Citations

Abstract Background FGFR alterations are known to be driver alterations in several tumor types. We aimed to assess the efficacy of pemigatinib, an oral FGFR1-3 inhibitor, in patients with metastatic or unresectable colorectal cancer whose tumors harbored FGF/FGFR alterations. Patients and Methods The ACCRU-GI-1701 is a single-arm phase II trial which enrolled patients with previously treated FGF/FGFR-altered metastatic colorectal cancer to receive oral pemigatinib daily in 21-day cycles. The primary endpoint is objective response. Secondary endpoints include clinical benefit, progression-free survival, overall survival, quality of life, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04096417). Results Of the 14 patients included in the interim analysis, the objective response rate as well as clinical benefit rate were 0%. Given these results, the trial closed to enrollment after stage one due to futility. A total of 42.9% of patients had at least one grade 3 or higher AE, the most common being anemia and fatigue. Conclusion Pemigatinib monotherapy did not lead to objective responses in patients with chemorefractory metastatic colorectal cancer harboring FGF/FGFR alterations, although it was overall relatively well tolerated with no new safety signals. Notably, 93% (n = 13) of patients had only FGF/FGFR mutations and amplifications; one patient had an FGFR3-WHSC1 fusion at a low cfDNA percentage (0.02%).

Significance Statement Nephron number currently can be estimated only from glomerular density on a kidney biopsy combined with cortical volume from kidney imaging. Because of measurement biases, refinement of this approach and validation across different patient populations have been needed. The prognostic importance of nephron number also has been unclear. The authors present an improved method of estimating nephron number that corrects for several biases, resulting in a 27% higher nephron number estimate for donor kidneys compared with a prior method. After accounting for comorbidities, the new nephron number estimate does not differ between kidney donors and kidney patients with tumor and shows consistent associations with clinical characteristics across these two populations. The findings also indicate that low nephron number predicts CKD independent of biopsy and clinical characteristics in both populations. Background Nephron number can be estimated from glomerular density and cortical volume. However, because of measurement biases, this approach needs refinement, comparison between disparate populations, and evaluation as a predictor of CKD outcomes. Methods We studied 3020 living kidney donors and 1354 patients who underwent radical nephrectomy for tumor. We determined cortex volume of the retained kidney from presurgical imaging and glomerular density by morphometric analysis of needle core biopsy of the donated kidney and wedge sections of the removed kidney. Glomerular density was corrected for missing glomerular tufts, absence of the kidney capsule, and then tissue shrinkage on the basis of analysis of 30 autopsy kidneys. We used logistic regression (in donors) and Cox proportional hazard models (in patients with tumor) to assess the risk of CKD outcomes associated with nephron number. Results Donors had 1.17 million nephrons per kidney; patients with tumor had 0.99 million nephrons per kidney. A lower nephron number was associated with older age, female sex, shorter height, hypertension, family history of ESKD, lower GFR, and proteinuria. After adjusting for these characteristics, nephron number did not differ between donors and patients with tumor. Low nephron number (defined by <5th or <10th percentile by age and sex in a healthy subset) in both populations predicted future risk of CKD outcomes independent of biopsy and clinical characteristics. Conclusions Compared with an older method for estimating nephron number, a new method that addresses several sources of bias results in nephron number estimates that are 27% higher in donors and 1% higher in patients with tumor and shows consistency between two populations. Low nephron number independently predicts CKD in both populations. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_06_22_JASN0000000000000124.mp3

139 Background: The fibroblast growth factor receptor (FGFR) pathway plays a key role in cellular proliferation, migration, survival and angiogenesis. Aberrant signaling through FGFR in colorectal cancer and other malignancies results from gene amplification or mutation, chromosomal translocation or ligand-dependent activation of the receptors. Pemigatinib is an oral inhibitor of FGFR1-3 with proven efficacy in FGFR-altered cholangiocarcinoma and myeloid/lymphoid neoplasms, among others. We hypothesized that pemigatinib would improve response rates compared to historical controls in patients with refractory FGF/FGFR-altered mCRC. Methods: ACCRU-GI-1701 was a multicenter, single-arm, Simon’s two-stage phase II clinical trial (NCT04096417) of the FGFR inhibitor pemigatinib in patients (pts) with FGF/FGFR-altered mCRC. Eligible pts had received prior fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF/anti-EGFR/anti-PD-1 if eligible. Pts received pemigatinib 13.5 mg once daily on d1-21 of each cycle, with option to escalate to 18 mg in c2 if well tolerated. The primary endpoint was (unconfirmed) objective response (OR). A sample size of 21 evaluable pts would provide 82% power to detect a true OR rate of 20% or greater compared to a historical control of 5 % with a one-sided type I error rate of 0.1. A prespecified interim analysis for futility was planned after 12 evaluable patients. Results: A total of 14 patients were enrolled in the first stage of the study, and all were evaluable for the primary endpoint. No OR were observed (out of 12) crossing the futility boundary and resulting in permanent closure of the study. Among all enrolled patients, median age was 60.5 years, 71.4% were male, 92.9% Caucasian, 42.9% with no prior exposure to TAS-102 or regorafenib, and 64.3% with left-sided primary tumors. Treated patients all had tumors with FGFR1-4 mutations and/or FGF/FGFR amplifications by tissue- and/or blood-based molecular testing; no FGFR translocations were present. OR rate for this study was 0% (95% CI, 0-23.2%), with one patient achieving stable disease as best response. Median progression-free survival was 9.1 weeks (95% CI, 7.9-not evaluable [NE]), and median overall survival was 7.9 months (95% CI, 3.4-NE). Grade 3+ adverse events (AE) were seen in 42.9% of treated patients (including 1 grade 5 AE). Most commonly occurring AEs of any grade were anemia, hyperphosphatemia, alkaline phosphatase increased, aspartate aminotransferase increase, and fatigue. Conclusions: Pemigatinib demonstrated evidence of safety but not clinical activity in this population of patients with FGF/FGFR-altered mCRC. It is unknown whether pemigatinib would be active in mCRC patients with FGFR translocations/fusions as these were not represented in our trial. Translational studies are planned to investigate mechanisms of resistance to this therapy. Clinical trial information: NCT04096417 .

Fertilization, the fusion of sperm and oocyte to form a zygote, is the first and arguably the most important cell–cell interaction event in an organism’s life. Forward and reverse genetic approaches in the nematode Caenorhabditis elegans have identified many genes that are required for gametogenesis and fertilization and thus are beginning to elucidate the molecular pathways that underlie these processes. We identified an allele of the spe‐49 gene in a second filial generation (F2) mutagenesis screen for spermatogenesis‐defective (spe) mutants. Mutant worms for spe‐49 produce sperm that have normal morphology, activate to form ameboid spermatozoa, and can migrate to and maintain their position in the hermaphrodite reproductive tract but fail to fertilize oocytes. This phenotype puts spe‐49 in the spe‐9 class of late‐acting genes that function in sperm at the time of fertilization. We cloned the spe‐49 gene through a combination of deficiency mapping, transgenic rescue, and genomic sequencing. spe‐49 messenger RNA (mRNA) is enriched in male germ cells, and the complementary DNA (cDNA) encodes a predicted 772‐amino‐acid six‐pass transmembrane protein that is homologous to SPE‐42. Indeed, SPE‐49 and SPE‐42 have identical predicted membrane topology and domain structure, including a large extracellular domain with six conserved cysteine residues, a DC‐STAMP domain, and a C‐terminal cytoplasmic domain containing a C4–C4 RING finger motif. The presence of two SPE‐42 homologs in animal genomes from worms to humans suggests that these proteins are highly conserved components of the molecular apparatus required for the sperm–oocyte recognition, binding, and fusion.