Zakharia, Yousef

Background Immune checkpoint inhibitor-based combinations represent the standard of care for advanced renal cell carcinoma. The OMNIVORE trial investigated a response-adaptive strategy, including treatment discontinuation in early nivolumab responders (Arm A) and salvage ipilimumab addition in non-responders (Arm B). Here we report outcomes with extended follow-up. Methods OMNIVORE was a phase II response-adaptive trial in which patients received induction nivolumab monotherapy. Patients achieving a confirmed complete or partial response discontinued nivolumab and entered observation (Arm A), while patients with stable disease or progressive disease received two doses of ipilimumab added to ongoing nivolumab (Arm B). This analysis characterizes long-term overall survival across the full study cohort and durability of response among patients who discontinued nivolumab following an early objective response. Results Of 83 patients who initiated treatment, 12 (14%) were allocated to Arm A and 57 (69%) to Arm B, with a median follow-up among living patients of 59.4 months (range 29.1–85.4 months) in Arm A and 31.4 months (range 4.6–62.6 months) in Arm B. The 3-year overall survival rate from nivolumab initiation was 64% (95% CI 51% to 74%) in the overall cohort, 83% (95% CI 48% to 96%) in Arm A, and 63% (95% CI 47% to 76%) in Arm B. Of the 12 Arm A patients, 6 (50%) remained off nivolumab at 1 year following treatment discontinuation, of whom 5 maintained responses beyond 43 months off therapy, with all remaining alive at last known follow-up, with overall survival ranging from 48.8 to 85.4 months from nivolumab initiation. Of the six patients who resumed treatment, only one achieved a durable complete response remaining on treatment at 83.2 months from nivolumab initiation. All 57 Arm B patients discontinued treatment with a median treatment duration of 3.7 months (range 1–24.8 months) and a median progression-free survival from nivolumab plus ipilimumab initiation of 4.6 months (95% CI 2.7 to 6.5 months). Conclusions With extended follow-up, a meaningful subset of patients achieving an early objective response to nivolumab maintained prolonged treatment-free survival following a short course of treatment. Salvage ipilimumab in nivolumab non-responders demonstrated limited benefit, reinforcing that upfront concurrent dual checkpoint blockade remains the preferred approach. Trial registration number NCT03203473 .

Adoptive cellular immunotherapy (ACT) has revolutionized hematologic malignancies, yet translation to solid tumors has historically been limited. This landscape shifted significantly in 2024 with US Food and Drug Administration approvals of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel, an engineered T-cell receptor (TCR) therapy for synovial sarcoma. These approvals mark the clinical arrival of ACT for solid tumors and highlight a rapidly expanding therapeutic landscape. Beyond these indications, multiple ACT platforms including TIL, TCR, chimeric antigen receptor (CAR) T-cell, CAR-natural killer, and CAR-macrophage therapies are under active clinical investigation across diverse solid tumor indications. Clinical experience to date has defined key barriers to efficacy, including impaired tumor trafficking, antigen heterogeneity, immunosuppressive tumor microenvironment, and limited cellular persistence. In parallel, rapid advances in cellular engineering are reshaping the field, with the development of armored constructs, logic-gated and multiantigen targeting strategies, innate immune–based platforms, and novel manufacturing approaches including allogeneic and in vivo cell engineering. As ACT enters clinical practice for select solid tumors, distinct toxicity profiles and logistical requirements necessitate careful patient selection and multidisciplinary coordination. Early biomarker testing, timely referral to specialized centers, and familiarity with evolving toxicity management frameworks are increasingly critical. Here, we seek to provide a practice-oriented framework for understanding emerging ACT platforms, clinical data, toxicity considerations, and implementation strategies relevant to contemporary solid tumor oncology care.

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety.

Abstract Purpose: Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients and Methods: Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. Results: No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent. Conclusions: SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Abstract Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines—RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL—and in the four ccRCC with sarcomatoid differentiation—RCJ41T1, RCJ41T2, RCJ41M, and UOK-127—indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Abstract Lessons Learned Background Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

BackgroundSystemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow‐growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature.MethodsThis was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient‐related outcomes. Wilcoxon 2‐sample rank‐sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan‐Meier survival curves were used to assess survival.ResultsOf 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25‐44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST.ConclusionsAS occurs frequently (32%) in real‐world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.