Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Therapeutic drug monitoring-based precision dosing of oral targeted therapies in oncology: a prospective multicenter study.

BACKGROUND: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems. PATIENTS AND METHODS: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments). RESULTS: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%). CONCLUSIONS: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.

Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors.

BACKGROUND: Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors. PATIENTS AND METHODS: This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy. RESULTS: Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms. CONCLUSION: Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models.

Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib.

This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI):1.457-12.746, P=0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI:1.013-4.044, P=0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.216-5.573, P=0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI:1.518-33.496, P=0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.

Patient-reported outcome measures in a pharmacokinetic study with sunitinib, a prospective cohort study.

PURPOSE: During treatment with tyrosine kinase inhibitors, such as sunitinib, patients experience treatment and/or disease-related symptoms. Although application of patient-reported outcome measures (PROMs) enhances early recognition of symptoms, early clinical trials are focused on symptom severity objectified by the Common Terminology Criteria for Adverse Events (CTCAE) in order to evaluate drug safety and to determine a personalized and/or safe dosage range. To gain insight into patient-reported symptoms in addition to healthcare professional-reported adverse events (AEs), a substudy was conducted in an ongoing pharmacokinetic-guided sunitinib dosing study. METHODS: In patients for whom sunitinib was considered standard therapy or patients with advanced/metastatic tumors for whom no standard therapy was available, patient-reported symptoms and well-being besides healthcare professional-reported AEs were assessed. RESULTS: Twenty-nine patients were included for analysis. Over 50% of them experienced a decreased well-being, caused by symptoms of mild and moderate intensity. Compared to healthcare professionals, all measured symptoms, with the exception of fatigue and vomiting, were reported statistically significantly more often by patients. CONCLUSIONS: Application of PROMs in early clinical trials on personalized or individualized oral targeted anticancer agents is feasible and enhances early recognition of symptom burden due to multiple CTCAE grade 1-2 AEs, just as pro-active symptom management and effect evaluation of interventions performed. Application of PROMs in these trials might be clinically relevant in obtaining dose-limiting toxicities.

Molecular Tumor Boards: current practice and future needs.

BACKGROUND: Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date. METHODS: Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation. RESULTS: Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, <50% of hospitals and only 5% of nonacademic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools, and workflow. This may not only lead to variation in quality of care but also hinders data sharing and thus creation of an effective learning community. CONCLUSIONS: This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.

Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis.

BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies.

BACKGROUND: Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio. PATIENTS AND METHODS: Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined. RESULTS: Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorff's α-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496]. CONCLUSION: The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS. CLINICALTRIALSGOV IDENTIFIER: NCT01566279.

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS: In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS: A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS: These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

BACKGROUND: Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels. METHODS: Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg. RESULTS: Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity. CONCLUSIONS: In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.

Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients.

PURPOSE: Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care. METHODS: A retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated. RESULTS: Liver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment. CONCLUSION: Our study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.

Sunitinib for the treatment of metastatic gastrointestinal stromal tumors: the effect of TDM-guided dose optimization on clinical outcomes.

BACKGROUND: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity. PATIENTS AND METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing. RESULTS: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002). CONCLUSIONS: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.

Quantification of sunitinib and N-desethyl sunitinib in human EDTA plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry: validation and application in routine therapeutic drug monitoring.

BACKGROUND: Given the low therapeutic index, the large interindividual variability in systemic exposure and the positive exposure-efficacy relationship of sunitinib, there is a rationale for therapeutic drug monitoring (TDM) of sunitinib. To support TDM, a method for determination of sunitinib and its active metabolite (N-desethyl sunitinib) has been developed and validated. METHODS: For determination of sunitinib and N-desethyl sunitinib in human EDTA plasma samples, high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used. Validation experiments according to Food and Drug Administration guidelines were performed. In addition, the results of 25 analytical runs with 58 patient samples using 8 calibrators and 3 levels of quality control (QC) samples per analysis were compared with the results of analyses using only 3 calibrators and 1 QC sample to accelerate sample turnaround time. The method comparison experiment was performed according to international guidelines. RESULTS: The HPLC-MS/MS method was validated over a linear range from 2.5 to 500 ng/mL using 50 µL plasma volumes, with good intra- and interassay accuracy and precision. In addition, the mean of the absolute differences between the compared methods was only -0.66 ng/mL (mean of relative differences, -0.85%), which is not a clinically relevant difference. CONCLUSIONS: This method has been applied successfully for routine TDM purposes for patients treated with sunitinib. Moreover, reliable results with a rapid turnaround time were obtained when performing a short analytical run containing only 3 calibrators and 1 QC sample.

The use of microtracers in food-effect trials: An alternative study design for toxic drugs with long half-lives exemplified by the case for alectinib.

The traditional design of food-effect studies has a high patient burden for toxic drugs with long half-lives (e.g., anticancer agents). Microtracers could be used to assess food-effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food-effect study during steady-state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half-life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food-effect). Power was defined as the fraction of clinical trials where a significant (p < 0.01) food-effect was identified. The proposed study design of 10 patients on steady-state treatment, 10 blood samples collected within 24 h after administration and an assumed food-effect of 40% had a power of 99.9%. The mean estimated food-effect was 39.8% (80% confidence interval: 31.0%-48.6%). The feasibility of microtracer food-effect studies was demonstrated. The design of the microtracer food-effect study allowed estimation of the food-effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half-lives.

Elevated preoperative serum interleukin-6 level is predictive for worse postoperative outcome after soft tissue sarcoma surgery.

BACKGROUND: The pro-inflammatory cytokine interleukin-6 (IL-6) plays a role in cancer development and progression, but research into the predictive value of IL-6 on postoperative outcome in soft tissue sarcoma (STS) is scarce. The purpose of this study is to investigate the predictive value of serum IL-6 level for the achievement of assumed (post)operative outcome after STS surgery, the so-called textbook outcome. METHODS: Preoperative IL-6 serum levels were collected in all patients with a STS at first presentation between February 2020 and November 2021. Textbook outcome was defined as a R0 resection, no complications, no blood transfusions, no reoperation within the postoperative period, no prolonged hospital stay, no hospital readmission within 90-days, and no mortality within 90-days. Factors associated with textbook outcome were determined by multivariable analysis. RESULTS: Among 118 patients with primary, non-metastatic STS, 35.6% achieved a textbook outcome. Univariate analysis showed that smaller tumor size (p = 0.026), lower tumor grade (p = 0.006), normal hemoglobin (Hb, p = 0.044), normal white blood cell (WBC) count (p = 0.018), normal C-reactive protein (CRP) serum level (p = 0.002) and normal IL-6 serum level (p = 1.5 × 10-5) were associated with achieving textbook outcome after surgery. Multivariable analysis showed that elevated IL-6 serum level (p = 0.012) was significantly associated with not achieving a textbook outcome. CONCLUSIONS: Increased IL-6 serum level is predictive for not achieving a textbook outcome after surgery for primary, non-metastatic STS.

Exposure-response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients.

INTRODUCTION: Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib. PATIENTS AND METHODS: An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration-time Curve and trametinib trough concentrations (Cmin), univariable and multivariable exposure-response analyses were performed. RESULTS: In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with Cmin ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib Cmin ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36-0.85, P = 0.007). Median PFS in patients with trametinib Cmin levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with Cmin below this threshold (P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47-1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities. CONCLUSIONS: Overall survival of metastasized melanoma patients with trametinib Cmin levels ≥ 15.6 ng/mL is ten months longer compared to patients with Cmin below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity.

Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC.

BACKGROUND: In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. PATIENTS AND METHODS: BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator's choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. RESULTS: Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. CONCLUSIONS: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.

Sex differences in patients with gastrointestinal stromal tumours: do they exist and does it affect survival?

BACKGROUND: Sex differences in cancer have gained attention in recent years. The role of sex as a prognostic factor in gastrointestinal stromal tumours (GIST) has not been well established. The aim of this research was to elucidate potential sex differences in GIST patients and the influence of sex on disease-specific survival (DSS). METHODS: A review of the literature was carried out to obtain an overview of all literature with sex as a covariate on GIST survival analyses. Furthermore, in the Dutch GIST Registry, GIST characteristics between males and females were compared and the influence of sex on DSS was analysed. RESULTS: A total of 118 articles from the review of the literature met our selection criteria; 58% of the articles found no sex difference in survival and 42% did find a sex difference. All differences favoured female patients, although there was substantial overlap of individual patients in the various reported groups. The Dutch GIST Registry cohort consisted of 1425 patients (46% female). Compared with female patients, male patients had larger tumours (mean 9.0 cm versus 7.9 cm) and higher mitotic rates (34.4% versus 28.0% >5 mitoses/5 mm2). GIST in males was more often metastasized at diagnosis (21.3% versus 13.7%) and incurable (38.5% versus 31.0%). Male patients less often received surgery of the primary tumour (71.7% versus 78.9%), but did experience more tumour ruptures (18.2% versus 13.3%). Male patients had a worse DSS than females. This was not statistically significant when corrected for differences in GIST characteristics. CONCLUSIONS: In case of sex differences in GIST in the literature, male patients have a worse outcome. In our Dutch GIST cohort a similar finding was made, but sex was shown not to be an independent factor. Male patients more often had aggressive GISTs, with larger tumours, higher mitotic rates, more tumour ruptures, and metastases, which could explain the sex differences in DSS.

Complete genomic characterization in patients with cancer of unknown primary origin in routine diagnostics.

BACKGROUND: In ∼3%-5% of patients with metastatic disease, tumor origin remains unknown despite modern imaging techniques and extensive pathology work-up. With long diagnostic delays and limited and ineffective therapy options, the clinical outcome of patients with cancer of unknown primary (CUP) remains poor. Large-scale genome sequencing studies have revealed that tumor types can be predicted based on distinct patterns of somatic variants and other genomic characteristics. Moreover, actionable genomic events are present in almost half of CUP patients. This study investigated the clinical value of whole genome sequencing (WGS) in terms of primary tumor identification and detection of actionable events, in the routine diagnostic work-up of CUP patients. PATIENTS AND METHODS: A WGS-based tumor type 'cancer of unknown primary prediction algorithm' (CUPPA) was developed based on previously described principles and validated on a large pan-cancer WGS database of metastatic cancer patients (>4000 samples) and 254 independent patients, respectively. We assessed the clinical value of this prediction algorithm as part of routine WGS-based diagnostic work-up for 72 CUP patients. RESULTS: CUPPA correctly predicted the primary tumor type in 78% of samples in the independent validation cohort (194/254 patients). High-confidence predictions (>95% precision) were obtained for 162/254 patients (64%). When integrated in the diagnostic work-up of CUP patients, CUPPA could identify a primary tumor type for 49/72 patients (68%). Most common diagnoses included non-small-cell lung (n = 7), gastroesophageal (n = 4), pancreatic (n = 4), and colorectal cancer (n = 3). Actionable events with matched therapy options in clinical trials were identified in 47% of patients. CONCLUSIONS: Genome-based tumor type prediction can predict cancer diagnoses with high accuracy when integrated in the routine diagnostic work-up of patients with metastatic cancer. With identification of the primary tumor type in the majority of patients and detection of actionable events, WGS is a valuable diagnostic tool for patients with CUP.

Monitoring of EGFR mutations in circulating tumor DNA of non-small cell lung cancer patients treated with EGFR inhibitors.

PURPOSE: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib. METHODS: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored. RESULTS: In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation. CONCLUSION: This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression.