kinase inhibitors (TKIs), targeting these and other kinases, for the treatment of patients with GIST, and culminated in the approval of imatinib for this indication in 2002. This revolutionized the treatment of GIST, which had a poor prognosis and were resistant to chemotherapy, extending median overall survival in patients with metastatic disease almost to 5 years.^11-13

Imatinib was also shown to benefit patients with surgically resectable disease and was subsequently approved in the adjuvant setting in 2008. A recent trial demonstrated that 3-year continuation of adjuvant imatinib resulted in a significantly longer progression-free survival (PFS) compared with 1 year of adjuvant imatinib, and even longer time periods are now being evaluated.^14,15 The TKIs sunitinib and regorafenib have also been approved for the treatment of patients who become resistant to imatinib.^16,17 Avapritinib, a newer, more specific inhibitor of KIT is also being evaluated in patients with GIST (Table).

Long-sought success for STS

Sunitinib and regorafenib include PDGFRα and the vascular endothelial growth factor receptors (VEGFRs) among their targets, receptors that play crucial roles in the formation of new blood vessels (angiogenesis). Many types of non-GIST sarcomas have been shown to be highly vascularized and express high levels of both of those receptors and other angiogenic proteins, which sparked interest in the development of multitargeted TKIs and other anti-angiogenic drugs in patients with STS.¹⁸

In 2012, pazopanib became the first FDA-approved molecularly targeted therapy for the treatment of non-GIST sarcomas. Approval in the second-line setting was based on the demonstration of a 3-month improvement in PFS compared with placebo.¹⁹ Four years later, the monoclonal antibody olaratumab, a more specific inhibitor of PDGFRα, was approved in combination with doxorubicin, marking the first front-line approval for more than 4 decades.²⁰Numerous other anti-angiogenic drugs continue to be evaluated for the treatment of advanced STS. Among them, anlotinib is being tested in phase 3 clinical trials, and results from the ALTER0203 trial were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).²¹ After failure of chemotherapy, 223 patients were randomly assigned to receive either anlotinib or placebo. Anlotinib significantly improved median PFS across all patients, compared with placebo (6.27 vs 1.4 months, respectively; hazard ratio [HR], 0.33; P < .0001), but was especially effective in patients with alveolar soft part sarcoma (ASPS; mPFS: 18.2 vs 3 months) and was well tolerated.²¹

Sarcoma secrets revealed

Advancements in genome sequencing technologies have made it possible to interrogate the molecular underpinnings of sarcomas in greater detail. However, their rarity presents a significant technical challenge, with a dearth of samples available for genomic testing. Large-scale worldwide collaborative efforts have facilitated the collection of sufficiently large patient populations to provide statistically robust data in many cases. The Cancer Genome Atlas has established a rare tumor characterization project to facilitate the genomic sequencing of rare cancer types like sarcomas.

Genome sequencing studies have revealed 2 types of sarcomas: those with relatively stable genomes and few molecular alterations, exemplified by Ewing sarcoma, which has a mutational load of 0.15 mutations/Megabase (Mb); and those that are much more complex with frequent somatic mutations, the prime example being leiomyosarcoma. The latter are characterized by mutations in the TP53 gene, dubbed the “guardian of the genome” for its essential role in genome stability.

The 2 types are likely to require very different therapeutic strategies. Although genomically complex tumors offer up lots of potential targets for therapy, they also display significant heterogeneity and it can be challenging to find a shared target across different tumor samples. The p53 protein would make a logical target but, to date, tumor suppressor proteins are not readily druggable.

The most common type of molecular alterations in sarcomas are chromosomal translocations, where part of a chromosome breaks off and becomes reattached to another chromosome. This can result in the formation of a gene fusion when parts of 2 different genes are brought together in a way in which the genetic code can still be read, leading to the formation of a fusion protein with altered activity.^22-25

In sarcomas, these chromosomal translocations predominantly involve genes encoding transcription factors and the gene fusion results in their aberrant expression and activation of the transcriptional programs that they regulate.

Ewing sarcoma is a prime example of a sarcoma that is defined by chromosomal translocations. Most often, the resulting gene fusions occur between members of theten-eleven translocation (TET) family of RNA-binding proteins and the E26 transformation-specific (ETS) family of transcription factors. The most common fusion is between the EWSR1 and FLI1 genes, observed in between 85% and 90% of cases.

Significant efforts have been made to target EWSR1-FLI1. Since direct targeting of transcription factors is challenging, those efforts focused on targeting the aberrant transcriptional programs that they initiate. A major downstream target is the insulin-like growth factor receptor 1 (IGF1R) and numerous IGF1R inhibitors were developed and tested in patients with Ewing sarcoma, but unfortunately success was limited. Attention turned to the mammalian target of rapamycin (mTOR) as a potential mechanism of resistance to IGF1R inhibitors and explanation for the limited responses. Clinical trials combining mTOR and IGF1R inhibitors also proved unsuccessful.²⁶

Although overall these trials were deemed failures, they were notable for the dramatic responses that were seen in 1 or 2 patients. Researchers are probing these “exceptional responses” using novel N-of-1 clinical trial designs that focus on a single patient (Figure 2).^27-30 More recently, the first drug to specifically target the EWSR1-FLI1 fusion protein was developed. TK216 binds to the fusion protein and prevents it from binding to RNA helicase A, thereby blocking its function.³¹

Another type of gene fusion, involving the neurotrophic tropomyosin receptor kinase (NTRK) genes, has recently come into the spotlight for the treatment of lung cancer. According to a recent study, NTRK fusions may also be common in sarcomas. They were observed in 8% of patients with breast sarcomas, 5% with fibrosarcomas, and 5% with stomach or small intestine sarcomas.³²

The NTRK genes encode TRK proteins and several small molecule inhibitors of TRK have been developed to treat patients with NTRK fusion-positive cancers. Another novel clinical trial design – the basket trial – is being used to test these inhibitors. This type of trial uses a tumor-agnostic approach, recruiting patients with all different histological subtypes of cancer that are unified by the shared presence of a specific molecular alteration.³³

Repurposing gynecologic cancer drugs

More recently, a third group of sarcomas was categorized, with intermediate genomic complexity. These tumors, including well/dedifferentiated liposarcomas, were characterized by amplifications of chromosome 12, involving genes such as cyclin-dependent kinase 4 (CDK4). In fact, more than 90% of patients with well/dedifferentiated sarcomas display CDK4 amplification, making it a logical therapeutic target.³⁶

CDK4 encodes CDK4 protein, a cell cycle-associated protein that regulates the transition from G1-S phase, known as the restriction point, beyond which the cell commits to undergoing mitosis. Aberrant expression of CDK4 in cancer drives the hallmark process of unchecked cellular proliferation.

Some small molecule CDK4/6 inhibitors have been developed and have shown significant promise in the treatment of breast cancer. They are also being evaluatedin patients with sarcoma whose tumors display CDK4 overexpression. In a recently published phase 2 trial of palbociclib in 60 patients with well/dedifferentiated liposarcomas, there was 1 CR.³⁷

Another group of drugs that has advanced the treatment of gynecologic cancers comprises the poly (ADP-ribose) polymerase (PARP) inhibitors. In this context, PARP inhibitors are used in patients with mutations in the breast cancer susceptibility genes, BRCA1/2. The BRCA and PARP proteins are both involved in DNA repair pathways and the inhibition of PARP in patients who already have a defective BRCA pathway renders a lethal double blow to the cancer cell. According to the Broad Institute Cancer Cell Line Encyclopedia, Ewing sarcomas express high levels of the PARP1 enzyme, which could render them sensitive to PARP inhibition. Preclinical studies seemed to confirm that sensitivity, however, so far this has yet to translate into success in clinical trials, with no objective responses observed as yet.³⁸
 

Expanding the field

Other treatment strategies being tested in patients with sarcoma are moving the field beyond conventional targeted therapies. There has been substantial focus in recent years on epigenetic alterations and their potential role in the development of cancer. Epigenetics is the secondary layer of regulation that acts on the genome and directs the spatial and temporal expression of genes.

Both DNA and the histone proteins they are packaged up with to form chromatin in nondividing cells can be modified by the attachment of chemical groups, such as acetyl and methyl groups, which can alter access to the DNA for transcription.

EZH2 is an enzyme that participates in histone methylation and thereby regulates transcriptional repression. Some types of sarcoma are characterized by a loss of expression of the INI1 gene, also known as SMARCB1. The INI1 protein is part of a chromatin remodeling complex that relieves transcriptional repression and when INI1 is lost, cells become dependent upon EZH2.³⁹Clinical trials of the EZH2 inhibitor tazemetostat are ongoing in several types of sarcoma. Results from a phase 2 study in adults with INI1-negative tumors were presented at ASCO in 2017. Among 31 patients treated with 800 mg tazemetostat in continuous 28-day cycles, mPFS was 5.7 months, disease control rate was 10%, and confirmed overall response rate was 13%. The FDA has granted tazemetostat orphan drug designation in this indication.⁴⁰A pediatric basket trial of tazemetostat is also ongoing, but the FDA recently placed it under a clinical hold as a result of a safety update from the trial in which a pediatric patient with advanced poorly differentiated chordoma developed a secondary T-cell lymphoma.⁴¹

Targeting the unique metabolism of sarcomas may offer a promising therapeutic strategy, although this is in the preliminary stages of evaluation. A recent study showed that the expression of the argininosuccinate synthase 1 enzyme, which is involved in the generation of arginine through the urea cycle, was lost in up to 90% of STS. A pegylated arginine deaminase (ADI-PEG20), is being evaluated in a phase 2 clinical trial.⁴²

Finally, the concept of using immunotherapy to boost the anti-tumor immune response is also being examined in sarcomas. A significant number of cases of STS, osteosarcoma and GIST have been shown to express programmed cell death protein-ligand 1, therefore the use of immune checkpoint inhibitors that block this ligand or its receptor and help to reactive tumor-infiltrating T cells, could be a beneficial strategy.

Limited activity has been observed in studies conducted to date, however combination therapies, especially with inhibitors of the indoleamine 2,3-dioxygenase (IDO) enzyme, which plays a key role in immunosuppression, could help to harness the power of these drugs. Studies have suggested that sarcomas may be infiltrated by immunosuppressive macrophages that express IDO.⁴³

It is generally believed that immunotherapy is most effective in tumors that are highly mutated because that allows a large number of cancer antigens to provoke an anti-tumor immune response. However, a single highly expressed antigen can also be strongly immunogenic. Synovial sarcomas have a relatively low mutational burden but they do express high levels of the cancer testis antigen NY-ESO-1.

NY-ESO-1 has provided a useful target for the development of adoptive cell therapies and vaccines for the treatment of sarcomas. CMB305 is an NY-ESO-1 vaccine that also incorporates a toll-like receptor 4 agonist. It is being evaluated in the phase 3 Synovate study as maintenance monotherapy in patients with locally advanced, unresectable or metastatic synovial sarcoma. In a phase 1 study, at a median follow-up of just under 18 months, the median OS for all 25 patients was 23.7 months.⁴⁴

The rarity and complexities of bone and soft tissue sarcomas pose a major challenge to effective treatment. Historically, there has been a blanket approach to treatment, but more recently that has begun to change thanks to genome profiling studies and novel clinical trial strategies. Here, we discuss the resulting enrichment of the therapeutic armamentarium with molecularly targeted and immune therapies.

A challenging tumor type

Sarcomas are a large group of histologically diverse cancers that arise in the mesenchymal cells. They can be broadly divided into bone and soft tissue sarcomas (STS) but are further subdivided according to the type of cell from which they derive; osteosarcomas in the bone, rhabdomyosarcomas in the skeletal muscle, liposarcomas in the fat tissues, leiomyosarcomas in the smooth muscle, and chondrosarcomas in the cartilaginous tissue, for example.

Each sarcoma subtype itself encompasses a range of different cancers with unique biology. Under the umbrella of liposarcoma, for example, are well/dedifferentiated liposarcomas and myxoid liposarcomas, which have very different pathologies and clinical courses.

As a whole, sarcomas are extremely rare tumors, accounting for less than 1% of all adult cancers, although they disproportionately affect children and young adults, with a prevalence closer to 15%.^1,2 Certain sarcoma subtypes are exceptionally rare, with only a few cases diagnosed worldwide each year, whereas liposarcomas are at the other end of the spectrum, comprising the most common form of STS (Figure 1).³

Magic bullet for GIST

Despite their clear heterogeneity and complexity, sarcomas have tended to be treated as a single entity. Chemotherapy has played a central role in the treatment of advanced sarcomas and continues to do so, with 2 newer drugs approved by the United States Food and Drug Administration (FDA) in the past several years.^6,7

The development of targeted therapy, on the other hand, for the most part proved unsuccessful. In general, studies examining the somatic mutation landscape in sarcomas found very few that were highly recurrent. The exception was gastrointestinal stromal tumors (GIST), which represent around 8% of STS.⁸ Frequent mutations in several highly targetable tyrosine kinases, notably KIT, which is mutated in around 85% of cases,⁹ and platelet-derived growth factor receptor alpha (PDGFRα) were identified in these tumors.¹⁰This prompted the development of tyrosine kinase inhibitors (TKIs), targeting these and other kinases, for the treatment of patients with GIST, and culminated in the approval of imatinib for this indication in 2002. This revolutionized the treatment of GIST, which had a poor prognosis and were resistant to chemotherapy, extending median overall survival in patients with metastatic disease almost to 5 years.^11-13

Imatinib was also shown to benefit patients with surgically resectable disease and was subsequently approved in the adjuvant setting in 2008. A recent trial demonstrated that 3-year continuation of adjuvant imatinib resulted in a significantly longer progression-free survival (PFS) compared with 1 year of adjuvant imatinib, and even longer time periods are now being evaluated.^14,15 The TKIs sunitinib and regorafenib have also been approved for the treatment of patients who become resistant to imatinib.^16,17 Avapritinib, a newer, more specific inhibitor of KIT is also being evaluated in patients with GIST (Table).

Long-sought success for STS

Sunitinib and regorafenib include PDGFRα and the vascular endothelial growth factor receptors (VEGFRs) among their targets, receptors that play crucial roles in the formation of new blood vessels (angiogenesis). Many types of non-GIST sarcomas have been shown to be highly vascularized and express high levels of both of those receptors and other angiogenic proteins, which sparked interest in the development of multitargeted TKIs and other anti-angiogenic drugs in patients with STS.¹⁸

In 2012, pazopanib became the first FDA-approved molecularly targeted therapy for the treatment of non-GIST sarcomas. Approval in the second-line setting was based on the demonstration of a 3-month improvement in PFS compared with placebo.¹⁹ Four years later, the monoclonal antibody olaratumab, a more specific inhibitor of PDGFRα, was approved in combination with doxorubicin, marking the first front-line approval for more than 4 decades.²⁰Numerous other anti-angiogenic drugs continue to be evaluated for the treatment of advanced STS. Among them, anlotinib is being tested in phase 3 clinical trials, and results from the ALTER0203 trial were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).²¹ After failure of chemotherapy, 223 patients were randomly assigned to receive either anlotinib or placebo. Anlotinib significantly improved median PFS across all patients, compared with placebo (6.27 vs 1.4 months, respectively; hazard ratio [HR], 0.33; P < .0001), but was especially effective in patients with alveolar soft part sarcoma (ASPS; mPFS: 18.2 vs 3 months) and was well tolerated.²¹

Sarcoma secrets revealed

Advancements in genome sequencing technologies have made it possible to interrogate the molecular underpinnings of sarcomas in greater detail. However, their rarity presents a significant technical challenge, with a dearth of samples available for genomic testing. Large-scale worldwide collaborative efforts have facilitated the collection of sufficiently large patient populations to provide statistically robust data in many cases. The Cancer Genome Atlas has established a rare tumor characterization project to facilitate the genomic sequencing of rare cancer types like sarcomas.

Genome sequencing studies have revealed 2 types of sarcomas: those with relatively stable genomes and few molecular alterations, exemplified by Ewing sarcoma, which has a mutational load of 0.15 mutations/Megabase (Mb); and those that are much more complex with frequent somatic mutations, the prime example being leiomyosarcoma. The latter are characterized by mutations in the TP53 gene, dubbed the “guardian of the genome” for its essential role in genome stability.

The 2 types are likely to require very different therapeutic strategies. Although genomically complex tumors offer up lots of potential targets for therapy, they also display significant heterogeneity and it can be challenging to find a shared target across different tumor samples. The p53 protein would make a logical target but, to date, tumor suppressor proteins are not readily druggable.

The most common type of molecular alterations in sarcomas are chromosomal translocations, where part of a chromosome breaks off and becomes reattached to another chromosome. This can result in the formation of a gene fusion when parts of 2 different genes are brought together in a way in which the genetic code can still be read, leading to the formation of a fusion protein with altered activity.^22-25

In sarcomas, these chromosomal translocations predominantly involve genes encoding transcription factors and the gene fusion results in their aberrant expression and activation of the transcriptional programs that they regulate.

Ewing sarcoma is a prime example of a sarcoma that is defined by chromosomal translocations. Most often, the resulting gene fusions occur between members of theten-eleven translocation (TET) family of RNA-binding proteins and the E26 transformation-specific (ETS) family of transcription factors. The most common fusion is between the EWSR1 and FLI1 genes, observed in between 85% and 90% of cases.

Significant efforts have been made to target EWSR1-FLI1. Since direct targeting of transcription factors is challenging, those efforts focused on targeting the aberrant transcriptional programs that they initiate. A major downstream target is the insulin-like growth factor receptor 1 (IGF1R) and numerous IGF1R inhibitors were developed and tested in patients with Ewing sarcoma, but unfortunately success was limited. Attention turned to the mammalian target of rapamycin (mTOR) as a potential mechanism of resistance to IGF1R inhibitors and explanation for the limited responses. Clinical trials combining mTOR and IGF1R inhibitors also proved unsuccessful.²⁶

Although overall these trials were deemed failures, they were notable for the dramatic responses that were seen in 1 or 2 patients. Researchers are probing these “exceptional responses” using novel N-of-1 clinical trial designs that focus on a single patient (Figure 2).^27-30 More recently, the first drug to specifically target the EWSR1-FLI1 fusion protein was developed. TK216 binds to the fusion protein and prevents it from binding to RNA helicase A, thereby blocking its function.³¹

Another type of gene fusion, involving the neurotrophic tropomyosin receptor kinase (NTRK) genes, has recently come into the spotlight for the treatment of lung cancer. According to a recent study, NTRK fusions may also be common in sarcomas. They were observed in 8% of patients with breast sarcomas, 5% with fibrosarcomas, and 5% with stomach or small intestine sarcomas.³²

The NTRK genes encode TRK proteins and several small molecule inhibitors of TRK have been developed to treat patients with NTRK fusion-positive cancers. Another novel clinical trial design – the basket trial – is being used to test these inhibitors. This type of trial uses a tumor-agnostic approach, recruiting patients with all different histological subtypes of cancer that are unified by the shared presence of a specific molecular alteration.³³

Repurposing gynecologic cancer drugs

More recently, a third group of sarcomas was categorized, with intermediate genomic complexity. These tumors, including well/dedifferentiated liposarcomas, were characterized by amplifications of chromosome 12, involving genes such as cyclin-dependent kinase 4 (CDK4). In fact, more than 90% of patients with well/dedifferentiated sarcomas display CDK4 amplification, making it a logical therapeutic target.³⁶

CDK4 encodes CDK4 protein, a cell cycle-associated protein that regulates the transition from G1-S phase, known as the restriction point, beyond which the cell commits to undergoing mitosis. Aberrant expression of CDK4 in cancer drives the hallmark process of unchecked cellular proliferation.

Some small molecule CDK4/6 inhibitors have been developed and have shown significant promise in the treatment of breast cancer. They are also being evaluatedin patients with sarcoma whose tumors display CDK4 overexpression. In a recently published phase 2 trial of palbociclib in 60 patients with well/dedifferentiated liposarcomas, there was 1 CR.³⁷

Another group of drugs that has advanced the treatment of gynecologic cancers comprises the poly (ADP-ribose) polymerase (PARP) inhibitors. In this context, PARP inhibitors are used in patients with mutations in the breast cancer susceptibility genes, BRCA1/2. The BRCA and PARP proteins are both involved in DNA repair pathways and the inhibition of PARP in patients who already have a defective BRCA pathway renders a lethal double blow to the cancer cell. According to the Broad Institute Cancer Cell Line Encyclopedia, Ewing sarcomas express high levels of the PARP1 enzyme, which could render them sensitive to PARP inhibition. Preclinical studies seemed to confirm that sensitivity, however, so far this has yet to translate into success in clinical trials, with no objective responses observed as yet.³⁸
 

Expanding the field

Other treatment strategies being tested in patients with sarcoma are moving the field beyond conventional targeted therapies. There has been substantial focus in recent years on epigenetic alterations and their potential role in the development of cancer. Epigenetics is the secondary layer of regulation that acts on the genome and directs the spatial and temporal expression of genes.

Both DNA and the histone proteins they are packaged up with to form chromatin in nondividing cells can be modified by the attachment of chemical groups, such as acetyl and methyl groups, which can alter access to the DNA for transcription.

EZH2 is an enzyme that participates in histone methylation and thereby regulates transcriptional repression. Some types of sarcoma are characterized by a loss of expression of the INI1 gene, also known as SMARCB1. The INI1 protein is part of a chromatin remodeling complex that relieves transcriptional repression and when INI1 is lost, cells become dependent upon EZH2.³⁹Clinical trials of the EZH2 inhibitor tazemetostat are ongoing in several types of sarcoma. Results from a phase 2 study in adults with INI1-negative tumors were presented at ASCO in 2017. Among 31 patients treated with 800 mg tazemetostat in continuous 28-day cycles, mPFS was 5.7 months, disease control rate was 10%, and confirmed overall response rate was 13%. The FDA has granted tazemetostat orphan drug designation in this indication.⁴⁰A pediatric basket trial of tazemetostat is also ongoing, but the FDA recently placed it under a clinical hold as a result of a safety update from the trial in which a pediatric patient with advanced poorly differentiated chordoma developed a secondary T-cell lymphoma.⁴¹

Targeting the unique metabolism of sarcomas may offer a promising therapeutic strategy, although this is in the preliminary stages of evaluation. A recent study showed that the expression of the argininosuccinate synthase 1 enzyme, which is involved in the generation of arginine through the urea cycle, was lost in up to 90% of STS. A pegylated arginine deaminase (ADI-PEG20), is being evaluated in a phase 2 clinical trial.⁴²

Finally, the concept of using immunotherapy to boost the anti-tumor immune response is also being examined in sarcomas. A significant number of cases of STS, osteosarcoma and GIST have been shown to express programmed cell death protein-ligand 1, therefore the use of immune checkpoint inhibitors that block this ligand or its receptor and help to reactive tumor-infiltrating T cells, could be a beneficial strategy.

Limited activity has been observed in studies conducted to date, however combination therapies, especially with inhibitors of the indoleamine 2,3-dioxygenase (IDO) enzyme, which plays a key role in immunosuppression, could help to harness the power of these drugs. Studies have suggested that sarcomas may be infiltrated by immunosuppressive macrophages that express IDO.⁴³

It is generally believed that immunotherapy is most effective in tumors that are highly mutated because that allows a large number of cancer antigens to provoke an anti-tumor immune response. However, a single highly expressed antigen can also be strongly immunogenic. Synovial sarcomas have a relatively low mutational burden but they do express high levels of the cancer testis antigen NY-ESO-1.

NY-ESO-1 has provided a useful target for the development of adoptive cell therapies and vaccines for the treatment of sarcomas. CMB305 is an NY-ESO-1 vaccine that also incorporates a toll-like receptor 4 agonist. It is being evaluated in the phase 3 Synovate study as maintenance monotherapy in patients with locally advanced, unresectable or metastatic synovial sarcoma. In a phase 1 study, at a median follow-up of just under 18 months, the median OS for all 25 patients was 23.7 months.⁴⁴

The rarity and complexities of bone and soft tissue sarcomas pose a major challenge to effective treatment. Historically, there has been a blanket approach to treatment, but more recently that has begun to change thanks to genome profiling studies and novel clinical trial strategies. Here, we discuss the resulting enrichment of the therapeutic armamentarium with molecularly targeted and immune therapies.

A challenging tumor type

Sarcomas are a large group of histologically diverse cancers that arise in the mesenchymal cells. They can be broadly divided into bone and soft tissue sarcomas (STS) but are further subdivided according to the type of cell from which they derive; osteosarcomas in the bone, rhabdomyosarcomas in the skeletal muscle, liposarcomas in the fat tissues, leiomyosarcomas in the smooth muscle, and chondrosarcomas in the cartilaginous tissue, for example.

Each sarcoma subtype itself encompasses a range of different cancers with unique biology. Under the umbrella of liposarcoma, for example, are well/dedifferentiated liposarcomas and myxoid liposarcomas, which have very different pathologies and clinical courses.

As a whole, sarcomas are extremely rare tumors, accounting for less than 1% of all adult cancers, although they disproportionately affect children and young adults, with a prevalence closer to 15%.^1,2 Certain sarcoma subtypes are exceptionally rare, with only a few cases diagnosed worldwide each year, whereas liposarcomas are at the other end of the spectrum, comprising the most common form of STS (Figure 1).³

Magic bullet for GIST

Despite their clear heterogeneity and complexity, sarcomas have tended to be treated as a single entity. Chemotherapy has played a central role in the treatment of advanced sarcomas and continues to do so, with 2 newer drugs approved by the United States Food and Drug Administration (FDA) in the past several years.^6,7

The development of targeted therapy, on the other hand, for the most part proved unsuccessful. In general, studies examining the somatic mutation landscape in sarcomas found very few that were highly recurrent. The exception was gastrointestinal stromal tumors (GIST), which represent around 8% of STS.⁸ Frequent mutations in several highly targetable tyrosine kinases, notably KIT, which is mutated in around 85% of cases,⁹ and platelet-derived growth factor receptor alpha (PDGFRα) were identified in these tumors.¹⁰This prompted the development of tyrosine kinase inhibitors (TKIs), targeting these and other kinases, for the treatment of patients with GIST, and culminated in the approval of imatinib for this indication in 2002. This revolutionized the treatment of GIST, which had a poor prognosis and were resistant to chemotherapy, extending median overall survival in patients with metastatic disease almost to 5 years.^11-13

Imatinib was also shown to benefit patients with surgically resectable disease and was subsequently approved in the adjuvant setting in 2008. A recent trial demonstrated that 3-year continuation of adjuvant imatinib resulted in a significantly longer progression-free survival (PFS) compared with 1 year of adjuvant imatinib, and even longer time periods are now being evaluated.^14,15 The TKIs sunitinib and regorafenib have also been approved for the treatment of patients who become resistant to imatinib.^16,17 Avapritinib, a newer, more specific inhibitor of KIT is also being evaluated in patients with GIST (Table).

Long-sought success for STS

Sunitinib and regorafenib include PDGFRα and the vascular endothelial growth factor receptors (VEGFRs) among their targets, receptors that play crucial roles in the formation of new blood vessels (angiogenesis). Many types of non-GIST sarcomas have been shown to be highly vascularized and express high levels of both of those receptors and other angiogenic proteins, which sparked interest in the development of multitargeted TKIs and other anti-angiogenic drugs in patients with STS.¹⁸

In 2012, pazopanib became the first FDA-approved molecularly targeted therapy for the treatment of non-GIST sarcomas. Approval in the second-line setting was based on the demonstration of a 3-month improvement in PFS compared with placebo.¹⁹ Four years later, the monoclonal antibody olaratumab, a more specific inhibitor of PDGFRα, was approved in combination with doxorubicin, marking the first front-line approval for more than 4 decades.²⁰Numerous other anti-angiogenic drugs continue to be evaluated for the treatment of advanced STS. Among them, anlotinib is being tested in phase 3 clinical trials, and results from the ALTER0203 trial were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).²¹ After failure of chemotherapy, 223 patients were randomly assigned to receive either anlotinib or placebo. Anlotinib significantly improved median PFS across all patients, compared with placebo (6.27 vs 1.4 months, respectively; hazard ratio [HR], 0.33; P < .0001), but was especially effective in patients with alveolar soft part sarcoma (ASPS; mPFS: 18.2 vs 3 months) and was well tolerated.²¹

Sarcoma secrets revealed

Advancements in genome sequencing technologies have made it possible to interrogate the molecular underpinnings of sarcomas in greater detail. However, their rarity presents a significant technical challenge, with a dearth of samples available for genomic testing. Large-scale worldwide collaborative efforts have facilitated the collection of sufficiently large patient populations to provide statistically robust data in many cases. The Cancer Genome Atlas has established a rare tumor characterization project to facilitate the genomic sequencing of rare cancer types like sarcomas.

Genome sequencing studies have revealed 2 types of sarcomas: those with relatively stable genomes and few molecular alterations, exemplified by Ewing sarcoma, which has a mutational load of 0.15 mutations/Megabase (Mb); and those that are much more complex with frequent somatic mutations, the prime example being leiomyosarcoma. The latter are characterized by mutations in the TP53 gene, dubbed the “guardian of the genome” for its essential role in genome stability.

The 2 types are likely to require very different therapeutic strategies. Although genomically complex tumors offer up lots of potential targets for therapy, they also display significant heterogeneity and it can be challenging to find a shared target across different tumor samples. The p53 protein would make a logical target but, to date, tumor suppressor proteins are not readily druggable.

The most common type of molecular alterations in sarcomas are chromosomal translocations, where part of a chromosome breaks off and becomes reattached to another chromosome. This can result in the formation of a gene fusion when parts of 2 different genes are brought together in a way in which the genetic code can still be read, leading to the formation of a fusion protein with altered activity.^22-25

In sarcomas, these chromosomal translocations predominantly involve genes encoding transcription factors and the gene fusion results in their aberrant expression and activation of the transcriptional programs that they regulate.

Ewing sarcoma is a prime example of a sarcoma that is defined by chromosomal translocations. Most often, the resulting gene fusions occur between members of theten-eleven translocation (TET) family of RNA-binding proteins and the E26 transformation-specific (ETS) family of transcription factors. The most common fusion is between the EWSR1 and FLI1 genes, observed in between 85% and 90% of cases.

Significant efforts have been made to target EWSR1-FLI1. Since direct targeting of transcription factors is challenging, those efforts focused on targeting the aberrant transcriptional programs that they initiate. A major downstream target is the insulin-like growth factor receptor 1 (IGF1R) and numerous IGF1R inhibitors were developed and tested in patients with Ewing sarcoma, but unfortunately success was limited. Attention turned to the mammalian target of rapamycin (mTOR) as a potential mechanism of resistance to IGF1R inhibitors and explanation for the limited responses. Clinical trials combining mTOR and IGF1R inhibitors also proved unsuccessful.²⁶

Although overall these trials were deemed failures, they were notable for the dramatic responses that were seen in 1 or 2 patients. Researchers are probing these “exceptional responses” using novel N-of-1 clinical trial designs that focus on a single patient (Figure 2).^27-30 More recently, the first drug to specifically target the EWSR1-FLI1 fusion protein was developed. TK216 binds to the fusion protein and prevents it from binding to RNA helicase A, thereby blocking its function.³¹

Another type of gene fusion, involving the neurotrophic tropomyosin receptor kinase (NTRK) genes, has recently come into the spotlight for the treatment of lung cancer. According to a recent study, NTRK fusions may also be common in sarcomas. They were observed in 8% of patients with breast sarcomas, 5% with fibrosarcomas, and 5% with stomach or small intestine sarcomas.³²

The NTRK genes encode TRK proteins and several small molecule inhibitors of TRK have been developed to treat patients with NTRK fusion-positive cancers. Another novel clinical trial design – the basket trial – is being used to test these inhibitors. This type of trial uses a tumor-agnostic approach, recruiting patients with all different histological subtypes of cancer that are unified by the shared presence of a specific molecular alteration.³³

Repurposing gynecologic cancer drugs

More recently, a third group of sarcomas was categorized, with intermediate genomic complexity. These tumors, including well/dedifferentiated liposarcomas, were characterized by amplifications of chromosome 12, involving genes such as cyclin-dependent kinase 4 (CDK4). In fact, more than 90% of patients with well/dedifferentiated sarcomas display CDK4 amplification, making it a logical therapeutic target.³⁶

CDK4 encodes CDK4 protein, a cell cycle-associated protein that regulates the transition from G1-S phase, known as the restriction point, beyond which the cell commits to undergoing mitosis. Aberrant expression of CDK4 in cancer drives the hallmark process of unchecked cellular proliferation.

Some small molecule CDK4/6 inhibitors have been developed and have shown significant promise in the treatment of breast cancer. They are also being evaluatedin patients with sarcoma whose tumors display CDK4 overexpression. In a recently published phase 2 trial of palbociclib in 60 patients with well/dedifferentiated liposarcomas, there was 1 CR.³⁷

Another group of drugs that has advanced the treatment of gynecologic cancers comprises the poly (ADP-ribose) polymerase (PARP) inhibitors. In this context, PARP inhibitors are used in patients with mutations in the breast cancer susceptibility genes, BRCA1/2. The BRCA and PARP proteins are both involved in DNA repair pathways and the inhibition of PARP in patients who already have a defective BRCA pathway renders a lethal double blow to the cancer cell. According to the Broad Institute Cancer Cell Line Encyclopedia, Ewing sarcomas express high levels of the PARP1 enzyme, which could render them sensitive to PARP inhibition. Preclinical studies seemed to confirm that sensitivity, however, so far this has yet to translate into success in clinical trials, with no objective responses observed as yet.³⁸
 

Expanding the field

Other treatment strategies being tested in patients with sarcoma are moving the field beyond conventional targeted therapies. There has been substantial focus in recent years on epigenetic alterations and their potential role in the development of cancer. Epigenetics is the secondary layer of regulation that acts on the genome and directs the spatial and temporal expression of genes.

Both DNA and the histone proteins they are packaged up with to form chromatin in nondividing cells can be modified by the attachment of chemical groups, such as acetyl and methyl groups, which can alter access to the DNA for transcription.

EZH2 is an enzyme that participates in histone methylation and thereby regulates transcriptional repression. Some types of sarcoma are characterized by a loss of expression of the INI1 gene, also known as SMARCB1. The INI1 protein is part of a chromatin remodeling complex that relieves transcriptional repression and when INI1 is lost, cells become dependent upon EZH2.³⁹Clinical trials of the EZH2 inhibitor tazemetostat are ongoing in several types of sarcoma. Results from a phase 2 study in adults with INI1-negative tumors were presented at ASCO in 2017. Among 31 patients treated with 800 mg tazemetostat in continuous 28-day cycles, mPFS was 5.7 months, disease control rate was 10%, and confirmed overall response rate was 13%. The FDA has granted tazemetostat orphan drug designation in this indication.⁴⁰A pediatric basket trial of tazemetostat is also ongoing, but the FDA recently placed it under a clinical hold as a result of a safety update from the trial in which a pediatric patient with advanced poorly differentiated chordoma developed a secondary T-cell lymphoma.⁴¹

Targeting the unique metabolism of sarcomas may offer a promising therapeutic strategy, although this is in the preliminary stages of evaluation. A recent study showed that the expression of the argininosuccinate synthase 1 enzyme, which is involved in the generation of arginine through the urea cycle, was lost in up to 90% of STS. A pegylated arginine deaminase (ADI-PEG20), is being evaluated in a phase 2 clinical trial.⁴²

Finally, the concept of using immunotherapy to boost the anti-tumor immune response is also being examined in sarcomas. A significant number of cases of STS, osteosarcoma and GIST have been shown to express programmed cell death protein-ligand 1, therefore the use of immune checkpoint inhibitors that block this ligand or its receptor and help to reactive tumor-infiltrating T cells, could be a beneficial strategy.

Limited activity has been observed in studies conducted to date, however combination therapies, especially with inhibitors of the indoleamine 2,3-dioxygenase (IDO) enzyme, which plays a key role in immunosuppression, could help to harness the power of these drugs. Studies have suggested that sarcomas may be infiltrated by immunosuppressive macrophages that express IDO.⁴³

It is generally believed that immunotherapy is most effective in tumors that are highly mutated because that allows a large number of cancer antigens to provoke an anti-tumor immune response. However, a single highly expressed antigen can also be strongly immunogenic. Synovial sarcomas have a relatively low mutational burden but they do express high levels of the cancer testis antigen NY-ESO-1.

NY-ESO-1 has provided a useful target for the development of adoptive cell therapies and vaccines for the treatment of sarcomas. CMB305 is an NY-ESO-1 vaccine that also incorporates a toll-like receptor 4 agonist. It is being evaluated in the phase 3 Synovate study as maintenance monotherapy in patients with locally advanced, unresectable or metastatic synovial sarcoma. In a phase 1 study, at a median follow-up of just under 18 months, the median OS for all 25 patients was 23.7 months.⁴⁴

CHICAGO – Single-agent lurbinectedin (PM1183, Zepsyre) showed “encouraging” activity against advanced Ewing’s Sarcoma in previously treated adults, results of a phase 2 study indicated.

Among 28 adults with Ewing’s sarcoma (ES) that had relapsed after up to two prior lines of therapy, treatment with lurbinectedin was associated with five partial responses and six cases of stable disease, reported Vivek Subbiah, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“Treatment in combination with other agents is warranted in this patient population,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

Lurbinectedin’s mechanism of action is through blocking DNA transcription and inducing DNA double-strand breaks, which leads to programmed cell death.

“Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, lurbinectedin might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins,” the investigators wrote.

This agent is being investigated against ES as part of a phase 2 basket trial, which is testing the drug against a variety of malignancies. The ES cohort in this study included 15 adults who had received up to two prior chemotherapy regimens. The trial rules called for recruitment of a minimum of 10 more patients if at least one of the first 15 had a confirmed response. There were two responses among the 15 patients, leading to an expansion cohort with 13 patients, for a total of 28 in the current analysis.

The median patient age was 33 years (range, 18-74 years). The majority of patients had good performance status, with Eastern Cooperative Oncology Group scores of 0 (11 patients) or 1 (15 patients); one patient had an ECOG PS score of 2, and one had unknown status.

All but one patient had received a minimum of two prior lines of therapy.

The patients were treated with lurbinectedin 3.2 mg/m² in a 1-hour infusion on day 1 of every 21-day cycle, with the longest duration of therapy out to 14 cycles.

Among 25 evaluable patients, eight had tumor shrinkage, ranging from less than 5% (two patients) to more than 45% (four patients).

Median progression-free survival (PFS) was 2.7 months. The 4-month PFS rate was 42.9%, and the 6-month rates was 21.4%.

A total of 11 patients had some clinical benefit, including five partial responses and six cases of stable disease.

Grade 3 or 4 treatment-related adverse events included febrile neutropenia (two events grade 3 and two grade 4), anemia (five events, all grade 3), neutropenia (five grade 3 and 10 grade 4), thrombocytopenia (four grade 3 events), and elevated alanine aminotransferase levels (two grade 3 events).

Myelosuppression was transient and manageable with granulocyte colony-stimulating factor, the investigators said.

The study was supported by PharmaMar. Dr. Subbiah disclosed travel, accommodations, and/or expenses from the company and from Bayer; a consulting or advisory role with MedImmune; and institutional research funding from PharmaMar and multiple other companies.

SOURCE: Subbiah V et al. ASCO 2018, Abstract 11519.

CHICAGO – Single-agent lurbinectedin (PM1183, Zepsyre) showed “encouraging” activity against advanced Ewing’s Sarcoma in previously treated adults, results of a phase 2 study indicated.

Among 28 adults with Ewing’s sarcoma (ES) that had relapsed after up to two prior lines of therapy, treatment with lurbinectedin was associated with five partial responses and six cases of stable disease, reported Vivek Subbiah, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“Treatment in combination with other agents is warranted in this patient population,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

Lurbinectedin’s mechanism of action is through blocking DNA transcription and inducing DNA double-strand breaks, which leads to programmed cell death.

“Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, lurbinectedin might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins,” the investigators wrote.

This agent is being investigated against ES as part of a phase 2 basket trial, which is testing the drug against a variety of malignancies. The ES cohort in this study included 15 adults who had received up to two prior chemotherapy regimens. The trial rules called for recruitment of a minimum of 10 more patients if at least one of the first 15 had a confirmed response. There were two responses among the 15 patients, leading to an expansion cohort with 13 patients, for a total of 28 in the current analysis.

The median patient age was 33 years (range, 18-74 years). The majority of patients had good performance status, with Eastern Cooperative Oncology Group scores of 0 (11 patients) or 1 (15 patients); one patient had an ECOG PS score of 2, and one had unknown status.

All but one patient had received a minimum of two prior lines of therapy.

The patients were treated with lurbinectedin 3.2 mg/m² in a 1-hour infusion on day 1 of every 21-day cycle, with the longest duration of therapy out to 14 cycles.

Among 25 evaluable patients, eight had tumor shrinkage, ranging from less than 5% (two patients) to more than 45% (four patients).

Median progression-free survival (PFS) was 2.7 months. The 4-month PFS rate was 42.9%, and the 6-month rates was 21.4%.

A total of 11 patients had some clinical benefit, including five partial responses and six cases of stable disease.

Grade 3 or 4 treatment-related adverse events included febrile neutropenia (two events grade 3 and two grade 4), anemia (five events, all grade 3), neutropenia (five grade 3 and 10 grade 4), thrombocytopenia (four grade 3 events), and elevated alanine aminotransferase levels (two grade 3 events).

Myelosuppression was transient and manageable with granulocyte colony-stimulating factor, the investigators said.

The study was supported by PharmaMar. Dr. Subbiah disclosed travel, accommodations, and/or expenses from the company and from Bayer; a consulting or advisory role with MedImmune; and institutional research funding from PharmaMar and multiple other companies.

SOURCE: Subbiah V et al. ASCO 2018, Abstract 11519.

CHICAGO – Single-agent lurbinectedin (PM1183, Zepsyre) showed “encouraging” activity against advanced Ewing’s Sarcoma in previously treated adults, results of a phase 2 study indicated.

Among 28 adults with Ewing’s sarcoma (ES) that had relapsed after up to two prior lines of therapy, treatment with lurbinectedin was associated with five partial responses and six cases of stable disease, reported Vivek Subbiah, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“Treatment in combination with other agents is warranted in this patient population,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

Lurbinectedin’s mechanism of action is through blocking DNA transcription and inducing DNA double-strand breaks, which leads to programmed cell death.

“Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, lurbinectedin might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins,” the investigators wrote.

This agent is being investigated against ES as part of a phase 2 basket trial, which is testing the drug against a variety of malignancies. The ES cohort in this study included 15 adults who had received up to two prior chemotherapy regimens. The trial rules called for recruitment of a minimum of 10 more patients if at least one of the first 15 had a confirmed response. There were two responses among the 15 patients, leading to an expansion cohort with 13 patients, for a total of 28 in the current analysis.

The median patient age was 33 years (range, 18-74 years). The majority of patients had good performance status, with Eastern Cooperative Oncology Group scores of 0 (11 patients) or 1 (15 patients); one patient had an ECOG PS score of 2, and one had unknown status.

All but one patient had received a minimum of two prior lines of therapy.

The patients were treated with lurbinectedin 3.2 mg/m² in a 1-hour infusion on day 1 of every 21-day cycle, with the longest duration of therapy out to 14 cycles.

Among 25 evaluable patients, eight had tumor shrinkage, ranging from less than 5% (two patients) to more than 45% (four patients).

Median progression-free survival (PFS) was 2.7 months. The 4-month PFS rate was 42.9%, and the 6-month rates was 21.4%.

A total of 11 patients had some clinical benefit, including five partial responses and six cases of stable disease.

Grade 3 or 4 treatment-related adverse events included febrile neutropenia (two events grade 3 and two grade 4), anemia (five events, all grade 3), neutropenia (five grade 3 and 10 grade 4), thrombocytopenia (four grade 3 events), and elevated alanine aminotransferase levels (two grade 3 events).

Myelosuppression was transient and manageable with granulocyte colony-stimulating factor, the investigators said.

The study was supported by PharmaMar. Dr. Subbiah disclosed travel, accommodations, and/or expenses from the company and from Bayer; a consulting or advisory role with MedImmune; and institutional research funding from PharmaMar and multiple other companies.

SOURCE: Subbiah V et al. ASCO 2018, Abstract 11519.

CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.

The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.

Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.

“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.

To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).

They calculated disease-free survival at the study median follow-up of 8 years.

The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.

A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.

The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).

Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).

The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.

The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
 

SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
 

CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.

The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.

Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.

“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.

To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).

They calculated disease-free survival at the study median follow-up of 8 years.

The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.

A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.

The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).

Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).

The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.

The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
 

SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
 

CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.

The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.

Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.

“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.

To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).

They calculated disease-free survival at the study median follow-up of 8 years.

The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.

A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.

The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).

Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).

The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.

The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
 

SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
 

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.

Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.

One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.

“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.

“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.

The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.

They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”

The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.

The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.

In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.

The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.

At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.

“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.

SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
 

CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.

Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.

One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.

“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.

“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.

The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.

They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”

The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.

The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.

In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.

The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.

At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.

“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.

SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
 

CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.

Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.

One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.

“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.

“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.

The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.

They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”

The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.

The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.

In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.

The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.

At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.

“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.

SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
 

CHICAGO – In elderly patients with previously untreated metastatic soft-tissue sarcomas (STSs), the oral alkylating agent trofosfamide was associated with a lower overall response rate but long-lasting remissions among patients who had complete responses, investigators reported.

In a randomized phase 2 trial that compared trofosfamide with doxorubicin (Adriamycin), the 6-month progression-free survival (PFS) rate with trofosfamide, the primary endpoint, was 27. 6% versus 35.9% in the doxorubicin arm, said Joerg Thomas Hartmann, MD, from Franziskus Hospital in Bielefeld, Germany.

“Median age was 70 years, which means that the population included [patients] 10-15 years older as compared to other trials in metastatic adult sarcoma. The trial met its predefined endpoint, demonstrating that patients treated with trofosfamide attained a 6-month progression-free rate of more than 20%,” he said at the annual meeting of the American Society of Clinical Oncology.

Trofosfamide is an oral alkylating agent chemically related to cyclophosphamide and ifosfamide. It has been evaluated in a variety of hematologic and solid malignancies and has shown particular activity in patients with chemotherapy-naive and treatment-refractory adult STSs.

Dr. Hartmann and his colleagues conducted the phase 2 study to determine whether oral continuous or “metronomic” therapy with trofosfamide could produce a 6-month PFS rate of at least 20% in patients older than 60 years with previously untreated STSs. They selected this rate of 20% or higher based on the European Organisation for Research and Treatment of Cancer (EORTC) target criterion for doxorubicin of 25%.

They also compared grade 3 or greater toxicities of the two regimens, as well as overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) 1,0, and overall survival.

A total of 120 patients with histologically confirmed STSs with no prior first-line chemotherapy and with adequate bone marrow, renal, and liver function were enrolled. The histologies included pleomorphic sarcoma not otherwise specified, leiomyosarcoma, liposarcoma, and others not specified by Dr. Hartmann.

The patients were randomly assigned on a 1:2 basis to receive either intravenous doxorubicin 60 mg/m² on day 1 of each 21-day cycle for a total of 6 cycles (40 patients) or oral trofosfamide 300 mg/day for days 1 through 7 followed by 150 mg/day until disease progression or unacceptable toxicities (80 patients).

The median patient age in each arm was 70 years.

After a median follow-up of 18.4 months, the trial met its primary endpoint of a 6-months PFS with trofosfamide exceeding 20% (27.6%).

Overall response rates were 7.7% in the doxorubicin arm and 6.6% in the trofosfamide arm.

All three responses in the doxorubicin arm were partial. In the trofosfamide arm there were five responses, including two complete responses and three PR.

The duration of responses in the patients treated with trofosfamide who achieved a complete response were 8.8 and 46.6 months (median, 27.7 months). The median duration of response for trofosfamide-treated patients with a partial response was 8.2 months (range, 1.4-14.9 months).

In contrast, the median duration of response in the patients treated with doxorubicin who achieved a partial response was 4.3 months (range, 2.2-5.6 months).

SOURCE: Hartman JT et al. ASCO 2018, Abstract 11507.

CHICAGO – In elderly patients with previously untreated metastatic soft-tissue sarcomas (STSs), the oral alkylating agent trofosfamide was associated with a lower overall response rate but long-lasting remissions among patients who had complete responses, investigators reported.

In a randomized phase 2 trial that compared trofosfamide with doxorubicin (Adriamycin), the 6-month progression-free survival (PFS) rate with trofosfamide, the primary endpoint, was 27. 6% versus 35.9% in the doxorubicin arm, said Joerg Thomas Hartmann, MD, from Franziskus Hospital in Bielefeld, Germany.

“Median age was 70 years, which means that the population included [patients] 10-15 years older as compared to other trials in metastatic adult sarcoma. The trial met its predefined endpoint, demonstrating that patients treated with trofosfamide attained a 6-month progression-free rate of more than 20%,” he said at the annual meeting of the American Society of Clinical Oncology.

Trofosfamide is an oral alkylating agent chemically related to cyclophosphamide and ifosfamide. It has been evaluated in a variety of hematologic and solid malignancies and has shown particular activity in patients with chemotherapy-naive and treatment-refractory adult STSs.

Dr. Hartmann and his colleagues conducted the phase 2 study to determine whether oral continuous or “metronomic” therapy with trofosfamide could produce a 6-month PFS rate of at least 20% in patients older than 60 years with previously untreated STSs. They selected this rate of 20% or higher based on the European Organisation for Research and Treatment of Cancer (EORTC) target criterion for doxorubicin of 25%.

They also compared grade 3 or greater toxicities of the two regimens, as well as overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) 1,0, and overall survival.

A total of 120 patients with histologically confirmed STSs with no prior first-line chemotherapy and with adequate bone marrow, renal, and liver function were enrolled. The histologies included pleomorphic sarcoma not otherwise specified, leiomyosarcoma, liposarcoma, and others not specified by Dr. Hartmann.

The patients were randomly assigned on a 1:2 basis to receive either intravenous doxorubicin 60 mg/m² on day 1 of each 21-day cycle for a total of 6 cycles (40 patients) or oral trofosfamide 300 mg/day for days 1 through 7 followed by 150 mg/day until disease progression or unacceptable toxicities (80 patients).

The median patient age in each arm was 70 years.

After a median follow-up of 18.4 months, the trial met its primary endpoint of a 6-months PFS with trofosfamide exceeding 20% (27.6%).

Overall response rates were 7.7% in the doxorubicin arm and 6.6% in the trofosfamide arm.

All three responses in the doxorubicin arm were partial. In the trofosfamide arm there were five responses, including two complete responses and three PR.

The duration of responses in the patients treated with trofosfamide who achieved a complete response were 8.8 and 46.6 months (median, 27.7 months). The median duration of response for trofosfamide-treated patients with a partial response was 8.2 months (range, 1.4-14.9 months).

In contrast, the median duration of response in the patients treated with doxorubicin who achieved a partial response was 4.3 months (range, 2.2-5.6 months).

SOURCE: Hartman JT et al. ASCO 2018, Abstract 11507.

CHICAGO – In elderly patients with previously untreated metastatic soft-tissue sarcomas (STSs), the oral alkylating agent trofosfamide was associated with a lower overall response rate but long-lasting remissions among patients who had complete responses, investigators reported.

In a randomized phase 2 trial that compared trofosfamide with doxorubicin (Adriamycin), the 6-month progression-free survival (PFS) rate with trofosfamide, the primary endpoint, was 27. 6% versus 35.9% in the doxorubicin arm, said Joerg Thomas Hartmann, MD, from Franziskus Hospital in Bielefeld, Germany.

“Median age was 70 years, which means that the population included [patients] 10-15 years older as compared to other trials in metastatic adult sarcoma. The trial met its predefined endpoint, demonstrating that patients treated with trofosfamide attained a 6-month progression-free rate of more than 20%,” he said at the annual meeting of the American Society of Clinical Oncology.

Trofosfamide is an oral alkylating agent chemically related to cyclophosphamide and ifosfamide. It has been evaluated in a variety of hematologic and solid malignancies and has shown particular activity in patients with chemotherapy-naive and treatment-refractory adult STSs.

Dr. Hartmann and his colleagues conducted the phase 2 study to determine whether oral continuous or “metronomic” therapy with trofosfamide could produce a 6-month PFS rate of at least 20% in patients older than 60 years with previously untreated STSs. They selected this rate of 20% or higher based on the European Organisation for Research and Treatment of Cancer (EORTC) target criterion for doxorubicin of 25%.

They also compared grade 3 or greater toxicities of the two regimens, as well as overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) 1,0, and overall survival.

A total of 120 patients with histologically confirmed STSs with no prior first-line chemotherapy and with adequate bone marrow, renal, and liver function were enrolled. The histologies included pleomorphic sarcoma not otherwise specified, leiomyosarcoma, liposarcoma, and others not specified by Dr. Hartmann.

The patients were randomly assigned on a 1:2 basis to receive either intravenous doxorubicin 60 mg/m² on day 1 of each 21-day cycle for a total of 6 cycles (40 patients) or oral trofosfamide 300 mg/day for days 1 through 7 followed by 150 mg/day until disease progression or unacceptable toxicities (80 patients).

The median patient age in each arm was 70 years.

After a median follow-up of 18.4 months, the trial met its primary endpoint of a 6-months PFS with trofosfamide exceeding 20% (27.6%).

Overall response rates were 7.7% in the doxorubicin arm and 6.6% in the trofosfamide arm.

All three responses in the doxorubicin arm were partial. In the trofosfamide arm there were five responses, including two complete responses and three PR.

The duration of responses in the patients treated with trofosfamide who achieved a complete response were 8.8 and 46.6 months (median, 27.7 months). The median duration of response for trofosfamide-treated patients with a partial response was 8.2 months (range, 1.4-14.9 months).

In contrast, the median duration of response in the patients treated with doxorubicin who achieved a partial response was 4.3 months (range, 2.2-5.6 months).

SOURCE: Hartman JT et al. ASCO 2018, Abstract 11507.

CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.

Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.

This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.

All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.

“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.

Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.

The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m² infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.

Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.

Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.

After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.

The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.

An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).

In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.

Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.

In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.

Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.

Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).

Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.

SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.

CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.

Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.

This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.

All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.

“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.

Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.

The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m² infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.

Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.

Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.

After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.

The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.

An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).

In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.

Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.

In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.

Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.

Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).

Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.

SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.

CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.

Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.

This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.

All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.

“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.

Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.

The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m² infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.

Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.

Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.

After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.

The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.

An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).

In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.

Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.

In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.

Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.

Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).

Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.

SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.