Supplementation with CBM588, a bifidogenic live bacterial product, has been associated with improved clinical outcomes in persons with metastatic renal cell carcinoma (mRCC) receiving nivolumab and ipilimumab. However, its effect on those receiving tyrosine kinase inhibitor-based combinations is unknown. In this open-label, randomized, investigator-initiated, phase 1 study, 30 participants with locally advanced or mRCC with histological confirmation of clear cell, papillary or sarcomatoid component were randomized in a 2:1 fashion to receive cabozantinib (an inhibitor of vascular endothelial growth factor receptor, MET and AXL) and nivolumab (anti-programmed cell death protein 1) with or without CBM588 as first-line treatment. Metagenomic sequencing was performed on stool samples to characterize their gut microbiome at baseline and 13 weeks into treatment. The primary endpoint was a change in the relative abundance of Bifidobacterium spp.; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and toxicity profile. The primary endpoint of the study was not met and the addition of CBM588 to cabozantinib and nivolumab did not result in a difference in the relative abundance of Bifidobacterium spp. or alpha diversity (as measured by the Shannon index). However, ORR was significantly higher in participants treated with CBM588 compared to those in the control arm (14 of 19, 74% versus 2 of 10, 20%; P = 0.01). PFS at 6 months was 84% (16 of 19) and 60% (6 of 10) in the experimental and control arms, respectively. No significant difference in toxicity profile was seen between the study arms. Our results provide a preliminary signal of improved clinical activity with CBM588 in treatment-naive participants with mRCC receiving cabozantinib and nivolumab. Further investigation is needed to confirm these findings and better characterize the underlying mechanism driving this effect.ClinicalTrials.gov identifier: NCT05122546

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was −0.7 (range: −9.3 to 4.7) with R223+P and 0.1 (−11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was −0.6 (−7.4 to 5.3) with R223+P and −1.3 (−3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7–11.0) and 16.9 months [12.7–not reached (NR)], respectively, with R223+P and 5.7 (2.6–NR) and 16.0 (9.0–NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.

The CHAARTED trial investigated the long-term survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) with or without docetaxel (D). This analysis focuses on 10-year overall survival (OS) stratified by disease volume and on-therapy PSA levels at 6 months. OS was calculated using the Kaplan-Meier method from randomization to death or last known alive date. Patients were grouped based on baseline disease characteristics (high-volume/HV or low-volume/LV) and PSA levels at 6 months (<0.2 ng/mL vs. ≥0.2 ng/mL). Multivariable Cox regression analysis was used to evaluate correlation of PSA nadir with overall survival (OS) adjusted for treatment arm, disease volume, Gleason score, and prior local therapy. Of 790 patients, 225 were without recorded death after a median follow-up of 10 years. The 10-year OS was 25.9% (ADT+D) vs. 22.5% (ADT; HR: 0.78; p=0.004). HV patients treated with docetaxel had significantly higher OS (20.9% vs. 11.4%; p<0.0001). PSA <0.2 ng/mL at 6 months was associated with improved median OS in both ADT+D (100.3 vs. 45.4 months; p<0.0001) and ADT (116.8 vs. 31.8 months; p<0.0001) arms. PSA nadir <0.2 at 6 months was an independent predictor of improved OS (HR: 0.41; p<0.0001) adjusting for disease volume, prior local therapy, gleason score and treatment arm. Long-term follow-up confirms that ADT+D significantly improves OS in mHSPC patients with in HV disease. PSA nadir <0.2 ng/mL at 6 months is a strong prognostic marker for OS, supporting its use in response-adapted de-escalation strategies.

Summary: Facchinetti and colleagues provide key insights into the evolution of resistance to fibroblast growth factor receptor (FGFR) inhibitors, including the development of kinase domain mutations and activation of the PI3K–AKT signaling axis. In a separate study, Subbiah and colleagues report extensive preclinical data and initial clinical data for RLY-4008, an FGFR2-selective inhibitor that is poised to minimize toxicity and overcome resistance through greater potency and selectivity. See related article by Facchinetti et al., p. 1998 (5). See related article by Subbiah et al., p. 2012 (7).

Purpose of review: Antibody-drug conjugates (ADCs) are designed to carry cytotoxic payloads and deliver them to specific molecular targets within tumor cells. Several ADCs are already approved with many more in development across several disease types. In this review, we will provide an overview of the ADCs currently approved and those under investigation in solid tumors. Recent findings: Currently there are dozens of ADCs under clinical study evaluation of a variety of solid tumors, and preliminary results are promising. Multiple ADCs have received regulatory approval in disease such as breast cancer, non-small cell lung cancer, and bladder cancer. While some are approved in biomarker selected settings with disease specific indication (e.g. breast cancer), others have been approved irrespective of biomarker expression (urothelial carcinoma) and pan-cancer indications in biomarker selected patients (HER2 3+ expression). Summary: Cytotoxic chemotherapy has been the mainstay of systemic treatment for patients with various solid tumors. ADCs offer the advantage of carrying the cytotoxic payload onto a specific molecular receptor, thereby inducing a more selective response. Optimizing selection of target antigen, payload delivery and investigating biomarkers of response will be crucial for further expanding the therapeutic benefit of ADCs across solid tumors.