AbstractBRAF and MEK inhibitors are highly active in the setting of BRAFV600 mutant melanoma. Rarely, patients without previous testing present with fulminant progression necessitating emergent treatment prior to BRAF testing results. The safety and efficacy of empiric treatment in this setting is unclear. Herein, we present two patients treated with empiric BRAF and MEK inhibitors, resulting in dramatic clinical improvement in one patient later found to have a BRAF mutation, and lack of improvement (but no accelerated progression) in a patient lacking this mutation. Empiric BRAF and MEK inhibitor treatment should not be routinely pursued but may be given safely in rare, emergent situations.
TELEPRO: Patient‐Reported Carcinoid Syndrome Symptom Improvement Following Initiation of Telotristat Ethyl in the Real World
AbstractBackground.When carcinoid syndrome (CS) diarrhea (CSD) is inadequately controlled with long‐acting somatostatin analogs (SSAs), clinical practice guidelines recommend addition of the tryptophan hydroxylase inhibitor telotristat ethyl (TE). In a 12‐week multinational, randomized controlled trial, TE added to SSA reduced peripheral serotonin and the frequency of CSD. We evaluated real‐world effectiveness of TE using patient‐reported data from a nurse support program over 3 months.Materials and Methods.This study used a deidentified data set of patients initiating TE who opted into a nurse support program between March and November 2017 and reported CS symptom burden at baseline and at least one follow‐up time point at months 1, 2, and 3. Patients reported demographic and medical history information as well as frequency of bowel movements (BMs) and flushing episodes, severity of nausea, urgency and abdominal pain (0 “no/not at all” to 100 “worst imaginable/very urgent”), and stool form (1 “very hard” to 10 “watery”). Mean changes from baseline in CS symptom burden were reported using paired‐sample t tests and Wilcoxon signed‐rank tests.Results.Most patients initiating TE enrolled in the nurse program (791/898, 88%), of whom 369 (47%) were included in the analysis. Patients treated with TE reported significant reductions in CSD and other CS symptoms (all p < .001). At least half of patients treated with TE experienced ≥30% improvement from baseline in BM frequency and an average reduction of at least two BMs per day within 3 months.Conclusion.Patients taking SSA therapy showed substantial burden of disease before initiating TE and significant improvements with the addition of TE treatment in this real‐world effectiveness study.Implications for Practice.Patients with carcinoid syndrome diarrhea uncontrolled by high doses of long‐acting somatostatin analogs may be candidates for additional therapy with the tryptophan hydroxylase inhibitor telotristat ethyl. Understanding the real‐world prevalence of uncontrolled symptoms and the effectiveness of telotristat ethyl in clinical practice may further support clinical and policy decisions for these patients. This study investigated self‐reported carcinoid syndrome symptom burden and improvements among patients initiating telotristat ethyl and participating in a voluntary nurse support program. Disease burden and off‐label somatostatin analog treatment before initiating telotristat ethyl were high, and symptoms improved markedly over 1, 2, and 3 months of treatment.
Planned Pregnancy in Female Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitor Therapy
AbstractBackground.The aim of this study was to explore outcomes of planned pregnancy in female patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors (TKIs).Materials and Methods.Data of female patients proceeding with a planned pregnancy were retrospectively reviewed.Results.A total of 17 patients with CML who achieved at least a major molecular response (MMR) during imatinib (n = 13) or nilotinib (n = 4) therapy prior to a planned pregnancy were enrolled. At the time of TKI interruption, six were in MMR, two in molecular response 4 (MR4), and nine in molecular response 4.5 (MR4.5). TKI therapy was discontinued 6 weeks (range, 2–15 weeks) before conception in 4 patients and at gestational age of 4 weeks (range, 2–5 weeks) after determination of pregnancy in 13 patients. Apart from 1 patient who suffered a spontaneous abortion, 16 patients delivered uneventfully. A total of 10 patients lost MMR after stopping TKIs; 8 lost molecular response 2, and 3 lost complete hematological response. Log‐rank analyses showed achieving MR4 (p = .030) or MR4.5 (p = .031), complete cytogenetic response duration ≥3.5 years (p = .049), and MMR duration ≥3.5 years (p = .040) were significantly associated with longer MMR‐failure‐free survival during TKI interruption.Conclusion.Planned pregnancy might be pragmatic in female patients with CML on TKIs. Achieving deep molecular response and, importantly, MMR duration ≥3.5 years were significantly associated with maintaining MMR during pregnancy.Implications for Practice.Female patients with chronic myeloid leukemia on tyrosine kinase inhibitors (TKIs) wishing to conceive are currently advised to discontinue TKIs before conception. However, the ideal degree and duration of response before stopping TKI, in addition to whether there will be any adverse effect caused by a short exposure of TKI, is unknown. Data of 17 female patients, who achieved at least a major molecular response (MMR) before TKI interruption, was revised, and it was found that achieving deep molecular response and MMR duration ≥3.5 years was significantly associated with maintaining MMR during pregnancy. This provides direct evidence for a planned pregnancy strategy, and stopping TKI immediately after determination of pregnancy in female patients might be pragmatic.
Association Between Preanalytical Factors and Tumor Mutational Burden Estimated by Next‐Generation Sequencing‐Based Multiplex Gene Panel Assay
AbstractBackground.Tumor mutational burden (TMB) measured via next‐generation sequencing (NGS)‐based gene panel is a promising biomarker for response to immune checkpoint inhibitors (ICIs) in solid tumors. However, little is known about the preanalytical factors that can affect the TMB score.Materials and Methods.Data of 199 patients with solid tumors who underwent multiplex NGS gene panel (OncoPrime), which was commercially provided by a Clinical Laboratory Improvement Amendments‐licensed laboratory and covered 0.78 megabase (Mb) of capture size relevant to the TMB calculation, were reviewed. Associations between the TMB score and preanalytical factors, including sample DNA quality, sample type, sampling site, and storage period, were analyzed. Clinical outcomes of patients with a high TMB score (≥10 mutations per megabase) who received anti‐programmed cell death protein 1 antibodies (n = 22) were also analyzed.Results.Low DNA library concentration (<5 nM), formalin‐fixed paraffin‐embedded tissue (FFPE), and the prolonged sample storage period (range, 0.9–58.1 months) correlated with a higher TMB score. After excluding low DNA library samples from the analysis, FFPE samples, but not the sample storage period, exhibited a marked correlation with a high TMB score. Of 22 patients with a high TMB score, we observed the partial response in 2 patients (9.1%).Conclusion.Our results indicate that the TMB score estimated via NGS‐based gene panel could be affected by the DNA library concentration and sample type. These factors could potentially increase the false‐positive and/or artifactual variant calls. As each gene panel has its own pipeline for variant calling, it is unknown whether these factors have a significant effect in other platforms.Implications for Practice.A high tumor mutational burden score, as estimated via next‐generation sequencing‐based gene panel testing, should be carefully interpreted as it could be affected by the DNA library concentration and sample type.
Diagnostic Accuracy of Clinical Biomarkers for Preoperative Prediction of Lymph Node Metastasis in Endometrial Carcinoma: A Systematic Review and Meta‐Analysis
AbstractBackground.In endometrial carcinoma (EC), preoperative classification is based on histopathological criteria, with only moderate diagnostic performance for the risk of lymph node metastasis (LNM). So far, existing molecular classification systems have not been evaluated for prediction of LNM. Optimized use of clinical biomarkers as recommended by international guidelines might be a first step to improve tailored treatment, awaiting future molecular biomarkers.Aim.To determine the diagnostic accuracy of preoperative clinical biomarkers for the prediction of LNM in endometrial cancer.Methods.A systematic review was performed according to the Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies identified in MEDLINE and EMBASE were selected by two independent reviewers. Included biomarkers were based on recommended guidelines (cancer antigen 125 [Ca‐125], lymphadenopathy on magnetic resonance imaging, computed tomography, and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography [18FDG PET‐CT]) or obtained by physical examination (body mass index, cervical cytology, blood cell counts). Pooled sensitivity, specificity, area under the curve (AUC), and likelihood ratios were calculated with bivariate random‐effects meta‐analysis. Likelihood ratios were classified into small (0.5–1.0 or 1–2.0), moderate (0.2–0.5 or 2.0–5.0) or large (0.1–0.2 or ≥ 5.0) impact.Results.Eighty‐three studies, comprising 18,205 patients, were included. Elevated Ca‐125 and thrombocytosis were associated with a moderate increase in risk of LNM; lymphadenopathy on imaging with a large increase. Normal Ca‐125, cytology, and no lymphadenopathy on 18FDG PET‐CT were associated with a moderate decrease. AUCs were above 0.75 for these biomarkers. Other biomarkers had an AUC <0.75 and incurred only small impact.Conclusion.Ca‐125, thrombocytosis, and imaging had a large and moderate impact on risk of LNM and could improve preoperative risk stratification.Implications for Practice.Routine lymphadenectomy in clinical early‐stage endometrial carcinoma does not improve outcome and is associated with 15%–20% surgery‐related morbidity, underlining the need for improved preoperative risk stratification. New molecular classification systems are emerging but have not yet been evaluated for the prediction of lymph node metastasis. This article provides a robust overview of diagnostic performance of all clinical biomarkers recommended by international guidelines. Based on these, at least measurement of cancer antigen 125 serum level, assessment of thrombocytosis, and imaging focused on lymphadenopathy should complement current preoperative risk stratification in order to better stratify these patients by risk.
POETIC (Program for Enhanced Training in Cancer): An Initial Experience of Supporting Capacity Building for Oncology Training in Sub‐Saharan Africa
AbstractBackground.Sub‐Saharan Africa is simultaneously facing a rising incidence of cancer and a dearth of medical professionals because of insufficient training numbers and emigration, creating a growing shortage of cancer care. To combat this, Massachusetts General Hospital and Beth Israel Deaconess Medical Center partnered with institutions in South Africa, Tanzania, and Rwanda to develop a fellowship exchange program to supplement the training of African oncologists practicing in their home countries.Methods.In its initial year, 2018, the Program for Enhanced Training in Cancer (POETIC) hosted a pilot cohort of seven fellows for 3‐week observerships in their areas of interest. Researchers distributed questionnaires for program evaluation to participants prior to arrival and upon departure; additionally, three participated in semistructured interviews.Results.Five themes emerged from the qualitative data: expectations of POETIC, differences between oncology in the U.S. and in sub‐Saharan Africa, positive elements of the program, areas for improvement, and potential impact. Fellows identified several elements of Western health care that will inform their practice: patient‐centered care; clinical trials; and collaboration among medical, radiation, and surgical oncologists. From the quantitative data, feedback was primarily around logistical areas for improvement.Discussion.POETIC was found to be feasible and valuable. The results from the pilot year justify the program's continuation in hopes of strengthening global health partnerships to support oncology training in Africa. One weakness is the small number of fellows, which will limit the impact of the study and the relevance of its conclusions. Future research will report on the expansion of the program and follow‐up with former participants.Implications for Practice.This work presents a novel model for fellowship exchange between lower‐ and higher‐resourced areas. The program is a short‐term observership with tumor boards and didactic teaching sessions incorporated. By attracting oncologists who aim to practice in their home countries, it facilitates international collaboration without contributing to the preexisting lack of medical professionals in low‐ and middle‐income countries.
AbstractBackground.As scientific techniques evolve, historical informed consent forms may inadequately address modern research proposals, leading to ethical questions regarding research with archived biospecimens.Subjects, Materials, and Methods.We conducted focus groups among patients with cancer recruited from Massachusetts General Hospital to explore views on medical research, biobanking, and scenarios based on real biospecimen research dilemmas. Our multidisciplinary team developed a structured focus group guide, and all groups were recorded and transcribed. Transcripts were coded for themes by two independent investigators using NVivo software.Results.Across five focus groups with 21 participants, we found that most participants were supportive of biobanks and use of their own tissue to advance scientific knowledge. Many favor allowing research beyond the scope of the original consent to proceed if recontact is impossible. However, participants were not comfortable speaking for other patients who may oppose research beyond the original consent. This was viewed as a potential violation of participants’ rights or interests. Participants were also concerned with a “slippery slope” and potential scientific abuse if research were permitted without adherence to original consent. There was strong support for recontact and reconsent when possible and for the concept of broad consent at the time of tissue collection.Conclusion.Our participants support use of their tissue to advance research and generally support any productive scientific approach. However, in the absence of broad initial consent, when recontact is impossible, a case‐by‐case decision must be made regarding a proposal's potential benefits and harms. Many participants support broad use of their tissue, but a substantial minority object to use beyond the original consent.Implications for Practice.For prospective studies collecting tissue for future research, investigators should consider seeking broad consent, to allow for evolution of research questions and methods. For studies using previously collected tissues, researchers should attempt recontact and reconsent for research aims or methods beyond the scope of the original consent. When reconsent is not possible, a case‐by‐case decision must be made, weighing the scientific value of the biobank, potential benefits of the proposed research, and the likelihood and nature of risks to participants and their welfare interests. This study's data suggest that many participants support broad use of their tissue and prefer science to move forward.
Regorafenib in Patients with Antiangiogenic‐Naïve and Chemotherapy‐Refractory Advanced Colorectal Cancer: Results from a Phase 2b Trial
AbstractBackground.Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy‐naïve chemotherapy‐refractory advanced colorectal cancer.Patients and Methods.This single‐center, single‐arm, phase 2b study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy‐naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4‐week cycle. The primary endpoint was progression‐free survival (PFS) rate at week 8.Results.Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1–64.3); median PFS was 3.5 months (95% CI, 1.8–3.6). Median OS was 7.4 months (95% CI, 5.3–8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib‐related grade ≥3 adverse events were hypertension (36%), hand–foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib‐related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0–1 (5.4 months).Conclusion.These findings support the antitumor activity of regorafenib in antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC.Implications for Practice.The multikinase inhibitor regorafenib improved overall survival in the phase 3 CORRECT and CONCUR trials in heavily pretreated patients with treatment‐refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single‐center, single‐arm phase 2b study, regorafenib demonstrated antitumor activity in 59 antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand–foot skin reaction.
A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors
AbstractLessons Learned. The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.Background.Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.Methods.This phase Ib study included a dose‐escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose‐expansion phase to examine preliminary efficacy in treatment‐naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.Results.No patients in the dose‐escalation phase (n = 22) experienced dose‐limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose‐expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression‐free survival was 5.6 months (95% CI, 3.5–not reached).Conclusion.The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.
Impact of 21‐Gene Breast Cancer Assay on Treatment Decision for Patients with T1–T3, N0–N1, Estrogen Receptor‐Positive/Human Epidermal Growth Receptor 2‐Negative Breast Cancer: Final Results of the Prospective Multicenter ROXANE Study
AbstractBackground.The ROXANE Italian prospective study evaluated the impact of the 21‐gene Recurrence Score (RS) results on adjuvant treatment decision for patients with early breast cancer.Materials and Methods.Nine centers participated. Physicians used the RS test whenever unsure about adjuvant treatment recommendation for patients with estrogen receptor‐positive/human epidermal growth receptor 2‐negative, T1–T3, N0–N1 early breast cancer. Pre‐RS and post‐RS treatment recommendations were collected.Results.A total of 251 patients were included. N0 patients (61%) showed higher grade (p < .001) and higher Ki67 (p = .001) and were more frequently progesterone receptor negative (p = .012) as compared with N1 patients. RS results were as follows: <11, n = 63 (25.1%); 11–25, n = 143 (57%); and ≥26, n = 45 (17.9%). Higher RS was found in N0 vs. N1 patients (p = .001) and in cases of G3 (p < .001) and higher Ki67 (p < .001). The rate of change in treatment decision was 30% (n = 75), mostly from chemotherapy (CT) plus hormone therapy (CT + HT) to hormone therapy (HT; 76%, n = 57/75). The proportion of patients recommended to CT + HT was significantly reduced from pre‐RS to post‐RS (52% to 36%, p < .0001). CT use reduction was more evident for N1 patients (55% to 27%) than for N0 patients (50% to 42%) and was observed only in cases of RS ≤17.Conclusion.Physicians predominantly used the 21‐gene assay in N0 patients with a more aggressive biology or in N1 patients showing more indolent biology. In this selected patient population, the use of RS testing led to a 30% rate of change in treatment decision. In the N1 patient subgroup, the use of RS testing contributed to reduce CT use by more than half.Implications for Practice.This study shows that, even in a context in which physicians recommend a high proportion of patients to endocrine treatment alone before knowing the results of the Recurrence Score (RS) assay, the use of the RS test, whenever uncertainty regarding adjuvant treatment recommendation is present, significantly contributes in further reducing the use of chemotherapy, especially for N1 patients.
AbstractPurpose.Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non‐small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first‐line treatment for advanced NSCLC.Materials and Methods.Published and presented literature was searched using the key search terms “non‐small cell lung cancer” AND “checkpoint‐inhibitors” (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first‐line advanced NSCLC were identified.Results.Four first‐line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab‐chemotherapy, atezolizumab‐chemotherapy, and atezolizumab‐bevacizumab‐chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor‐negative (EGFR−)/ anaplastic lymphoma kinase gene (ALK)− NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab‐chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab‐ipilimumab in all‐comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab‐chemotherapy administered based on PD‐L1 status and histology is a preferred treatment option. Outcomes for atezolizumab‐bevacizumab‐chemotherapy in EGFR+/ALK+ patients are promising and require further exploration.Conclusion.First‐line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR−/ALK− and squamous advanced NSCLC.Implications for Practice.Single‐agent immune checkpoint inhibitors are now standard of care for advanced non‐small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE‐189 and IMPower‐130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE‐407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first‐line NSCLC. Programmed death ligand‐1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.
Cranial Irradiation for Patients with Epidermal Growth Factor Receptor (EGFR) Mutant Lung Cancer Who Have Brain Metastases in the Era of a New Generation of EGFR Inhibitors
AbstractBackground.Immediate whole brain radiation (WBRT) has been the standard for patients with lung cancer with brain metastases. The study aims to evaluate the effect of immediate cranial irradiation in patients with epidermal growth factor receptor (EGFR) mutant lung cancer in the era of a new generation of EGFR inhibitors.Materials and Methods.Medical records of 198 patients with EGFR mutant non‐small cell lung cancer and brain metastases at initial metastatic diagnosis were reviewed. Patients were categorized into four groups: immediate WBRT, immediate cranial stereotactic radiosurgery (SRS), delayed radiation upon progression of cranial lesions (DRT), and never cranial irradiation (NRT). Overall survival (OS) and progression‐free survival related to EGFR inhibitors were analyzed.Results.The SRS group had the fewest brain metastases and fewest extracranial lesions, and the DRT and NRT groups had the smallest brain metastases. Median survival were 18.5, 55.7, 21.1, and 18.2 months for the WBRT, SRS, DRT, and NRT groups, respectively. Patients who had received EGFR T790M inhibitors survived longer (41.1 vs. 19.8 months). In multivariate analysis, the OS of patients in the SRS group was longer than that in the NRT group (adjusted hazard ratio [aHR]: 0.315). Patients who had fewer extracranial lesions and who had received EGFR T790M inhibitor treatments also survived longer (aHR: 0.442 and 0.357, respectively).Conclusion.Immediate stereotactic radiosurgery but not whole brain radiation was associated with longer survival. Because of patient heterogeneity and the introduction of EGFR T790M inhibitors, the timing and modality of cranial irradiation should be determined individually, and cranial irradiation may be omitted for selected patients.Implications for Practice.Immediate whole brain radiation has been the standard for patients with lung cancer with brain metastases. In this study, it was observed that, for patients with epidermal growth factor receptor (EGFR) mutant advanced lung cancer who had brain metastases, there was no difference in survival between patients who never received cranial irradiation and those who received whole brain radiation immediately. Patients who received immediate stereotactic radiosurgery or who had ever received EGFR T790M inhibitors survived longer. Patients who received immediate stereotactic radiosurgery have fewer brain metastases. These findings suggest that the timing and modality of cranial irradiation should be determined individually, and cranial irradiation may be omitted in selected patients.
A First‐in‐Human Phase I Study of GC1118, a Novel Anti‐Epidermal Growth Factor Receptor Antibody, in Patients with Advanced Solid Tumors
AbstractLessons Learned. GC1118 is a novel fully human anti‐epidermal growth factor receptor (EGFR) antibody with unique binding epitopes and different ligand‐binding inhibitory activity compared with cetuximab or panitumumab.GC1118 showed promising antitumor activity, especially in patients with colorectal cancer resistant to prior EGFR antibody. Skin toxicities were more common and diarrhea was less frequent compared with other anti‐EGFR antibodies.Background.GC1118 is a novel monoclonal antibody targeting epidermal growth factor receptor (EGFR) with more potent ligand inhibition than cetuximab or panitumumab. We conducted a first‐in‐human, phase I study of GC118 in patients with refractory solid tumors.Methods.In the dose escalation part, GC1118 was administered on days 1, 8, 15, and 22, followed by a 2‐week rest, during which dose‐limiting toxicities (DLTs) were evaluated. In the expansion part, patients were enrolled into three cohorts (Cohort 1 [C1], patients with colorectal cancer [CRC] without prior anti‐EGFR treatment; Cohort 2 [C2], patients with CRC with tumors resistant to anti‐EGFR therapy; Cohort 3 [C3], EGFR‐overexpressing gastric cancer).Results.In the dose escalation part, 24 patients were treated at five dose levels: 0.3, 1.0, 3.0, 4.0, and 5.0 mg/kg. In the 5.0 mg/kg cohort, two patients experienced DLTs (skin toxicities). The maximum‐tolerated dose (MTD) was 4.0 mg/kg. Common adverse events were skin toxicities. In the expansion part, 39 patients were enrolled. In Cohort 1, stable disease (SD) was observed in 58%; in Cohort 2, partial response (PR) 17% and SD 8%; in Cohort 3, PR 8% and SD 17%.Conclusion.GC1118 showed promising antitumor activity and was well tolerated. Infrequent diarrhea compared with other anti‐EGFR antibodies might be advantageous for further development.
A Systematic Review and Network Meta‐Analysis of Regorafenib and TAS‐102 in Refractory Metastatic Colorectal Cancer
AbstractBackground.Regorafenib at different dosing strategies and TAS‐102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies.Materials and Methods.We searched different databases for randomized controlled trials evaluating TAS‐102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression‐free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta‐analysis based on White's multivariate meta‐regression to pool evidence from direct and indirect comparisons.Results.Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS‐102 as monotherapy were superior to best‐supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26–0.63; TAS‐102: HR, 0.46 CI, 0.40–0.52) and OS (Rego 160: HR, 0.67; CI, 0.48–0.93; TAS‐102: HR, 0.67; CI, 0.57–0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS‐102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23–0.84) and PFS (HR, 0.37; CI, 0.21–0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS‐102 and Rego 160.Conclusion.Regorafenib 160 and TAS‐102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102.Implications for Practice.Regorafenib at a dose of 160 mg and TAS‐102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best‐supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.
Long‐Term Survivors in Metastatic Pancreatic Ductal Adenocarcinoma: A Retrospective and Matched Pair Analysis
AbstractBackground.Metastatic pancreatic ductal adenocarcinoma (mPDAC) is an aggressive malignancy with a median overall survival (OS) of between 8 and 11 months. However, a significant number of patients experience a longer survival, more than 18 months. The aim of this study was to describe the “long‐term survivor” population and to evaluate clinical and pathological factors that might affect survival.Materials and Methods.All patients with mPDAC diagnosed in the Centre Leon Bérard (Lyon, France) between January 2010 and June 2015 and who survived more than 18 months were identified. They were compared with a control cohort matched on age, sex, performance status, stage at diagnosis, primary tumor localization, treatment, and liver metastasis. Their clinical features, treatment modalities, and outcomes were analyzed.Results.A total of 94 patients were included, 47 in each cohort. Both cohorts had identical characteristics as follows: women (51%), performance status ≤1 (95.7%), median age at diagnosis (60 years), and metastasis at diagnosis (83%). Median OS was 26.87 months (95% confidence interval [CI] 23–31.08) in the long‐term survivor group (LS group) and 9.79 months (95% CI 5.75–11.86) in the control group (C group). Potential factors of long‐term survival were explored with a logistic model (LS group vs. C group). Three factors were identified as significant prognostic factors in the univariate analysis: lymphopenia (odds ratio [OR] ref: yes = 0.26), neutrophil‐to‐lymphocyte ratio (NLR; OR ref >5 = 0.31), and peritoneal carcinomatosis (OR ref: yes = 0.40). NLR was the only remaining factor in our backward selection procedure.Conclusion.A significant subset of patients with mPDAC can achieve long‐term survival (≥18 months) in 2018. We identified low NLR as a significant prognostic factor associated with long‐term survival in mPDAC.Implications for Practice.Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the most lethal types of cancer. A subset of patients with mPDAC can achieve long‐term survival (≥18 months) with a modern chemotherapy regimen, such as FOLFIRINOX or gemcitabine/nab‐paclitaxel. We identified low neutrophil‐to‐lymphocyte ratio (NLR) as a significant prognostic factor associated with long‐term survival in mPDAC. Prognostic factors such as NLR might allow accurate selection of patients with mPDAC in order to consider individual therapeutic approaches. NLR should be used as a stratification factor in clinical trials.
Risk of Osteoporosis and Fractures in Patients with Thyroid Cancer: A Case‐Control Study in U.S. Veterans
AbstractBackground.Data on osteoporosis and fractures in patients with thyroid cancer, especially men, are conflicting. Our objective was to determine osteoporosis and fracture risk in U.S. veterans with thyroid cancer.Materials and Methods.This is a case‐control study using the Veterans Health Administration Corporate Data Warehouse (2004–2013). Patients with thyroid cancer (n = 10,370) and controls (n = 10,370) were matched by age, sex, weight, and steroid use. Generalized linear mixed‐effects regression model was used to compare the two groups in terms of osteoporosis and fracture risk. Next, subgroup analysis of the patients with thyroid cancer using longitudinal thyroid‐stimulating hormone (TSH) was performed to determine its effect on risk of osteoporosis and fractures. Other covariates included patient age, sex, median household income, comorbidities, and steroid and androgen use.Results.Compared with controls, osteoporosis, but not fractures, was more frequent in patients with thyroid cancer (7.3% vs. 5.3%; odds ratio [OR], 1.33; 95% confidence interval [CI], 1.18–1.49) when controlling for median household income, Charlson/Deyo comorbidity score, and androgen use. Subgroup analysis of patients with thyroid cancer demonstrated that lower TSH (OR, 0.93; 95% CI, 0.90–0.97), female sex (OR, 4.24; 95% CI, 3.53–5.10), older age (e.g., ≥85 years: OR, 17.18; 95% CI, 11.12–26.54 compared with <50 years), and androgen use (OR, 1.63; 95% CI, 1.18–2.23) were associated with osteoporosis. Serum TSH was not associated with fractures (OR, 1.01; 95% CI, 0.96–1.07).Conclusion.Osteoporosis, but not fractures, was more common in U.S. veterans with thyroid cancer than controls. Multiple factors may be contributory, with low TSH playing a small role.Implications for Practice.Data on osteoporosis and fragility fractures in patients with thyroid cancer, especially in men, are limited and conflicting. Because of excellent survival rates, the number of thyroid cancer survivors is growing and more individuals may experience long‐term effects from the cancer itself and its treatments, such as osteoporosis and fractures. The present study offers unique insight on the risk for osteoporosis and fractures in a largely male thyroid cancer cohort. Physicians who participate in the long‐term care of patients with thyroid cancer should take into consideration a variety of factors in addition to TSH level when considering risk for osteoporosis.
Characteristics of BRAF V600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients
AbstractBackground.BRAFV600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown.Materials and Methods.We built a multicenter clinico‐biological database gathering data from patients with BRAFV600E‐mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model.Results.We included 287 patients (median age, 67 years [28–95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97–27.04), and median progression‐free survival in the first‐line setting was 4.34 months (95% CI, 3.81–5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti‐epidermal growth factor receptor) were not associated with overall and progression‐free survival. Stage IV disease (synchronous metastases) and absence of curative‐intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009).Conclusion.Despite that BRAFV600E‐mutant mCRCs are associated with poor overall and progression‐free‐survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day‐to‐day practice.Implications for Practice.Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day‐to‐day practice to steer treatment decision making in patients with BRAFV600E‐mutant mCRC.
Dancing with Deterrents: Understanding the Role of Abuse‐Deterrent Opioid Formulations and Naloxone in Managing Cancer Pain
AbstractPrescription opioids are commonly prescribed for the relief of many kinds of pain syndromes, including cancer pain. In order to combat the growing rates of abuse and misuse of prescription opioids, the Centers for Disease Control and Prevention, along with the U.S. Food and Drug Administration and multiple pharmaceutical companies, have implemented many risk mitigation strategies. Abuse‐deterrent drug delivery technology and more consistent prescribing of the opioid antagonist, naloxone, are two of the mechanisms of reducing harm in patients on chronic opioid therapy. Abuse‐deterrent technology is implemented into different commercially available opioid products with the intent of discouraging manipulation of the opioid or making the use of the manipulated opioid less appealing. Use of the opioid antagonist, naloxone, for reversal of intentional or unintentional opioid overdose is a safe and effective means to reduce potential risk in patients who are on opioids for pain management. These mechanisms have multiple advantages and limitations that influence their practical use specifically in patients with cancer pain. Patients with cancer pain have unique therapeutic needs and goals, and their balance of treatment risks and benefits differs from that of other kinds of chronic pain disorders. This article provides an overview of the advantages and limitations of these specific harm‐reduction strategies and provides guidance on how to practically utilize them when caring for patients with cancer pain.Implications for Practice.Treating cancer pain has important and unique considerations compared with other chronic, noncancer pain disorders. The use of risk mitigation strategies for opioid prescribing as promoted by the Centers for Disease Control and Prevention does not translate seamlessly to patients with cancer. It is crucial to be wary of the advantages and pitfalls of all risk mitigation strategies related to opioid use in patients with cancer pain. Careful examination of patient‐specific risks and benefits should always be considered when implementing pharmacologic treatment and harm‐reduction strategies for the management of cancer pain.
Safety and Success of Repeat Lung Needle Biopsies in Patients with Epidermal Growth Factor Receptor‐Mutant Lung Cancer
AbstractBackground.Postprogression repeat biopsies are critical in caring for patients with lung cancer with epidermal growth factor receptor (EGFR) mutations. However, hesitation about invasive procedures persists. We assessed safety and tissue adequacy for molecular profiling among repeat postprogression percutaneous transthoracic needle aspirations and biopsies (rebiopsies).Materials and Methods.All lung biopsies performed at our hospital from 2009 to 2017 were reviewed. Complications were classified by Society of Interventional Radiology criteria. Complication rates between rebiopsies in EGFR‐mutants and all other lung biopsies (controls) were compared using Fisher's exact test. Success of molecular profiling was recorded.Results.During the study period, nine thoracic radiologists performed 107 rebiopsies in 75 EGFR‐mutant patients and 2,635 lung biopsies in 2,347 patients for other indications. All biopsies were performed with computed tomography guidance, coaxial technique, and rapid on‐site pathologic evaluation (ROSE). The default procedure was to take 22‐gauge fine‐needle aspirates (FNA) followed by 20‐gauge tissue cores. Minor complications occurred in 9 (8.4%) rebiopsies and 503 (19.1%; p = .004) controls, including pneumothoraces not requiring chest tube placement (4 [3.7%] vs. 426 [16.2%] in rebiopsies and controls, respectively; p < .001). The only major complication was pneumothorax requiring chest tube placement, occurring in zero rebiopsies and 38 (1.4%; p = .4) controls. Molecular profiling was requested in 96 (90%) rebiopsies and successful in 92/96 (96%).Conclusion.At our center, repeat lung biopsies for postprogression molecular profiling of EGFR‐mutant lung cancers result in fewer complications than typical lung biopsies. Coaxial technique, FNA, ROSE, and multiple 20‐gauge tissue cores result in excellent specimen adequacy.Implications for Practice.Repeat percutaneous transthoracic needle aspirations and biopsies for postprogression molecular profiling of epidermal growth factor receptor (EGFR)‐mutant lung cancer are safe in everday clinical practice. Coaxial technique, fine‐needle aspirates, rapid on‐site pathologic evaluation, and multiple 20‐gauge tissue cores result in excellent specimen adequacy. Although liquid biopsies are increasingly used, their sensitivity for analysis of resistant EGFR‐mutant lung cancers remains limited. Tissue biopsies remain important in this context, especially because osimertinib is now in the frontline setting and T790M is no longer the major finding of interest on molecular profiling.
The Oncologist RSS feed -- Early Online Editions of Accepted ArticlesSubscribe to Early View from The Oncologist feed