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DECT and Radiomics Models Predict Muscle Invasion in BCa

KEY TAKEAWAYS

  • The study aimed to evaluate the predictive value of DECT-based quantitative parameters and a radiomics model for preoperatively predicting muscle invasion in BCa.
  • The fusion model combining NIC and the optimal radiomics model effectively predicts muscle invasiveness in BCa.

Muscle-invasive bladder cancer (BCa) carries a poorer prognosis, often requiring more radical treatment than non-muscle invasive disease. Preoperative staging is crucial to guide management decisions. Dual-energy CT urography (DECTU) is a promising imaging modality for BCa evaluation.

Mengting Hu and the team aimed to develop and evaluate a model combining quantitative DECT parameters and radiomics to predict muscle invasion in BCa preoperatively.

The study included 126 patients with BCa who underwent dual-energy CT urography (DECTU) at the hospital. Patients were randomly divided into training and test cohorts in a 7:3 ratio. Quantitative parameters from DECTU were identified through univariate and multivariate logistic regression analysis to develop a DECT model. Radiomics features were extracted from 40, 70, and 100 keV images, as well as iodine-based material-decomposition (IMD) images in the venous phase.

These features were used to create radiomics models from individual and combined images using a support vector machine classifier, with the best-performing model selected as the final radiomics model. A fusion model was then established, combining the DECT parameters and the radiomics model.

The results demonstrated that the normalized iodine concentration (NIC) in DECT was an independent factor in diagnosing muscle invasion of BCa. The optimal multi-image radiomics model achieved predictive performance with an area under the curve (AUC) of 0.867 in the test cohort, outperforming NIC, which had an AUC of 0.704.

The fusion model showed enhanced performance, with an AUC of 0.893, although this difference was not statistically significant. Additionally, the fusion model demonstrated superior performance in decision curve analysis (DCA).

For lesions smaller than 3 cm, the fusion model exhibited high predictive capability, reaching an AUC of 0.911. There was a slight improvement in model performance, but this difference was also not statistically significant, as evidenced by the AUC values of the DECT and radiomics models, which were 0.726 and 0.884, respectively.

The study highlighted the potential of combining quantitative DECT parameters and radiomics in a fusion model to improve the preoperative prediction of muscle-invasive BCa. This approach may enhance treatment planning and patient outcomes.

No funding was provided.

Source: https://pubmed.ncbi.nlm.nih.gov/39285354/

Hu M, Wei W, Zhang J, et al. (2024). “Assessing muscle invasion in bladder cancer via virtual biopsy: a study on quantitative parameters and classical radiomics features from dual-energy CT imaging.” BMC Med Imaging. 2024;24(1):245. Published 2024 Sep 16. doi:10.1186/s12880-024-01427-w

177Lu-PNT2002 Enhances ORR and HRQoL in PSMA+ mCRPC

KEY TAKEAWAYS

  • The study aimed to investigate 177Lu-PNT2002’s efficacy in PSMA-positive in patienst with mCRPC after ARPI failure.
  • The primary endpoint was to determine rPFS and BICR.
  • Researchers noted that 177Lu-PNT2002 improved outcomes in PSMA-positive mCRPC compared to ARPI.

The metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition with significant unmet needs. 177Lu-PNT2002 is a beta-emitting radioisotope attached to a small-molecule ligand that targets PSMA.

Oliver Sartor and the team aimed to assess the efficacy and safety of 177Lu-PNT2002 in patients with PSMA-positive mCRPC.

They performed an inclusive analysis in the SPLASH open-label Phase 3 trial, which enrolled PSMA PET-positive patients with mCRPC who had progressed on 1 ARPI and had not received chemotherapy for castration-resistant disease. Patients were randomized 2:1 to receive either 177Lu-PNT2002 (6.8 GBq IV every 8 weeks for up to 4 cycles) or an alternate ARPI.

The primary endpoint was radiographic progression-free survival (rPFS), assessed by blinded independent central review (BICR) using RECIST 1.1/PCWG3 criteria. Additional key endpoints included overall survival (OS), objective response rate (ORR), PSA50, HRQoL, and safety. Crossover from the alternate ARPI to 177Lu-PNT2002 was permitted upon confirmation of disease progression by BICR.

About 488 patients were screened with PSMA PET, of whom 90.4% were PSMA positive. A total of 412 patients were randomized to receive either 177Lu-PNT2002 (n=276, median 4 cycles) or an alternate ARPI (n=136). Demographics and baseline characteristics were well balanced between the 177Lu-PNT2002 and ARPI groups: ECOG status 0 was 58.7% vs. 55.9%, and M0 status was 10.1% vs. 11.0%, respectively.

The crossover rate was 84.6% (77/91). The primary endpoint of rPFS was improved in patients receiving 177Lu-PNT2002 (9.5 months, 95% CI: 7.4, 10.0) compared to ARPI (6.0 months, 95% CI: 4.7, 7.9) (HR, 95% CI: 0.71, 0.55, 0.92; P=0.0088). Other efficacy outcomes are provided in the table.

The incidence of treatment-emergent adverse events (TEAEs) leading to treatment discontinuation and grade ≥3 TEAEs were both lower with 177Lu-PNT2002 compared to ARPI (1.9% vs. 6.2% and 30.1% vs. 36.9%, respectively). The most common TEAEs with 177Lu-PNT2002 were fatigue (53.5%), dry mouth (37.2%), and nausea (31.2%).

The trial was sponsored by POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/135

Clinical Trial: https://clinicaltrials.gov/study/NCT04647526

Sartor O, Jiang D.M, Smoragiewicz M, et al. (2024). “Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH).” Presented at ESMO 2024 (Abstract LBA65).

NKT2152 Shows Promising Efficacy in Pretreated Advanced RCC

KEY TAKEAWAYS

  • The phase 1 and 2 trial aimed to investigate the safety, pharmacokinetics, pharmacodynamics, and efficacy of NKT2152 in patients with accRCC.
  • NKT2152 showed strong anti-tumor activity in patients with heavily pretreated accRCC, with a consistent safety profile.

NKT2152, a novel oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, is being developed for treating advanced clear cell renal cell carcinoma (accRCC). HIF-2α plays a crucial role in tumour growth and progression, making it a promising therapeutic target.

In this ongoing Phase I/II trial, Eric Jonasch and the team aimed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy of NKT2152 in patients with accRCC who have progressed on prior therapies.

The study enrolled adult patients with accRCC who had progressed on at least 1 prior therapy and were not eligible for standard treatment. Patients received NKT2152 in 8 dose-escalation cohorts (4 daily and 4 loading/maintenance regimens), followed by a randomized expansion at 2 selected dose levels. The study included PK analysis, development of a population PK-erythropoietin model, and an exploratory exposure-response analysis.

About 96 patients were enrolled in the study, with a median follow-up of 12 months. The confirmed ORR was 24%, and the mPFS was 7.5 months. Notably, in a subset of 35 patients who had not received prior mTOR inhibitors, the ORR was 40%, and the mPFS was 9.4 months. NKT2152 exhibited dose-linear and time-independent pharmacokinetics. EPO suppression was observed at all dose levels. The safety profile was consistent with this class of agents.

NKT2152 demonstrated robust anti-tumor activity in heavily pre-treated patients with accRCC, particularly those without prior mTOR inhibitor exposure. The safety profile was consistent with other agents in its class. Further research is ongoing to evaluate the full therapeutic potential of NKT2152 in treating accRCC.

The trial is sponsored by NiKang Therapeutics, Inc.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/14

Clinical Trial: https://clinicaltrials.gov/study/NCT05119335

Jonasch E, McGregor BA, Msaouel P, et al. (2024). “NKT2152, a novel oral HIF-2α inhibitor, in participants (pts) with previously treated advanced clear cell renal carcinoma (accRCC): Preliminary results of a phase I/II study.” Presented at: ESMO Congress 2024; 2024; 1690O.

Impact of Isavuconazole on Sunitinib Pharmacokinetics in RCC

Impact of Isavuconazole on Sunitinib Pharmacokinetics in RCC

KEY TAKEAWAYS

  • The study aimed to investigate how isavuconazole interacts with sunitinib in advanced RCC treatment.
  • The results showed that isavuconazole significantly alters sunitinib metabolism, aiding in its therapeutic management.

Sunitinib, a multi-targeted tyrosine kinase inhibitor, has become a standard treatment option for individuals with advanced renal cell carcinoma (RCC).

Jinyu Hu and the team aimed to explore the mechanisms underlying the interaction between sunitinib and isavuconazole.

The study utilized ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to analyze and quantify sunitinib and its primary metabolite, N-desethyl sunitinib. They evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models.

For the in vivo study, 2 groups of Sprague-Dawley rats were randomly assigned to receive sunitinib with or without isavuconazole co-administration. Additionally, they investigated how isavuconazole affects the metabolic stability of sunitinib and N-desethyl sunitinib in RLM in vitro.

The results demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. In HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM.

In vivo studies indicated that isavuconazole significantly enhanced the pharmacokinetic (PK) characteristics of sunitinib, with AUC(0→t), AUC(0→∞), and Tmax increasing to approximately 211.38%, 203.92%, and 288.89%, respectively, compared to the control group (5 mg/kg sunitinib alone).

The PK characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib.

The study concluded that isavuconazole significantly impacts the metabolism of sunitinib, offering crucial insights for optimizing its therapeutic use.

No funding was provided.

Source: https://pubmed.ncbi.nlm.nih.gov/39261851/

Hu J, Xia H, Chen X, et al. (2024). “Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism.” BMC Cancer. 2024;24(1):1131. Published 2024 Sep 11. doi:10.1186/s12885-024-12904-4

TAR-200 + CET vs CET Alone in Patients With MIBC: SR-4 Interim

KEY TAKEAWAYS

  • The SunRISe-4 phase 2 trial aimed to assess the efficacy and safety of neoadjuvant TAR-200 plus cetrelimab vs cetrelimab alone in patients with MIBC.
  • The primary endpoint was to determine pCR, and the secondary endpoints were pOR rate & safety.
  • Researchers noticed a favorable safety profile and compelling efficacy data; further investigation is needed.

Standard treatment for muscle-invasive bladder cancer (MIBC) typically involves radical cystectomy (RC) in combination with neoadjuvant chemotherapy (NAC). However, approximately 50% of patients are ineligible for NAC, and the 5-year survival rate for RC alone is ≤50%, highlighting the need for novel therapies. TAR-200 is an intravesical drug delivery system designed to release gemcitabine locally within the bladder for sustained treatment.

In this SR-4 study randomized phase 2 trial, Andrea Necchi, and the team aimed to evaluate the efficacy and safety of neoadjuvant TAR-200 + CET (anti-PD-1) versus CET alone in patients with MIBC scheduled for RC who are either ineligible for or refuse NAC.

They performed an inclusive analysis involving patients with ECOG PS 0-1, histologically confirmed cT2-T4a N0M0 MIBC, who were ineligible for or refused NAC and scheduled for RC. These patients were randomized in a 5:3 ratio to receive either TAR-200 + CET (Cohort 1 [C1]) or CET alone (Cohort 2 [C2]).

Randomization was stratified based on visibly complete versus incomplete (≤3 cm) resection on TURBT and tumor stage (cT2 vs cT3-4a) at MIBC diagnosis. The primary outcome measure was the pathologic complete response (pCR; ypT0N0) rate. Additional outcomes assessed included the pathologic overall response (pOR; ≤ ypT1N0) rate and safety.

About 120 patients were treated at the data cutoff of May 31, 2024. The median age was 73 years; 85% were male; 20% ECOG PS 1; 81% cT2; 18% with residual disease divided into (Cohort 1 [C1] n=79; Cohort 2 [C2] n=41).

In the efficacy evaluable set, centrally confirmed pCR rates were 42% in C1 and 23% in C2. Treatment-related adverse events (TRAEs) were observed in 72% of patients in C1 and 44% in C2, with most TRAEs classified as Grade 1-2. Discontinuation rates due to TRAEs were 8% for TAR-200 and 8% for CET in C1, while 0% discontinued CET in C2 due to TRAEs.

The study concluded that neoadjuvant TAR-200 + CET therapy demonstrated compelling pCR and pathologic overall response (pOR) rates with a manageable safety profile, supporting the addition of TAR-200 to anti-PD-1 treatment in patients with MIBC. In the cT2 subgroup, over 2/3 of patients who received TAR-200 + CET were downstaged to ≤ T1 at RC, and approximately half achieved pCR. The SR-4 interim results endorse further investigation of TAR-200 + CET in patients with MIBC.

The trial was sponsored by Janssen Research & Development, LLC.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/175

Clinical Trial: https://clinicaltrials.gov/study/NCT04919512

Necchi A, Guerrero-Ramos F, Crispen P.L, et al. (2024). “TAR-200 plus cetrelimab (CET) or CET alone as neoadjuvant therapy in patients (pts) with muscle-invasive bladder cancer (MIBC) who are ineligible for or refuse neoadjuvant cisplatin-based chemotherapy (NAC): Interim analysis of SunRISe-4 (SR-4).” Presented at ESMO 2024 (Abstract LBA84).

DARO Enhances Survival and Efficacy in Metastatic Prostate Cancer

KEY TAKEAWAYS

  • The ARANOTE phase III trial compared the effectiveness of DARO plus ADT vs ADT alone in patients with mHSPC.
  • The primary endpoint was to determine rPFS.
  • The DARO showed significant efficacy and good tolerability in mHSPC.

In the ARASENS trial, combining darolutamide (DARO) with androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) compared to ADT plus docetaxel alone for patients with metastatic hormone-sensitive prostate cancer (mHSPC). The incidence of treatment-emergent adverse events (TEAEs) was similar across both treatment groups.

Fred Saad and the team aimed to compare the efficacy of DARO plus ADT versus ADT alone in patients with mHSPC.

The inclusion criteria for eligible patients was mHSPC, confirmed by imaging, with an ECOG performance status of 0-2 and had started ADT within the past 12 weeks.

The selected patients were randomly assigned in a 2:1 ratio to receive either DARO 600 mg twice daily or a placebo, both along with ADT. The primary goal was to measure radiological progression-free survival (rPFS), while secondary goals included OS, time to further therapy, and safety.

The results showed that 669 patients were enrolled (DARO: 446; placebo: 223), with a median age of 70 years. Of all, 31% were Asian, 9.7% were Black, the median PSA at baseline was 21.3 ng/mL, and 71% had high-volume HSBC. The DARO + ADT combination significantly improved rPFS compared to placebo + ADT (HR 0.54; 95% CI: 0.41-0.71, P<0.0001), showing consistent benefits across different patient subgroups.

DARO also demonstrated a positive trend in OS (HR 0.81; 95% CI: 0.59-1.12) and showed benefits in secondary endpoints like time to CRPC (HR 0.40; 95% CI: 0.32–0.51), PSA progression (HR 0.31; 95% CI 0.23–0.41), subsequent therapy (HR 0.40; 95% CI, 0.29–0.56) and pain progression (HR 0.72, 95% CI: 0.54-0.96). The TEAE was similar between groups, with fewer discontinuations due to adverse events (AEs) in the DARO group (6.1% vs. 9.0%).

The study concluded that DARO demonstrates strong efficacy and favorable tolerability in mHSPC, as confirmed by ARANOTE. ARASENS and ARANOTE show DARO’s benefits with and without chemotherapy, offering personalized treatment options with minimal progression and treatment burden.

The trial was sponsored by Bayer.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/18

Clinical Trials: https://clinicaltrials.gov/study/NCT04736199

Saad F, Vjaters E, Shore ND, et al. (2024). “Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial.” Presented at ESMO-2024 (Abstract LBA68)

Impact of ctDNA Clearance With D+T+EV in MIBC: VOLGA SRI

KEY TAKEAWAYS

  • The VOLGA phase 3 trial aimed to investigate the link between plasma ctDNA clearance and clinical outcomes in patients with MIBC receiving neoadjuvant D+T+EV.
  • The primary endpoints were to determine Pathologic Response & EFS.
  • Researchers observed that plasma ctDNA clearance may predict better outcomes with neoadjuvant D+T+EV in MIBC; further investigation is ongoing.

The VOLGA safety run-in (SRI) for neoadjuvant durvalumab (D) + tremelimumab (T) + enfortumab vedotin (EV) in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) showed promising results. This exploratory analysis focuses on plasma ctDNA data from the SRI.

Alexandra Drakaki and the team aimed to assess the correlation between plasma ctDNA clearance and clinical outcomes in patients receiving neoadjuvant D+T+EV for MIBC.

They performed an inclusive analysis involving eligible patients aged ≥18 years with cisplatin-ineligible MIBC (clinical stage T2-4aN0-N1M0/T1N1M0). Patients received 3 cycles of neoadjuvant therapy every 3 weeks: D (1500 mg; day 1 each cycle) + T (75 mg; day 1 cycle 1, and day 8 cycle 2) + EV (1.25 mg/kg; days 1 and 8 each cycle), followed by radical cystectomy (RC) and then 9 cycles of adjuvant D (every 4 weeks; day 1 each cycle) and T (day 1, cycle 1 only).

Cell-free DNA from plasma samples was assessed using GRAIL’s cancer research solution, which detects methylation indicative of ctDNA (GRAIL, LLC). ctDNA detection at baseline (C1D1) and on/after neoadjuvant treatment prior to RC (C3D1 and pre-RC time points) was evaluated for its association with pathologic response at RC and event-free survival (EFS).

About 69 plasma samples collected at baseline, pre-RC, and post-RC time points were analyzed, with 66 (96%) passing ctDNA processing quality control. Of the 17 patients in the SRI cohort, 16 had baseline plasma samples, with a ctDNA-positive rate of 62.5% (10/16 patients).

Among these, 13 underwent RC and had a pre-RC sample. The ctDNA-positive rate at C3D1/pre-RC was 23% (3/13 patients); 7 patients exhibited ctDNA clearance, which was associated with pathologic response (table) and EFS with an EFS hazard ratio of 0.18 (95% CI, 0.016-2.1). Additionally, ctDNA detection status alone at C3D1/pre-RC was also associated with pathologic response.

The study concluded that plasma ctDNA clearance during neoadjuvant D + T + EV treatment in patients with MIBC may be associated with improved clinical outcomes, suggesting it as a potential surrogate for treatment efficacy. These findings will be further explored in the ongoing VOLGA study.

The trial was sponsored by AstraZeneca.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/139

Clinical Trial: https://clinicaltrials.gov/study/NCT04960709

Drakaki A, Powles T.B, Wang Y, et al. (2024). “Circulating tumor DNA (ctDNA) clearance with neoadjuvant durvalumab (D) + tremelimumab (T) + enfortumab vedotin (EV) for cisplatin-ineligible muscle-invasive bladder cancer (MIBC) from the safety run-in cohort of the phase III VOLGA trial.” Presented at ESMO 2024 (Abstract 1970MO).

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