A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in Patients With Advanced Head and Neck Tumors.

PURPOSE: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). METHODS AND MATERIALS: Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). RESULTS: The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. CONCLUSIONS: Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

Survival after introduction of adjuvant treatment in stage III melanoma: a nationwide registry-based study.

BACKGROUND: Adjuvant treatments with PD-1 and BRAF+MEK inhibitors statistically significantly prolong recurrence-free survival in stage III cutaneous melanoma. Yet, the effect on overall survival is still unclear. Based on recurrence-free survival outcomes, these treatments have been approved and widely implemented. The treatments have considerable side effects and costs, and overall survival effect remains a highly anticipated outcome. METHODS: Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage III melanoma between 2016 and 2020. The patients were divided depending on if they were diagnosed before or from July 2018, based on the timepoint when adjuvant treatment was introduced in Sweden. Patients were followed up until the end of 2021. In this cohort study, melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox-regression analyses. RESULTS: There were 1371 patients diagnosed with stage III primary melanoma in Sweden in 2016-2020. The 2-year overall survival rates, comparing the 634 patients in the precohort and the 737 in the postcohort, were 84.3% (95% confidence interval [CI] = 81.4% to 87.3%) and 86.1% (95% CI = 83.4% to 89.0%), respectively, with an adjusted hazard ratio of 0.91 (95% CI = 0.70 to 1.19, P = .51). Further, no statistically significant overall or melanoma-specific survival differences were seen when comparing the precohort and the postcohort in different subgroups for age, sex, or tumor characteristics. CONCLUSIONS: In this nationwide population-based and registry-based study, no survival benefit was detected in patients diagnosed before or after the implementation of adjuvant treatment in stage III melanoma. These findings encourage a careful assessment of the current recommendations on adjuvant treatment.

A biomarker panel predicts recurrence-free survival in ulcerated primary cutaneous melanoma.

BACKGROUND: Ulceration is an independent adverse prognostic factor in cutaneous malignant melanoma (CMM). There is, however, a need for additional prognostic markers to identify patients with ulcerated stage I-II CMM who have a high-risk for recurrence. The aim of this study was to examine the prognostic impact of BRAF mutation, proliferation and presence of tumour infiltrating lymphocytes (TILs) in primary ulcerated CMM. MATERIAL AND METHODS: We have used a consecutive cohort consisting of 71 primary ulcerated CMM (T1b-T4b). BRAF mutation was detected using Cobas test and pyrosequencing. Protein expression of the proliferation marker Ki67 was analysed using immunohistochemistry. Presence of TILs was evaluated in representative hematoxylin-eosin stained formalin-fixed paraffin-embedded tumour sections. RESULTS: Proportion of BRAF mutated alleles, proliferation and presence of TILs all had a statistically significant impact on recurrence free survival in univariate analyses (HR 2.44, 95% CI 1.23-4.84, p = 0.011; HR 2.66, 95% CI 1.32-5.35, p = 0.006 respectively HR 0.48, 95% CI 0.24-0.98, p = 0.045). A trend test found a statistically significant decrease in the proportion of recurrence by including the three favourable factors (BRAF wildtype/low proportion of BRAF mutated alleles, low proliferation and high presence of TILs) (p = 0.0004). When at least two out of three factors were present there was a statistically significant association with longer recurrence free survival in the multivariate analysis (HR 0.30, 95% CI 0.15-0.61, p = 0.001) when adjusted for Breslow thickness, an established independent prognostic marker for CMM. CONCLUSION: Thus, this panel of markers could be an interesting novel concept for predicting the clinical outcome in patients with high-risk stage I-II ulcerated CMM.

[Overview of immune-related side effects from immune checkpoint inhibitors. Part 2: Endocrine, rheumatologic and skin toxicity]. / Immunrelaterade biverkningar i hud, endokrina organ och leder.

In the past decade, immunotherapy with checkpoint inhibitors has revolutionized the field of oncology. Checkpoint inhibitors have been approved for several types of cancer and thousands of patients in Sweden now receive oncological immunotherapy annually. Immune-related side effects are common and can occur in almost any organ. These side effects are different from those that occur with traditional oncological treatments. The side effects are usually mild, but can be serious and even lethal. In a short time, health care providers have had to readjust to be able to handle these side effects. Early and correct diagnosis of immune-related side effects, proper management and a multidisciplinary approach is crucial. Here, we give an overview of the presentation, diagnosis and treatment of immune-related side effects, with emphasis on endocrine, rheumatologic and skin toxicity.

Presence of immune cells, low tumor proliferation and wild type BRAF mutation status is associated with a favourable clinical outcome in stage III cutaneous melanoma.

BACKGROUND: The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma. METHODS: We have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples. RESULTS: Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel. CONCLUSIONS: We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse.

[Register for new drugs in cancer care provides a picture of how the drugs are used in the daily clinical practice]. / Register för nya läkemedel i cancervården ger värdefull hjälp - Visar en bra bild av hur läkemedlen används ­ patienten kan följas i den kliniska vardagen.

Register for new drugs in cancer care provides a picture of how the drugs are used in the daily clinical practice Today, an increasing number of cancer drugs are approved before traditional well-controlled phase 3 studies have been conducted and in many registration studies there is no participation of Swedish departments. This article describes the general experience of a caregiver initiated systematic follow-up of new cancer drugs that shows the possibility of obtaining a picture of the drug's use in routine care. From the register "New Pharmaceuticals in Cancer care", registrations from Stockholm-Gotland region are reported. The structure of the registry can be used with advantage in other therapeutic areas than cancer and can be supplemented with data from national and regional registers as well as quality registers including patient experiences. The knowledge is important to many actors in health care and can contribute to an evidence based, patient-safe and equal healthcare in accordance with current guidelines.

High expression of glycolytic and pigment proteins is associated with worse clinical outcome in stage III melanoma.

There are insufficient numbers of prognostic factors available for prediction of clinical outcome in patients with stage III malignant cutaneous melanoma, even when known adverse pathological risk factors, such as macrometastasis, number of lymph node metastases, and ulceration are taken into consideration. The aim of this study was therefore to identify additional prognostic factors to better predict patients with a high risk of relapse, thus enabling us to better determine the need for adjuvant treatment in stage III disease. An RNA oligonucleotide microarray study was performed on first regional lymph node metastases in 42 patients with stage III melanoma: 23 patients with short-term survival (≤ 13 months) and 19 with long-term survival (≥ 60 months), to identify genes associated with clinical outcome. Candidate genes were validated by real-time PCR and immunohistochemical analysis. Several gene ontology (GO) categories were highly significantly differentially expressed including glycolysis (GO: 0006096; P<0.001) and the pigment biosynthetic process (GO: 0046148; P<0.001), in which overexpression was associated with short-disease-specific survival. Three overexpressed glycolytic genes, GAPDHS, GAPDH, and PKM2, and two pigment-related genes, TYRP1 and OCA2, were selected for validation. A significant difference in GAPDHS protein expression between short- and long-term survivors (P=0.021) and a trend for PKM2 (P=0.093) was observed in univariate analysis. Positive expression of at least two of four proteins (GAPDHS, GAPDH, PKM2, TYRP1) in immunohistochemical analysis was found to be an independent adverse prognostic factor for disease-specific survival (P=0.011). Our results indicate that this prognostic panel in combination with established risk factors may contribute to an improved prediction of patients with a high risk of relapse.

Surgical treatment of skeletal metastases in 31 melanoma patients.

The authors retrospectively studied 31 patients with malignant melanoma who were surgically treated for 34 skeletal metastases between 1987 and 2007. The aim was to evaluate the role of orthopaedic surgery and to identify factors related to survival. The patients were operated on for spinal cord compression (n = 12) and metastatic destruction in a long bone (n = 17), or other locations (n = 5). The median survival after surgery was 1.9 months (range: 0-40). The survival rate was 039 at 3 months, and 0.13 at 1 year. Four of 34 operations led to failure necessitating reoperation. A prolonged delay between diagnosis and surgery, radical excision, a solitary skeletal metastasis, radiotherapy, a perioperative lactate dehydrogenase (LDH) level < or = 8 microkat/L (p = 0.04) and a preoperative haemoglobin level > 11.5 mg/dL (p = 0.003) had a favourable prognostic impact. A vertebral localization was unfavourable. These prognostic factors may help identify which melanoma patients with symptomatic skeletal metastases will benefit from orthopaedic surgery. This study represents the largest reported cohort surgically treated for skeletal metastasis of malignant melanoma at a single institution.