FGFR Inhibition in Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain. METHODS: Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms "FGFR" and "bladder cancer". An international expert panel with extensive experience in FGFR inhibitor treatment was convened to synthesize a collaborative narrative review. KEY FINDINGS AND LIMITATIONS: Somatic FGFR3 alterations are found in up to 70% of low-grade non-muscle-invasive bladder cancers; these activate downstream signaling cascades and culminate in cellular proliferation. Beyond a link to lower-grade/lower-stage tumors, there is little consistency regarding whether these alterations confer prognostic risks for cancer recurrence or progression. FGFR3-altered tumors have been linked to a non-inflamed tumor microenvironment, but paradoxically do not seem to impact the response to systemic immunotherapy. Several pan-FGFR inhibitors have been investigated in mUC. With the introduction of novel intravesical drug delivery systems, FGFR inhibitors are poised to transform the therapeutic landscape for early-stage UC. CONCLUSIONS AND CLINICAL IMPLICATIONS: With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer.

Efficacy and safety of pembrolizumab in patients with advanced urothelial carcinoma deemed potentially ineligible for platinum-containing chemotherapy: Post hoc analysis of KEYNOTE-052 and LEAP-011.

BACKGROUND: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility. METHODS: Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age ≥80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety. RESULTS: A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n = 370) and LEAP-011 (n = 242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups. CONCLUSIONS: Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used.

Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development.

BACKGROUND: Understanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies. METHODS: The study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy. Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages. RESULTS: A total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit. A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies. CONCLUSION: The MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.

Real-world Study of Avelumab First-line Maintenance Treatment in Patients with Advanced Urothelial Carcinoma in France: Overall Results from the Noninterventional AVENANCE Study and Analysis of Outcomes by Second-line Treatment.

BACKGROUND: Avelumab first-line maintenance treatment was approved for patients with advanced urothelial carcinoma (aUC) without progression following platinum-based chemotherapy (PBC), based on the results from the JAVELIN Bladder 100 phase 3 trial. OBJECTIVE: To report the results from AVENANCE, a real-world study of avelumab first-line maintenance treatment. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective and prospective, noninterventional study (NCT04822350). Eligible patients with aUC without progression on first-line PBC were enrolled at 82 centers in France between July 2021 and May 2022. The effectiveness population included 595 patients. The median follow-up was 26.3 mo. INTERVENTION: Previous, ongoing, or planned avelumab first-line maintenance treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) from avelumab initiation (primary endpoint) and safety were evaluated. RESULTS AND LIMITATIONS: The median age was 73.0 yr, and performance status was 0/1 in 91% of patients and ≥2 in 9.3%. The most common prior first-line chemotherapy regimen was carboplatin plus gemcitabine (61%). At data cutoff (December 7, 2023), the median duration of avelumab treatment was 5.6 mo, 125 patients remained on avelumab, and 55% had received second-line treatment. The median OS from avelumab initiation was 21.3 mo (95% confidence interval [CI], 17.6-24.6), and the median progression-free survival was 5.7 mo (95% CI, 5.2-6.5). In exploratory analyses of this population without disease progression on PBC, the median OS from the start of first-line PBC was 26.5 mo overall, and in subgroups that received second-line enfortumab vedotin (n = 55) or PBC (n = 79), it was 41.5 and 24.5 mo, respectively. CONCLUSIONS: Real-world data from AVENANCE confirm the effectiveness and safety of avelumab first-line maintenance treatment in a heterogeneous population, supporting its recommendation for cisplatin-eligible and cisplatin-ineligible patients with aUC who are progression free after first-line PBC. In an exploratory analysis, a small subgroup that received a treatment sequence of first-line PBC without disease progression followed by avelumab first-line maintenance and second-line enfortumab vedotin had a median OS of >3 yr. PATIENT SUMMARY: A French real-world study, called AVENANCE, looked at avelumab maintenance treatment in people with advanced urothelial cancer whose tumor disappeared, shrank, or stopped growing with chemotherapy. Overall, results were consistent with those seen in a previous clinical trial, and on average, people treated with avelumab maintenance lived for 26.5 mo from the start of chemotherapy. Analyses of different groups of people found that survival varied, with people living for an average of 18-42 mo depending on what treatment they received after they finished avelumab treatment.

Bempegaldesleukin plus nivolumab in first-line advanced/metastatic urothelial carcinoma: Results from a phase II single-arm study (PIVOT-10).

BACKGROUND: In PIVOT-02, bempegaldesleukin (BEMPEG), a pegylated interleukin-2 cytokine prodrug, in combination with nivolumab (NIVO), a Programmed cell death protein 1 inhibitor, demonstrated the potential to provide additional benefits over immune checkpoint inhibitor monotherapy in patients with urothelial carcinoma, warranting further investigation. We evaluated BEMPEG plus NIVO in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: This open-label, multicenter, single-arm, phase II study enrolled patients with locally advanced/surgically unresectable or metastatic urothelial carcinoma and who were ineligible for cisplatin-based treatment. Patients received BEMPEG plus NIVO were administered intravenously every 3 weeks for ≤2 years or until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR) in patients with low programmed death ligand-1 (PD-L1) expression. Secondary endpoints included ORR and duration of response in the overall population. Progression-free survival (PFS) and overall survival (OS) were exploratory endpoints. RESULTS: One hundred and eighty-eight patients were enrolled; 123 patients were PD-L1 low (combined positive score [CPS] <10; 65.4%), 59 were PD-L1 high (31.4%; CPS ≥10), and 6 had PD-L1 status unknown (3.2%). ORR per blinded independent central review in patients with PD-L1-low tumors was 17.9% (95% confidence interval [CI] 11.6-25.8) while in all treated patients was 19.7% (95% CI 14.3-26.1). Median PFS and OS in the overall population were 3.0 months and 12.6 months, respectively. BEMPEG plus NIVO combination was well tolerated, with a safety profile similar to previously reported trials; no new or unexpected safety signals were reported. CONCLUSIONS: BEMPEG plus NIVO did not meet the efficacy threshold for ORR in patients with previously untreated locally advanced or metastatic urothelial carcinoma and low PD-L1 expression.

Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.

PURPOSE: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes. PATIENTS AND METHODS: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1). RESULTS: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone. CONCLUSIONS: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.

Treatments for Patients with Metastatic Castration-resistant Prostate Cancer Who Previously Received Triplet Therapy at the Metastatic Hormone-sensitive Stage.

The level of evidence for the management of prostate cancer progressing after triplet therapy is currently low. Molecular profiling of patients and enrolment in clinical trials are strongly recommended.

The genomic and transcriptomic landscape of metastastic urothelial cancer.

Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases.

Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies.

PURPOSE: Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies. EXPERIMENTAL DESIGN: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies. RESULTS: Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y. CONCLUSIONS: At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.

Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.

TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy.

PURPOSE: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with an SN-38 payload, approved for patients with locally advanced (LA) or metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report results from Cohort 2 of TROPHY-U-01 trial, evaluating the efficacy and safety of SG in patients with mUC. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Cohort 2 includes patients with LA or mUC who have had progression or recurrence after a CPI and were cisplatin-ineligible at study initiation. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end point was objective response rate (ORR) per central review; secondary end points were clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS) per central review and safety. RESULTS: Cohort 2 included 38 patients (61% male; median age 72.5 years; 66% visceral metastases [29% liver]; 50% received previous PT-based chemotherapy as previous [neo]adjuvant therapy]). At a median follow-up of 9.3 months, ORR was 32% (95% CI, 17.5 to 48.7), CBR 42% (95% CI, 26.3 to 59.2), median DOR 5.6 months (95% CI, 2.8 to 13.3), median PFS 5.6 months (95% CI, 4.1 to 8.3), and median overall survival 13.5 months (95% CI, 7.6 to 15.6). Grade ≥3 treatment-emergent adverse events occurred in 87% of patients, most commonly neutropenia (34%), anemia (24%), leukopenia (19%), fatigue (18%), and diarrhea (16%). CONCLUSION: SG monotherapy demonstrated a relatively high ORR with rapid responses; this was feasible with a manageable toxicity profile in cisplatin-ineligible patients who had progression after CPI therapy. Limitations include a moderate sample size and lack of random assignment. These results warrant further evaluation of SG alone and in combinations in patients with LA/mUC.

Is Local Ablative Stereotactic Radiation Therapy a Valuable Rescue Strategy for Time on Drug in Patients Enrolled in Phase I Trials?

PURPOSE: Patients with advanced tumors enrolled in phase I trials display strong treatment expectations and few therapeutic alternatives. When oligoacquired resistance (OAR; ≤3 lesions of disease progression) occurs, local ablative stereotactic radiation therapy (SRT) could allow disease control and continuing the experimental systemic treatment. METHODS AND MATERIALS: Data from patients enrolled in phase I trials evaluating systemic treatments, who experienced OAR while on the phase I systemic therapy and subsequently received SRT between January 2014 and April 2023, were retrospectively analyzed. Progression-free survival (PFS)1 (trial entry to OAR), PFS2 (SRT to first subsequent relapse), time to next systemic treatment (TTNT), and overall survival (OS) were assessed. First subsequent patterns of relapse after SRT were distinguished as OAR2, which could be locally rechallenged, or systemic acquired resistance (SAR; >3 lesions of disease progression). When available, correlations between molecular profile and pathway enrichments of OAR and SAR were explored. RESULTS: Forty-two patients with 52 oligoprogressive lesions were analyzed. The median follow-up was 24 months. SRT allowed a median PFS2 of 7.1 months and a median TTNT of 12.8 months. PFS2 included 49% OAR2 and 51% SAR. Median time to first subsequent relapse (9.6 vs 3.5 months; P = .014) and TTNT (22.4 vs 7.6 months; P < .001) were longer for OAR2 compared with that for SAR. No severe toxicities were reported. A PFS1 of <6 months and de novo oligoprogressive lesions were associated with the presence of SAR. More diverse enriched gene pathways were observed for SAR compared with that for OAR2. CONCLUSIONS: In patients enrolled in phase I trials, OAR managed with SRT may increase time on investigational systemic treatments. Predictive factors reflecting tumor aggressiveness and clonal heterogeneity could help deciphering OAR2 from SAR and maximize SRT output in the oligoprogressive setting.

Assessing actionability and incidental findings of germline variants in two precision oncology trials.

INTRODUCTION: High-throughput sequencing techniques have revolutionized oncology. Paired germline-tumor DNA analysis has emerged as a comprehensive strategy to uncover actionable alterations in advanced cancer patients (ACP) enrolled in precision oncology trials. However, challenges persist in variant interpretation and managing incidental germline findings. METHODS: We conducted a study involving 288 ACP from MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials to assess germline variants impacting cancer-related genes. Germline DNA sequencing was performed using a panel of 250 cancer-related genes, and the results were discussed during tumor molecular board sessions. RESULTS: Germline pathogenic variants (PV) were classified according to the ESCAT classification. Lung cancer (36.8 %), followed by prostate (18.4 %) and breast cancer (17.7 %), comprised the most prevalent tumor types. PVs were found in 12.5 % of patients. Most PVs were classified as ESCAT X (63.9 %), highlighting limited therapeutic actionability. Notably,2 % of patients had actionable variants (ESCAT I-A/II-A). Incidental findings included 7.3 % of patients with PVs in cancer-predisposition genes, with 2.4 % having very high-risk potential, necessitating mandatory oncogenetic counseling. Nearly one in five patients (21.9 %) had at least one VUS. DISCUSSION: Our study underscores the significance of germline sequencing in identifying actionable alterations and the need for improved variant interpretation as well as pretest counseling plans in precision oncology trials.

Exploring the Role of Target Expression in Treatment Efficacy of Antibody-Drug Conjugates (ADCs) in Solid Cancers: A Comprehensive Review.

PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) offer a promising path for cancer therapy, leveraging the specificity of monoclonal antibodies and the cytotoxicity of linked drugs. The success of ADCs hinges on precise targeting of cancer cells based on protein expression levels. This review explores the relationship between target protein expression and ADC efficacy in solid tumours, focusing on results of clinical trials conducted between January 2019 and May 2023. RECENT FINDINGS: We hereby highlight approved ADCs, revealing their effectiveness even in low-expressing target populations. Assessing target expression poses challenges, owing to variations in scoring systems and biopsy types. Emerging methods, like digital image analysis, aim to standardize assessment. The complexity of ADC pharmacokinetics, tumour dynamics, and off-target effects emphasises the need for a balanced approach. This review underscores the importance of understanding target protein dynamics and promoting standardized evaluation methods in shaping the future of ADC-based cancer therapies.

Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations.

BACKGROUND: In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1. There have been no reports of the Japanese subgroup results yet. METHODS: THOR Cohort 1 randomized patients to erdafitinib once daily or docetaxel/vinflunine once every 3 weeks. Primary endpoint was OS. Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). No specific statistical power was set for this Japanese subgroup analysis. RESULTS: Of 266 patients randomized, 27 (14 erdafitinib; 13 chemotherapy) were Japanese. Baseline characteristics were generally similar between treatments and to the overall population, except for more males, lower body weight, and more upper tract primary tumors among Japanese patients. Compared with chemotherapy, erdafitinib showed improved OS (median 25.4 versus 12.4 months), PFS (median 8.4 versus 2.9 months) and ORR (57.1% versus 15.4%). Any grade treatment-related adverse events (AEs) occurred in all patients from both arms but Grade 3/4 AEs and AEs leading to discontinuation were lower in the erdafitinib arm. No new safety signals were observed in the Japanese subgroup. CONCLUSION: In the Japanese subgroup, erdafitinib showed improved survival and response compared to chemotherapy, with no new safety concerns. These results support erdafitinib as a treatment option for Japanese mUC patients with FGFR alterations, and early FGFR testing after diagnosis of mUC should be considered.

Final Results from SAUL, a Single-arm International Study of Atezolizumab in Unselected Patients with Pretreated Locally Advanced/Metastatic Urinary Tract Carcinoma.

BACKGROUND AND OBJECTIVE: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data. METHODS: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS). KEY FINDINGS AND LIMITATIONS: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities. PATIENT SUMMARY: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years.

Optimizing the Use of Next-Generation Sequencing Assays in Patients With Urothelial Carcinoma: Recommendations by the 2023 San Raffaele Retreat Panel.

BACKGROUND: The application of precision medicine in clinical practice implies a thorough evaluation of actionable genomic alterations to streamline therapeutic decision making. Comprehensive genomic profiling of tumor via next-generation sequencing (NGS) represents a great opportunity but also several challenges. During the 2023 San Raffaele Retreat, we aimed to provide expert recommendations for the optimal use of NGS in urothelial carcinoma (UC). MATERIALS AND METHODS: A modified Delphi method was utilized, involving a panel of 12 experts in UC from European and United States centers, including oncologists, urologists, pathologists, and translational scientists. An initial survey, conducted before the meeting, delivered 15 statements to the panel. A consensus was defined when ≥70% agreement was reached for each statement. Statements not meeting the consensus threshold were discussed during the meeting. RESULTS: Nine of the 15 statements covering patient selection, cancer characteristics, and type of NGS assay, achieved a consensus during the survey. The remaining six statements addressing the optimal timing of NGS use, the ideal source of tumor biospecimen for NGS testing, and the subsequent need to evaluate the germline nature of certain genomic findings were discussed during the meeting, leading to unanimous agreement at the end of the conference. CONCLUSION: This consensus-building effort addressed multiple unanswered questions regarding the use of NGS in UC. The opinion of experts was in favor of broader use of NGS. In a setting where recommendations/guidelines may be limited, these insights may aid clinicians to provide informed counselling and raise the bar of precision and personalized therapy.

Cost-effectiveness of avelumab first-line maintenance therapy for adult patients with locally advanced or metastatic urothelial carcinoma in France.

BACKGROUND: This study evaluated the cost-effectiveness of avelumab first-line (1L) maintenance therapy plus best supportive care (BSC) versus BSC alone for adults with locally advanced or metastatic urothelial carcinoma (la/mUC) that had not progressed following platinum-based chemotherapy in France. METHODS: A three-state partitioned survival model was developed to assess the lifetime costs and effects of avelumab plus BSC versus BSC alone. Data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) were used to inform estimates of clinical and utility values considering a 10-year time horizon and a weekly cycle length. Cost data were estimated from a collective perspective and included treatment acquisition, administration, follow-up, adverse event-related hospitalization, transport, post-progression, and end-of-life costs. Health outcomes were measured in quality-adjusted life-years (QALYs) and life-years gained. Costs and clinical outcomes were discounted at 2.5% per annum. Incremental cost-effectiveness ratios (ICERs) were used to compare cost-effectiveness and willingness to pay in France. Uncertainty was assessed using a range of sensitivity analyses. RESULTS: Avelumab plus BSC was associated with a gain of 2.49 QALYs and total discounted costs of €136,917; BSC alone was associated with 1.82 QALYs and €39,751. Although avelumab plus BSC was associated with increased acquisition costs compared with BSC alone, offsets of -€20,424 and -€351 were observed for post-progression and end-of-life costs, respectively. The base case analysis ICER was €145,626/QALY. Sensitivity analyses were consistent with the reference case and showed that efficacy parameters (overall survival, time to treatment discontinuation), post-progression time on immunotherapy, and post-progression costs had the largest impact on the ICER. CONCLUSIONS: This analysis demonstrated that avelumab plus BSC is associated with a favorable cost-effectiveness profile for patients with la/mUC who are eligible for 1L maintenance therapy in France.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

Patients with advanced cancer, previously treated with immune checkpoint blockade therapy, may retain residual treatment when undergoing the initial infusion of experimental monotherapy in phase 1 clinical trials. ANV419, an antibody-cytokine fusion protein, combines interleukin-2 (IL-2) with an anti-IL-2 monoclonal antibody, aiming to stimulate the expansion of CD8 T and natural killer lymphocytes while restricting regulatory T lymphocytes. In the recent publication of the phase 1 dose escalation study of ANV419, a notable gap exists in detailed information regarding patients' prior antitumoral treatments, specifically programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) targeted monoclonal antibodies. Some patients likely retained residual anti-PD-1/PD-L1 monoclonal antibodies, potentially influencing the outcomes of ANV419. In a separate clinical cohort, we retrospectively measured the residual concentration of nivolumab and pembrolizumab, revealing persistent serum concentrations of anti-PD-1/PD-L1 antibodies even months after treatment cessation. This underscores the importance of comprehensively documenting prior immunotherapy details in clinical trials. Such information is crucial for understanding potential interactions that may impact both immunological and clinical effects.