Kalle E. Mattila

Background: Cabozantinib is a treatment for metastatic renal cell carcinoma (mRCC), typically recommended at a 60 mg daily starting dose. However, a lower dose is often used in clinical practice to improve tolerability. Objectives: This study investigates the impact of cabozantinib starting dose on survival and safety in a real-world cohort from Southwest Finland. Design and Methods: This study utilized electronic healthcare data from the Hospital District of Southwest Finland, including adult patients with mRCC initiating cabozantinib monotherapy between March 2018 and December 2021. Patients were stratified by treatment line (first-line [1L] or second/later line [2L+]) and starting dose (40 mg or 60 mg daily). Outcomes assessed were overall survival (OS), time to next treatment (TTNT), and safety (CTCAE v5.0). Results: Of 71 patients, 34 (48%) received cabozantinib as 1L and 37 (52%) as 2L+ treatment. Median OS was 24 months for 1L and 10 months for 2L+, with no significant difference between starting doses. Median follow-up was 16 months (IQR 9.9, 23.4) for 1L and 9 months (IQR 3.6, 16.5) for 2L+. Median treatment duration was 11 months (IQR 4.3, 15.8) for 1L and 6 months (IQR 3.0, 10.0) for 2L+. At 8 months, 86% of 1L and 92% of 2L+ patients did not start the next treatment line. Dose reduction or schedule modification was needed for 79% of patients starting 1L cabozantinib at 60mg daily, compared to 45% at 40mg. Diarrhea and hand-foot syndrome were more common than elevated liver enzymes, with grade 3 adverse events being rare. Conclusion: This study suggests that no statistically significant difference in survival outcomes was observed between patients starting cabozantinib at 40 mg versus 60 mg, while fewer dose modifications and adverse events were observed with the lower starting dose.

Purpose: To compare prostate-specific membrane antigen (PSMA) and fibroblast activation-protein inhibitor (FAPI) targeted PET/CT imaging to assess possible theranostic combination strategies of both tracers in metastatic prostate cancer (mPC). Methods: This prospective study enrolled patients with mPC who underwent long-axial field-of-view whole-body PET/CT with ¹⁸ F-DCFPyL and ¹⁸ F-FAPI-74 within two weeks. Fifteen patients had hormone sensitive (mHSPC) and 24 castration-resistant (mCRPC) disease. Scans were reviewed according to predefined criteria, with up to five metastases per anatomical region evaluated. Lesions were categorized in four groups as skeletal, pelvic nodal, extrapelvic nodal, or visceral. SUVmax and volumetric parameters were measured for each lesion and at the patient level. Results: A total of 1365 lesions were identified in 39 patients. ¹⁸ F-DCFPyL PET/CT detected 1351 lesions (99%). In contrast, ¹⁸ F–FAPI-74 identified only 788 (58%) lesions in the PSMA-guided analysis and 523 (38%) lesions in the independent analysis. Median lesion SUVmax was higher for PSMA (24) than for FAPI (5.4) (p < 0.001). Visceral metastases constituted 3% of lesions with both tracers and tended to be more often FAPI-avid (64%) compared to other lesion groups. Only 14 (1%) of lesions were FAPI-positive and PSMA-negative. In whole-tumor burden analysis, median tracer-positive tumor volume on ¹⁸ F-DCFPyL PET/CT was 85 mL and on ¹⁸ F-FAPI-74 PET/CT only 10 mL (p < 0.001). Conclusion: In mPC, PSMA PET/CT remains the preferred molecular imaging method. Our findings suggest only a limited role of FAPI radioligand therapy. FAPI theranostics should focus on patients with visceral metastases and specific histological subtypes beyond acinar adenocarcinoma. Clinical Trial Registration: EudraCT: 2022–003788-13. Registered 21 September 2023

Background and purpose: Optimal postoperative follow-up for high-risk cutaneous melanomas (CM) is unclear. We aimed to evaluate disease recurrences in patients with stage III CM before modern adjuvant therapies.Patient/material and methods: Three hundred and fifty patients with a median follow-up of 8.9 years at Helsinki University Hospital Comprehensive Cancer Center after complete resection of stage IIIA–D CM between 2008 and 2017 were identified. Information on baseline characteristics, recurrence patterns and survival were collected from electronic medical records.Results: One hundred and ninety patients (54.3%) developed disease recurrence with 258 recurrence events documented. Local recurrence occurred in 14.5, 27.0, 32.3 and 44.4% and distant metastases in 21.7, 40.5, 52.4 and 83.3% of patients with stage IIIA, IIIB, IIID and IIID, respectively. Median recurrence-free survival was not reached and 7.4 years in stage IIIA and IIIB compared to 2.9 and 0.9 years in IIIC and IIID. Routine computed tomography (CT) imaging revealed 51% of all recurrences and 64% of distant meta­stases. 13.2% of distant recurrences involved skin and soft tissues, 31.4 lungs, 34.0 other visceral organs and 21.5% brain. First recurrences occurred mostly during the first 2 years of follow-up (59.5–100% in stage IIIB–D) except for stage IIIA (45.0%). Most of recurrences detected by patients (58.0%), physical exams or ultrasound (76.1%) and routine CT (61.2%) occurred during the first 2 years.Interpretation: High rate of recurrences and distant metastases supports routine physical exams and CT particularly during the first years of postoperative follow-up, especially in stage IIIB–D CM.

Background and purpose: Antibiotic treatment (ABT) has been associated with worse outcomes of cancer immunotherapy. However, this association might be confounded by other poor prognostic factors. We aimed to evaluate the use of ABT and outcomes of immune checkpoint inhibitors (ICI) in metastatic kidney cancer (mRCC).Patient/material and methods: We identified retrospectively 192 patients treated with ICI for mRCC between 2015 and 2021 at three academic hospitals in Finland. Information on patient characteristics, ABT, and immunotherapy was collected from electronic medical records. Cox regression and Kaplan-Meier methods were used for survival analyses. Results: A total of 61 (32%) patients had received early ABT (3 months before and 1 month after the first dose of ICI), of whom 31 (51%) had ABT > 7 days. Patients with early ABT had shorter median overall survival (mOS) than patients without early ABT (20.4 vs 27.9 months, p = 0.046). Patients with ABT > 7 days had shorter mOS than patients with ABT 0–7 days (17.2 vs 27.5 months, p = 0.015). After adjustment for International Metastatic Renal Cell Carcinoma Database Consortium risk groups, histological renal cell carcinoma subtype, baseline levels of C-reactive protein, and tumor burden, the risk of death was higher in patients with ABT > 7 days (hazard ratio 1.83 (95% confidence interval 1.06–3.17). No significant differences in progression-free survival times (PFS) were observed.Interpretation: Early ABT and prolonged ABT duration were associated with shorter OS, but not with PFS, in patients treated with ICI for mRCC. Prolonged ABT indicated poor prognosis regardless of other risk factors.

Objectives: Adjuvant pembrolizumab has improved overall survival after surgery for clear cell renal cell carcinoma (ccRCC) with an intermediate‐high and high risk of recurrence according to the inclusion criteria of Keynote‐564 study, but non‐RCC mortality is common during postoperative follow‐up. We aimed to evaluate the competing risk of death after surgery in patients with ccRCC stratified according to the risk of recurrence with Keynote‐564, Three‐feature and Leibovich models.Material and Methods: A total of 1108 patients with ccRCC operated with curative intent between 2005 and 2021 before the use of adjuvant immunotherapy were identified from two academic centres in Finland and Sweden. Patients with cytoreductive nephrectomy, multiple kidney tumours or non‐ccRCC were excluded. Baseline characteristics and survival outcomes were described, and the Kaplan–Meier method was used to estimate overall survival.Results: During the median postoperative follow‐up of 5.0 years, 134 (12%) patients had died from RCC with a median time to death of 3.7 years (IQR 1.6–6.6) while for 220 (20%) patients the cause of death was other than RCC, most commonly other cancers (n = 59, 5%) and cardiovascular diseases (n = 54, 5%). According to the Keynote‐564 criteria, 34 (3%) patients were classified as having high risk of recurrence, 336 (30%) patients intermediate‐high risk and 738 (67%) patients low risk of recurrence with 41% of RCC deaths observed in this subgroup. Limitations of this study include the lack of information on performance status, comorbidities and systemic treatments for recurrent RCC.Conclusions: In addition to deaths from RCC, deaths from other cancers and cardiovascular diseases were common after surgery for ccRCC. As 41% of RCC deaths were observed among patients currently excluded from adjuvant therapy, more research on patient selection for perioperative immunotherapy is needed as well as interventions improving the treatment of comorbidities and lifestyle after nephrectomy.

Clear cell renal cell carcinoma (ccRCC) is among the most immune-infiltrated cancers, where high inflammation correlates with poor clinical outcomes. While epithelial-to-mesenchymal transition (EMT), immunosuppression, and cancer-associated fibroblasts (CAFs) have been linked with poor prognosis in metastatic ccRCC, their relevance and interplay in localized disease remain uncertain. To address this gap, we performed single-cell spatial profiling of highly inflamed localized tumors to characterize interactions between EMT-associated cancer cells and immune subsets, aiming to identify tumor microenvironment cell subsets and states responsible for the poor prognosis in highly inflamed ccRCC. Multiplexed immunofluorescence imaging with a 33-marker panel was applied to 1,728 tissue cores collected from tumor centers, invasive borders, and adjacent benign tissue from 435 localized ccRCC patients. Independent discovery (n=196) and validation (n=239) cohorts were used to confirm the significance of identified prognostic markers. Hierarchical clustering revealed TME subsets enriched for CD45⁺ immune cells, CD31⁺ endothelial cells, or fibroblasts. High CD45⁺ cell density significantly correlated with poor recurrence-free survival across tumor regions, including tumor center, invasive border, and adjacent benign tissue. Within tumors exhibiting high CD45⁺ infiltration, EMT-associated cancer cells strongly expressed fibroblast activation protein (FAP) at invasive borders, independently predicting worse prognosis and increased risk of liver metastasis. Furthermore, CD45 ^high tumors with elevated FAP expression featured immunosuppressive FAP⁺ CAFs, M2-like macrophages, exhausted T cells, and regulatory T cells. Tumor-cell-specific FAP expression was validated as an independent prognostic biomarker in both early-stage localized ccRCC (pT1-2) and patients subsequently developing metastases who received sunitinib, highlighting its potential for improved patient stratification. Significance: FAP expression identifies an aggressive, immunosuppressive EMT-associated subtype of localized ccRCC, uncovering critical interactions between cancer cells and the TME and revealing novel biological insights and therapeutic vulnerabilities driving early-stage ccRCC progression. Graphical Tumor-cell FAP Expression Defines an Aggressive, Immunosuppressive EMT Subtype in Highly Inflamed Localized ccRCC: Localized ccRCC tumors were stratified by CD45⁺ immune infiltration, revealing that CD45 ^high tumors were associated with significantly poorer recurrence-free survival (5-year RFS rate: 39%). Among these, tumor cell-specific expression of fibroblast activation protein (FAP) identified a particularly aggressive subtype marked by epithelial-to-mesenchymal transition (EMT), reduced endothelial content, and an immunosuppressive tumor microenvironment enriched with M2-like macrophages, regulatory T cells, exhausted T cells, and FAP⁺ cancer-associated fibroblasts (CAFs). FAP⁺ tumors had an even lower 5-year RFS rate of 26%, compared to 50% in FAP⁻ CD45 ^high tumors. Tumor-cell FAP thus provides an additional layer of risk stratification within the CD45 ^high subgroup and reflects a biologically distinct, immune-evasive tumor state. These findings highlight FAP as both a potential therapeutic target and imaging biomarker in localized ccRCC.

Aim: First-line (1L) immunotherapy has yielded superior overall survival (OS) in metastatic melanoma (MM) but some patients are ineligible for immunotherapy or need rapid response with 1L targeted therapy (TT).Materials & methods: Retrospective cohort study of real-world patients treated with 1L immunotherapy (144 BRAF wild type, 85 BRAF-mutated) or 1L TT (143 BRAF-mutated) for MM in Finland during 2014-2021.Results: Baseline brain metastases, liver metastases and elevated LDH were less common, 2-year OS rates were higher (60.3-63.5% vs. 33.8%) and more patients were alive without the next-line treatment (38.0-43.8% vs. 23.3%) in patients with 1L immunotherapy.Conclusion: Real-world patients with 1L immunotherapy for MM had favorable baseline characteristics and better treatment outcomes than observed in patients with 1L TT.

Immune checkpoint inhibitors (ICI) have improved survival in several cancer types. Still, most patients develop disease progression during or after treatment. We evaluated the reasons for treatment discontinuation and their effect on treatment outcomes in adult patients with advanced cancer with ICI in the first or later treatment lines in Southwest Finland between 1 January 2015 and 31 December 2021. Baseline characteristics and treatment outcomes were retrospectively obtained from the electronic medical records. There were 317 patients with 15 different cancer types, most commonly non-small cell lung cancer, melanoma, and kidney cancer, treated with ICI outside clinical trials. During follow-up, 94% of the patients had discontinued treatment. A total of 62% was due to disease progression, 17% due to immune-related adverse events (irAEs), 12% after achieving disease control or radiological response, and 9% due to poor performance status. The median progression-free survival (mPFS) was 5.4 months and the median overall survival (mOS) was 20.3 months in the whole cohort. Longer mPFS and mOS were observed in patients who discontinued ICI due to irAEs (24.3 and 49.2 months) and after disease control (49.7 months and not reached). In total, 46% of the patients who discontinued ICI after irAEs or disease control remained alive and progression-free during follow-up.