Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

/pdf/sorafenib-in-advanced-hepatocellular-carcinoma-3xdq9sbovw.pdf

Sorafenib in Advanced Hepatocellular Carcinoma

BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

/pdf/pd-1-blockade-in-tumors-with-mismatch-repair-deficiency-1eb0ztv7j7.pdf

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.07-9574LSF

Dose translation from animal to human studies revisited

Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

/pdf/idh1-and-idh2-mutations-in-gliomas-1er88anbwg.pdf

IDH1 and IDH2 Mutations in Gliomas

BackgroundWe assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. MethodsWe assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. ResultsCommon side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1501824

Pembrolizumab for the treatment of non-small cell lung cancer

516 A phase 1 dose-escalation study to examine the safety and tolerability of LY2603618 administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m2, determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m2, however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m2. Although NMF peak plasma concentrations (Cmax) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m2 dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m2. Cmaxs and AUCs at this dose were significantly lower than those that were demonstrated to induce cytotoxicity, and differentiating, chemosensitizing, and radiosensitizing effects in preclinical studies suggesting that further clinical evaluations of NMF may not be warranted.

Assessment of N-methylformamide (NMF) administered orally on a three times weekly schedule: a phase I study

e20556 Background: Communicating difficult news is a frequent activity in cancer care. Many providers have had limited communication skills (CS) training, leading to stress, dissatisfaction, and bu...

Across the cancer continuum: A communication skills curriculum for oncology fellows.

Taxol (T): An active new drug in ovarian epithelial cancer (OVCA)

179 Background: Alongside persistent disparities in healthcare outcomes in HO, there is an inability to adequately recruit, maintain and promote a diverse and inclusive work force nationwide. To our knowledge, a structured approach to DEI education/recruitment in HO training is lacking. We sought to establish a longitudinal curriculum aimed at educating HO trainees in structural barriers impacting cancer equity and developing tools to enhance Underrepresented in Medicine (URiM) recruitment. Methods: Trainee-led DEI framework was presented to program leadership and officially adopted into the curriculum for the 2021-22 academic year. This consisted of initiatives across 4 domains: 1. Curricular Development (emphasis on disparities during trainee orientation, didactic lectures on cancer disparities, financial toxicity, workforce diversity, pandemic impact on cancer inequities) ; 2. Recruitment & Retention (implicit bias training, targeted recruitment from HBCUs, trainee-led discussions on enhancing recruitment); 3. Engagement & Mentorship (local community mentorship within institution, external mentorship through ASCO URM MSR program); 4. Disparities Research (career guidance sessions with invited faculty, development of registry-based studies to evaluate disparities). Impact of new curriculum was measured through anonymous surveys, at 1, 7, and 12 months during the academic year. A 5-point Likert scale (strongly disagree to strongly agree) was utilized. Results: At baseline, surveyed trainees were predominantly PGY5 (33%), ages 31-40 (66%), and self-identified as White or Caucasian (47%). Over the academic year, trainee recognition of structural barriers that prevented oncologic care delivery increased. More trainees felt departmental/fellowship-wide DEI efforts were transparent and impactful leading to quantifiable changes, and creation of new mentorship opportunities. Trainees rated the following as most helpful to address biases in the workplace: opportunities to mentor minority high school/college-level students, implicit bias training, and formal lectures. Anonymous qualitative feedback from fellows favored small group discussions and encouraged a top-down approach to promoting diversity in leadership. One trainee-mentored URiM medical student presented work at the ASCO annual conference on cancer disparities, while program leadership efforts led to incoming trainee class comprised of 25% URiM. Conclusions: We demonstrate feasibility of a longitudinal DEI curriculum in HO trainee education and recruitment that raises awareness and creates opportunity for URiM. Future efforts will build on this curriculum utilizing trainee feedback and departmental buy-in with the goal of building an oncologic workforce that better reflects the patients we care for.

Ross C. Donehower

Papers

516 A phase 1 dose-escalation study to examine the safety and tolerability of LY2603618 administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

Assessment of N-methylformamide (NMF) administered orally on a three times weekly schedule: a phase I study

Across the cancer continuum: A communication skills curriculum for oncology fellows.

Taxol (T): An active new drug in ovarian epithelial cancer (OVCA)

Innovation in recruitment and curricular design for diversity, equity, and inclusion (DEI) education for hematology-oncology (HO) trainees.