A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies.

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies.

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. METHODS: Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). RESULTS: In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline. CONCLUSIONS: Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment. TRIAL REGISTRATION NUMBER: NCT02460224.

High-Efficiency Ultrasound-Guided Regional Nerve Block Workshop for Emergency Medicine Residents.

Audience: This small-group workshop is designed for emergency medicine residents. This workshop can also be offered to medical students or faculty interested in reviewing and practicing ultrasound-guided regional nerve blocks. Introduction: Ultrasound-guided regional nerve block (UGRNB) is a method used to administer local anesthesia to otherwise unreachable locations on the body and may be used in the management of various painful conditions seen in the emergency department. The ultrasound curriculum of our residency program is longitudinal. All residents spend time with the ultrasound director throughout their training, engage in daily bedside ultrasound, and have regular skills training on the various clinical applications of ultrasound. Additionally, all residents have a required ultrasound rotation dedicated to performing bedside ultrasound in the Emergency Department. Although others have outlined approaches to teaching emergency medicine residents the techniques needed to perform UGRNBs, the value of taking a one-day, high-efficiency teaching strategy with a narrow focus on practical application has yet to be appreciated. Educational Objectives: The objective of this workshop is to provide emergency medicine residents the confidence and skill sets needed to effectively perform five commonly used UGRNBs for conditions encountered in the emergency department. Through this one-day, accelerated workshop, residents will be given an opportunity to sharpen their UGRNB technique prior to applying them in the clinical environment. By the end of this workshop, learners will be able to: 1) recognize the clinical situations in which UGRNBs can be utilized and understand the associated risks, 2) list the commonly used local anesthetic medications and their proper dosing in respect to regional nerve blocks, 3) demonstrate proper ultrasound probe positioning and identify relevant anatomical landmarks for each nerve block on both standardized patients and cadavers, 4) describe the common steps involved to perform each nerve block, 5) perform the five UGRNB techniques outlined in this workshop. Educational Methods: Small group activity combining didactic learning, case-based learning, and procedural simulation. The didactic component may be delivered in an asynchronous learning or "flipped classroom" format. Research Methods: In-person interviews of the learners were obtained following the debriefing session during which they were asked about their enjoyment and satisfaction with the workshop. In addition, learners were asked about the value of the activities for their clinical practices and to provide formative feedback regarding the design of the workshop. Results: Overall, participants reported high levels of enjoyment, and many verbalized their satisfaction with the expeditious and pragmatic nature of the workshop. Some participants commented that they were looking forward to future workshops of similar design. Participants also stated that they felt more confident performing nerve blocks and looked forward to applying these skills in the clinical setting. Discussion: A focused small-group workshop directed towards developing the confidence and skill set necessary to perform UGRNBs can be successfully offered to emergency medicine residents in a single-day workshop. Topics: Ultrasound, nerve block, local anesthesia, injection, pain, resident, workshop.

Cardiovascular Effects of Energy Drinks in the Pediatric Population.

ABSTRACT: Consumption of energy drinks in the pediatric population is correlated with more emergency department visits and causes adverse reactions, such as neurological, psychiatric, gastrointestinal, renal, and cardiovascular effects. These cardiovascular complications include increased cardiometabolic risk with high intake of sugar, short-term blood pressure increases and a decrease in cerebral blood flow due to the caffeine content, increased or decreased blood pressure from taurine, unmasked cardiac conditions, such as channelopathies, and atrial and ventral fibrillations. Cardiovascular complications can also arise when energy drinks are mixed with pharmaceutical drugs, such as amiodarone, potent CYP1A2 inhibitors, warfarin, digoxin, or corticosteroids. Combining energy drinks with alcohol also precipitates adverse cardiovascular events, posing a risk to the health of children and adolescents. This review further explores the ingredients in energy drinks and their mechanism of action in causing these cardiovascular complications.

Revisiting MET: Clinical Characteristics and Treatment Outcomes of Patients with Locally Advanced or Metastatic, MET-Amplified Esophagogastric Cancers.

BACKGROUND: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. PATIENTS AND METHODS: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. RESULTS: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). CONCLUSION: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. IMPLICATIONS FOR PRACTICE: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.

A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer.

Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2, MET, or FGFR2 or mutations in PIK3CA, EGFR, or BRAF. Ganetespib which is a novel triazolone heterocyclic inhibitor of HSP90, is a potentially biologically rational treatment strategy for advanced EG cancers with these gene amplification. This multicenter, single-arm phase 2 trial enrolled patients with histologically confirmed advanced EG cancer with progression on at least one line of systemic therapy. Patients received Ganetespib 200 mg/m2 IV on Days 1, 8, and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). Secondary endpoints included: Progression Free Survival (PFS); to correlate the presence of HSP clients with ORR and PFS; evaluating the safety, tolerability and adverse events profile. In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single-agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug.

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors.

Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.

Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer.

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.

Author Correction: Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers.

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.

Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.

IMPORTANCE: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. OBJECTIVE: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. INTERVENTIONS: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. MAIN OUTCOMES AND MEASURES: R0 resection rate. RESULTS: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). CONCLUSIONS AND RELEVANCE: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01821729.

Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors.

PURPOSE: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors.Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. RESULTS: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%-17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%-50.2%) in MET-amplified patients; median (range) duration of response was 202 (51-1,430+) days in all patients and 197 (64-1,430+) days in MET-amplified patients. CONCLUSIONS: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.See related commentary by Ma, p. 2375.

Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial.

Importance: Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted. Objective: To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy. Design, Setting, and Participants: A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion. Interventions: Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine. Main Outcomes and Measures: The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS). Results: Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%. Conclusions and Relevance: Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01591733.

Primary tumor sidedness is an independent prognostic marker for survival in metastatic colorectal cancer: Results from a large retrospective cohort with mutational analysis.

Recent reports demonstrate inferior outcomes associated with primary right-sided vs left-sided colorectal tumors in patients with metastatic colorectal cancer (mCRC). We sought to describe our experience with mCRC patients on whom we have molecular data to determine whether primary tumor sidedness was an independent prognostic marker for overall survival (OS). mCRC patients with documented primary tumor sidedness who received mutational profiling between 2009 and 2014 were identified (n = 367, median follow-up 30.4 months). Mutational profiling for >150 mutations across commonly mutated cancer genes including RAS, PIK3CA, BRAF, and PTEN as well as treatment data, including receipt of a biologic agent, were collected. Univariable/multivariable models were used to analyze relationships between collected data and OS. Among 367 patients, sidedness breakdown was as follows: 234 left (64%), 133 right (36%). 56% were male, with a median age at diagnosis of 57 (range 24-89). A total of 143 patients had RAS mutations. Five-year OS was 41%, median OS was 54 months (range 1-149). Five-year OS for left- vs right-sided tumors was 46% vs 24% (P < .0001). On univariable analysis, among both RAS wildtype and mutant tumors, left-sided tumors continued to have improved OS vs right-sided tumors (HR: 0.49, 95% CI: 0.34-0.69 RAS wildtype; HR: 0.61, 95% CI: 0.40-0.95 RAS mutant). Left-sidedness was an important prognostic factor for OS among RAS wildtype patients despite treatment with or without a biologic agent (P < .05). Left-sidedness remained significant for improved OS on multivariable analysis (P < .0001). Left-sided primary tumor remained most important prognostic factor for OS, even when adjusting for mutational status and receipt of biologic agent.

Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer.

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivoIn vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome.Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417-27. ©2018 AACR.See related commentary by Janku, p. 389See related article by Corcoran et al., p. 428This article is highlighted in the In This Issue feature, p. 371.

Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma.

OBJECTIVES: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. METHODS: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. RESULTS: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. CONCLUSIONS: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease.

Tolerability and Long-term Outcomes of Dose-Painted Neoadjuvant Chemoradiation to Regions of Vessel Involvement in Borderline or Locally Advanced Pancreatic Cancer.

PURPOSE: We reviewed our experience involving patients with borderline resectable or locally advanced pancreatic cancer, treated with the dose-painted (DP) boost technique to regions of vessel involvement which preclude upfront surgical resection. We evaluated patient outcomes with respect to tolerability and treatment outcomes. MATERIALS AND METHODS: We retrospectively reviewed 99 patients with borderline resectable (n=25) or locally advanced pancreatic cancer (n=74) treated with DP-neoadjuvant chemoradiation from 2010 to 2015. Tumor and regional lymph nodes were prescribed 50.4 Gy and the region around the involved blood vessel was boosted to 58.8 Gy in 28 fractions. The primary outcome was acute toxicity and late duodenal toxicity. Secondary outcomes included conversion to surgical resectability, local failure, disease-free survival, and overall survival (OS). Cox proportional hazards models were performed to evaluate for predictors of survival. RESULTS: All but 1 patient completed chemoradiation. The rates of grade 2+ and 3+ nausea were 40% and 12%, respectively. With regards to late toxicity, 5 patients developed potential RT-related grade 3+ duodenal complications including duodenal ulceration/bleeding (n=3) and duodenal stricture (n=2). With a median follow-up of 15 months, the median OS was 18.1 months. Among 99 patients in our study, 37 patients underwent surgical resection. For patients who underwent surgical resection (n=37), the median OS was 30.9 months. On multivariate analysis, only normalization of CA 19-9 post-RT was associated with improved OS. CONCLUSIONS: We found that DP-neoadjuvant chemoradiation to regions of vessel involvement is both feasible and well tolerated. In addition, we demonstrated that over one third of patients with initially deemed unresectable disease were able to undergo surgical resection after receiving neoadjuvant therapy including DP-chemoradiation.

Phase II Study of Proton-Based Stereotactic Body Radiation Therapy for Liver Metastases: Importance of Tumor Genotype.

Background: We evaluated the efficacy and safety of risk-adapted, proton-based stereotactic body radiation therapy (SBRT) for liver metastases from solid tumors. Methods: This single-arm phase II single institutional study (NCT01239381) included patients with limited extrahepatic disease, 800 mL or greater of uninvolved liver, and no cirrhosis or Child-Pugh A, who had received proton-based SBRT to one to four liver metastases from solid tumors. Treatment comprised 30 to 50 Gray equivalent (GyE) in five fractions based on the effective volume of liver irradiated. Sample size was calculated to determine if local control (LC) at one year was greater than 70%. The cumulative incidence of local failure was used to estimate LC. The association of tumor characteristics, including genetic alterations in common cancer genes such as BRAF, EGFR, HER2, KRAS, NRAS, PIK3CA, and TP53 with local tumor control, was assessed. All statistical tests were two-sided. Results: Eighty-nine patients were evaluable (colorectal, n = 34; pancreatic, n = 13; esophagogastric, n = 12; other, n = 30). Median tumor size was 2.5 cm (range = 0.5-11.9 cm). Median dose was 40 GyE (range = 30-50 GyE), and median follow-up was 30.1 months (range = 14.7-53.8 months). There was no grade 3 to 5 toxicity. Median survival time was 18.1 months. The one- and three-year LC rates were 71.9% (95% confidence limit [CL] = 62.3% to 80.9%) and 61.2% (95% CL = 50.8% to 71.8%), respectively. For large tumors (≥6 cm), one-year LC remained high at 73.9% (95% CL = 54.6% to 89.8%). Mutation in the KRAS oncogene was the strongest predictor of poor LC (P = .02). Tumor with both mutant KRAS and TP53 were particularly radioresistant, with a one-year LC rate of only 20.0%, compared with 69.2% for all others (P = .001). Conclusions: We report the largest prospective evaluation to date of liver SBRT for hepatic metastases, and the first with protons. Protons were remarkably well tolerated and effective even for metastases that were 6 cm or larger. KRAS mutation is a strong predictor of poor LC, stressing the need for tumor genotyping prior to SBRT and treatment intensification in this patient subset.

Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dose-painted IMRT per RTOG 0529.

PURPOSE: To describe the outcomes and toxicities of the largest cohort to date of patients with anal squamous cell carcinoma uniformly treated with concurrent chemoradiation using dose-painted intensity modulated radiation therapy (DP-IMRT) according to RTOG 0529. METHODS AND MATERIALS: We identified 99 eligible patients with anal cancer who were treated at our institution with definitive chemoradiation using DP-IMRT between 2005 and 2015 per RTOG 0529 dosing guidelines. Primary study endpoints included event-free survival (defined as recurrence, colostomy, or death) and overall survival. Secondary endpoints were treatment duration and acute and late toxicity. RESULTS: At a median follow-up of 49 months (range, 2-114 months), 92% of patients had a clinical complete response. Fifteen percent underwent colostomy, including 4 pretreatment colostomies, 6 planned abdominoperineal resections (APRs), 4 salvage APRs, and 1 APR for treatment-related complications. Thirteen patients developed local recurrence, of whom 6 developed synchronous metastatic disease. The 4-year overall survival was 85.8%, and 4-year event-free survival was 75.5%. Median treatment duration was 43 days (range, 10-68 days). The overall rate of non-hematologic grade 3+ acute and grade 2+ late toxicities was 20% and 15%, respectively. CONCLUSIONS: Long-term outcomes and tolerability were excellent In the largest cohort to date of patients with anal cancer who received DP-IMRT prescribed per RTOG 0529.

A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.

Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors.Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg (n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1,200 mg (n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design.Results: TAK-117 once-daily dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1,200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated).Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted. Clin Cancer Res; 23(17); 5015-23. ©2017 AACR.