Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Osteogenic Sarcoma of the Head and Neck: Is Chemotherapy Needed?

OPINION STATEMENT: Head and neck osteosarcoma (HNOS) is a rare subtype of sarcoma that most commonly arises in the mandible or maxilla. Treatment for HNOS typically involves a multidisciplinary and multimodal approach depending on the size, grade, and histological subtype. Surgery by sarcoma-experienced head and neck surgeons and orthopedic oncologists remains a crucial component of treatment in all subtypes of HNOS, particularly for those with low-grade histology, which can be treated definitively with surgical resection if negative margins are obtained. Negative surgical margins are of utmost prognostic importance, and neoadjuvant or adjuvant radiation should be considered in patients with positive (or anticipated positive) margins/residual postoperative disease. Current data favors the use of (neo)adjuvant chemotherapy in patients with high-grade HNOS to improve overall survival but must be individualized to weigh benefits and risks of the short- and long-term effects of treatment. Our center uses a multidisciplinary treatment plan and notes anecdotal improvement in treatment outcomes with a combined surgical and ifosfamide-containing chemotherapeutic approach with radiotherapy for local control if positive margins. Large volume cohorts and adequate randomized control trials assessing the efficacy of chemotherapy in HNOS are scant and additional research and multi-institutional collaboration are needed to study polychemotherapeutic and radiation treatment regimens and outcomes more adequately.

Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial.

BACKGROUND: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study.

BACKGROUND: Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. MATERIALS AND METHODS: Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. PERIOD: Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. RESULTS: Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3-4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. CONCLUSION: Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. IMPLICATIONS FOR PRACTICE: Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.

A nonrandom association of breast implants and the formation of desmoid tumors.

BACKGROUND: Studies suggest that surgical breast augmentation with implants is a risk factor for breast desmoid tumors. The statistical strength of this correlation is unknown, as evidence is limited to anecdotal reports. METHODS: Patients with breast desmoid tumors and a history of breast implants seen at a single center between 2000 and 2021 were identified via radiology, breast, and sarcoma databases. The standardized incidence ratio (SIR) was calculated to assess the correlation between breast desmoid tumors and breast implants. The cases were pooled with published cases for analyses. Progression-free survival curves and hazard ratios were estimated using the Kaplan-Meier method and Cox proportional-hazards modeling. RESULTS: Fourteen patients from one institution and 66 cases in the literature were identified. All patients were female, and the mean age was 38 years old (range 20-66). 63 patients (82%) underwent resection, 9 (12%) received chemotherapy, 3 (4%) received sorafenib, 11 (14%) received hormonal therapy, and 3 (4%) underwent active surveillance. After resection, the 2-year recurrence-free survival rate was 77% (95% CI 65%-89%). The recurrence risk was lower for resection with no residual tumor (R0) compared to microscopic (R1) or macroscopic (R2) residual tumor (HR: 0.15; 95% CI 0.02-0.8; p < 0.05). The SIR was 482 (95% CI 259-775) to 823 (95% CI 442-1322), suggesting a 482-823 times higher risk of developing a breast desmoid tumor after breast augmentation than the general population. CONCLUSION: We present a nonrandom association between breast implants and desmoid tumors. Whether the tumors arise from the surgical trauma or the implant's biomaterial is unknown. When surgery is indicated, negative margins reduce the risk of recurrence.

Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months (0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). INTERPRETATION: Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. FUNDING: Deciphera Pharmaceuticals.

Overall survival and histology-specific subgroup analyses from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

BACKGROUND: We performed a randomized phase 3 study of trabectedin versus dacarbazine in previously-treated patients with liposarcoma/leiomyosarcoma (LPS/LMS). METHODS: Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every 3 weeks. The primary objective was overall survival (OS). Secondary objectives were progression-free survival, objective response rate, safety, and patient-reported outcomes, all previously reported and demonstrating superior disease control with trabectedin. Results of the final OS analysis in preplanned subgroups of patients with LPS/LMS are presented. RESULTS: At the time of the final OS analysis, 577 patients had been assigned randomly, including 423 (73%) with LMS and 154 (27%) with LPS. The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (≥6 cycles: 42% vs 22%). This pattern was consistent across histological subgroups: the median number of treatment cycles (4 vs 2 for both subgroups) and proportion of patients with ≥6 treatment cycles (LMS, 43% vs 24%; LPS, 40% vs 16%). Despite improved disease control by trabectedin, no improvement in OS was observed; the final median OS for trabectedin versus dacarbazine was 13.7 versus 13.1 months (P = .49). Sensitivity analyses of OS suggest confounding by post-study anticancer therapies, which were utilized in most patients in both treatment arms (71% vs 69%, respectively). CONCLUSION: The final OS results demonstrated comparable survival between LPS/LMS patients receiving trabectedin or dacarbazine, which is consistent with the interim analysis results. Both LPS and LMS demonstrated improved disease control with trabectedin.

Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor.

BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.

MRI T2 mapping assessment of T2 relaxation time in desmoid tumors as a quantitative imaging biomarker of tumor response: preliminary results.

Objectives: Because size-based imaging criteria poorly capture biologic response in desmoid-type fibromatosis (DF), changes in MRI T2 signal intensity are frequently used as a response surrogate, but remain qualitative. We hypothesized that absolute quantification of DF T2 relaxation time derived from parametric T2 maps would be a feasible and effective imaging biomarker of disease activity. Methods: This IRB-approved retrospective study included 11 patients with DF, managed by observation or systemic therapy, assessed by 3T MRI. Tumor maximum diameter, volume, and T2-weighted signal intensity were derived from manual tumor segmentations. Tumor:muscle T2 signal ratios were recorded. Two readers measured tumor T2 relaxation times using a commercial T2 scanning sequence, manual ROI delineation and commercial calculation software enabling estimation of reader reliability. Objective response rates based on RECIST1.1 and best responses were compared between size-based and signal-based parameters. Results: Median patient age was 52.6 years; 8 subjects were female (73%). Nine patients with longitudinal assessments were followed for an average of 314 days. Median baseline tumor diameter was 7.2 cm (range 4.4 - 18.2 cm). Median baseline T2 was 65.1 ms (range 40.4 - 94.8 ms, n=11); median at last follow-up was 44.3 ms (-32% from baseline; range 29.3 - 94.7 ms, n=9). T2 relaxation times correlated with tumor:muscle T2 signal ratios, Spearman p=0.78 (p<0.001). T2 mapping showed high inter-reader reliability, ICC=0.84. The best response as a percentage change in T2 values was statistically significant (mean -17.9%, p=0.05, paired t-test) while change in diameter was not (mean -8.9%, p=0.12). Conclusions: Analysis of T2 relaxation time maps of DF may offer a feasible quantitative biomarker for assessing the extent of response to treatment. This approach may have high inter-reader reliability.

Musculoskeletal Metastasis From Soft-tissue Sarcomas: A Review of the Literature.

Soft-tissue sarcomas are a rare and extremely heterogeneous group of cancers, representing <1% of all human malignancies. The lungs are the most common site of distant metastasis, followed by the bone, lymph nodes, liver, brain, and subcutaneous tissue. Clinical experience suggests that skeletal metastasis is part of the natural history affecting the prognosis and quality of life in these patients. Approximately 2.2% of patients have skeletal metastasis at diagnosis. However, up to 10% will develop skeletal metastasis after a mean interval of 21.3 months. Although systemic therapy with conventional chemotherapy remains the primary treatment modality for those with metastatic sarcoma, increased survival has been achieved in selected patients who receive multimodality therapy, including surgery, for their metastatic disease. The 5-year overall survival of patients with isolated bone metastases was 41.2% (26.9% to 54.9%), which decreased to 32.9% (21.2% to 45.1%) in the setting of combined bone and lung metastases. Moreover, the resection of the primary soft-tissue sarcoma is a predictor of survival, resulting in a 58% decrease in mortality after surgery (hazard ratio, 0.42, P = 0.013). Understanding the effect of these metastases on patient survival may influence imaging, surveillance, and treatment decisions.

Radiologic screening and surveillance in hereditary cancers.

Hereditary cancer syndromes comprise an important subset of cancers caused by pathogenic germline mutations that can affect various organ systems. Radiologic screening and surveillance for solid tumors has emerged as a critical component of patient management in permitting early cancer detection. Although imaging surveillance may be tailored for organ-specific cancer risks, surveillance protocols frequently utilize whole-body MRI or PET/CT because of their ability to identify neoplasms in different anatomic regions in a single exam. In this review, we discuss the basic tenets of imaging screening and surveillance strategies in these syndromes, highlighting the more common neoplasms and their associated multimodality imaging findings.

Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma.

Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate-refractory gastrointestinal stromal tumors). This single-institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty-eight patients were enrolled, and 35% were heavily pretreated (≥ 2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression-free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1 and 2.5 and 13.6 months, respectively. The 3-month progression-free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma and MFH were 75% and 69.2%, 60%, and 62.5% and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low-grade disease could have been included and the small numbers, a 3-month progression-free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.

Clinical Outcomes for Primary and Radiation-Associated Angiosarcoma of the Breast with Multimodal Treatment: Long-Term Survival Is Achievable.

BACKGROUND: The optimal management of primary angiosarcoma (PAS) and radiation-associated angiosarcoma (RAAS) of the breast remains undefined. Available data show persistently poor survival outcomes following treatment with surgery or chemotherapy alone. The objective of this study was to evaluate long-term outcomes in patients treated with multimodality therapy. METHODS: Patients diagnosed with stage I-III PAS or RAAS of the breast were identified from our local tumor registry (2010-2020). Patient demographics, tumor characteristics, and treatment were collected. Primary outcomes were local recurrence (LR), distant recurrence (DR), and median overall survival (OS). A secondary outcome was pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC). Mann-Whitney U, chi-squared, or Fisher exact tests were used to analyze data. Kaplan-Meier curves compared OS for PAS and RAAS. RESULTS: Twenty-two patients met inclusion criteria, including 11 (50%) with RAAS and 11 (50%) with PAS. Compared to PAS patients, RAAS patients were older and had more comorbidities. For RAAS patients, median time from radiation to diagnosis was 6 years (IQR: 5-11). RAAS patients were more likely to have a pCR to NAC (40% vs. 20%, p = 0.72). RAAS patients had a higher LR rate (43% vs. 38%, p = 0.83), and PAS patients were more likely to develop a DR (38% vs. 0%, p = 0.07). Median OS was 81 months in PAS patients and 90 months in RAAS patients (p = 1.00). DISCUSSION: Long-term survival can be achieved in patients with PAS and RAAS who undergo multimodality treatment. NAC can result in pCR. The long-term clinical implications of pCR warrant further investigation.

Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous KIT/PDGFRA Mutations in the Phase III INVICTUS Study.

PURPOSE: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. PATIENTS AND METHODS: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. RESULTS: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan-Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. CONCLUSIONS: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.

Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis.

We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.

Identification of Genetic Alterations by Circulating Tumor DNA in Leiomyosarcoma: A Molecular Analysis of 73 Patients.

Background: Leiomyosarcoma is a malignant mesenchymal tumor of cells of smooth muscle lineage arising commonly in retroperitoneum, uterus, large veins, and the limbs. The genetics of leiomyosarcomas are complex and there is very limited understanding of common driver mutations. Circulating tumor DNA (ctDNA) offers a rapid and noninvasive method of next-generation sequencing (NGS) that could be used for diagnosis, therapy, and detection of recurrence. Methods: ctDNA testing was performed using Guardant360, which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in 73 genes using NGS. Results: Of 73 patients, 59 were found to have one or more cancer-associated genomic alteration. Forty-five (76%) were female with a median age of 63 (range, 38-87) years. All samples were designated metastatic. The most common alterations were detected in Tp53 (65%), BRAF (13%), CCNE (13%), EGFR (12%), PIK3CA (12%), FGFR1 (10%), RB1(10%), KIT (8%), and PDGFRA (8%). Some of the other alterations included RAF1, ERBB2, MET, PTEN TERT, APC, and NOTCH1. Potentially targetable mutations, by Food and Drug Administration-approved or clinical trials, were found in 24 (40%) of the 73 patients. Four patients (5%) were found to have incidental germline TP53 mutations. Conclusion: NGS of ctDNA allows identification of genomic alterations in plasma from patients with leiomyosarcoma. Unfortunately, there is limited activity of current targeted agents in leiomyosarcomas. These results suggest opportunities to develop therapy against TP53, cell cycle, and kinase signaling pathways. Further validation and prospective evaluation is warranted to investigate the clinical utility of ctDNA for patients with leiomyosarcoma.

Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib.

BACKGROUND: Sunitinib inhibits KIT and other members of the split-kinase-domain family of receptor tyrosine kinases. Sunitinib prolongs survival in adult patients with imatinib-resistant gastrointestinal stromal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib. PROCEDURE: Sunitinib therapy was provided through a treatment-use protocol. Patients were 10-17 years old at enrollment. All patients had GIST resistant to imatinib therapy. Sunitinib was administered daily for 4 weeks in 6-week treatment cycles. KIT and platelet-derived growth factor receptor alpha (PDGFRA) genotyping of tumor tissue were performed. RESULTS: One patient achieved a partial response, five patients had stable disease and one patient had progressive disease on sunitinib. The duration of disease stabilization was between 7 and 21+ months, with a mean of 15 months. Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients. Two patients experienced grade 3 adverse events. All other adverse events were grade 1-2. None of the five patients tested had mutations in KIT or PDGFRA. CONCLUSION: Sunitinib treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST.

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib.

Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants: This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions: Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Neutropenic enterocolitis (typhilitis) associated with docetaxel therapy in a patient with non-small-cell lung cancer: case report and review of literature.

Neutropenic enterocolitis (NE) is an unusual acute complication of neutropenia, most often associated with leukemia and lymphoma which is characterized by segmental cecal and ascending colon ulceration that may progress to necrosis, perforation, and septicemia. We present a case of neutropenic enterocolitis in a patient with non-small-cell lung cancer who received docetaxel and flavopiridol as part of a phase I clinical trial and review cases in the literature where docetaxel was involved. Given the increased use of docetaxel and other taxanes in the treatment of advanced lung cancer, physicians should be aware of this potential toxicity of therapy.