Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy.

Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. Methods: Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. Results: Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm. Discussion: These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.

Nivolumab Switch Maintenance Therapy After Tyrosine Kinase Inhibitor Induction in Metastatic Renal Cell Carcinoma: A Randomized Clinical Trial by the Interdisciplinary Working Group on Renal Tumors of the German Cancer Society (NIVOSWITCH; AIO-NZK-0116ass).

BACKGROUND: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined. OBJECTIVE: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. DESIGN, SETTING, AND PARTICIPANTS: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function. INTERVENTION: Intravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis. RESULTS AND LIMITATIONS: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36-4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study. CONCLUSIONS: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC. PATIENT SUMMARY: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.

Couples coping with advanced prostate cancer: An explorative study on treatment decision making, mental deterioration, partnership, and psychological burden.

OBJECTIVES: The aim of this study was to evaluate the role of spouses and the relevance of quality of life (QoL) and life expectancy (LE) in the treatment decision-making process of patients with advanced prostate cancer (CaP). We also addressed the role of possible mental deterioration, partnership quality, QoL, distress, anxiety, and depression in patients and their spouses. METHODS AND MATERIAL: This was a cross-sectional non-interventional explorative study. We administered questionnaires to 96 patients with advanced CaPand their spouses. Both patients and their spouses were asked about the influence of the spouses on treatment decision making, if they prefer quality of life or life expectancy as main goal of treatment and the perceived deterioration of the patients' mental abilities. Additional questionnaires were used to assess medical history, partnership, global quality of life, distress, depression, and anxiety. We performed statistical tests to compare patients with spouses and correlations to detect associations between variables. RESULTS: The spouses (65 ± 9 years) were significantly younger than the patients (69 ± 9 years). Ninety-five percent of the patients and 91% of the spouses reported that the spouses were involved in making treatment decisions. There was a high similarity within couples with regard to their preference for QoL or LE during treatment. Between couples, this preference differed markedly. Emotional control and motivation were the areas most commonly reported to have deteriorated among patients' mental abilities. The quality of the partnership was rated as being higher than average by both partners. Among the spouses, the quality of partnership correlated significantly with the preference for LE with regard to treatment decision making. Patients and spouses reported high psychological burdens in all areas, with higher levels of distress and anxiety in spouses (P< 0.01). Reduced quality of life and greater distress, depression, and anxiety were significantly correlated with the amount of deterioration of the patients' mental abilities. CONCLUSIONS: Spouses of patients with advanced CaP seem to respond to different aspects of the disease by adjusting both their involvement in treatment decision making and their preferred goal of treatment. Due to mental deterioration in the patients and pronounced anxiety in their spouses, we suggest that it is important for the attending physician to provide detailed information and support to both partners. Overall, the high-stress situation seems to affect both partners to similar degrees.

Pasotuxizumab, a BiTE® immune therapy for castration-resistant prostate cancer: Phase I, dose-escalation study findings.

Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 µg/d; cIV: n = 16, 5-80 µg/d). The SC maximum tolerated dose was 172.0 µg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).

Patient expectations are better for immunotherapy than traditional chemotherapy for cancer.

PURPOSE: The main aim of the study was to explore the expectations and knowledge of advanced-stage cancer patients about immunotherapy. METHODS: This mixed methods study included 53 cancer patients on immune checkpoint inhibitors (ICIs), 55 cancer patients undergoing chemotherapy (CT), and 53 non-cancer patients. Participants' expectations about ICIs and CT were compared. Additional qualitative data were derived from semi-structured interviews. RESULTS: Among patients who did not receive ICIs, 63 (58%) had never heard of ICIs and 94 (87%) had large gaps in their knowledge of ICIs. Among ICI patients, 33 (62%) simply described ICIs without errors. ICI perception was positive, regardless of whether respondents received or had heard of ICIs, which became particularly evident when compared to CT. ICIs were rated as more promising, and all adverse effects were expected to be significantly lower than those of CT. Knowledge about ICIs was also limited in the interviewed ICI patients. Some patients reported adverse effects of ICIs that were mostly mild and well-tolerated or easily treated. CONCLUSIONS: The lack of understanding of ICIs should be improved by activities to increase the knowledge of ICI patients and the general population. In contrast to CT, ICIs invoked fewer negative associations with efficacy and toxicity. Therefore, attention should be paid to risk awareness when educating patients. (Clinical trial registration number: DRKS00011868) Trial Registration: German clinical trials register, www.germanctr.de , number DRKS00011868.

Systemic treatment of advanced/metastatic renal cell carcinoma in the context of SARS-CoV-2 pandemic: recommendations from the interdisciplinary working group for renal tumors (IAG-N).

This letter summarizes recommendations from the interdisciplinary working group of renal tumors (IAGN) of the German Cancer Society for the systemic treatment of advanced/metastatic renal cell carcinoma in the context of the current SARS-CoV-2 pandemic.

High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer -Results from a prospective pilot study using a 37 gene panel.

BACKGROUND: Defects in DNA damage repair genes characterize a subset of men with prostate cancer and provide an attractive opportunity for precision oncology approaches. The prevalence of such perturbations in newly diagnosed, treatment-naïve patients with a high risk for lethal disease outcome, however, has not been sufficiently explored. PATIENTS AND METHODS: Prostate cancer specimens from 67 men with newly diagnosed early onset, localized high-risk/locally advanced or metastatic prostate cancer were included in this prospective pilot study. Tumor samples, including 30 prostate biopsies, were analyzed by targeted next generation sequencing using a formalin-fixed, paraffin-embedded tissue-optimized 37 DNA damage repair and checkpoint gene panel. RESULTS: The drop-out rate due to an insufficient quantity of DNA was 4.5% (3 of 67 patients). In the remaining 64 patients, the rate of pathogenic DNA damage repair gene mutations was 26.6%. The highest rate of pathogenic DNA damage repair and checkpoint gene mutations was found in men with treatment-naïve metastatic prostate cancer (38.9%). In addition, a high number of likely pathogenic mutations and gene deletions were detected. Altogether, one or more pathogenic mutation, likely pathogenic mutation or gene deletion affected 43 of 64 patients (67.2%) including 29 of 36 patients (80.6%) with treatment-naïve metastatic prostate cancer. Men with metastatic prostate cancer showed a high prevalence of alterations in TP53 (36.1%). CONCLUSIONS: This pilot study demonstrates the feasibility, performance and clinical relevance of somatic targeted next generation sequencing using a unique 37 DNA damage repair and checkpoint gene panel under routine conditions. Our results indicate that this approach can detect actionable DNA repair gene alterations, uncommon mutations as well as mutations associated with therapy resistance in a high number of patients, in particular patients with treatment-naïve metastatic prostate cancer.

Patient-Reported Outcomes from the Phase III Randomized IMmotion151 Trial: Atezolizumab + Bevacizumab versus Sunitinib in Treatment-Naïve Metastatic Renal Cell Carcinoma.

PURPOSE: Patient-reported outcomes (PRO) were evaluated in the phase III IMmotion151 trial (NCT02420821) to inform overall treatment/disease burden of atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients were randomized 1:1 to receive atezolizumab 1,200 mg intravenous (i.v.) infusions every 3 weeks (q3w) plus bevacizumab 15 mg/kg i.v. q3w or sunitinib 50 mg per day orally 4 weeks on/2 weeks off. Patients completed the MD Anderson Symptom Inventory (MDASI), National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and Brief Fatigue Inventory (BFI) at baseline, q3w during treatment, at end of treatment, and during survival follow-up. Longitudinal and time to deterioration (TTD) analyses for core and RCC symptoms and their interference with daily life, treatment side-effect bother, and health-related quality of life (HRQOL) were evaluated. RESULTS: The intent-to-treat population included 454 and 461 patients in the atezolizumab plus bevacizumab and sunitinib arms, respectively. Completion rates for each instrument were 83% to 86% at baseline and ≥ 70% through week 54. Milder symptoms, less symptom interference and treatment side-effect bother, and better HRQOL at most visits were reported with atezolizumab plus bevacizumab versus sunitinib. The TTD HR (95% CI) favored atezolizumab plus bevacizumab for core (HR, 0.50; 0.40-0.62) and RCC symptoms (HR, 0.45; 0.37-0.55), symptom interference (HR, 0.56; 0.46-0.68), and HRQOL (HR, 0.68; 0.58-0.81). CONCLUSIONS: PROs in IMmotion151 suggest lower overall treatment burden with atezolizumab plus bevacizumab compared with sunitinib in patients with treatment-naïve mRCC and provide further evidence for clinical benefit of this regimen.

Microsatellite instability and survival after adjuvant chemotherapy among stage II and III colon cancer patients: results from a population-based study.

Previous studies have reported conflicting results regarding the benefit of administering 5-FU-based chemotherapy to colon cancer (CC) patients with microsatellite-instable (MSI-high) tumors, and results from stage-specific analyses are scarce. Patients with stage II or III CC were recruited as part of a population-based study between 2003 and 2015. The Cox regression models including propensity score weighting were used to calculate hazard ratios and confidence intervals for the association between chemotherapy and cancer-specific (CSS), relapse-free (RFS), and overall survival (OS) by stage of disease and MSI status of the tumor. Median follow-up was 6.2 years. A total of 1010 CC patients were included in the analysis (54% stage II, 46% stage III, 20% MSI-high). Adjuvant chemotherapy was administered to 48 (8.7%) stage II and 366 (79%) stage III patients. Overall, patients who received adjuvant chemotherapy had better CSS [HR = 0.65 (0.49-0.86)] than those who received surgery alone. Among stage II patients, only 64 (12%) cancer-related deaths occurred, none of which in MSI-high patients who received chemotherapy. Patients with MSI-high tumors who received adjuvant treatment showed better CSS and a tendency toward better RFS compared to MSI-high patients who did not receive chemotherapy [HRCSS  = 0.36 (0.15-0.82), HRRFS  = 0.49 (0.22-1.06)]. Patients with microsatellite-stable (MSS) tumors receiving adjuvant chemotherapy also had significantly better survival [HRCSS  = 0.65 (0.48-0.87) and HRRFS  = 0.68 (0.52-0.88)]. In this population-based study including stage II and III CC patients, we observed a survival benefit of adjuvant chemotherapy for both MSS and MSI-high tumors. Adjuvant chemotherapy seemed to be beneficial among high-risk stage II patients with MSI-high tumors.

Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma.

BACKGROUND: Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC. METHODS: Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n = 394), 65-74 (n = 201) and ≥75 years (n = 63). RESULTS: PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41-0.68), 0.53 (95% CI: 0.37-0.77) and 0.38 (95% CI: 0.18-0.79) for <65, 65-74 and ≥75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54-0.95), 0.66 (95% CI: 0.44-0.99) and 0.57 (95% CI: 0.28-1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups. CONCLUSIONS: Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy.

Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers.

Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class  (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.

The BRCA2 mutation status shapes the immune phenotype of prostate cancer.

Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.

Tumor response to irinotecan is associated with CYP3A5 expression in colorectal cancer.

Recently, a tumor-autonomous cytochrome P450 (CYP)-3A5-mediated resistance to cancer therapy has been demonstrated in pancreatic ductal adenocarcinoma. Expression of CYP3A5, which is involved in the degradation of irinotecan, has also been reported in colorectal cancer (CRC). The aim of the present study was to analyze CYP3A5 expression in the normal colon, colon adenoma, CRC and normal tissues, as well as to examine whether CYP3A5 expression in CRC has an impact on tumor response to irinotecan treatment. Immunohistochemistry was used to assess 85 tissue samples from 65 patients with CRC, along with 15 samples of normal colon and 45 samples of colon adenoma (including tubular, tubulovillous, and sessile serrated adenomas), and a tissue microarray (TMA) comprised of 26 different normal tissue types. Expression of CYP3A5 was evaluated with a semi-quantitative score. Tumor response to irinotecan therapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. In normal tissues, CYP3A5 was expressed in epithelial cells of the colon, gallbladder, kidney, liver, small intestine, stomach, thyroid gland and tonsil, as well as in nerves. Expression in colon mucosa was heterogeneous, with only weak staining in the minority of specimens. CYP3A5 exhibited markedly higher expression in adenomas compared with normal colon tissues. A statistically significant inverse correlation was identified between CYP3A5 expression in CRC tissues and tumor response to irinotecan therapy. Irinotecan treatment itself did not alter CYP3A5 expression in CRC tissues. As CYP3A5 is involved in the degradation of irinotecan, the significantly higher intratumoral expression of CYP3A5 in patients with CRC who do not respond to irinotecan-based chemotherapy may indicate a causal role of CYP3A5 in tumor resistance.

Clinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate.

BACKGROUND: Neuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited. METHODS: Retrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017. RESULTS: Of 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years. CONCLUSIONS: EP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.

Correlation between genomic index lesions and mpMRI and 68Ga-PSMA-PET/CT imaging features in primary prostate cancer.

Magnetic resonance imaging (MRI) and prostate specific membrane antigen (PSMA)- positron emission tomography (PET)/computed tomography (CT)-imaging of prostate cancer (PCa) are emerging techniques to assess the presence of significant disease and tumor progression. It is not known, however, whether and to what extent lesions detected by these imaging techniques correlate with genomic features of PCa. The aim of this study was therefore to define a genomic index lesion based on chromosomal copy number alterations (CNAs) as marker for tumor aggressiveness in prostate biopsies in direct correlation to multiparametric (mp) MRI and 68Ga-PSMA-PET/CT imaging features. CNA profiles of 46 biopsies from five consecutive patients with clinically high-risk PCa were obtained from radiologically suspicious and unsuspicious areas. All patients underwent mpMRI, MRI/TRUS-fusion biopsy, 68Ga-PSMA-PET/CT and a radical prostatectomy. CNAs were directly correlated to imaging features and radiogenomic analyses were performed. Highly significant CNAs (≥10 Mbp) were found in 22 of 46 biopsies. Chromosome 8p, 13q and 5q losses were the most common findings. There was an strong correspondence between the radiologic and the genomic index lesions. The radiogenomic analyses suggest the feasibility of developing radiologic signatures that can distinguish between genomically more or less aggressive lesions. In conclusion, imaging features of mpMRI and 68Ga-PSMA-PET/CT can guide to the genomically most aggressive lesion of a PCa. Radiogenomics may help to better differentiate between indolent and aggressive PCa in the future.

Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2.

Cabozantinib is a receptor tyrosine kinase inhibitor (TKI) with activity against a broad range of targets, including MET, RET, AXL, VEGFR2, FLT3, and c-KIT. Activity of cabozantinib towards a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Cabozantinib is clinically approved for the treatment of medullary thyroid cancer (MTC) and for renal cell cancer (RCC) in the second line. In MTC gain of function mutations, mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC up to 50% of cases RET mutations occur. Both MET and AXL have been described as mechanisms facilitating resistance against VEGFR-targeted tyrosine kinase therapy in clear cell RCC. Accordingly, cabozantinib has shown activity in RCC patients progressing after first-line VEGFR-TKI therapy in the pivotal METEOR trial. This phase III trial reported a benefit of 4.9 months in survival and an increase in response rate compared to standard everolimus over all patient subgroups. Of particular interest are the effects on patients with bone metastasis, which have a worse prognosis. In these patients, the beneficial effects of cabozantinib over everolimus were even more pronounced. Side effects of interest include diarrhea, hypertension, fatigue, and hand-foot syndrome.

Lenvantinib: A Tyrosine Kinase Inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, KIT and RET.

Lenvatinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor-alpha (PDGFRα), and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the treatment of advanced renal cell carcinoma following anti-VEGF treatment. In hepatocellular carcinoma lenvatinib was non inferior to sorafenib in first line with an improved progression-free survival and approval in this indication is expected. Lenvatinib is currently investigated for further indications as single agent and in combinations. Side effects include typical TKI induced toxicities such as hypertension, diarrhea, hypothyroidism, and fatigue.

Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial.

BACKGROUND: To assess the predictive value of early metabolic response (ΔSUV) after short-term treatment with first-line cetuximab in patients (pts) with RAS-wt metastatic colorectal cancer (mCRC). METHODS: In this prospective phase II study, RAS-wt mCRC pts received a single-agent cetuximab run-in therapy of 2 weeks. ΔSUV was assessed with FDG-PET/CT on days 0 and 14. Early clinical response (ECR) was evaluated with CT on day 56 after treatment with FOLFIRI-cetuximab. Primary endpoint was the predictive significance of ΔSUV for ECR. Secondary endpoints were PFS (progression free survival), OS and the influence of ΔSUV on survival. RESULTS: Forty pts were enroled and 33 pts were evaluable for the primary endpoint. The CT response rate was 57.6%. For responders, ΔSUV was significantly higher (p = 0.0092). A significant association of ΔSUV with ECR was found (p = 0.02). Median PFS was 11.7 months and median OS was 33.5 months with a 1-year survival rate of 87.9%. ΔSUV was found to significantly impact the hazard for OS (p = 0.045). CONCLUSIONS: We demonstrate that cetuximab induces metabolic responses in mCRC pts. The study endpoint was met with the ΔSUV discriminating between responders and non-responders. However, these data should be validated in larger patient cohorts.