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Background: With the rapid influx of novel anti-cancer agents, phase I clinical trials in oncology are evolving. Historically, response rates on early phase trials have been modest with the clinical benefit and ethics of enrolment debated. However, there is a paucity of real-world data in this setting. Aim(s): To better understand the changing landscape of phase I oncology trials, we performed a retrospective review at our institution to examine patient and trial characteristics, screening outcomes, and treatment outcomes. Methods and Results: We analyzed all consecutive adult patients with advanced solid organ malignancies who were screened across phase I trials from January 2013 to December 2018 at a single institution. During this period, 242 patients were assessed for 28 different trials. Median age was 64 years (range 30-89) with an equal sex distribution. Among 257 screening visits, the overall screen failure rate was 18%, resulting in 212 patients being enrolled onto a study. Twenty-six trials (93%) involved immunotherapeutic agents or molecular targeted agents either alone or in combination, with only two trials of cytotoxic agents (7%). Twenty-two (13.4%) of the 209 treated patients experienced a total of 33 grade 3 or higher treatment-related adverse events. There was one treatment-related death (0.5%). Of 190 response-evaluable patients, 7 (4%) had a complete response, 34 (18%) a partial response, and 59 (31%) experienced stable disease for a disease control rate of 53%. The median overall survival for our cohort was 8.0 (95% CI: 6.8-9.2) months. Conclusion(s): The profile of phase I trials at our institution are consistent with the changing early drug development landscape. Response rates and overall survival in our cohort are superior to historically reported rates and comparable to contemporaneous studies. Severe treatment-related toxicity was relatively uncommon, and treatment-related mortality was rare.Copyright © 2021 The Authors. Cancer Reports pub

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC)+/-nivolumab, in patients with selected tumors. Patients and Methods: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n=96) or BMS-986148 0.8 mg/kg nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. Result(s): In CA008-002, the most common (>= 10%) treatmentrelated adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 +/- nivolumab. No association between mesothelin expression and response was detected. Conclusion(s): BMS-986148 _ nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.Copyright © 2022 American Association for Cancer Research Inc.. All rights reserved.

Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.

Aims: Chemotherapy-induced nausea and vomiting is the most common non-haematological toxicity of chemotherapy. Our objective was to determine the optimal duration of dexamethasone treatment in preventing chemotherapy-induced nausea and vomiting. Method(s): Searches were conducted inMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov. Eligible studies were randomised controlled studies comparing a short course (1-2 days) to a long course (3 or more days) of dexamethasone in patients receiving chemotherapy. The same regimen of adjunctanti-emetics was required in both arms. Primary outcome was complete responsewith no nausea or vomiting and the secondary outcome was adverse effects. Screening and data extraction were conducted independently by two authors. A random effects model was used for both outcomes. Subgroup analysis was performed by chemotherapy emetogenicity and use of an NK1 inhibitor. Risk of bias was assessed with the Cochrane risk of bias tool. Result(s): One thousand thirty-five articles were screened to identify the 11 studies included in the review. Nine studies of 1892 patients were included in meta-analysis. There was no significant difference in complete response of nausea and vomiting between a short or long course of dexamethasone (RR 0.98, 95% CI 0.89-1.07, P = .58) There were no differences in subgroup analysis. There was a lower risk of adverse events with a short course of dexamethasone as compared to a long course of dexamethasone (RR 0.80, 95% CI 0.64-0.99, P = .04). No heterogeneity was found in either analysis. Conclusion(s): There was no significant difference between a short or long course of dexamethasone in preventing nausea or vomiting, but a short course was associated with fewer adverse effects. Further research is required to determine the appropriate duration of dexamethasone for different chemotherapy protocols when used with modern anti-emetic regimens.

Background: With the rapid influx of novel anti-cancer agents, phase I clinical trials in oncology are evolving. Historically, response rates on early phase trials have been modest with the clinical benefit and ethics of enrolment debated. However, there is a paucity of real-world data in this setting. Aim(s): To better understand the changing landscape of phase I oncology trials, we performed a retrospective review at our institution to examine patient and trial characteristics, screening outcomes, and treatment outcomes. Methods and Results: We analyzed all consecutive adult patients with advanced solid organ malignancies who were screened across phase I trials from January 2013 to December 2018 at a single institution. During this period, 242 patients were assessed for 28 different trials. Median age was 64 years (range 30-89) with an equal sex distribution. Among 257 screening visits, the overall screen failure rate was 18%, resulting in 212 patients being enrolled onto a study. Twenty-six trials (93%) involved immunotherapeutic agents or molecular targeted agents either alone or in combination, with only two trials of cytotoxic agents (7%). Twenty-two (13.4%) of the 209 treated patients experienced a total of 33 grade 3 or higher treatment-related adverse events. There was one treatment-related death (0.5%). Of 190 response-evaluable patients, 7 (4%) had a complete response, 34 (18%) a partial response, and 59 (31%) experienced stable disease for a disease control rate of 53%. The median overall survival for our cohort was 8.0 (95% CI: 6.8-9.2) months. Conclusion(s): The profile of phase I trials at our institution are consistent with the changing early drug development landscape. Response rates and overall survival in our cohort are superior to historically reported rates and comparable to contemporaneous studies. Severe treatment-related toxicity was relatively uncommon, and treatment-related mortality was rare.Copyright © 2021 The Authors. Cancer Reports pub

PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) {plus minus} nivolumab in patients with selected tumors. EXPERIMENTAL DESIGN: In an international phase 1/2a study (NCT02341625 [CA008-002]), patients received BMS-986148 monotherapy (0.1-1.6 mg/kg IV Q3W or 0.4 or 0.6 mg/kg IV QW; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg IV Q3W (n = 30). The primary endpoint was safety and tolerability. RESULT(S): In CA008-002, the most common ({greater than or equal to} 10%) treatment-related adverse events (TRAEs) included increased AST, ALT, and ALP. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 Q3W monotherapy, 3 (25%) receiving BMS-986148 QW monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab Q3W. Overall, 17 of 126 patients (13%) discontinued due to a TRAE. The maximum tolerated dose of BMS-986148 was 1.2 mg/kg IV Q3W.The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (Q3W and QW). Preliminary clinical activity was observed with BMS-986148 {plus minus} nivolumab. No association between mesothelin expression and response was detected. CONCLUSION(S): BMS-986148 {plus minus} nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

Purpose: Combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs. Patients and Methods: CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission partial remission stable disease). Result(s): Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7-10.5] and overall survival was 14.8 months (95% CI: 4.1-21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events. Conclusion(s): Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.Copyright © 2020 American Association for Cancer Research.

Background: Adrenocortical carcinoma is a rare malignancy, with poor prognosis and limited treatment options for patients with advanced disease. Chemotherapy is the current standard first-line treatment, providing only a modest survival benefit. There is only limited treatment experience with immunotherapy using single-agent anti-PD-1/PD-L1 therapy. To date no clinical trials have been reported using combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade in this patient population. Method(s): CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Participants received the anti-PD-1 antibody nivolumab (3 mg/kg IV) and the anti-CTLA-4 antibody ipilimumab (1 mg/kg IV) every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. Response was assessed every 12 weeks by RECIST version 1.1. Primary endpoint was clinical benefit rate (complete response, partial response, stable disease at 12 weeks). Result(s): Six patients with adrenocortical carcinoma were enrolled and received treatment. Two patients (33%) have an ongoing partial response (10 and 25 months +) and two patients (33%) stable disease leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instable phenotype. One patient rapidly progressed shortly after enrollment into the trial and did not undergo restaging. Immunotherapy-related toxicity was reported in all patients, with four patients (67%) experiencing grade 3/4 hepatitis leading to discontinuation of treatment. Conclusion(s): This is the first treatment experience using ipilimumab and nivolumab combination immunotherapy in patients with advanced adrenocortical carcinoma. Durable responses have been observed in a subset of patients suggesting that this treatment regimen should be further investigated in this patient population.Copyright © 2021 The Author(s). Publis

Background: Patterns in oncology phase I clinical trials have changed significantly in recent years due to new classes of therapies, more combination treatments and changing patient demographics. We performed a retrospective review at our institution to examine patient and trial characteristics, screening outcomes and treatment outcomes. Method(s): We analysed all consecutive adult patients with advanced solid organ malignancies who were screened across phase I trials from January 2013 to December 2018 at a single institution. Result(s): During this period, 242 patients were assessed for 28 different trials. Median age was 64 years (range 30-89) with an equal sex distribution. Amongst 257 screening visits, the overall screen failure rate was 18%, resulting in 212 patients being enrolled onto a study. Twenty-six trials (93%) involved immunotherapeutic agents or molecular targeted agents either alone or in combination, with only two trials of cytotoxic agents (7%). Twenty-two (13.4%) of the 209 treated patients experienced a total of 33 grade 3 or higher treatment-related adverse events. There was one treatment-related death (0.5%). Of 190 response-evaluable patients, seven (4%) had a complete response, 34 (18%) a partial response, and 59 (31%) experienced stable disease for a disease control rate of 53%. The overall response rate for immuno-oncology (IO) trials was superior to non-IO trials (28% vs. 14%, P = .022). Furthermore, combination trials yielded a superior ORR than single-agent studies (33% vs. 16%; P = .005) The median overall survival for our cohort was 8.0 (95% CI, 6.8-9.2) months. Conclusion(s): The profile of phase I trials at our institution are consistent with the changing early drug development landscape. Response rates and overall survival in our cohort are superior to historically reported rates and comparable to contemporaneous studies. Severe treatmentrelated toxicity was relatively uncommon, and treatment-related mortality was rare.

Background: The impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non-small-cell lung cancer (NSCLC) is unclear. Material(s) and Method(s): We identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use. Result(s): A total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had >= 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not. Conclusion(s): In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.Copyright © 2020

Background Patients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers. Methods This multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). Results The objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (>=1% on tumor cells) but was independent of TMB. Conclusions Ipilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malig

Introduction: In patients with extensive-stage small cell lung cancer (ES-SCLC), the addition of an anti-PD-L1 regimen to chemotherapy demonstrated limited benefit, with an increase in survival by 2 months (Horn et al. N Engl J Med. 2018;379:2220-2229). Therefore, future prospects for better outcomes in SCLC lie in novel medicines and new treatment combinations. Fucosyl-GM1 is a monosialoganglioside expressed in 50%-70% of SCLC with limited expression in normal tissues (Brezicka et al. APMIS. 1991;99:797-802; Brezicka et al. Tumour Biol. 1992;13:308-315). BMS-986012 is a nonfucosylated, fully human monoclonal antibody with high binding specificity for fucosyl-GM1 engineered to enhance antibody-dependent, cell-mediated cytotoxicity (Ponath et al. Clin Cancer Res. 2018;24:5178-5189). We previously reported that the combination of BMS-986012 and nivolumab in patients with relapsed/refractory SCLC was well tolerated and demonstrated preliminary antitumor activity (Chu et al. Ann Oncol. 2017;28(suppl 5). Abstract 1528PD). Here, we report updated safety and antitumor activity results from the phase 1/2 trial of the combination of BMS-986012 and nivolumab in patients with relapsed/refractory SCLC (NCT02247349). Method(s): Patients with relapsed/refractory SCLC who had not received prior checkpoint inhibitor (CPI) therapy received BMS-986012 400 or 1000 mg with nivolumab 360 mg intravenously every 3 weeks. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), median duration of response (mDOR), median progression-free survival (mPFS), and pharmacokinetics. Median overall survival (mOS) was an exploratory endpoint. Result(s): As of July 22, 2020, 29 patients received BMS-986012 (400 mg, n=21; 1000 mg, n=8) with nivolumab, with a follow-up of 18.6 months (range, 0.6&-41.1 months). Median age of patients was 65 years (range, 46-79 years) and 52% were male; ECOG performance status was 0 (38%) or 1 (62%). The combinati

Background: Half of all gynaecological malignancies are considered rare and have limited access to evidence-based systemic treatment leading to poor outcomes. Dual immune checkpoint inhibitors (ICI) have demonstrated broad antitumour activity but have not been studied in this population. Method(s):We conducted an Australian multi-centre, phase 2 study, of combination ICI in advanced rare gynaecological cancers. Eligible patients were 18 years or older, with either a pre-treated or treatment naive, stage IV, histologically confirmed rare cancer of the female genital tract. Participants received induction ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks for four cycles, followed by maintenance nivolumab 3 mg/kg every 2 weeks or 480 mg every 4 weeks for up to two years or disease progression. The primary endpoint was disease control rate (DCR) at 12 weeks by RECIST 1.1. Secondary endpoints included the evaluation of tumour agnostic biomarkers inclusive of PD-L1 expression and tumour mutational burden (TMB). Result(s): Forty-three patients were enrolled with 10 tumour types; most (42) had received prior therapy (1-7 lines). Objective responses were observed in 12 patients (28%), and an addition seven had stable disease, corresponding to a DCR of 44%. Responses were obtained across a range of tumours including: uterine leiomyosarcoma (3/5), uterine and ovarian carcinosarcoma (3/9), ovarian clear cell (2/6), low grade serous ovarian carcinoma (1/4), vulva/vaginal SCC (1/5) and uterine serous carcinoma (1/8). No responses were observed in patients with ovarian sex cord stromal tumours (0/4). Immune-related adverse events occurred in 31 (72%) of patients with grade 3+ events in 7 (16%). Responses were higher in PD-L1 expressing tumours but were independent of TMB. Conclusion(s): Ipilimumab and nivolumab are active in a range of advanced rare gynaecological cancers with a manageable safety profile. Expanded cohorts are planned to better characterise: response rates wit

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38-76); median number of prior systemic therapies was 5(range 0-10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) >= 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation. Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).Copyright © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Background: Adrenocortical carcinoma is a rare malignancy, with poor prognosis and limited treatment options for patients with advanced disease. Chemotherapy is the current standard first-line treatment, providing only a modest survival benefit. There is only limited treatment experience with immunotherapy using single-agent anti-PD-1/PD-L1 therapy. To date no clinical trials have been reported using combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade in this patient population. Methods: CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Participants received the anti-PD-1 antibody nivolumab (3 mg/kg IV) and the anti-CTLA-4 antibody ipilimumab (1 mg/kg IV) every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. Response was assessed every 12 weeks by RECIST version 1.1. Primary endpoint was clinical benefit rate (complete response, partial response, stable disease at 12 weeks). Results: Six patients with adrenocortical carcinoma were enrolled and received treatment. Two patients (33%) have an ongoing partial response (10 and 25 months +) and two patients (33%) stable disease leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instable phenotype. One patient rapidly progressed shortly after enrollment into the trial and did not undergo restaging. Immunotherapy-related toxicity was reported in all patients, with four patients (67%) experiencing grade 3/4 hepatitis leading to discontinuation of treatment. Conclusions: This is the first treatment experience using ipilimumab and nivolumab combination immunotherapy in patients with advanced adrenocortical carcinoma. Durable responses have been observed in a subset of patients suggesting that this treatment regimen should be further investigated in this patient population.

BACKGROUND: Patients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers. METHODS: This multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). RESULTS: The objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB. CONCLUSIONS: Ipilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological ma

Background: Despite increasing evidence of benefit supporting CGP in personalizing cancer therapy, its widespread uptake remains limited. Barriers include low patient understanding, unmet patient expectations related to low utility, clinician concerns over cost-effectiveness, perceived value, and discomfort in management of complex genomic results. Method(s): This prospective cross-institutional demonstration study was designed to evaluate implementation of CGP in the care of adult and paediatric advanced cancer pts, incorporating pt reported outcomes (PROMs), discrete choice experiment (DCE), ongoing process optimization and clinician evaluations. DNA sequencing of FFPE tumor and matched blood was completed with CGP (PMCC Comprehensive Cancer Panel; 391 genes) via central laboratory. A tumor board reported results weekly with emphasis on therapeutic relevance. Oncologists performed consent and results delivery. Pts completed pre-and post-test surveys, including validated and study-specific questions, DCE and if eligible, semi-structured interviews. Qualitative interviews were undertaken with study clinicians and laboratory staff to evaluate processes. Result(s): 86% (315) of 365 enrolled pts had successful CGP; of these 63% (199) had relevant therapeutic, diagnostic or germline results. 50 (16%) had treatment change at 6m, 49 (16%) had germline mutations. 293 (88% of adult pts) completed PROMs. 17 of 19 clinicians/laboratory staff approached consented to an interview. At consent pts cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test pts remained consistently satisfied with accessing CGP; valuing research contribution, taking opportunities and information for family. 21% struggled with understanding results but there were low levels of decisional regret following participation (89% had nil/mild regret). Pt-elicited preferences (via DCE) indicated priority for h

Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti-PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Method(s): 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Result(s): Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 -25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusion(s): Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable resp

Background: Sitravatinib is an investigational, orally bioavailable, receptor tyrosine-kinase inhibitor with immune modulatory and potential antitumor activity. Tislelizumab is an investigational, humanized IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death receptor-1 (PD-1). We assessed the safety and antitumor activity of sitravatinib plus tislelizumab in patients with advanced solid tumors. Method(s): This is an open-label, multicenter, non-randomized, phase Ib study (NCT03666143). This cohort evaluated anti-PD-(L)1 antibody-naive patients with recurrent, platinum-resistant, epithelial ovarian cancer who were treated with 120 mg of sitravatinib once daily in combination with 200 mg tislelizumab every 3 weeks until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination. The primary objective was to assess the safety and tolerability of this combination therapy. Overall response rate, duration of response (DOR), disease control rate, and progression-free survival (PFS) were assessed as secondary endpoints. Result(s): As of 17 July 2019, 20 patients (median age, 66.0 years) were enrolled; median number of prior regimens was 5 (range, 2-12). All 20 patients received study drugs and were included in the safety analysis. Common (frequency >=10%) grade >=3 treatment-emergent adverse events (TEAEs) assessed as related to sitravatinib by investigators were hypertension (25%) and fatigue (10%). Six patients had AEs that led to sitravatinib discontinuation. The common (frequency >=10%) grade >=3 TEAE assessed as related to tislelizumab by investigators was increased transaminases (10%). Three patients had AEs that led to tislelizumab discontinuation. Of 17 efficacy-evaluable patients, 4 achieved confirmed partial response, 11 had stable disease, and 2 had progressive disease per RECIST version 1.1. Median PFS was 18.0 weeks; median DOR was not reached (NR) (both ranges, 12.29 weeks-NR). Concl

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF- or K-RAS/N-RAS-mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade $ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF-mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF-mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS-mutated endometrial cancer and K-RAS codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS-mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS-mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or

Background: Preclinical studies have shown potential synergism from blocking both programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1). BGB-A333 is an investigational humanized monoclonal antibody against PD-L1 that has antitumor activity in xenograft models. Tislelizumab, a clinical-stage anti-PD-1 antibody, showed clinical activity in patients (pts) with advanced solid tumors. We report results from the expansion cohort (phase IIB) of an open-label phase I/II study (NCT03379259) of BGB-A333 plus tislelizumab in pts with previously treated advanced urothelial carcinoma (UC). Method(s): Patients received BGB-A333 1350 mg IV Q3W + tislelizumab 200 mg IV Q3W. Eligible pts had locally advanced or metastatic UC without prior PD-(L)1 therapy, could not tolerate or progressed during/after treatment with platinum-based chemotherapy, and had an ECOG performance status of <=1. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Key secondary endpoints included duration of response (DoR) per RECIST v1.1, progression-free survival (PFS) estimated with Kaplan-Meier analysis, and the safety/tolerability profile evaluated by monitoring adverse events (AEs). Result(s): As of 10 March 2020, 12 pts (median age, 69.5 yr; 92% male) with UC were enrolled; median study follow-up, 8.3 mo. Most pts (n=10, 83%) had 1 prior systemic therapy. Median duration of treatment for both BGB-A333 and tislelizumab was 5.5 mo (range: 1.2, 9.9). Confirmed ORR was 42% (95% CI: 15.2, 72.3); 3 pts had complete responses, 2 had partial responses, 4 had stable disease (SD; 2 had SD >6 mo), 2 had progressive disease, and 1 was not evaluable (due to missing postbaseline assessment). Median DoR was not reached; median PFS was 6.1 mo (95% CI: 1.9, not estimable). Across the entire study (n=39), treatment-related AEs (TRAEs) occurred in 19 pts. Of the 24 pts receiving combination treatment, four pts (including one with UC) had grade >=3 TRAEs. One

Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to Fc 3R on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. Methods Patients (aged >=18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab

Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Method(s): 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Result(s):39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune -related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusion(s): Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite s

Background: CS1003 is a novel humanized IgG4 anti-PD-1 monoclonal antibody. In phase 1a dose-escalation, CS1003 showed a well-tolerated safety profile with no dose-limiting toxicity, and a wide therapeutic window at doses up to 10 mg/kg Q3W (maximum administrated dose, MAD) in patients (pts) with solid tumors. Two fixed-dose regimens were explored in the phase Ib portion of this ongoing clinical trial in pts with selected solid tumors. Method(s): Pts were enrolled in cohort A (200 mg Q3W) or cohort B (400 mg Q6W) to receive CS1003 intravenously. Safety, preliminary tumor activity (overall response per RECIST v1.1 by investigators) and PK were assessed. Result(s): As of 21 Mar 2020, 29 and 30 pts were enrolled in cohorts A and B, with a median treatment duration of 15.0 (range: 3.0-50.4) and 14.4 (range: 4.7-27.7) weeks, respectively. Following the first dose, the mean Cmax value of CS1003 in cohort B was around doubling of that in cohort A (112 vs 44 mug/ml) but lower than that (189 mug/ml) at the MAD, demonstrating sufficient safety margin. The mean Ctrough value of cohorts A and B were 9.2 and 18.8 mug/ml, respectively, expecting a complete PD-1 receptor occupancy throughout the dosing intervals with both regimens. The steady-state PK data of cohort B will be updated. In cohorts A and B, 97% (28/29) and 93% (28/30) pts had treatment-emergent adverse events; 41% (12/29) and 47% (14/30) pts had all-grade treatment-related adverse events (TRAEs), respectively. The TRAE profiles were comparable in both cohorts overall with two Grade (G) >= 3 events (G3 dermatitis and G4 Type 1 diabetes mellitus in cohort B), and the rest were G1/2. Among the 29 efficacy-evaluable pts in cohort A, there were 3 complete response (2 confirmed), 3 partial response (PR, 2 confirmed) and 5 stable disease (SD). Among the 27 efficacy-evaluable pts in cohort B, there were 4 PR (1 confirmed) and 13 SD. Conclusion(s): The preliminary safety and efficacy profiles of CS1003 at 200 mg Q3W and 400 m

Background: Chemotherapy-induced nausea and vomiting (CINV) is the most common non-haematological toxicity of chemotherapy. Method(s): A systematic review and meta-analysis comparing short course (1-2 days) with long course (3+ days) dexamethasone in preventing CINV was performed in accordance with the PRISMA statement. Result(s): 1535 articles were screened to identify the 11 studies included in the review. Nine studies of 1892 patients were included in meta-analysis. There was no significant difference in complete response of nausea and vomiting between a short or long course of dexamethasone (RR 0.98, 95 % CI 0.89-1.07, p = 0.58). There was a lower risk of adverse events with a short course of dexamethasone (RR 0.80, 95 % CI 0.64-0.99, p = 0.04). Conclusion(s): There was no significant difference between a short or long course of dexamethasone in preventing nausea or vomiting, but a short course was associated with fewer adverse effects. PROSPERO protocol: CRD42019133785Copyright © 2020 Elsevier B.V.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.Copyright © 2019 American Association for Cancer Research.

Background: Sitravatinib is an investigational, orally bioavailable, receptor tyrosinekinase inhibitor with immune modulatory and potential antitumor activity. Tislelizumab is an investigational, humanized IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death receptor-1 (PD-1). We assessed the safety and antitumor activity of sitravatinib plus tislelizumab in patients with advanced solid tumors. Method(s): This is an open-label, multicenter, non-randomized, phase Ib study (NCT03666143). This cohort evaluated anti-PD-(L)1 antibody-naive patients with recurrent, platinum-resistant, epithelial ovarian cancer who were treated with 120 mg of sitravatinib once daily in combination with 200 mg tislelizumab every 3 weeks until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination. The primary objective was to assess the safety and tolerability of this combination therapy. Overall response rate, duration of response (DOR), disease control rate, and progression-free survival (PFS) were assessed as secondary endpoints. Result(s): As of 17 July 2019, 20 patients (median age, 66.0 years) were enrolled; median number of prior regimens was 5 (range, 2-12). All 20 patients received study drugs and were included in the safety analysis. Common (frequency >=10%) grade>=3 treatmentemergent adverse events (TEAEs) assessed as related to sitravatinib by investigators were hypertension (25%) and fatigue (10%). Six patients had AEs that led to sitravatinib discontinuation. The common (frequency >=10%) grade>=3 TEAE assessed as related to tislelizumab by investigators was increased transaminases (10%). Three patients had AEs that led to tislelizumab discontinuation. Of 17 efficacy-evaluable patients, 4 achieved confirmed partial response, 11 had stable disease, and 2 had progressive disease per RECIST version 1.1. Median PFS was 18.0 weeks; median DOR was not reached (NR) (both ranges, 12.29 weeks-NR). Conclusio

Background: Programmed cell death protein-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Although both pathways have overlapping elements, each has a distinct mechanism of action. Nonclinical studies have demonstrated that potential synergistic antitumor effects can result from blocking both PD-1 and PD-L1. BGB-A333 is an investigational humanized IgG1 monoclonal antibody against PD-L1 that has antitumor activity in xenograft models. Tislelizumab, a clinical-stage anti-PD-1 antibody engineered to minimize binding to FcgammaR on macrophages in order to abrogate antibody-dependent phagocytosis, has demonstrated clinical activity in patients with advanced solid tumors. Here we report preliminary results from the phase 1 component of an open-label phase 1/2 study (NCT03379259) of BGB-A333 alone and in combination with tislelizumab in patients with advanced solid tumors. Method(s): Phase 1 of this study consisted of two parts. In Part A, patients received single-agent BGB-A333 IV Q3W at increasing doses; in Part B patients received BGB-A333 1350 mg IV Q3W + tislelizumab 200 mg IV Q3W. Eligible patients had unresectable advanced or metastatic cancer and an ECOG performance status of <=1. Safety/tolerability profile (primary endpoint) was examined by monitoring adverse events (AEs); secondary endpoints included antitumor activity, assessed by RECIST v1.1, and the pharmacokinetic (PK) parameters of each antibody. Result(s): As of Oct 30, 2019, 15 patients were enrolled in Part A (450 mg, n=3; 900 mg, n=3; 1350 mg, n=6; 1800 mg, n=3) and 12 in Part B. Across both parts, patients were female (n=17/29; 63%); squamous cell carcinoma of either skin or head and neck (n=5) and ovarian cancer (n=4) were the most common tumor types. Thirteen patients (48%) had >=2 lines of prior systemic therapy. The most common treatment-related AEs (TRAEs) were fatigue (N=5; Part A, n=3; Part B, n=2) and nausea (N=4; n

Importance: Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. Objective(s): To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. Design, Setting, and Participant(s): The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. Intervention(s): Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. Main Outcomes and Measures: The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. Result(s): Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to =23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were repor

PURPOSE: Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF- or K-RAS/N-RAS-mutated solid tumors. METHODS: During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS: The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF-mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF-mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS-mutated endometrial cancer and K-RAS codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS-mutated colorectal cancer (n = 20). CONCLUSION: Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS-mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alon