Surveillance evaluations in patients with stage I, II, III, or resectable IV melanoma who were treated with curative intent: A systematic review.

PURPOSE: Appropriate surveillance of patients with melanoma treated with curative intent is vital to improve patient outcomes. A systematic review was conducted to capture locoregional recurrence and metastatic disease, and to evaluate the effectiveness of various surveillance strategies. METHODS: MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews, and National Cancer Institute Clinical Trials Database were searched. Randomized controlled trials (RCTs) and comparative studies reporting at least one patient-related outcome were included. Exclusion criteria included: published in non-English or recruited >20 % or an uncertain percentage of non-target patients without conducting a subgroup analysis for the target patients. This review was registered at PROSPERO (CRD42021246482). RESULTS: Among 17,978 publications from the literature search, one RCT and five non-randomized comparative studies were included and comprised 4016 patients. The aggregate evidence certainty was low for the RCT and very low for the comparative studies, as assessed by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. For patients with stage IA-IIC melanoma, a reduced follow-up schedule with clinical follow-up strategies alone may be safe and cost-effective. For stage IIC-IIIC patients, at least two serial PET/CT or whole-body CT and brain MRI imaging within a median follow-up of 31.2 months may detect 50 % of recurrences that lead to additional management, such as surgery. PET/CT may have a higher positive predictive value and lower false positive rate compared with CT alone in detecting recurrence in stage I-III patients. CONCLUSION: Surveillance protocols should be based on individual risk of recurrence and established best practices when formulating follow-up strategies, as suggested by the studies reviewed. Future high-quality studies are needed to clarify the frequency of imaging follow-up strategies, especially in patients with high-risk stage II melanoma.

Multisystem Immune-Related Adverse Events from Dual-Agent Immunotherapy Use.

BACKGROUND: little is known about the incidence and characteristics of multisystem immune-related adverse events (irAEs) associated with dual-agent ipilimumab and nivolumab use. METHODS: A retrospective cohort review was completed that included cancer patients seen at the Juravinski Cancer Centre who received at least one dose of ipilimumab and nivolumab from 2018 to 2022. Patient characteristics, cancer types, and irAEs were recorded. Multivariate logistic and cox regressions were completed, comparing those who developed multisystem irAEs, single irAE, and no irAE. RESULTS: A total of 123 patients were included in this study. Out of 123 patients, 72 (59%) had melanoma, 50/123 (41%) had renal cell carcinoma (RCC), and 1/123 (1%) had breast cancer. Multisystem irAEs were seen in 40% of the overall cohort. The most common irAE type was dermatitis (22%), followed by colitis (19%) and hepatitis (17%). CONCLUSIONS: Our study demonstrated that multisystem irAEs are prevalent amongst patients receiving ipilimumab and nivolumab. It is important for both physician education and the counseling and consent of patients to monitor the potential for multiple irAEs.

Pembrolizumab-induced immune-related sclerosing cholangitis.

Immunotherapy is increasingly used to treat various types of cancer; however, it can often result in immune-related adverse events (irAEs). Immune-related sclerosing cholangitis (irSC) is a rare type of hepatic irAE that has been described only in a few cases, and much remains unknown about its optimal treatment. In this report, we describe the case of a man in his 70s who was diagnosed with metastatic melanoma and treated with pembrolizumab. He experienced multiple irAEs, including irSC, which did not respond to initial prednisone treatment (2 mg/kg daily dosing). However, subsequent treatment with ursodeoxycholic acid (UDCA) resulted in complete resolution of symptoms and normalisation of laboratory and radiographic abnormalities related to irSC. Our case suggests that steroids, which are traditionally used to treat irAEs, may be ineffective for irSC and that UDCA may be a better alternative. Clinicians should be aware of this rare irAE.

Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review.

Immune-related adverse events (irAEs) are toxicities resulting from use of immune checkpoint inhibitors (ICIs). These side effects persist in some patients despite withholding therapy and using immunosuppressive and immune-modulating agents. Little is known about chronic irAEs and they are felt to be rare. We performed a systematic review to characterize non-endocrine chronic irAEs reported in the literature and describe their management. Ovid MEDLINE and Embase databases were searched for reports of adult patients with solid cancers treated with ICIs who experienced chronic (>12 weeks) non-endocrine irAEs. Patient, treatment and toxicity data were collected. Of 6843 articles identified, 229 studies including 323 patients met our inclusion criteria. The median age was 65 (IQR 56-72) and 58% were male. Most patients (75%) had metastatic disease and the primary cancer site was melanoma in 43% and non-small cell lung cancer in 31% of patients. The most common ICIs delivered were pembrolizumab (24%) and nivolumab (37%). The chronic irAEs experienced were rheumatological in 20% of patients, followed by neurological in 19%, gastrointestinal in 16% and dermatological in 14%. The irAE persisted for a median (range) of 180 (84-2370) days and 30% of patients had ongoing symptoms or treatment. More than half (52%) of patients had chronic irAEs that persisted for >6 months. The ICI was permanently discontinued in 60% of patients and 76% required oral and/or intravenous steroids. This is the first systematic review to assess and report on moderate/severe chronic non-endocrine irAEs after treatment with ICI in the literature. These toxicities persisted for months-years and the majority required discontinuation of therapy and initiation of immunosuppression. Further research is needed to better understand chronic irAEs, which hold potential substantial clinical significance considering the expanded use of ICIs and their integration into the (neo)adjuvant settings.

Immune-Checkpoint Induced Skin Toxicity Masked as Squamous Cell Carcinoma: Case Report on Mimickers of Dermatological Toxicity with PD-1 Inhibition.

BACKGROUND: Immune checkpoint inhibitors (ICI) are increasingly the mainstay of oncology treatment. Immune-related adverse events (irAEs) from ICI therapy differ from cytotoxic adverse events. Cutaneous irAEs are one of the most common irAEs and require careful attention to optimize the quality of life for oncology patients. PATIENT AND METHODS: These are two cases of patients with advanced solid-tumour malignancies treated with PD-1 inhibitor therapy. RESULTS: Both patients developed multiple pruritic hyperkeratotic lesions, which were initially diagnosed as squamous cell carcinoma from skin biopsies. The presentation as squamous cell carcinoma was atypical and, upon further pathology review, the lesions were more in keeping with a lichenoid immune reaction stemming from the immune checkpoint blockade. With the use of oral or topical steroids and immunomodulators, the lesions resolved. CONCLUSIONS: These cases emphasize that patients on PD-1 inhibitor therapy who develop lesions resembling squamous cell carcinoma on initial pathology may require an additional pathology review to assess for immune-mediated reactions, allowing appropriate immunosuppressive therapy to be initiated.

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma.

Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. Conclusions: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation.

OBJECTIVES: Parts 4 and 5 of the phase 1/2 KEYNOTE-022 study investigated the maximum tolerated dose (MTD), safety, and efficacy of pembrolizumab plus trametinib in solid tumours and BRAF wild-type melanoma. PATIENTS AND METHODS: Patients received intermittent or concurrent dosing of pembrolizumab plus trametinib. Concurrent dosing was 2 or 4 weeks of trametinib run-in followed by concurrent pembrolizumab every 3 weeks (Q3W) plus trametinib once daily (QD). Intermittent dosing was 2 weeks of trametinib run-in followed by pembrolizumab plus intermittent trametinib (1 week off/2 weeks on). A 3 + 3 dose escalation was used, followed by dose confirmation. RESULTS: Forty-two patients were enrolled. No dose-limiting toxicities (DLTs) occurred at initial dose levels (DL). At subsequent DLs, 10 of 38 evaluable patients had DLTs. For concurrent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg QD, with a 2-week trametinib 1.5 mg QD run-in (concurrent DL2a); in concurrent DL2a group, five (31%) patients had grade 3/4 treatment-related adverse events (TRAEs); the objective response rate (ORR) was 0%. ORR was 40% in concurrent DL1 and 0% in concurrent DL2b. For intermittent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 2 mg QD with a 2-week trametinib 2 mg QD run-in (intermittent DL2); in the intermittent DL2 group, seven (47%) patients had grade 3/4 TRAEs; ORR was 27%. ORR in intermittent DL1 was 33%. CONCLUSIONS: MTDs for concurrent and intermittent dosing of pembrolizumab with trametinib were identified. The combination had limited antitumour activity, numerically higher ORR with intermittent versus concurrent dosing, and manageable safety. CLINICALTRIALS. GOV IDENTIFIER: NCT02130466.

Systemic adjuvant therapy for adult patients at high risk for recurrent melanoma: A systematic review.

Cutaneous melanoma is typically treated with wide local excision and, when appropriate, a sentinel node biopsy. Many patients are cured with this approach but for patients who have cancers with high risk features there is a significant risk of local and distant relapse and death. Interferon-based adjuvant therapy was recommended in the past but had modest results with significant toxicity. Recently, new therapies (immune checkpoint inhibitors and targeted therapies) have been found to be effective in the treatment of patients with metastatic melanoma and many of these therapies have been evaluated and found to be effective in the adjuvant treatment of high risk patients with melanoma. This systematic review of adjuvant therapies for cutaneous and mucosal melanoma was conducted for Ontario Health (Cancer Care Ontario) as the basis of a clinical practice guideline to address the question of whether patients with completely resected melanoma should be considered for adjuvant systemic therapy and which adjuvant therapy should be used.

Is Access to Care Associated With Stage at Presentation and Survival for Melanoma Patients?

BACKGROUND: Melanoma incidence increases with socioeconomic status but the effect of rurality and access to primary care or dermatology on patient outcomes is unclear. OBJECTIVES: The objectives of this study were to determine whether access to care, rurality, or socioeconomic status are associated with melanoma stage at presentation and prognosis. METHODS: Linked administrative databases from Ontario, Canada, were retrospectively analyzed to identify a population-based cohort of patients diagnosed with melanoma between 2004 and 2012. Rurality was assessed using the rural index of Ontario (RIO) score, and the number of visits to dermatology and primary care was used to evaluate access to care. RESULTS: We identified 18 776 melanoma patients, of whom 9591 had completed pathological staging. Patients with higher RIO scores, living further from a cancer center or in a rural community, were less likely to see a dermatologist in the year prior to diagnosis (P < .001 for all). Patients seen by a dermatologist within 365 days prior to diagnosis were less likely to present with stage III or IV disease (odds ratio 0.63, P < .001) and had improved overall survival (hazard ratio [HR] for death 0.77, P < .001). There was a nonlinear association between number of family physician visits and melanoma prognosis, with patients who had 3 to 5 visits per year having the best overall survival (HR 0.88, P = .003). CONCLUSION: Our findings strengthen the known association between access to dermatology and melanoma outcomes by linking individual patients' prediagnosis access to care to pathological stage at diagnosis and overall survival.

Cobimetinib- and vemurafenib-induced granulomatous dermatitis and erythema induratum: A case report.

Metastatic melanoma is an aggressive malignancy. Survival can be increased with the combination of BRAF and MEK inhibition. BRAF inhibitor-induced cutaneous toxicities can be attenuated with MEK inhibition. Here, we describe the first reported case of a patient with metastatic melanoma who developed granulomatous dermatitis and erythema induratum when treated with combination BRAF (vemurafenib) and MEK inhibitor (cobimetinib) therapy and discuss the clinical features and management of dermatologic side-effects secondary to BRAF +/- MEK inhibition.

Update on Immunotherapeutics in the Management of Metastatic Melanoma

Today, a number of treatment options are now available for metastatic melanoma. Within the last decade, the development of novel immunotherapies for cancer has significantly altered the course of the disease in patients with melanoma. With more patients receiving these potentially life-saving treatments, not only have we learned more about the interplay between the immune system and melanoma, but more importantly, which treatment options are most appropriate given the clinical picture.

A phase II study of cediranib, an oral VEGF inhibitor, in previously untreated patients with metastatic or recurrent malignant melanoma.

PURPOSE: A two stage multi-institution Phase II study was undertaken by the Princess Margaret Hospital Consortium to evaluate the efficacy and toxicity of oral cediranib, an inhibitor of vascular endothelial growth factor receptors 1 and 2, in patients with previously untreated advanced malignant melanoma. PATIENTS AND METHODS: Between May 2006 and April 2008, 24 patients (median age 65 years) with advanced malignant melanoma were treated with oral cediranib. Cediranib was given on a continuous, oral once daily schedule of 45 mg, on a 28 day cycle. RESULTS: Of the 17 patients evaluable for response, there was stable disease in 8 patients, and progressive disease in 9 patients, with no objective responses seen. Only 2 patients had stable disease >/= 6 months, thus the study was terminated at the end of stage 1 accrual. The overall median survival was 9.9 months, and the median time to progression was 3.5 months. The most frequent non-hematologic adverse events were hypertension (78%), fatigue (69%), diarrhea (69%) and anorexia and nausea (each 57%). CONCLUSIONS: Although 2 patients had stable disease at 6 months, the short median time to progression and lack of any objective responses indicate that single agent cediranib at this dose and schedule is not sufficiently active to warrant study continuation.

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041).

BACKGROUND: There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity. METHODS: Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2. RESULTS: Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment. CONCLUSIONS: The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.

A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or gastro esophageal junction (GEJ) adenocarcinoma: a trial of the PMH phase II consortium.

PURPOSE: The Src family of kinases may play a role in the development and progression of gastric cancer. We evaluated the activity and safety of saracatinib an oral, anilinoquinazolone, non-receptor tyrosine kinase inhibitor targeting Src kinases, in patients with metastatic or locally advanced gastric carcinoma. METHODS: Eligible patients who had received ≤1 prior line of chemotherapy for metastatic disease received saracatinib 175 mg/day of a 28 day cycle until progression. The primary endpoint was the objective response and/or prolonged stable disease rate (pSD ≥ 16 weeks). RESULTS: Ten patients with gastric carcinoma and 11 with adenocarcinoma of the gastroesophageal junction received a median of 2 cycles (range 1-10 cycles) of treatment per patient. 17 patients were evaluable for response. No objective response was seen. One patient experienced prolonged Stable disease (pSD). Three patients had SD and 13 progressive disease. Median overall survival was 7.8 months (95% CI, 3.9-12.2 months) and median time to progression was 1.8 months (95% CI: 1.5-1.9 months). Grade 3 events possibly related to saracatinib included: fatigue (2 patients), hypoxia (2) anemia (3) and lymphopenia (2). CONCLUSION: Saracatinib has insufficient activity as a single agent in patients with advanced gastric adenocarcinoma to warrant further investigation. Further development in gastric cancer would require rational drug combinations or identification of a tumor phenotype sensitive to Src inhibition.

A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium.

BACKGROUND: Sorafenib is an oral multikinase inhibitor that blocks cell proliferation via the ERK pathway and angiogenesis via the VEGF pathway. This phase II trial was conducted to determine the efficacy and tolerability of sorafenib for the treatment of patients with metastatic urothelial cancer (UC) who had not had prior chemotherapy for advanced disease. PATIENTS AND METHODS: Seventeen chemo-naïve UC patients with adequate performance status and organ function were treated with sorafenib 400 mg twice daily on a continuous basis until progression or unacceptable toxicity. The primary endpoint was objective tumor response rate as measured by RECIST criteria. Secondary endpoints included rate of prolonged stable disease (>3 months), time to progression, median and 1 yr survival and safety and tolerability. RESULTS: There were no objective responses. Only one patient had stable disease by RECIST criteria and remained on treatment more than 3 months. Three patients had stable disease by RECIST criteria but were on treatment less than 3 months due to progressive disease (PD) or adverse events (AE). Eight patients had PD by RECIST criteria as their best overall response. Two patients had symptomatic PD prior to cycle 2 evaluation, and three patients were inevaluable (1 death, 1 AE, 1 withdrew consent).The time to progression was 1.9 months (range 0.7-8.7 months) and median survival was 5.9 months. The most common grade 3+ toxicities were abdominal pain, back pain, hand-foot reaction and bladder infection. CONCLUSIONS: Sorafenib does not show sufficient activity as a single agent in first-line metastatic urothelial cancer to warrant further investigation.

Baseline radiological staging in primary breast cancer: impact of educational interventions on adherence to published guidelines.

RATIONALE: The purpose of baseline radiological staging in newly diagnosed breast cancer patients is to rule out overt metastatic disease. We have previously compared the use of radiological staging at our institution with the recommendations of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI). Our results demonstrated that between January 2000 to December 2002, a high proportion of our cohort (n = 135) of patients underwent unnecessary investigations. OBJECTIVES: To implement and assess an educational intervention to encourage staging guideline utilization in a cohort of early breast cancer patients. METHODS: In January 2003, multidisciplinary educational rounds were held, highlighting the CCOPGI guidelines, and reporting results of the audit of staging investigations. The staging guidelines were then included in the Clinical Practice Guidelines of the Breast Disease Site Group, Toronto-Sunnybrook Regional Cancer Centre. A retrospective chart review was completed that assessed staging investigations from a random sample of a similar group of patients (n = 134) from January 2003 to April 2005, to explore the effects of these educational interventions on clinical practice. RESULTS: For patients with Stage I breast cancer, there was a significant decrease (P < 0.004) in each type of investigation: a twofold decrease in chest X-rays; 2.5-fold decrease bone scans and fourfold decrease in the number of abdominal ultrasounds. For patients in Stage II, there was no significant change in the proportion of patients undergoing radiological investigations. There was a non-significant trend towards appropriately receiving all three investigations for patients with Stage III disease. CONCLUSIONS: Our results demonstrate that prior to the educational intervention, many patients with early breast cancer were undergoing inappropriate radiological staging. Since 2003 however, for Stage I patients there has been a significant improvement in adherence with the guidelines. We hypothesize that our educational intervention had a positive impact on improving the utilization of baseline radiological staging in patients with primary breast cancer.