Neurodevelopmental Outcomes in Children After Fetoscopic Endoluminal Tracheal Occlusion for Severe Congenital Diaphragmatic Hernia: Results From a Multidisciplinary Clinic.

BACKGROUND: We compared early neurodevelopmental morbidity in young children with severe CDH who underwent FETO to those without fetal therapy. METHODS: We conducted a prospective study of severe CDH patients undergoing FETO (n = 18) at a single North American center from 2015 to 2021 (NCT02710968). Outpatient survivors (n = 12) were evaluated by a multidisciplinary team and compared to expectantly managed CDH patients. Neurodevelopmental outcomes were assessed using the Capute Scales [Clinical Linguistic and Auditory Milestone Scales (CLAMS) and Cognitive Adaptive Test (CAT)], with a developmental quotient (DQ) < 85 indicative of at-risk for delay. RESULTS: At one year, 58% (n = 7) of FETO patients underwent evaluation, with notable concern for language delay (CLAMS median DQ, 80.1 [interquartile range, 67.6-86.7]). FETO scores improved by 24-months, whereas high severity/non-FETO scores declined [CLAMS median DQ (Difference in DQ), 92.3 (+12.2) vs. 77.1 (-13.4), respectively; p = 0.049]. On the initial CAT, FETO patients had concern for visual motor and problem-solving delays, with a median DQ of 81.3 (62.1-89.4). At 24-months, FETO patients had improving scores [Median CAT DQ, 90.8 (+9.5)], whereas high severity/non-FETO [87.5 (-3.0), p = 0.28] had declining scores. CONCLUSION: These initial data suggest that FETO is associated with favorable neurodevelopmental outcomes at 24-months compared to severe CDH under expectant management. LEVEL OF EVIDENCE: III.

Unmet Needs, Quality of Life, and Financial Toxicity Among Survivors of Lung Cancer.

Importance: Despite a growing population of survivors of lung cancer, there is limited understanding of the survivorship journey. Survivors of lung cancer experience unmet physical, social, emotional, and medical needs regardless of stage at diagnosis or treatment modalities. Objective: To investigate the association of unmet needs with quality of life (QOL) and financial toxicity (FT) among survivors of lung cancer. Design, Setting, and Participants: This survey study was conducted at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center thoracic oncology clinics between December 1, 2020, and September 30, 2021, to assess needs (physical, social, emotional, and medical), QOL, and FT among survivors of lung cancer. Patients had non-small cell lung cancer of any stage and were alive longer than 1 year from diagnosis. A cross-sectional survey was administered, which consisted of an adapted needs survey developed by the Mayo Survey Research Center, the Comprehensive Score for Financial Toxicity measure, and the European Organization for Research and Treatment of Cancer QLQ-C30 QOL scale. Demographic and clinical information was obtained through retrospective medical record review. Data analysis was performed between May 9 and December 8, 2022. Main Outcomes and Measures: Separate multiple linear regression models, treating QOL and FT as dependent variables, were performed to assess the adjusted association of total number of unmet needs and type of unmet need (physical, emotional, social, or medical) with QOL and FT. Results: Of the 360 survivors of lung cancer approached, 232 completed the survey and were included in this study. These 232 respondents had a median age of 69 (IQR, 60.5-75.0) years. Most respondents were women (144 [62.1%]), were married (165 [71.1%]), and had stage III or IV lung cancer (140 [60.3%]). Race and ethnicity was reported as Black (33 [14.2%]), White (172 [74.1%]), or other race or ethnicity (27 [11.6%]). A higher number of total unmet needs was associated with lower QOL (ß [SE], -1.37 [0.18]; P < .001) and higher FT (ß [SE], -0.33 [0.45]; P < .001). In the context of needs domains, greater unmet physical needs (ß [SE], -1.24 [0.54]; P = .02), social needs (ß [SE], -3.60 [1.34]; P = .01), and medical needs (ß [SE], -2.66 [0.98]; P = .01) were associated with lower QOL, whereas only greater social needs was associated with higher FT (ß [SE], -3.40 [0.53]; P < .001). Conclusions and Relevance: The findings of this survey study suggest that among survivors of lung cancer, unmet needs were associated with lower QOL and higher FT. Future studies evaluating targeted interventions to address these unmet needs may improve QOL and FT among survivors of lung cancer.

Lung Cancer Survivorship: Physical, Social, Emotional, and Medical Needs of NSCLC Survivors.

BACKGROUND: Newer therapies prolong survival for patients with lung cancer. Beyond extending survival, the needs of lung cancer (LC) survivors are poorly described. METHODS: We conducted a single-institution needs assessment survey of LC survivors alive ≥1 year from diagnosis. Needs were rated on a 5-point Likert scale for 4 domains (physical, social, emotional, and medical). Multiple regression models identified demographic or treatment characteristics associated with more needs in each category. A subset analysis of survivors with metastatic LC was performed. RESULTS: Of 360 patients approached, 235 surveys were completed. Among completed survey respondents, the median age was 69 years; most were female (62%), married (71%), and White (74%); and 41% had stage IV cancer. Finding support resources (34%) was the most common medical need. Fatigue (70%), sleep disturbance (60%), memory and concentration (57.5%), weakness (54%), and trouble breathing (51%) were physical needs affecting more than half of respondents. The most common social need was managing daily activities (42%). Emotional needs were highly prevalent, with 79% of respondents reporting a fear of recurrence and 74.5% reporting living with uncertainty. Multiple regression analysis identified that receipt of multiple lines of systemic therapy and lower household income were associated with higher physical and social needs. Younger age was associated with having a greater number of social and emotional needs. Similar results were found in the subset of survivors with metastatic disease at diagnosis. CONCLUSIONS: The needs of LC survivors are diverse across multiple domains. Several clinical and demographic factors are independently associated with higher numbers of patient-reported needs. Our study identifies critical gaps in survivorship care for LC survivors with all stages of disease and highlights areas of future intervention.

Clinical and Genomic Characterization of Long-Term Responders Receiving Immune Checkpoint Blockade for Metastatic Non-Small-Cell Lung Cancer.

OBJECTIVES: Understand from a real-world cohort the unique clinical and genomic determinants of a durable response to immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: This is a retrospective study of patients with NSCLC who received any ICI-based regimen as first or second line therapy. Long-term responders (LTR) achieved an overall survival (OS) ≥ 3 years from time of treatment start, while nonresponders (NR) were patients who had an OS of 6 to 12 months from time of treatment start. Clinical and demographic covariables were collected from electronic medical records. Fisher's exact test and Mann-Whitney test were used to analyze the association of a long-term response to ICI in relation to clinical and genomic variables. All P-values were considered significant at P-value < .05. RESULTS: A total of 72 patients were included in this study (LTR n = 37, NR n = 35). There were no significant differences in age, sex, race, and BMI between groups. The presence of liver metastases at the time of ICI initiation and PD-L1 status were not associated with LTR to ICIs. Patients in the LTR were more likely to experience irAEs at 3-,6- and 12-months. KRAS mutant tumors were numerically more common in the LTR group (n = 13 vs. 8). CONCLUSION: We observe no strong clinical and biomarkers of a prolonged response to ICIs. Additional large prospective cohort studies are needed to investigate the genomic footprint of long-term responders.

Infectious Complications in Patients With Non-small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are standard treatment for nonsmall cell lung cancer (NSCLC). However, the burden of infectious complications during ICI therapy is poorly described. MATERIALS AND METHODS: We conducted a retrospective study of patients with NSCLC treated with ICIs between 2007 and 2020 at a tertiary academic center. The incidence, characteristics, and healthcare utilization outcomes of infections during ICI therapy and within 3 months of ICI discontinuation are presented using descriptive statistics. Cox proportional hazard models are used to examine infection-free survival by demographic and treatment factors. Associations between patient or treatment characteristics and hospitalization or ICU admission are analyzed by logistic regression, presented as odds ratios (OR). RESULTS: Of 298 patients, infections occurred in 54.4% (n = 162). Of these patients, 59.3% (n = 96) required hospitalization and 15.4% (n = 25) required ICU admission. The most common infection was bacterial pneumonia. Fungal infections occurred in 12 patients (7.4%). Patients with chronic obstructive pulmonary disease (COPD) (OR 2.15, 95% CI, 1.01-4.58), corticosteroid treatment within 1 month prior to infection onset (OR 3.04, 95% CI, 1.47-6.30), and concomitant irAE and infection (OR 5.48, 95% CI, 2.15-14.00) had higher odds of hospitalization. Corticosteroid use was associated with higher odds of ICU admission (OR 3.09, 95% CI, 1.29-7.38). CONCLUSION: In this large single-institution study we identify that more than half of patients with ICI-treated NSCLC develop infectious complications. We identify that patients with COPD, recent corticosteroid use, and concomitant irAE and infection have higher odds of hospitalization, and that unusual infections (eg, fungal) can occur. This highlights clinical awareness of infections as important complications during ICI therapy in patients with NSCLC.

Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes.

The measurable residual disease (MRD) assessment provides an attractive predictor of allogeneic hematopoietic cell transplnat (alloHCT) outcomes. Cell-free DNA (cfDNA) has been applied to diagnosis, early detection, and disease burden monitoring in various tumors, but its utility as an MRD test in myeloid malignancies has not been systematically evaluated. We sought to determine the differential sensitivity between bone marrow (BM) and cfDNA MRD and to assess the effect of cfDNA MRD on alloHCT outcomes. The technical and clinical validation cohorts, including 82 patients participating in clinical trials (Bone Marrow Transplant Clinical Trials Network-0201 and 0402), were used. Ultradeep error-corrected targeted sequencing was performed on plasma and BM-derived DNA. We demonstrated that 94.6% (range, 93.9-95.3) of cfDNA was derived from hematopoietic tissue. The mutant allele fraction was congruent between BM and cfDNA (rho = 0.8; P < .0001); however, cfDNA seemed to be more sensitive in detecting clones with a variant allele frequency (VAF) of <0.26%. cfDNA-MRD clearance by day 90 after alloHCT (D90) was associated with improved relapse-free survival (RFS, median survival not reached vs 5.5 months; P < .0001) and overall survival (OS, median survival not reached vs 7.3 months; P < .0001) when compared with patients with persistent MRD. Irrespective of pre-alloHCT MRD, D90 cfDNA MRD was associated with inferior 2-year OS (16.7% vs 84.8%; P < .0001) and RFS (16.7% vs 80.7%; P < .0001). cfDNA seems to be an accurate, minimally invasive alternative to BM aspirates in MRD assessment and confers important prognostic implications in patients with myeloid malignancies undergoing alloHCT.

Sex-Specific Differences in Congenital Diaphragmatic Hernia Mortality.

OBJECTIVE: To compare disease severity and mortality differences between female and male patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We queried the CDH Study Group (CDHSG) database for CDH neonates managed between 2007 and 2018. Female and males were compared in statistical analyses using t tests, χ² tests, and Cox regression, as appropriate (P ≤ .05). RESULTS: There were 7288 CDH patients, of which 3048 (41.8%) were female. Females weighed less on average at birth than males (2.84 kg vs 2.97 kg, P < .001) despite comparable gestational age. Females had similar rates of extracorporeal life support (ECLS) utilization (27.8% vs 27.3%, P = .65). Although both cohorts had equivalent defect size and rates of patch repair, female patients had increased rates of intrathoracic liver herniation (49.2% vs 45.9%, P = .01) and pulmonary hypertension (PH) (86.6% vs 81.1%, P < .001). Females had lower survival rates at 30-days (77.3% vs 80.1%, P = .003) and overall lower survival to discharge (70.2% vs 74.2%, P < .001). Subgroup analysis revealed that increased mortality was significant among those who underwent repair but were never supported on ECLS (P = .005). On Cox regression analysis, female sex was independently associated with mortality (adjusted hazard ratio 1.32, P = .02). CONCLUSION: After controlling for the established prenatal and postnatal predictors of mortality, female sex remains independently associated with a higher risk of mortality in CDH. Further study into the underlying causes for sex-specific disparities in CDH outcomes is warranted.

Adagrasib: a novel inhibitor for KRASG12C-mutated non-small-cell lung cancer.

Adagrasib is a recently US FDA-approved novel KRASG12C targeted therapy with clinical efficacy in patients with advanced, pretreated KRASG12C-mutated non-small-cell lung cancer. KRYSTAL-I reported an objective response rate of 42.9% with median duration of response of 8.5 months. Treatment-related adverse events were primarily gastrointestinal and occurred in 97.4% of patients, with grade 3+ treatment-related adverse events occurring in 44.8% of patients. This review details the preclinical and clinical data for adagrasib in the treatment of non-small-cell lung cancer. We also outline practical clinical administration guidelines for this novel therapy, including management of toxicities. Finally, we discuss the implications of resistance mechanisms, summarize other KRASG12C inhibitors currently in development and outline future directions for adagrasib-based combination therapies.

Adagrasib is a new oral (taken by mouth) treatment option for patients with non-small-cell lung cancer (NSCLC) with KRAS^G12C mutations. KRAS is a gene that regulates signaling pathways, which are responsible for cell growth and division. A mutation in KRAS can cause cells to multiply and cause cancer. Clinical trials have shown that adagrasib causes cancer reduction or resolution in 42.9% of people with NSCLC with KRAS^G12C mutations who receive the drug. Side effects of adagrasib are primarily gastrointestinal (nausea, vomiting, diarrhea). This review outlines guidelines for the management of side effects. New studies are looking at how adagrasib can be safely combined with other therapies to better treat NSCLC with KRAS^G12C mutations.

Racial and Ethnic Disparities in Outcomes Among Newborns with Congenital Diaphragmatic Hernia.

Importance: There is some data to suggest that racial and ethnic minority infants with congenital diaphragmatic hernia (CDH) have poorer clinical outcomes. Objective: To determine what patient- and institutional-level factors are associated with racial and ethnic differences in CDH mortality. Design, Setting, and Participants: Multicenter cohort study of 49 US children's hospitals using the Pediatric Health Information System database from January 1, 2015, to December 31, 2020. Participants were patients with CDH admitted on day of life 0 who underwent surgical repair. Patient race and ethnicity were guardian-reported vs hospital assigned as Black, Hispanic (White or Black), or White. Data were analyzed from August 2021 to March 2022. Exposures: Patient race and ethnicity: (1) White vs Black and (2) White vs Hispanic; and institutional-level diversity (as defined by the percentage of Black and Hispanic patients with CDH at each hospital): (1) 30% or less, (2) 31% to 40%, and (3) more than 40%. Main Outcomes and Measures: The primary outcomes were in-hospital and 60-day mortality. The study hypothesized that hospitals managing a more racially and ethnically diverse population of patients with CDH would be associated with lower mortality among Black and Hispanic infants. Results: Among 1565 infants, 188 (12%), 306 (20%), and 1071 (68%) were Black, Hispanic, and White, respectively. Compared with White infants, Black infants had significantly lower gestational ages (mean [SD], White: 37.6 [2] weeks vs Black: 36.6 [3] weeks; difference, 1 week; 95% CI for difference, 0.6-1.4; P < .001), lower birthweights (White: 3.0 [1.0] kg vs Black: 2.7 [1.0] kg; difference, 0.3 kg; 95% CI for difference, 0.2-0.4; P < .001), and higher extracorporeal life support use (White: 316 patients [30%] vs Black: 69 patients [37%]; χ21 = 3.9; P = .05). Black infants had higher 60-day (White: 99 patients [9%] vs Black: 29 patients [15%]; χ21 = 6.7; P = .01) and in-hospital (White: 133 patients [12%] vs Black: 40 patients [21%]; χ21 = 10.6; P = .001) mortality . There were no mortality differences in Hispanic patients compared with White patients. On regression analyses, institutional diversity of 31% to 40% in Black patients (hazard ratio [HR], 0.17; 95% CI, 0.04-0.78; P = .02) and diversity greater than 40% in Hispanic patients (HR, 0.37; 95% CI, 0.15-0.89; P = .03) were associated with lower mortality without altering outcomes in White patients. Conclusions and Relevance: In this cohort study of 1565 who underwent surgical repair patients with CDH, Black infants had higher 60-day and in-hospital mortality after adjusting for disease severity. Hospitals treating a more racially and ethnically diverse patient population were associated with lower mortality in Black and Hispanic patients.

Two Cases of Subsequent Hepatocellular Carcinoma in Immune Checkpoint Inhibitor-Responsive NSCLC: A Case Report.

As novel therapeutic regimens continue to lead to increased survival of patients with lung cancer, it is imperative to remain mindful of the accompanying increase in the incidence of new primary malignancies. Although the most common secondary malignancies in patients with lung cancer have historically included colon, rectal, esophageal, and thyroid cancers, we report here two rare cases of new primary hepatocellular carcinomas in patients receiving immune checkpoint inhibitor therapy for NSCLC. In both cases, the diagnosis of hepatocellular carcinoma, rather than assuming a hepatic metastasis, was crucial for determining the appropriate approach for treatment. These cases thus underscore the importance of appropriate diagnostics to ensure that the proper therapeutics are chosen and present important considerations for the lung cancer community going forward.

Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced, Unresectable KRAS-mutated Non-Small Cell Lung Cancer.

BACKGROUND: Consolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes. METHODS: We conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression. RESULTS: Of 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015). CONCLUSION: Patients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.

Reimagining Undergraduate Medical Education in a Post-COVID-19 Landscape.

Online education due to the COVID-19 pandemic caused many medical schools to increasingly employ asynchronous and virtual learning that favored student independence and flexibility. At the same time, the COVID-19 pandemic highlighted existing shortcomings of the healthcare field in providing for marginalized and underserved communities. This perspective piece details the authors' opinions as medical students and medical educators on how to leverage the aspects of pandemic medical education to train physicians who can better address these needs.

Multiple 9-1-1 complexes promote homolog synapsis, DSB repair, and ATR signaling during mammalian meiosis.

DNA damage response mechanisms have meiotic roles that ensure successful gamete formation. While completion of meiotic double-strand break (DSB) repair requires the canonical RAD9A-RAD1-HUS1 (9A-1-1) complex, mammalian meiocytes also express RAD9A and HUS1 paralogs, RAD9B and HUS1B, predicted to form alternative 9-1-1 complexes. The RAD1 subunit is shared by all predicted 9-1-1 complexes and localizes to meiotic chromosomes even in the absence of HUS1 and RAD9A. Here, we report that testis-specific disruption of RAD1 in mice resulted in impaired DSB repair, germ cell depletion, and infertility. Unlike Hus1 or Rad9a disruption, Rad1 loss in meiocytes also caused severe defects in homolog synapsis, impaired phosphorylation of ATR targets such as H2AX, CHK1, and HORMAD2, and compromised meiotic sex chromosome inactivation. Together, these results establish critical roles for both canonical and alternative 9-1-1 complexes in meiotic ATR activation and successful prophase I completion.

Poly(ADP-Ribose) Polymerase Inhibition in Small Cell Lung Cancer: A Review.

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with high and rapid relapse rates and poor outcomes. Treatment for SCLC has historically been limited by the lack of targetable driver genomic lesions, however recent developments in the underpinnings of genomic instability in SCLC and understanding of its transcriptional subtypes have led to increased interest in the use of poly(ADP-ribose) polymerase (PARP) inhibitors as a rationale therapy. Poly(ADP-ribose) polymerase inhibitors, historically designed to target BRCA1/2-mutated malignancies, capitalize on synthetic lethality in homologous recombination-deficient tumors. In this review, we outline the mechanistic rationale for the use of PARP inhibitors in treating SCLC and detail key clinical trials investigating their use in combination with chemotherapy and immunotherapy. We describe developments in the understanding of biomarkers for sensitivity to therapy and highlight further investigational directions for the use of PARP inhibitors in treating SCLC.

Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics.

MET dysregulation promoting tumorigenesis in non-small cell lung cancer (NSCLC) is associated with worse outcomes following chemotherapy as compared to non-driver mutated NSCLC and occurs either through mutations causing MET exon 14 skipping (METex14) or gene amplification and overexpression that result in enhanced receptor signaling. Capmatinib is the first FDA-approved targeted therapy for NSCLC with METex14 skipping mutations, approved in 2020. FoundationOne® CDx, a comprehensive genomic profiling test for solid tumors, was concurrently approved as a companion diagnostic for capmatinib use. The GEOMETRY mono-1 phase II trial of capmatinib monotherapy demonstrated an overall response rate (ORR) of 68% in treatment naïve (n=28) and 41% in pre-treated (n=69) METex14 skipping advanced NSCLC; in MET amplified advanced NSCLC (gene copy number ≥ 10) ORRs of 40% in treatment naïve and 29% in pre-treated disease was seen. This review outlines the clinical data supporting capmatinib approval in the treatment of NSCLC and FoundationOne® CDx approval as a companion diagnostic. We detail the practical clinical administration of capmatinib, including dosing and toxicity management, compare capmatinib to other approved and investigational MET-targeted therapies, discuss limitations of capmatinib, and highlight ongoing trials of capmatinib in combinatorial approaches.

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study. METHODS: In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096. FINDINGS: Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7-20·1). 21 (39·6% [95% CI 26·5-54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events. INTERPRETATION: Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study. FUNDING: Eisai and Merck.

Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma.

BACKGROUND: In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC). METHODS: Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed. RESULTS: Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0. CONCLUSIONS: Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.

A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine.

BACKGROUND: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. METHODS: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. RESULTS: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. CONCLUSIONS: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.

Prolonged duration of response in lenvatinib responders with thyroid cancer.

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2%; 95% confidence interval (CI) 54.2-66.1) was 30.0 months (95% CI 18.4-36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99% CI 0.17-0.35; nominal P < 0.0001). In lenvatinib responders, median PFS was 33.1 months (95% CI 27.8-44.6) vs 7.9 months (95% CI 5.8-10.7) in non-responders. The median DOR of 30.0 months seen with patients who achieved complete or partial responses with lenvatinib (60.2%) demonstrates that lenvatinib responders can have prolonged, durable and clinically meaningful responses. Prolonged PFS (33.1 months) was also observed in these lenvatinib responders.