Platinum-based chemotherapy is widely used in cancer care but carries a substantial risk of cochleotoxicity and vestibulotoxicity. This study aimed to characterize early (3-month) and long-term (1-year) auditory and vestibular effects of platinum derivatives in adults, with the goal of improving monitoring strategies. A total of 110 adults (34–81 years; 63 female) received cisplatin (n = 73), carboplatin (n = 22), or sequential cisplatin followed by carboplatin (ciscarbo; n = 15). Assessments at baseline, 3 months, and 1 year included conventional and extended high-frequency (EHF) audiometry, distortion product otoacoustic emissions (DPOAEs), speech perception, auditory brainstem response (ABR), and envelope following response (EFR). Vestibular testing comprised vHIT and cVEMP. Ototoxicity was classified using ASHA (1994) and graded with TUNE. Linear mixed models assessed treatment- and time-related changes. Cisplatin induced significant threshold shifts across the audiogram, including low, mid, high, and extended high frequencies, with progression up to 1 year. Low- and mid-frequency thresholds remained largely stable in the carboplatin group, while the ciscarbo group showed early mid- and EHF deterioration. EHF thresholds increased across all groups. ASHA-defined ototoxicity was present in 73.5

BACKGROUND:Papillary renal cell cancer (pRCC) represents the largest subgroup within non-clear cell (ncc) RCC. Compared with clear cell RCC (ccRCC), pRCC is considered less sensitive to currently available systemic therapies. Here, we report exploratory results from the pRCC subgroup of the SUNNIFORECAST trial comparing ipilimumab/nivolumab with standard of care (SOC) based on central pathological review. METHODS AND PATIENTS:SUNNIFORECAST was a prospective, investigator-initiated, phase II trial evaluating ipilimumab/nivolumab versus SOC in patients with untreated, advanced nccRCC. The primary endpoint was the 12-month overall survival (OS) rate. Secondary endpoints included OS, progression-free survival (PFS), and overall response rate (ORR). PD-L1 expression was assessed exploratory. RESULTS:Of 309 randomized patients, 127 had confirmed papillary histology, in 56/173 cases the local diagnosis of pRCC required revision. Among the 127 patients with pRCC, 64 received ipilimumab/nivolumab and 63 SOC, predominantly TKI monotherapy. In the pRCC subgroup, the 12-month OS rate was 74.77% in the ipilimumab/nivolumab arm and 63.44% in the SOC arm (p = 0.085). Median OS was 24.89 months with ipilimumab/nivolumab versus 18.88 months with SOC. PD-L1 expression was evaluable in 116 of 127 patients. A CPS > 1 was more frequently observed with increasing IMDC risk category. Among patients with CPS < 1, the 12-month OS rate was 75.00% with ipilimumab/nivolumab and 68.36% with SOC (p = 0.963). In patients with CPS > 1, the 12-month OS rate was 82.38% in the ipilimumab/nivolumab arm and 63.33% in the SOC arm. DISCUSSION:This exploratory analysis has several limitations; however, it suggests that patients with pRCC treated with ipilimumab/nivolumab may derive a benefit in terms of 12-month OS rate, median OS, and ORR compared with SOC, particularly among those with CPS > 1. (Funded by Bristol Myers Squibb grant CA209-499; ClinicalTrials.gov, EUDRACT Number: 2016-000706-12; NCT03075423.).

Synthetic data have been proposed to facilitate data sharing in privacy-sensitive contexts, including clinical trials. It remains unclear, however, how well original treatment effect estimates can be replicated in synthetic data analyses. Therefore, we synthesized and reanalyzed 128 treatment comparisons from 115 phase 3 randomized oncology trials using sixteen different generative models. Our findings demonstrate that careful methodological choices are essential for drawing valid statistical conclusions from synthetic data analyses. Naive analyses frequently yield falsely significant treatment effects, occurring in up to half of the trials created by deep generative models. Correcting standard errors to reflect the uncertainty inherent in synthetic data generation reduces these false positives, but primarily suffices for trials generated by parametric models. Although this correction entails some power loss, it can be mitigated by increasing the synthetic sample size. Thus, at present, large synthetic trials generated by parametric models and analyzed with corrected standard errors are more likely to preserve inferential utility. Advancing valid statistical inference from synthetic data created by deep generative models remains an important direction for future research.

To evaluate the feasibility of incorporating both standard and novel audiological and vestibular assessments into routine oncology care. A secondary objective was to characterize audiovestibular status prior to platinum-based chemotherapy and identify potential risk factors for cochleotoxicity and vestibulotoxicity. This single-center, cross-sectional prospective study enrolled 110 adults scheduled for their first platinum-based chemotherapy cycle. All assessments were performed at one time point prior to treatment initiation. Pre-treatment assessments included tympanometry, pure-tone audiometry, speech audiometry in quiet and noise (SPIQ and SPIN), distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs), envelope following responses (EFRs), video head impulse testing (vHIT), and cervical vestibular evoked myogenic potentials (cVEMP). All patients underwent tympanometry and pure-tone audiometry. A broader audiological test battery was completed in 96 patients (87.3

Abstract 5T4, a Type I transmembrane glycoprotein, has limited expression in normal adult tissues but is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 and WNT signaling pathways contributing to epithelial to mesenchymal transition and correlates with poorer clinical outcomes among a range of cancers, such as NSCLC, CRC and ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels and poor intrinsic internalization kinetics. Patients with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive intravenous JK06 monotherapy once every 3 weeks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two dose levels to identify RP2D in NSCLC and breast cancer. Fresh and archival tumor biopsies are collected for retrospective correlation of 5T4 expression to efficacy and safety. Responses are assessed every 9 weeks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. To date, sixty-nine (69) refractory metastatic solid tumor patients (n = 38 in dose escalation; n = 31 in cohort expansions) have been treated, median age of 61.5 years and > 74% of treated patients have had ≥ 3 prior lines of therapy. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (30%), alopecia (16%), decreased appetite (10%), dry eye (10%) and peripheral sensory neuropathy (PSN) (10%). At the target doses being considered for optimization, four patients (out of 62 treated patients) have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, keratitis and PSN, that resolved, with one able to continue treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Three patients underwent dose reductions, and three additional patients were discontinued due to TRAEs. One patient sustained Gr 5 treatment-related pneumonitis at a higher dose that is not being evaluated in cohort expansion. Among 13 response-evaluable NSCLC patients in dose escalation, a 38% ORR has been observed, with 1 confirmed complete response (cCR) and 4 confirmed partial responses (cPR) (one with CNS response), with the longest continuing therapy for 51 weeks. One of six evaluable breast cancer patients (17% ORR) achieved a cPR and remained on treatment for > 27 weeks. To date, JK06 demonstrates promising clinical activity among refractory NSCLC and breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated dose escalation data and initial expansion cohort data will be presented. Citation Format: Omar Saavedra, Fabricio Racca, Valentina Boni, Emiliano Calvo, Brant Delafontaine, Sylvie Rottey, Bernd Dekeyser, Hans Prenen, Maria deMiguel, Valentina Gambardella, Lionel d'Hondt, Vladimir Galvao, Judit W. Johnson, Jonathan P. McNally, Jennifer Lindelien, Alice Drumheller, Jijun Dong, Samuel P. Murphy, Shalabh Singhal, Naimish Pandya, Nuria Kotecki. A phase 1b / 2 study of JK06, a 5T4-targeted antibody drug conjugate, in patients with unresectable locally advanced or metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT250.

e16591 Background: Limited biomarkers are available to predict response and outcome in metastatic urothelial carcinoma (mUC) patients treated with pembrolizumab. The Belgian multicenter CORPORA study evaluates the use of tissue, plasma and urine RNA as companion diagnostic in this setting. Results for plasma and urine will be presented. Methods: Baseline plasma (n = 41) and urine (n = 27) were prospectively collected in mUC patients receiving pembrolizumab (200 mg Q3W). Cell-free RNA (cfRNA) isolation and library prep, using Illumina RNA prep with enrichment, was followed by short read RNA sequencing (15M reads/sample). Data analysis included principal component analysis (PCA), differential gene expression (DGE), and gene set enrichment analysis (GSEA). Association to response (RECIST 1.1), survival, and occurrence of immune-related adverse events (irAEs) was determined. Results: PCA of plasma and urine did not reveal any sample clustering. Further downstream DGE indicated no significant difference in plasma cfRNA single gene abundance for response, outcome, or irAEs. In contrast, DGE in urine identified four significantly downregulated genes ( C12orf75 , RPS28P7 , ENSG00000267469 , RPL36AP37 ) and one significantly upregulated gene ( CIDEC ) that differentiate responders from non-responders. Regarding outcome, 5 genes ( ALKBH8 , FSIP1 , GDE1 , HMGB3 , and RHOU ) were identified as candidates for progression-free survival (PFS) and overall survival (OS, Table). A total of 271 genes, including the five genes identified for outcome, were significantly differentially abundant between patients who developed grade 3+ irAEs compared to those with milder grade 1-2 toxicity. GSEA indicated responders to exhibit cellular reprogramming toward enhanced metabolic fitness and tissue remodeling, whereas non-responders show a more stress-associated transcriptional state with altered immune, cell death, and mitochondrial respiration programs. Development of irAEs on the other hand was associated with broad immune hyperactivation and tissue remodeling programs, accompanied by suppression of mitochondrial oxidative metabolism. Conclusions: Urinary cfRNA contains candidate biomarkers for pembrolizumab response prediction, prolonged survival, and the occurrence of more severe irAEs. Further research is ongoing, including comparison to tissue RNA, and study of circular RNA, fusion genes, and immune cell enumeration via deconvolution. Cox regression univariate analysis for urine mRNA and survival. PFS OS Gene HR (95% CI)* P HR (95% CI)* P ALKBH8 0.46 (0.27-0.78) 0.004 0.58 (0.35-0.95) 0.030 FSIP1 0.55 (0.31-0.96) 0.036 0.37 (0.19-0.71) 0.003 GDE1 0.49 (0.25-0.94) 0.032 0.53 (0.29-0.96) 0.037 HMGB3 0.51 (0.31-0.84) 0.009 0.36 (0.17-0.73) 0.005 RHOU 0.57 (0.34-0.94) 0.028 0.38 (0.19-0.79) 0.009 *HRs representing change in risk per one standard deviation increase in gene expression.

PURPOSE:The Belgian Precision initiative aims to implement tumor-agnostic next-generation sequencing (NGS) in patients with advanced cancer and expand genotype-matching drug availability. The present investigator-driven trial aimed to study the efficacy of afatinib in patients with advanced solid tumors harboring an activating HER2, EGFR, or HER3 mutation. PATIENTS AND METHODS:This open-label phase II trial has three cohorts: HER2-, EGFR-, and HER3-mutated previously treated solid tumors. The primary end point was objective response rate (ORR). For each cohort, a Simon two-stage design was used. Observation of ≥2 responses in the first 10 patients prompted a further 19 to be included. Secondary end points were disease control rate (DCR), duration of response (DOR), progression-free survival, overall survival, and safety. RESULTS:A total of 45 patients were included, with a median age of 62 years. For the HER2 cohort (n = 30), ORR was 3.3% (one partial response) and DCR was 23.3%. In the EGFR cohort, a total of seven patients were included, resulting in an ORR in 2/7 (28.6%) patients, with a DOR of 6.6 and 15.4 months. In the HER3 cohort, a total of eight patients were included, but none demonstrated an objective response. Safety data were consistent with the known safety profile of afatinib. CONCLUSION:The present phase II study, investigating afatinib in HER2-, EGFR-, orHER3-mutant pretreated solid tumors did not reach its primary end point in the HER2 cohort. Neither the EGFR nor the HER3 cohort reached full accrual, but clinically meaningful responses were observed in two EGFR-mutated patients. Further exploration of HER targeting in solid tumors is warranted.

Immune cells expressing the adenosine A2A receptor (A2AR) and A2B receptor (A2BR) present in an adenosine-rich tumor microenvironment have suppressed effector functions, such as proinflammatory cytokine release, antigen presentation, and others, making them inert to cancer cells. Simultaneous blockade of the downstream effects mediated by both receptor subtypes with a dual inhibitor has the potential to reverse adenosine-mediated suppression of tumor immune surveillance as either a single-agent treatment or in combination with other immunotherapy agents such as anti-PD-1/PD-L1 monoclonal antibodies. This publication describes the discovery and optimization of a novel series of potent and selective dual A2AR/A2BR antagonists, resulting in compound 46 (MK-1088) being identified for progression to human clinical studies.

3038 Background: 5T4, a Type I transmembrane glycoprotein, is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 & WNT signaling pathways contributing to epithelial to mesenchymal transition contributing to metastatic progression & correlates with poor clinical outcomes among a range of cancers, such as NSCLC, CRC & ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels & poor intrinsic internalization kinetics. Methods: Pts with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive IV JK06 monotherapy once every 3 wks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two doses of JK06 to identify an RP2D in NSCLC & breast cancer. Fresh & archival tumor biopsies are being collected for retrospective correlation of 5T4 expression to efficacy & safety. Responses are assessed every 9 wks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. Results: To date, 80 refractory metastatic solid tumor pts (n = 39 in dose esc; n = 41 in cohort expansions) have been treated, median age of 60 yrs, >70% treated with ≥ 3 prior lines of therapy, including >75% of treated pts with prior taxane exposure. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (35%), alopecia (18%), decreased appetite (18%), dry eye (10%) & peripheral sensory neuropathy (PSN) (9%). Among 70 pts have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, gait disturbance, keratitis, vomiting, corneal ulcer, & PSN, that resolved, with two continuing treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Four pts underwent dose reductions, and five additional pts were discontinued due to TRAEs. Among 19 response-evaluable NSCLC pts to date, a 32% ORR has been observed, with 1 confirmed complete response (cCR), 4 confirmed partial responses (cPR) (one with CNS response) & 1 with unconfirmed partial responses (uPR), with the longest continuing therapy for 51 wks. Responses have been observed in adenomatous, squamous & EGFR mutant NSCLC pts. One of seven evaluable breast cancer pts (14% ORR) achieved a cPR and remained on treatment for >27 wks. Conclusions: To date, JK06 demonstrates promising emerging clinical activity in refractory NSCLC & breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated safety & clinical activity data from both dose escalation & expansion cohorts, including the initial assessment of dose randomization, will be presented. Clinical trial information: NCT06667960 .

Background Patients with advanced cancer participating in phase I clinical trials often face limited survival while experiencing significant symptom burden. Despite evidence supporting early palliative care integration alongside active cancer treatment to improve quality of life, the role of palliative care in phase I trials remains unclear.Objective To explore perspectives of patients, informal caregivers, and healthcare providers on quality of life and palliative care in phase I oncology trials, including perceived benefits, barriers, and integration strategies.Methods We conducted a multi-perspective qualitative interview study across three Belgian university hospitals from September 2022 to July 2024, using convenience and snowball sampling. The semi-structured interviews were analyzed using qualitative content analysis. Ethical approval was gained from the relevant institutions.Results Participants included sixteen patients, five informal caregivers, twelve phase I staff, six oncologists, five palliative care specialists, and four general practitioners. Patients generally reported positive experiences with trial participation, often viewing it as a final opportunity that provided hope and structure. However, quality of life support was inconsistently addressed and largely reactive. While patients reported feeling supported, non-trial providers and caregivers noted limited person-centered care. No systematic approach for introducing palliative care was in place. Palliative care was rarely discussed, hindered by misconceptions such as equating palliative care with terminal care, reluctance from patients and clinicians, and lack of communication between providers. Participants suggested the introduction of routine yet flexible palliative care conversations, as well as improved communication between providers, as strategies towards integration.Conclusion Despite recognized care needs, palliative care is not systematically integrated in phase I oncological trials. Quality of life remains a secondary concern. Integrating palliative care in a structured yet flexible manner could support more holistic, patient-centered care. These findings underscore the need to normalize palliative care as a complementary component of phase I oncological trials.

Background/Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care for muscle-invasive bladder cancer (MIBC) for two decades, yet a substantial proportion of patients derive no benefit. As antibody–drug conjugates and immune checkpoint inhibitors reshape perioperative treatment, it is unclear which patients retain meaningful benefit from platinum. We describe long-term outcomes and exploratory paired immune and genomic analyses in a single-centre cohort treated with dose-dense MVAC (dd-MVAC). Methods: We retrospectively identified 54 consecutive patients with MIBC treated with neoadjuvant dd-MVAC between November 2013 and November 2019. Forty-two underwent radical cystectomy and are assessable for pathologic response. Immunohistochemistry for CD3, CD8, FOXP3, PD-1, PD-L1, PD-L2, and NY-ESO-1 was evaluable in 31 baseline specimens and 22 paired specimens; paired genomic profiling was evaluable in 12 cases, with paired tumour mutational burden (TMB) in 10 by whole-exome sequencing and 7 by TSO-500. Paired analyses necessarily exclude patients achieving a pathologic complete response (pCR), who have no residual tumour, and most early progressors. Results: pCR was achieved in 11/42 operated patients (26%, 95% CI 15–41). Median follow-up was 87 months (IQR 24–104). Hydronephrosis was the only baseline factor associated with absence of pCR (p = 0.016). Within the operated cohort, pCR was associated with longer recurrence-free survival (log-rank p = 0.017), but the difference in overall survival did not reach significance (p = 0.121). NAC reduced intratumoral FOXP3 (q = 0.001), NY-ESO-1 (q = 0.013), PD-L2 (q = 0.013), and CD3 (q = 0.043) after correction for multiple comparisons, whereas TMB showed no significant change (TSO-500 p = 0.67; WES p = 0.86). No statistically significant association was detected between any baseline immune marker, including PD-L1, and pCR. The mutational landscape was largely concordant before and after NAC. Conclusions: This study was exploratory and was not powered to validate predictive biomarkers. In this long-term cohort, dd-MVAC was associated with measurable depletion of intratumoral immune populations in chemoresistant tumours, while paired genomic profiles remained broadly concordant. No pre-treatment biomarker identified platinum-refractory patients, but the small evaluable subsets mean these are hypothesis-generating rather than negative findings, and prospective studies with pre-specified biomarker endpoints are required.

MK-7602 is a first-in-class dual-plasmepsin inhibitor being developed to treat malaria. Safety, tolerability, and pharmacokinetics (PK) of MK-7602 following single and multiple doses were evaluated in two phase 1 studies (7602-001; 7602-002). Study 7602-001 included two parts: part 1, a randomized, single-ascending-dose (10-400 mg), placebo-controlled, double-blind study (n = 24); and part 2, a non-randomized, fixed-sequence, open-label study (n = 12) to assess the effect of itraconazole (200 mg), a cytochrome P450 3A and P-glycoprotein inhibitor, on the PK of MK-7602 (25 mg). Study 7602-002 was a randomized, placebo-controlled, multiple-ascending-dose study (n = 40); participants received MK-7602 (50-300 mg) or placebo for 7 days. Single and multiple doses of MK-7602 were generally well tolerated. Headaches were the most common adverse event (7602-001 part 1: 54.5%; 7602-002: 36.7%). MK-7602 median time to maximal concentration (Tmax) was 1.5-3.0 h, with dose-proportional increases in maximum concentration (Cmax) and the area under the curve over the dosing interval (AUC0-tau) at single and multiple doses of ≥50 mg. Terminal half-life was 31.3-41.4 h following multiple dosing, the accumulation ratio for daily dosing was 1.03-2.20, and steady-state concentrations were reached by day 3. Coadministration with itraconazole resulted in a 6- and 12-fold increase in Cmax and area under the concentration-time curve to infinity, respectively. The primary hypothesis that a well-tolerated dose of MK-7602 would achieve a trough concentration of ≥0.017 μM was met in both studies. Safety and PK characteristics support continued development of MK-7602.

Abstract Background Belzutifan plus lenvatinib significantly improved progression-free survival and objective response rate versus cabozantinib, and had manageable safety, in participants with advanced renal cell carcinoma (RCC) that progressed on or after anti-programmed cell death protein 1 and anti-programmed cell death ligand 1 (anti–PD-[L]1) therapy in the phase 3 LITESPARK-011 study (NCT04586231). We report health-related quality of life (HRQoL) outcomes from LITESPARK-011. Methods Participants ≥18 years of age with advanced RCC that progressed on or after anti–PD-(L)1 therapy as the immediate prior treatment were randomly assigned 1:1 to receive belzutifan 120 mg plus lenvatinib 20 mg by mouth once daily or cabozantinib 60 mg by mouth once daily. HRQoL was evaluated in participants who received ≥1 dose of study treatment and completed ≥1 patient-reported outcome (PRO). Prespecified exploratory end points included time to deterioration (TTD) and least squares mean (LSM) change from baseline in Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index-Disease Related Symptoms (FKSI-DRS), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status/quality of life (GHS/QoL), physical functioning, and role functioning subscales. Questionnaires were completed electronically on day 1 of week 1, 3, 5, and 9, every 4 weeks thereafter, at treatment discontinuation, and 30 days after last dose. The analysis timepoint was week 45 (last timepoint where completion and compliance rates of ∼60% and ≥80%, respectively, were observed). PROs were not formally statistically tested. Results The PRO analysis population included 731 participants (n = 365, belzutifan plus lenvatinib; n = 366, cabozantinib). At data cutoff (Apr 9, 2025), median study follow-up was 29.0 months (range, 19.3-49.2). Completion rates for FKSI-DRS and QLQ-C30 were >85% at baseline (compliance >86%) and >55% at week 45 (compliance >89%) in each arm. TTD and LSM change from baseline in FKSI-DRS, QLQ-C30 GHS/QoL, physical functioning, and role functioning scores were similar between arms (Table). Conclusions Belzutifan plus lenvatinib had similar TTD for FKSI-DRS, and GHS/QoL, physical functioning, and role functioning versus cabozantinib. LSM changes in HRQoL and disease-specific symptoms from baseline to week 45 were also similar for both arms. Combined with efficacy and safety data, results support belzutifan plus lenvatinib as a new treatment option for advanced RCC that progressed after anti–PD-(L)1 therapy. 2026 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2026 ASCO Annual Meeting. All rights reserved.

Background/Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care for muscle-invasive bladder cancer (MIBC) for two decades, yet a substantial proportion of patients derive no benefit. With antibody–drug conjugates and immune checkpoint inhibitors now reshaping the treatment landscape, characterising the determinants of platinum resistance and the consequences for treatment sequencing has become clinically pressing. We aimed to describe, in a single-centre cohort with long follow-up, the patient trajectories, survival, immune microenvironment, tumour mutational burden (TMB) and genetic alterations associated with response to NAC. Methods: We retrospectively identified 54 consecutive patients with MIBC treated with neoadjuvant dose-dense MVAC (dd-MVAC) between November 2013 and November 2019. Pathologic response, recurrence, survival and subsequent therapy lines were recorded. Immunohistochemistry for CD3, CD8, FOXP3, PD-1, PD-L1, PD-L2 and NY-ESO-1, and paired genetic profiling (whole-exome sequencing and TSO-500) were performed on transurethral resection (TURBT) and cystectomy specimens. Marker changes after NAC were tested with Wilcoxon signed-rank tests; associations with pathologic complete response (pCR) with Fisher exact and Mann–Whitney tests; survival differences with the log-rank test. Results: pCR was achieved in 11/42 operated patients; 12 patients did not undergo cystectomy. Median follow-up was 87 months (IQR 24–104). Hydronephrosis (p = 0.016) was associated with absence of pCR. Overall and recurrence-free survival differed significantly by pathologic response (log-rank p = 0.040 and p = 0.026). NAC significantly reduced intratumoral FOXP3 (p < 0.001), NY-ESO-1 (p = 0.004), PD-L2 (p = 0.007) and CD3 (p = 0.029), whereas TMB was unchanged (TSO-500 p = 0.67; WES p = 0.86). No baseline immune marker, including PD-L1, predicted pCR. The mutational landscape was largely concordant before and after NAC. Conclusions: NAC remodels the bladder cancer immune microenvironment without altering the tumour genome or TMB. Baseline immune and genomic markers did not identify platinum-refractory patients, underscoring the need for better predictive biomarkers to guide patient selection and treatment sequencing in the antibody–drug conjugate era.

BACKGROUND:Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. METHODS:Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). RESULTS:Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. CONCLUSIONS:Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.

BACKGROUND:Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined subgroup of non-clear cell RCC (nccRCC) lacking an approved standard treatment. We report the exploratory analysis of this entity within the SUNNIFORECAST trial. METHODS:SUNNIFORECAST evaluated ipilimumab/nivolumab versus standard of care (SOC) in previously untreated, advanced nccRCC. The primary endpoint was the 12-months overall survival (OS) rate. Secondary endpoints included median OS, progression free survival (PFS) and overall response rate (ORR). PD-L1 expression was assessed exploratorily. RESULTS:Of 309 randomized patients, 30 had centrally confirmed FH-deficient RCC (ipilimumab/nivolumab, n=14; SOC, n= 16). The 12-months OS rate was 85.7% (95% confidence interval [CI] 53.9-96.2%) versus 73.3% (95% CI 43.6-89.1%), median OS was 35.7 months (95% CI 16.8 months-NE) versus 24.7 months (95% CI 10.6-37.7 months, hazard ratio [HR] 0.46 [0.17-1.20]), and ORR 42.9% versus 33.3%, favoring ipilimumab/nivolumab. Twenty-four patients were evaluable for PD-L1 expression; 21 had a combined positive score (CPS) ≥1. In this subgroup, the 12-months OS rate was 80.0% (95% CI 40.9-94.6%) versus 72.7% (95% CI 37.1-90.3%), median OS 38.3 months (95% CI 8.8 months-NE) versus 24.7 months (95% CI 8.8 months-NE, HR 0.43 [0.14-1.34]) and ORR 40.0% versus 36.4% for ipilimumab/nivolumab versus SOC, respectively. INTERPRETATION / DISCUSSION:Exploratory analyses suggest trends toward improved 12-months OS-rate, median OS and ORR with ipilimumab/nivolumab versus SOC in FH-deficient RCC. The majority of tumors demonstrated PD-L1-expression (e.g. CPS ≥ 1), warranting further investigation in prospective studies.