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Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising in the gastrointestinal tract. Their systemic treatment is based on the use of tyrosine kinase inhibitors (TKIs) with imatinib, sunitinib, and regorafenib being the preferred agents. Assessment of tumor response to TKI treatment in GISTs is traditionally done according the Response Evaluation Criteria in Solid Tumors (RECIST), while Choi criteria have also been proposed as alternative tool assessing both volumetric and density changes on computer tomography (CT) scans. EORTC STBSG 1317 'CaboGIST' was a single-arm prospective Phase 2 trial which met its primary endpoint, as 60% of patients previously treated with imatinib and sunitinib were progression-free at 12 weeks (95% CI 45–74%) based on local RECIST assessment. We report here an exploratory analysis of local versus central RECIST version 1.1 assessment and a comparison of RECIST version 1.1 versus Choi criteria. Comparisons between local and central RECIST version 1.1 at week 12 revealed discrepancies in 17/43 evaluable cases (39.5%). When comparing Choi with local and central RECIST version 1.1, discrepancies were observed in 27/43 (62.8%) and 21/43 (48.8%) cases, respectively. A total of 68% of evaluable patients were progression-free and alive at week 12 based on local RECIST, 84% according to central RECIST analysis and 81% when applying Choi criteria. Central assessment upgraded the treatment response both with RECIST version 1.1 and Choi. The results of this exploratory analysis support the conclusion that cabozantinib is active in patients with metastatic or recurrent GIST after treatment with imatinib and sunitinib and confirm once again the limitations of RECIST to capture response to TKI in GIST, and the importance to include density changes in the response evaluation in this setting. Clinical trial number: EORTC 1317, NCT02216578 [ABSTRACT FROM AUTHOR]

Locally advanced soft tissue sarcoma (STS) management may include neoadjuvant or adjuvant treatment by radiotherapy (RT), chemotherapy (CT) or chemoradiotherapy (CRT) followed by wide surgical excision. While pathological complete response (pCR) to preoperative treatment is prognostic for survival in osteosarcomas, its significance for STS is unclear. We aimed to evaluate the prognostic significance of pCR to pre-operative treatment on 3-year disease-free survival (3y-DFS) in STS patients. This is an observational, retrospective, international, study of adult patients with primary non-metastatic STS of the extremities and trunk wall, any grade, diagnosed between 2008 and 2012, treated with at least neoadjuvant treatment and surgical resection and observed for a minimum of 3 years after diagnosis. The primary objective was to evaluate the effect of pCR. (≤5% viable tumor cells or ≥95% necrosis/fibrosis) on 3y-DFS. Effect on local recurrence-free survival (LRFS), distant recurrence-free survival (MFS) overall survival (OS) at 3 years was also analyzed. Statistical univariate analysis utilized chi-square independence test and odds ratio confidence interval (CI) estimate, multivariate analysis was performed using LASSO. A total of 330 patients (median age 56 years old, range:19–95) treated by preoperative RT (67%), CT (15%) or CRT (18%) followed by surgery were included. pCR was achieved in 74/330 (22%) of patients, of which 56/74 (76%) had received RT. 3-yr DFS was observed in 76% of patients with pCR vs 61% without pCR (p < 0.001). Multivariate analysis showed that pCR is statistically associated with better MFS (95% CI, 1.054–3.417; p = 0.033), LRFS (95% CI, 1.226–5.916; p = 0.014), DFS (95% CI, 1.165–4.040; p = 0.015) and OS at 3 years (95% CI, 1.072–5.210; p = 0.033). In a wide, heterogeneous STS population we showed that pCR to preoperative treatment is prognostic for survival. [ABSTRACT FROM AUTHOR]

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation–positive unresectable or metastatic melanoma and Erdheim‐Chester disease. This phase 1, open‐label, single‐arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14C‐labeled vemurafenib in patients with BRAFV600 mutation–positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14C‐labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14C‐labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose‐normalized area under the curve during the dosing interval (AUCτ) following oral vemurafenib dose to dose‐normalized AUC from time 0 extrapolated to infinity (AUC0‐inf) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment‐emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade‐4 anaphylactic reaction occurring during infusion of 14C‐labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors most often caused by activating mutations of the KIT gene. KIT tyrosine kinase inhibitors provide targeted therapy for the underlying genetic mutation, and adjuvant therapy is indicated for patients who are at significant risk of relapse following GIST resection. This is a report of the safety of imatinib in patients with GIST in the adjuvant setting in an expanded access program. Methods: In this multicenter, open-label, single-arm trial, safety was assessed based on the frequency of adverse events (AEs). Results: Three hundred patients were treated and analyzed; 40 patients discontinued treatment. Median overall exposure during the program was 181 days (range 9–420); most patients (260/300 treated) completed the study. Six patients had disease recurrence, 4 of whom discontinued. In line with previously published reports, the most frequent AEs were nausea, diarrhea, and periorbital edema. The AEs were mild to moderate in most cases (76%). Conclusions: These findings are in agreement with the known safety profile of imatinib and confirm the safety of imatinib at 400 mg/day in the adjuvant setting. The incidence of severe AEs was low. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Plain Language Summary Pexidartinib is effective in patients with tenosynovial giant cell tumor (TGCT) for whom surgery is not feasible. Durability of response after discontinuation of pexidartinib and the safety and efficacy of restarting pexidartinib have not been previously recorded. This phase 4 study was designed to mimic the real‐world experience with pexidartinib to evaluate the effects of discontinuation of and retreatment with pexidartinib in patients with TGCT who previously benefited from the drug.This was a global, multicenter, phase 4 study that enrolled patients with TGCT who were experiencing clinical benefit from pexidartinib in one of four prior phase 1 or phase 3 studies investigating pexidartinib in the disease. Patients could choose to continue pexidartinib at the same dose (the treatment‐continuation cohort) or discontinue treatment with the option to restart pexidartinib (the treatment‐free/retreatment cohort). Tumor progression determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, patient‐reported outcomes (the Patient‐Reported Outcomes Measurement Information System–Physical Function [PROMIS‐PF] questionnaire and the EuroQol 5‐dimension, 5‐level [EQ‐5D‐5L] visual analog scale), and safety were assessed every 3 months. The primary end point was the proportion of patients in the treatment‐free/retreatment cohort who remained treatment‐free at month 12 and 24; this did not depend on disease progression.Thirty‐two patients were enrolled: 21 chose to enter the treatment‐continuation cohort, and 11 entered the treatment‐free/retreatment cohort. During the treatment‐free period, six of 11 (54.5%) patients in the treatment‐free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1, whereas no patient in the treatment‐continuation cohort had disease progression. Over the 24‐month study, three of 11 (27.3%) patients in the treatment‐free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symptomatic progression, or both (n = 1 each). The probability of remaining treatment‐free in the treatment‐free/retreatment cohort was 73% (95% confidence interval, 37%–90%). In the treatment‐free/retreatment cohort, the median progression‐free survival of the treatment‐free period was 22.8 months (95% confidence interval, 1.6 months to not estimable). By 6 months of retreatment, all retreated patients achieved new disease stabilization with no new safety concerns; two patients had clinically significant improvements in PROMIS‐PF and EQ‐5D‐5L visual analog scale scores. The mean PROMIS‐PF and EQ‐5D‐5L scores remained stable throughout the study. There was no hepatotoxicity and no new safety signal in either cohort.In this small phase 4 study designed to evaluate outcomes in patients who stopped and restarted pexidartinib, 54.5% of patients who discontinued pexidartinib showed PD, with a median progression‐free survival of 22.8 months. Each of the three patients who restarted pexidartinib stopped progressing, and some reported a new gain in physical function. No PD was detected in patients who remained on treatment, and the safety profile did not indicate long‐term hepatotoxicity or any new safety concerns. Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended. This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed. Thirty‐two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years. Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened. Restarting pexidartinib was safe and effective in these patients. Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended.This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed.Thirty‐two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years.Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened.Restarting pexidartinib was safe and effective in these patients. [ABSTRACT FROM AUTHOR]

The selection of colorectal cancer patients for anti-epidermal growth factor receptor (EGFR) antibody therapy is based on the determination of their RAS mutation status—a strongly negative predictive factor—since the protein target, EGFR, is not a reliable predictor of therapeutic response. In this study, we revisited the EGFR protein issue using a cohort of 90 patients with KRAS exon2 wild-type colorectal cancer who have been treated with cetuximab therapy. Twenty-nine of these patients had metastatic tissue available for analysis. The level of EGFR protein expression in the patients was determined by immunohistochemistry and evaluated by H-score (HS) methodology. Progression-free survival (PFS) and overall survival (OS) of the patients were determined according to the EGFR-HS ranges of both the primary and metastatic tissues using Kaplan–Meyer statistics. In the case of primary tumors, EGFR scores lower than HS = 200 were associated with significantly longer OS. In the case of metastatic tissues, all levels lower than the EGFR-HS range chosen were associated with significantly longer OS. These results are explained by the fact that metastatic tissues rarely maintained the expression levels of the primary tumors. On the other hand, high EGFR expression levels in either primary tumors or metastatic tissues were associated with multiple metastatic disease. This suggests a negative prognostic role of EGFR expression. However, in a multivariate analysis, one-sidedness remained a strong independent predictive factor of survival. Previous studies demonstrated that the EGFR expression level depends on sidedness. Therefore, a subgroup analysis of the left- and right-sided cases was performed on both primary and metastatic tissues. In the case of metastic tissues, an analysis confirmed a better OS in low EGFR protein-expressing cases than in high EGFR protein-expressing cases. Collectively, these data suggest that EGFR protein expression is another negative predictive factor of the efficacy of cetuximab therapy of KRAS exon2 wild-type colorectal cancer. [ABSTRACT FROM AUTHOR]

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAF V600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUC τ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC 0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of 14 C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation., (© 2020, The American College of Clinical Pharmacology.)