[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Immune-related adverse events secondary to immunotherapy in oncology: A guide for general practice.

BACKGROUND: Immunotherapy has reshaped the prognoses for many cancers and is increasingly used in both metastatic and adjuvant settings. There is a high prevalence of immunotherapy side effects, or immune-related adverse events (irAEs), which can affect any organ. Some irAEs can cause permanent or prolonged morbidity and, in rare cases, may be fatal. irAEs can present with mild, non-specific symptoms, resulting in delays to identification and management. OBJECTIVE: We aim to provide a general overview of immunotherapy and irAEs, highlighting common clinical scenarios and general principles of management. DISCUSSION: Cancer immunotherapy toxicity is an important clinical problem that is increasingly relevant to general practice, where patients with adverse events may first present. Early diagnosis and timely intervention are important in limiting the severity and morbidity of these toxicities. The management of irAEs should follow treatment guidelines, in consultation with patients' treating oncology teams.

A Phase 1/2 study of the PD-L1 inhibitor, BGB-A333, alone and in combination with the PD-1 inhibitor, tislelizumab, in patients with advanced solid tumours.

BACKGROUND: Many patients do not respond or eventually relapse on treatment with programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors due to secondary or acquired resistance; therefore, there is a need to investigate novel PD-1/PD-L1 inhibitors. METHODS: This open-label, non-randomised study investigated the safety and anti-tumour activity of BGB-A333, a PD-L1 inhibitor, alone and in combination with tislelizumab in patients with advanced solid tumours with progression during/after standard therapy. The primary objectives were to determine the recommended Phase 2 dose (RP2D), safety and tolerability for BGB-A333 alone and in combination with tislelizumab (Phase 1a/1b) and to determine the overall response rate (ORR) with BGB-A333 plus tislelizumab (Phase 2). RESULTS: Overall, 39 patients across Phase 1a (N = 15), 1b (N = 12) and 2 (N = 12) were enroled. In Phase 1a, an RP2D of 1350 mg was determined. In Phase 1a and 1b/2, serious treatment-emergent adverse events (TEAEs) were reported in five and eight patients, respectively. Two patients experienced TEAEs that led to death. In Phase 2, the ORR was 41.7% (n = 5/12; 95% confidence interval: 15.17%, 72.33%). CONCLUSIONS: TEAEs reported with BGB-A333 were consistent with other PD-L1 inhibitors. Encouraging preliminary anti-tumour activity was observed with BGB-A333 in combination with tislelizumab. CLINICAL TRIAL REGISTRATION: NCT03379259.

SAFFRON-103: a phase 1b study of the safety and efficacy of sitravatinib combined with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer.

BACKGROUND: Some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the outcomes. This open-label, multicenter, phase 1b trial investigated the combination of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, plus anti-PD-1 antibody tislelizumab. METHODS: Patients with locally advanced/metastatic NSCLC were enrolled (Cohorts A, B, F, H, and I; N=22-24 per cohort). Cohorts A and F included patients previously treated with systemic therapy, with anti-PD-(L)1-resistant/refractory non-squamous (cohort A) or squamous (cohort F) disease. Cohort B included patients previously treated with systemic therapy, with anti-PD-(L)1-naïve non-squamous disease. Cohorts H and I included patients without prior systemic therapy for metastatic disease, no prior anti-PD-(L)1/immunotherapy, with PD-L1-positive non-squamous (cohort H) or squamous (cohort I) histology. Patients received sitravatinib 120 mg orally one time per day plus tislelizumab 200 mg intravenously every 3 weeks, until study withdrawal, disease progression, unacceptable toxicity, or death. The primary endpoint was safety/tolerability among all treated patients (N=122). Secondary endpoints included investigator-assessed tumor responses and progression-free survival (PFS). RESULTS: Median follow-up was 10.9 months (range: 0.4-30.6). Treatment-related adverse events (TRAEs) occurred in 98.4% of the patients, with ≥Grade 3 TRAEs in 51.6%. TRAEs led to discontinuation of either drug in 23.0% of the patients. Overall response rate was 8.7% (n/N: 2/23; 95% CI: 1.1% to 28.0%), 18.2% (4/22; 95% CI: 5.2% to 40.3%), 23.8% (5/21; 95% CI: 8.2% to 47.2%), 57.1% (12/21; 95% CI: 34.0% to 78.2%), and 30.4% (7/23; 95% CI: 13.2% to 52.9%) in cohorts A, F, B, H, and I, respectively. Median duration of response was not reached in cohort A and ranged from 6.9 to 17.9 months across other cohorts. Disease control was achieved in 78.3-90.9% of the patients. Median PFS ranged from 4.2 (cohort A) to 11.1 months (cohort H). CONCLUSIONS: In patients with locally advanced/metastatic NSCLC, sitravatinib plus tislelizumab was tolerable for most patients, with no new safety signals and overall safety profiles consistent with known profiles of these agents. Objective responses were observed in all cohorts, including in patients naïve to systemic and anti-PD-(L)1 treatments, or with anti-PD-(L)1 resistant/refractory disease. Results support further investigation in selected NSCLC populations. TRIAL REGISTRATION NUMBER: NCT03666143.

A capability framework to inform the fundamental requirements for clinical trial unit development, growth and long term success in outer metropolitan and rural areas.

Background: Participation in clinical trials is linked to improved patient outcomes. Despite this, most trial participants either reside in, or are treated in metropolitan areas. TrialHub developed hub-and-spoke models to support and grow clinical trial units in outer metropolitan and regional/rural centres in order to boost clinical trial engagement and reduce demands of trial participation on patients from outer metropolitan and regional/rural areas. The aim of this project was to establish a capability framework for clinical trial unit growth and development. Methods: An integrative methods study design was used to inform the co-design and development of the capability framework based on data collected in Victoria during 2020-21. This included reviews of the literature and of existing local resources, infrastructure, and staffing; as well as education, mentoring and support, and a needs assessment through multidisciplinary working groups. Results: We developed a capability framework based on the level of support required for outer metropolitan and regional/rural centres with diverse existing capabilities across Victoria. The framework applies a maturity model to assess resources, processes and practices which impact the capacity and capability of centres to conduct trials safely and sustainably. Each level of the model uses a consistent set of factors to describe the core elements required for safe clinical trial delivery. This benchmarking allows targeted investment to ensure safe and high-quality delivery of trials at newly establishing trial units. Conclusion: The capability framework developed by TrialHub provides a basis for staged, planned and successful trial unit development and trial implementation. Further validation of the framework is required.

A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors.

BACKGROUND: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability. RESULTS: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup. CONCLUSIONS: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily. GOV ID: NCT03507543.

The role of surveillance imaging for resected high-risk melanoma.

BACKGROUND: Recommendations for surveillance imaging for resected melanoma vary considerably. This study examined the utility of imaging in patients with a high-risk primary melanoma undergoing a protocolized imaging schedule. METHODS: This retrospective study involved data collection regarding imaging, recurrence, and outcome characteristics for patients referred to the Victorian Melanoma Service from January 2016-April 2020 and managed for resected stage IIC or III melanoma. Patients with a T4b tumor who did not undergo a sentinel lymph node biopsy were included (T4bNX). Recurrences were "clinically detected" if they were primarily detected by patient symptoms or physical examination, or 'imaging-detected' if the patient was asymptomatic. Cox regression models including time-varying co-variates were used to assess the impact of imaging-detected versus clinically-detected recurrence on overall survival. RESULTS: Over a median follow-up time of 2.7 years, 199 patients underwent surveillance imaging (T4bNX:22, IIC:33, IIIA:22, IIIB:60, IIIC:61, IIID:1), and 44% (n = 88) experienced disease recurrence. Imaging detected over half (53%) of all recurrences. In adjusted analyses, mortality risk was reduced after an imaging-detected compared to clinically-detected recurrence at any given time from the start of surveillance (hazard ratio 0.25, 95% confidence interval 0.10-0.66, p = .005). CONCLUSION: Our study indicates that routine imaging in the early follow-up period of resected T4bNX, stage IIC and III melanoma plays an important role in the detection of asymptomatic recurrences. Imaging-detected recurrence may be associated with a survival benefit and studies with more prolonged follow-up are required to confirm these findings.

Immune checkpoint inhibitors and the risk of major atherosclerotic cardiovascular events in patients with high-risk or advanced melanoma: a retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with immune-mediated adverse effects, potentially involving any organ. ICI has also been associated with an increased risk of cardiovascular disease in cancer populations. OBJECTIVE: To characterize the incidence and risk of major atherosclerotic cardiovascular events associated with ICI use in a high-risk and advanced melanoma population. METHODS: We conducted a retrospective cohort study of patients with high-risk or advanced melanoma (AJCC stage II, III or IV) presenting to an academic tertiary hospital between 2015-2020. The main outcome was major atherosclerotic cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, acute limb ischemia and coronary revascularization. RESULTS: The study cohort consisted of 646 patients, including 289 who had been treated with ICI. The incidence of MACE was higher in the ICI treated group (3.6 vs. 0.9 events per 100-person years). After adjusting for age, sex, smoking history and prior BRAF and/or MEK inhibitor use, ICI treatment was associated with an increased risk of MACE (HRadj 2.8, 95% CI 1.1-6.9, p = 0.03). Elevated risk was especially pronounced in patients with a past history of MACE (HR 14.4, 95% CI 1.9-112.3, p = 0.01). CONCLUSION: Patients with high-risk or advanced melanoma are at an increased risk of atherosclerotic cardiovascular events following ICI treatment, particularly those with a history of cardiovascular disease.

BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extraterminal Domain Proteins, in Patients with Selected Advanced Solid Tumors: Results from a Phase 1/2a Trial.

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75-4.5 mg), B (14 days on, 7 days off; 2.0-3.0 mg), and C (7 days on, 14 days off; 2.0-4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1-4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.

Cardiovascular disease and malignant melanoma.

In the last decade, systemic therapies such as immune checkpoint inhibitors and BRAF-MEK inhibitors have improved the prognosis of high-risk and advanced melanoma. With improved survival, melanoma survivorship is increasingly important, particularly in patients who have a good prognosis or are diagnosed at a younger age. It is increasingly recognized that cancer and its treatment is associated with increased cardiovascular morbidity and mortality. Indeed, data from observational studies and meta-analyses of randomized controls trials in melanoma show that systemic therapies may be associated with cardiac toxicities, such as myocardial infarction, heart failure, myocarditis and stroke. Our review will discuss cardiovascular disease and risk factors in the context of melanoma and outline the importance of cardiovascular risk modification in this population.

Yield of baseline imaging for distant metastases in high-risk primary melanoma.

BACKGROUND: The yield of baseline imaging in patients presenting with higher risk primary tumours, at least American Joint Committee on Cancer 8th edition stage IIC or III melanoma, is unclear. METHODS: This retrospective study included patients referred to the Victorian Melanoma Service from January 2017 to April 2020, diagnosed with at least stage IIC or stage III melanoma. Patients with a T4b tumour and no sentinel lymph node biopsy were included as 'T4bNX'. RESULTS: One hundred and sixty-four patients (median age 65 years) with baseline imaging (T4bNX: 19, IIC: 30, IIIA: 21, IIIB: 43, IIIC: 50, IIID: 1) were included. The majority were male (73%), and those with T4bNX melanoma tended to be older (median age 79 years). Distant metastases were detected in 21% (4/19) of T4bNX, 3% (1/30) of stage IIC, 0% (0/21) of stage IIIA, and 6% (6/94) of stages IIIB-D melanoma patients. All stage III patients with distant metastases had palpable lymphadenopathy a presentation. Two patients had brain metastases, both of whom had T4bNX melanoma and synchronous extra-cranial metastases. CONCLUSIONS: Compared to stage IIC, baseline imaging detects higher rates of extra-cranial distant disease in stages IIIB-D and T4bNX melanoma. Intracranial imaging has greater yield in patients with distant extra-cranial disease.

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours.

BACKGROUND: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER: NCT02361723.

A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and Pembrolizumab Combination Therapy in Patients with Advanced Renal Cell Carcinoma.

BACKGROUND: This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. PATIENTS AND METHODS: This was an open-label, two-part, multicenter study involving treatment-naïve patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. RESULTS: Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. CONCLUSIONS: Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.

Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC.

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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.

Standard-Dose Osimertinib in EGFR-Mutated Non-Small-Cell Lung Adenocarcinoma With Leptomeningeal Disease.

PURPOSE: Leptomeningeal disease (LMD) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma is associated with a poor prognosis and limited treatment options. Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor with confirmed CNS penetration. This study reports on outcomes of patients with EGFR-mutated non-small-cell lung cancer who developed LMD and were subsequently treated with osimertinib. METHODS: We identified patients treated with osimertinib 80 mg PO daily under a compassionate access scheme across nine tertiary Australian institutes between July 2017 and July 2020. Patient demographics, tumor characteristics, and treatment history were collected. Median overall survival, median progression-free survival, disease control rates (DCR), and overall response rates (ORR) were assessed. Kaplan-Meier analysis was performed and descriptive statistics were used. RESULTS: Thirty-nine patients were analyzed of which 74% were female. Exon 19 deletions (49%) and L858R point mutations (41%) were the most common EGFR mutations. Forty-nine percentage of patients were Eastern Cooperative Oncology Group 1. The median duration of osimertinib therapy was 6 months. The extracranial DCR and ORR were 60% and 54%, and the intracranial DCR and ORR were 68% and 53%, respectively. Median overall survival was 10.5 months (95% CI, 8.17 to 15.05 months). CONCLUSION: There are limited treatment options for LMD in EGFR-positive lung cancer, and osimertinib at a dose of 80 mg daily is an active therapeutic option for these patients.

First-in-human phase 1 study of MK-1248, an anti-glucocorticoid-induced tumor necrosis factor receptor agonist monoclonal antibody, as monotherapy or with pembrolizumab in patients with advanced solid tumors.

BACKGROUND: Ligation of glucocorticoid-induced tumor necrosis factor receptor (GITR) decreases regulatory T cell-mediated suppression and enhances T-cell proliferation, effector function, and survival. MK-1248 is a humanized immunoglobulin G4 anti-GITR monoclonal antibody agonist. METHODS: In patients with advanced solid tumors, MK-1248 (starting dose, 0.12 mg) was tested alone and with pembrolizumab (200 mg) according to a 3 + 3 dose escalation design (ClinicalTrials.gov identifier NCT02553499); both treatments were administered intravenously every 3 weeks for ≤4 and ≤35 cycles, respectively. The safety and tolerability, maximum tolerated dose, and pharmacokinetics/pharmacodynamics were explored. RESULTS: Twenty patients received MK-1248 monotherapy; 17 received combination therapy. The most frequent tumor types were colorectal cancer (n = 8), melanoma (n = 6), and renal cell carcinoma (n = 4). MK-1248 was generally well tolerated at the maximum tested doses of 170 (monotherapy) and 60 mg (combination). No dose-limiting toxicities (DLTs) or treatment-related deaths occurred. Adverse events (AEs) occurred in 36 of the 37 patients (97%); the most common were vomiting (n = 13 [35%]), anemia (n = 10 [27%]), and decreased appetite (n = 10 [27%]). Grade 3 to 5 AEs occurred in 19 of the 37 patients (51%). Treatment-related AEs occurred in 18 of the 37 patients (49%): 9 of the 20 patients (45%) on monotherapy and 9 of the 17 patients (53%) on combination therapy. Among the 17 patients receiving combination therapy, 1 achieved a complete response and 2 achieved a partial response, for an objective response rate of 18%; no patients achieved an objective response with monotherapy. The disease control rate (stable disease or better) was 15% with monotherapy and 41% with combination therapy. CONCLUSIONS: MK-1248 was generally well tolerated at doses up to 170 (monotherapy) and 60 mg (combination), with no DLTs or treatment-related deaths. Combination therapy provided limited antitumor responses.

Stereotactic Radiation Therapy Combined With Immunotherapy Against Metastatic Melanoma: Long-Term Results of a Phase 1 Clinical Trial.

PURPOSE: To determine the maximum tolerated dose (MTD) of stereotactic ablative radiation therapy (SABR) in combination with immunotherapy for the treatment of patients with metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy. METHODS: Metastatic melanoma patients with at least 2 metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3 + 3 design, patients were escalated through 3 SABR doses (10 Gy, 15 Gy, and 20 Gy) delivered at 3 different time points (with cycle 1, 2, or 3 of immunotherapy). Dose-limiting toxicities (DLT) were defined as grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or Cox regressions were used to assess the impact of SABR dose and timing on the progression free (PFS) and overall survival (OS) of this cohort. RESULTS: Twenty-four patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs; 1 DLT occurred at a SABR-treated site, and all patients received 15 Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10 Gy. The 2-year PFS was 21.9% (95% CI, 7.1%-41.8%) and 2-year OS was 49.6% (95% CI, 28.7%-67.6%). The median PFS for those receiving 10 Gy was numerically higher than for those receiving 15 Gy, 8.3 months versus 2.1 months (P = .38). The only treatment-related factor associated with both improved PFS (HR 0.08, P < .01) and OS (HR 0.008, P ≤ .01) was receiving SABR with cycle 3. SABR dose (PFS P = .17, OS P = .50) was not significant. CONCLUSIONS: SABR at 10 Gy can be safely combined with immunotherapy. SABR timing appears to influence efficacy more than dose and warrants consideration in research attempting to optimize synergism.

A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia.

PURPOSE: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. METHODS: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. RESULTS: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3-28.9). CONCLUSION: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02492789.