Background Circulating tumor DNA (ctDNA) testing can identify molecular residual disease after radical cystectomy for muscle-invasive bladder cancer (MIBC), yet it remains unknown how clinicians have adopted it into practice. We evaluated trends in ctDNA testing and its association with adjuvant therapy. Materials and methods Using the Flatiron Health Research Database, we identified adults with nonmetastatic MIBC diagnosed on or after 1 January 2021, who underwent radical cystectomy and had at least 12 weeks of observable follow-up. The primary exposure was a documented postcystectomy ctDNA result (Signatera), defined by a result report 4-24 weeks after cystectomy. Logistic regression evaluated trends in documented results. Modified Poisson regression estimated adjusted risk ratios (RRs) for adjuvant therapy within 24 weeks among patients whose ctDNA result preceded the treatment decision. Results Among 4533 patients, the median age was 70 years, 77.4% were male, and 74.6% were White. The odds of a documented ctDNA result increased by 16% per calendar quarter [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.13-1.19]. Patients with high-risk pathology were nearly twice as likely to have a documented result (9.0% versus 5.3%; RR 1.71, 95% CI 1.35-2.17). Patients with a documented result more often received adjuvant therapy than patients without (49.6% versus 33.5%; RR 1.48, 95% CI 1.32-1.66). Among 200 patients whose ctDNA result preceded the treatment decision, detectable ctDNA (n = 59) was associated with greater adjuvant therapy use in unadjusted analysis (45.8% versus 21.3%; RR 2.15, 95% CI 1.41-3.28), but this association was attenuated and no longer significant after adjustment (adjusted RR 1.34, 95% CI 0.89-2.02). High-risk pathology remained strongly associated with treatment (adjusted RR 9.45, 95% CI 3.07-29.10). Conclusions Postcystectomy ctDNA testing increased rapidly, particularly among patients with high-risk pathology. Pathologic risk remained the factor most strongly associated with adjuvant treatment, whereas the association with detectable ctDNA was attenuated after adjustment, although precision was limited.
Background The prognostic significance of programmed death-ligand 1 (PD-L1) in high-grade serous ovarian cancer (HGSOC) remains uncertain, because of heterogeneity in assays, scoring systems, and assessment of tumor and immune compartments across studies. We therefore evaluated its biological and prognostic relevance using a standardized pathological approach in a large, well-annotated phase III trial cohort. Materials and methods In this ancillary retrospective biomarker analysis of PAOLA-1/ENGOT-ov25, PD-L1 was assessed by 22C3 pharmDx immunohistochemistry on whole-slide sections from 324 International Federation of Gynecology and Obstetrics stage III-IV HGSOCs. Three predefined scoring systems commonly used in PD-L1 assessment were applied: tumor proportion score (TPS ≥1%), immune cell score (IC ≥1%), and combined positive score (CPS ≥1). Associations with homologous recombination deficiency (HRD), BRCA1/2 status, and survival were examined using multivariable Cox models adjusted for major clinicopathological factors. Results PD-L1 positivity was observed in 38.2% of tumors by TPS, 62.4% by IC, and 66.1% by CPS. Positivity did not significantly vary by sampling site or timing of tissue collection relative to chemotherapy. PD-L1 positivity was enriched in HRD-positive tumors (TPS: 42.3% versus 28.0%, P = 0.017; IC: 65.1% versus 52.0%, P = 0.030; CPS: 70.4% versus 53.0%, P = 0.003) and remained independently associated with improved overall survival in adjusted analyses [TPS: adjusted hazard ratio (aHR) 0.70 (95% confidence interval 0.49-1.00), P = 0.046; IC: aHR 0.68 (0.49-0.95), P = 0.025; CPS: aHR 0.70 (0.50-0.97), P = 0.037]. Associations with progression-free survival were not statistically significant after adjustment. Conclusions In advanced HGSOC, standardized whole-slide PD-L1 assessment identifies an HRD-associated PD-L1-positive immune context independently associated with improved overall survival. Immune-integrated scoring approaches capture this signal more effectively than tumor-cell–restricted assessment and provide a robust framework for future ovarian cancer studies.
Background Somatostatin analogs (SSAs) and targeted therapies have shown efficacy for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in the past decades. To explore the therapeutic efficacy of SSA and targeted therapy combination, we conducted a phase I/II study to evaluate the toxicity and efficacy of cabozantinib and lanreotide in patients with advanced grade 1/2 or 3 progressive GEP-NETs for which molecular targeted therapies or chemotherapy have failed (SCALET trial). Patients and methods Lanreotide (120 mg) was given on day 1 every 4 weeks. A 3 + 3 design was used in phase I to determine the maximum tolerated dose of cabozantinib (40 or 60 mg daily). The primary endpoint in phase II was progression-free survival (PFS). The secondary endpoints were overall response rate (ORR), overall survival, and toxicity of this regimen. Results A total of 42 patients were enrolled and treated. Among the 10 patients in phase I, no dose-limiting toxicity was observed. The recommended dose for cabozantinib was 60 mg daily for the 32 patients in phase II. Among the 31 patients evaluated per protocol, the median PFS (mPFS) was 25.2 months [95% confidence interval (CI) 6.7-43.7]. The mPFS in patients with pancreatic NET and extra-pancreatic NET were 27.5 months (95% CI 22.4-32.6) and 12.0 months (95% CI 7.2-16.8), respectively. The ORR was 35.5%. The median overall survival was not reached. These toxicities were comparable to those of cabozantinib and lanreotide reported in other trials. Conclusion This phase I/II study highlights the efficacy of cabozantinib and lanreotide for advanced GEP-NETs (NCT05048901).
Background Results from the third interim analysis of the phase 3 KEYNOTE-585 study (NCT03221426) showed superior pathological complete response (pCR) with perioperative pembrolizumab and chemotherapy followed by adjuvant pembrolizumab versus placebo plus chemotherapy, then adjuvant placebo in locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma; differences in event-free survival (EFS) were not statistically significant. We present results from a complementary cohort that evaluated pembrolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) versus placebo plus FLOT. Patients and methods KEYNOTE-585 is a randomized, phase 3 study conducted at 143 medical centers. Participants were randomly assigned 1 : 1 to pembrolizumab plus FLOT or placebo plus FLOT. In this exploratory cohort, the primary endpoint was safety. Post hoc exploratory endpoints included pCR rate per the Mandard scale by blinded independent central review, EFS per RECIST v1.1 by investigator, and overall survival (OS). Results Overall, 203 participants were randomly assigned (pembrolizumab group, n = 100; placebo group, n = 103). Median time from randomization to data cut-off (16 February 2024) was 43.8 months (range, 36.5-69.8). Grade 3 or 4 treatment-related adverse event rates were 72.7% and 62.1%, respectively. Treatment-related deaths occurred in three participants (3.0%) in the pembrolizumab group and one participant (1.0%) in the placebo group. The pCR rate was 17.0% [95% confidence interval (CI), 10.2-25.8] in the pembrolizumab group and 6.8% (95% CI, 2.8-13.5) in the placebo group. Median EFS was not reached (NR; 95% CI, 28.2-NR) versus 31.6 months (95% CI, 22.8-NR), respectively [hazard ratio (HR) 0.75, 95% CI 0.50-1.13]. Median OS was NR in either group (HR 0.81, 95% CI 0.53-1.25); 36-month OS rates were 66.0% and 59.2%. Conclusion Neoadjuvant/adjuvant pembrolizumab plus FLOT was feasible and showed an acceptable safety profile. Exploratory efficacy endpoints showed numerical trends consistent with those of the main cohort in locally advanced resectable gastric or gastroesophageal junction adenocarcinoma.
Background In resected liver-limited metastatic colorectal cancer (LL-mCRC), disease-free survival (DFS) and postsurgical overall survival (psOS) have been found to be weakly related in heterogeneous retrospective series, challenging the role of DFS as a surrogate biomarker of psOS. Additionally, it remains unclear whether early relapses (DFS <6 months) are associated with overall survival (OS) benefit. Patients and methods We analyzed individual data of patients with LL-mCRC enrolled in nine randomized trials of first-line chemotherapy plus biologics. Correlation and surrogacy between DFS and psOS were calculated with ρ and R2. psOS of resected patients with DFS <6 months was compared with time from minimum disease load (post-min OS) of unresected patients, with stratification according to baseline tumor burden score (TBS). Time on systemic therapy was also evaluated. Results Eight hundred fifty-five patients with LL-mCRC were included and 357 (42%) were radically resected. DFS and psOS were highly correlated (ρ = 0.73), with R2 at the patient and trial levels for surrogacy of 0.70 and 0.32, respectively. psOS and post-min OS in resected patients with early relapse (n= 115) and unresected patients (n = 498) were comparable [hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.70-1.11, P = 0.29]. However, a benefit from surgery was detected in patients with high baseline TBS (HR 0.69, 95% CI 0.45-1.05, P = 0.09) but not in patients with low/medium baseline TBS (HR 1.12, 95% CI 0.74-1.69, P = 0.59) (p interaction = 0.10). Resection was associated with a lower percentage of time on systemic therapy (26%) regardless of DFS (47% if <6 months, 26% if ≥6 months) (P < 0.001). Conclusions In LL-mCRC resected after first-line chemotherapy plus biologics, DFS is highly correlated with psOS, with high patient-level surrogacy. In high-burden patients, liver surgery seems associated with a trend toward long-term benefit, also after early relapse (<6 months), whereas time on systemic therapy is reduced.
