Race-free renal function estimation equations and potential impact on Black patients: Implications for cancer clinical trial enrollment.

BACKGROUND: Black patients face disparities in cancer outcomes. Additionally, Black patients are more likely to be undertreated and underrepresented in clinical trials. The recent recommendation to remove race from the estimated glomerular filtration rate (eGFR) results in lower eGFR values for Black patients. The ramifications of this decision, both intended and unintended, are still being elucidated in the medical community. Here, the authors analyze the removal of race from eGFR for Black patients with cancer, specifically with respect to clinical trial eligibility. METHODS: In a cohort of self-identified Black patients who underwent nephrectomy at a tertiary referral center from 2009 to 2021 (n = 459), eGFR was calculated with and without race in commonly used equations (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease [MDRD]). The distribution of patients and changes within chronic kidney disease stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated on the basis of the utilization of the race coefficient. RESULTS: The median eGFR from CKD-EPI was significantly higher with race (76 ml/min/1.73 m2 ) than without race (66 ml/min/1.73 m2 ; p < .0001). The median eGFR from MDRD was significantly higher with race (71.0 ml/min/1.73 m2 ) than without race (58 ml/min/1.73 m2 ; p < .0001). Observing results in the context of common clinical trial cutoff points, the authors found that 13%-22%, 6%-12%, and 2%-3% more Black patients would fall under common clinical trial cutoffs of 60, 45, and 30 ml/min, respectively, depending on the equation used. A subanalysis of stage III-IV patients only was similar. CONCLUSIONS: Race-free renal function equations may inadvertently result in increased exclusion of Black patients from clinical trials. This is especially concerning because of the underrepresentation and undertreatment that Black patients already experience. PLAIN LANGUAGE SUMMARY: Black patients experience worse oncologic outcomes and are underrepresented in clinical trials. Kidney function, as estimated by glomerular filtration rate equations, is a factor in who can and cannot be in a clinical trial. Race is a variable in some of these equations. For Black patients, removing race from these equations leads to the calculation of lower kidney function. Lower estimated kidney function may result in more black patients being excluded from clinical trials. The inclusion of all races in clinical trials is important for offering best care to everyone and for making results from clinical trials applicable to everyone.

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. METHODS: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m2 /dose, with a de-escalation DL of 100 mg/m2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1. RESULTS: The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects. CONCLUSIONS: The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m2 /dose.

Improving oncology first-in-human and Window of opportunity informed consent forms through participant feedback.

BACKGROUND: Although patient advocates have developed templates for standard consent forms, evaluating patient preferences for first in human (FIH) and window of opportunity (Window) trial consent forms is critical due to their unique risks. FIH trials are the initial use of a novel compound in study participants. In contrast, Window trials give an investigational agent over a fixed duration to treatment naïve patients in the time between diagnosis and standard of care (SOC) surgery. Our goal was to determine the patient-preferred presentation of important information in consent forms for these trials. METHODS: The study consisted of two phases: (1) analyses of oncology FIH and Window consents; (2) interviews of trial participants. FIH consent forms were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH information); Window consents were analyzed for the location(s) of information stating the trial may delay SOC surgery (delay information). Participants were asked about their preferred placement of the information in their own trial's consent form. The location of information in the consent forms was compared to the participants' suggestions for placement. RESULTS: 34 [17 FIH; 17 Window] of 42(81%) cancer patients approached participated. 25 consents [20 FIH; 5 Window] were analyzed. 19/20 FIH consent forms included FIH information, and 4/5 Window consent forms included delay information. 19/20(95%) FIH consent forms contained FIH information in the risks section 12/17(71%) patients preferred the same. Fourteen (82%) patients wanted FIH information in the purpose, but only 5(25%) consents mentioned it there. 9/17(53%) Window patients preferred delay information to be located early in the consent, before the "Risks" section.  3/5(60%) consents did this. CONCLUSIONS: Designing consents that reflect patient preferences more accurately is essential for ethical informed consent; however, a one-size fits all approach will not accurately capture patient preferences. We found that preferences differed for FIH and Window trial consents, though for both, patients preferred key risk information early in the consent. Next steps include determining if FIH and Window consent templates improve understanding.

Phase 1 study to evaluate the effects of rifampin on pharmacokinetics of pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors.

Pevonedistat (TAK-924/MLN4924) is an investigational small molecule inhibitor of the NEDD8-activating enzyme that has demonstrated clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase 1 study evaluating the effect of rifampin, a strong CYP3A inducer, on the pharmacokinetics (PK) of pevonedistat in patients with advanced solid tumors (NCT03486314). Patients received a single 50 mg/m2 pevonedistat dose via a 1-h infusion on Days 1 (in the absence of rifampin) and 10 (in the presence of rifampin), and daily oral dosing of rifampin 600 mg on Days 3-11. Twenty patients were enrolled and were evaluable for PK and safety. Following a single dose of pevonedistat at 50 mg/m2, the mean terminal half-life of pevonedistat was 5.7 and 7.4 h in the presence and in the absence of rifampin, respectively. The geometric mean AUC0-inf of pevonedistat in the presence of rifampin was 79% of that without rifampin (90% CI: 69.2%-90.2%). The geometric mean Cmax of pevonedistat in the presence of rifampin was similar to that in the absence of rifampin (96.2%; 90% CI: 79.2%-117%). Coadministration of pevonedistat with rifampin, a strong metabolic enzyme inducer, did not result in clinically meaningful decreases in systemic exposures of pevonedistat. The study results support the recommendation that no pevonedistat dose adjustment is needed for patients receiving concomitant CYP3A inducers. CLINICALTRIALS.GOV IDENTIFIER: NCT03486314.

Webinar as an Informational Resource on Trastuzumab Biosimilars: Planning, Promotion, Execution, and Evaluation.

Despite the incorporation of trastuzumab biosimilars (to treat HER2-positive breast cancer) in clinical practice guidelines, gaps remain such as patient and clinician education. We hosted a webinar comprised of a panel of biosimilars experts, oncologists, pharmacist, infusion nurse, and a patient advocate. The outcomes of the webinar include audience responses to pre- and post-webinar questionnaires, educational benefits, real-time opportunities to ask questions, and a recording. Education needs to be tailored to the needs of both, patients and clinicians.

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations.

OBJECTIVE: To review the available data for the efficacy and safety of daratumumab in the treatment of multiple myeloma (MM), both in the newly diagnosed and relapsed/refractory settings, as well as provide additional guidance to clinicians on operational, safety, and supportive care considerations. DATA SOURCES: A literature search of PubMed (1966 to October 2021) was conducted using the keywords daratumumab, Darzalex, and myeloma. Data were also obtained from prescribing information and unpublished abstracts from meetings. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles, prescribing information, and unpublished meeting abstracts on daratumumab for the treatment of MM were reviewed. DATA SYNTHESIS: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of MM. The addition of daratumumab to proteasome inhibitor and immunomodulatory drug-based regimens has led to a consistent improvement in progression-free survival and response rates in relapsed/refractory MM as per the POLLUX, CASTOR, APOLLO, and CANDOR trials. The ALCYONE and MAIA phase III trials have demonstrated an overall survival benefit when adding daratumumab to frontline regimens for transplant-ineligible patients with newly diagnosed MM. In transplant-eligible patients, daratumumab-based quadruplet regimens have improved depth of response in the CASSIOPIEA and GRIFFIN trials. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Operational and safety considerations that clinicians need to account for do exist, including different administration and infusion strategies, infusion-related reactions, increased risk for infectious complications, and interference with blood transfusion management. CONCLUSIONS: Daratumumab has led to a shift in the treatment paradigm of both newly diagnosed and relapsed/refractory MM, leading to improvements in outcomes such as response rates, depth of response, and progression-free survival.

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial.

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer.

OBJECTIVE: To review the pharmacology, efficacy, and safety of sacituzumab govitecan (-hziy; IMMU-132, Trodelvy) for patients with metastatic triple-negative breast cancer (mTNBC) who have received at least 2 prior therapies for metastatic disease. DATA SOURCES: A literature search was conducted utilizing PubMed and MEDLINE databases, applicable published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and September 3, 2020. Keywords included sacituzumab govitecan (-hziy), IMMU-132, Trop-2 (trophoblast cell-surface antigen 2), and TACSTD2. STUDY SELECTION AND DATA EXTRACTION: All English-language trials involving sacituzumab govitecan for mTNBC were included and discussed. DATA SYNTHESIS: Sacituzumab govitecan is an antibody-drug conjugate targeted for Trop-2 and conjugated to the topoisomerase-1 inhibitor SN-38. It was granted accelerated Food and Drug Administration approval based on a phase I/II single-arm, multicenter study (n = 108), which reported an overall response rate of 33.3% and median duration of response of 7.7 months (95% CI = 4.9-10.8 months). Common adverse reactions include nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, abdominal pain, and respiratory infection. A confirmatory, randomized phase III clinical trial is ongoing (NCT02574455). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review covers the efficacy, safety, and clinical use of sacituzumab govitecan, a third-line drug with activity in mTNBC. CONCLUSION: Sacituzumab govitecan is a novel targeted treatment with promising activity in mTNBC.

International Society of Oncology Pharmacy Practitioners (ISOPP) position statement: Role of the oncology pharmacy team in cancer care.

The Oncology Pharmacy Team (OPT), consisting of specialty-trained pharmacists and/or pharmacy technicians, is an integral component of the multidisciplinary healthcare team (MHT) involved with all aspects of cancer patient care. The OPT fosters quality patient care, safety, and local regulatory compliance. The International Society of Oncology Pharmacy Practitioners (ISOPP) developed this position statement to provide guidance on five key areas: 1) oncology pharmacy practice as a pharmacy specialty; 2) contributions to patient care; 3) oncology pharmacy practice management; 4) education and training; and 5) contributions to oncology research and quality initiatives to involve the OPT. This position statement advocates that: 1) the OPT be fully incorporated into the MHT to optimize patient care; 2) educational and healthcare institutions develop programs to continually educate OPT members; and 3) regulatory authorities develop certification programs to recognize the unique contributions of the OPT in cancer patient care.

Adiposity may predict survival in patients with advanced stage cancer treated with immunotherapy in phase 1 clinical trials.

BACKGROUND: Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS: A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS: The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P < .001]) and PFS (hazard ratio, 0.38; 95% CI, 0.20-0.72 [P = .003]) compared with patients at intermediate risk (those with an SFI <73 and IFI <3.4) and poor risk (those with an SFI <73 and IFI ≥3.4). The Uno concordance statistics were found to be higher for fat risk groups than BMI in predicting OS (0.603 vs 0.574; P = .581) and PFS (0.602 vs 0.586; P = .71). CONCLUSIONS: Increased BMI, increased SFI, and decreased IFI may be associated with prolonged survival in patients with cancer who are treated with immunotherapy. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.

Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma.

BACKGROUND: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. METHODS: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. RESULTS: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. CONCLUSIONS: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. CLINICAL TRIAL REGISTRATION: NCT01218555.

Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice.

Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy.

BACKGROUND: Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. METHODS: We performed a retrospective review of 90 patients enrolled on immunotherapy-based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias-adjusted log-rank test. A four-level risk stratification was used to create low-risk (PLR <242 and nonsarcopenic), intermediate-risk (PLR <242 and sarcopenic), high-risk (PLR ≥242 and nonsarcopenic), and very-high-risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival. RESULTS: Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high-risk, high-risk, and intermediate-risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65-27.01; p < .001; HR, 5.32; CI, 1.96-14.43; p = .001; and HR, 4.01; CI, 1.66-9.68; p = .002, respectively) and progression-free survival (HR, 12.29; CI, 5.15-29.32; p < .001; HR, 3.51; CI, 1.37-9.02; p = .009; and HR, 2.14; CI, 1.12-4.10; p = .022, respectively) compared with low-risk patients. CONCLUSION: Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy-treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents. IMPLICATIONS FOR PRACTICE: Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk-stratification system that combined sarcopenia and platelet-to-lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk-stratify patients who are beginning treatment with immunotherapy.

Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC.

The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy.

BACKGROUND: Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO. METHODS: A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used. RESULTS: The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052). CONCLUSIONS: Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.

Pharmacokinetic Study of Osimertinib in Cancer Patients with Mild or Moderate Hepatic Impairment.

Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (n = 7) or moderate hepatic impairment (n = 5) versus normal hepatic function (n = 10): C max was reduced to 51% and 61%, respectively; area under the curve was reduced to 63% and 68%, respectively. PK results for the metabolites were similar. No apparent differences in the safety profile were found between patients with normal hepatic function and patients with mild or moderate hepatic impairment. Comparison of these study results with National Cancer Institute-Organ Dysfunction Working Group criteria from population PK analysis showed osimertinib exposure was not affected by hepatic impairment. No dose adjustment is required for osimertinib when treating patients with mild or moderate hepatic impairment. No apparent differences in the safety of osimertinib were found between patients with normal hepatic function and mild or moderate hepatic impairment.

Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors.

Purpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with solid tumors. Methods Patients received pevonedistat with docetaxel (arm 1, n = 22), carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25 mg/m2 (arm 1) or 20 mg/m2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with clinical benefit in arm 2. Conclusion Pevonedistat with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained clinical responses were observed in pretreated patients receiving pevonedistat with carboplatin and paclitaxel. ClinicalTrials.gov identifier: NCT01862328.

Clinical outcomes of advanced stage cancer patients treated with sequential immunotherapy in phase 1 clinical trials.

Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naïve patients had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49-12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naïve patients per Kaplan-Meier estimation. Within the ICI-naïve group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naïve patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.