Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

The incidence of Head and Neck cancer is rapidly growing, now representing the sixth most common non-skin cancer worldwide

Purpose: This analysis evaluated the influence of tissue and liquid biopsy concordance on outcomes in patients enrolled in the ROME trial. Patients and Methods: The ROME trial, a phase II multicenter study, enrolled 1,794 patients with advanced solid tumors. Next-generation sequencing was performed on tissue and liquid biopsies using FoundationOne CDx and FoundationOne Liquid CDx. A centralized molecular tumor board reviewed results to identify actionable alterations, with 400 patients randomly assigned to tailored therapy (TT) or standard-of-care groups. TT improved objective response rate and progression-free survival (PFS) in the intention-to-treat population. Concordance was defined as the detection of the same druggable alteration in both biopsy types; discordance indicated detection in only one. Results: Concordance was present in 49% of cases, with alterations detected exclusively in tissue (35%) or liquid (16%) biopsies. Patients in the concordant group receiving TT experienced improved survival outcomes. The median overall survival was 11.05 versus 7.70 months in the standard-of-care group [HR = 0.74; 95% confidence interval, 0.51–1.07], and the median PFS was 4.93 versus 2.80 months (HR = 0.55; 95% confidence interval, 0.40–0.76), respectively. In contrast, the survival benefit of TT was less pronounced or absent in patients with discordant results. Overall survival was higher in the T + L group (11.05 months), followed by tissue-only (9.93 months) and liquid-only (4.05 months) groups. PFS followed a similar pattern, with the longest PFS in the T + L group (4.93 months) versus 3.06 months in tissue-only and 2.07 months in liquid-only groups. Conclusions: The study highlights the potential value of integrating both biopsy modalities in selected clinical contexts. See related commentary by Saldanha and Siu, p. 7

Purpose: In estrogen receptor–positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. Experimental Design: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. Results: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04–2.94)], rs749292 [sHR 2.11, (1.12–3.94)], and rs727479 [sHR 2.62, (1.17–5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). Conclusions: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Purpose: This phase IIIb study prospectively evaluated the prognostic and predictive value of baseline and dynamic circulating tumor DNA (ctDNA) in postmenopausal patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC) treated with first-line ribociclib/letrozole. Experimental Design: A total of 287 patients were enrolled, with ctDNA analyzed at baseline (n = 263), day 15 of cycle 1 (C1D15; n = 238), C2D1 (n = 241), and first imaging (n = 206). The primary objective was to identify ctDNA alterations, characterize their evolution across treatment time points, and assess their association with progression-free survival (PFS). Results: Median PFS was 23.4 months (95% confidence interval, 20.8 to not estimable). At baseline, the most frequently altered genes were PIK3CA (22.1%) and TP53 (15.5%). Alterations in TP53, MYC, and HER− and cyclin-dependent kinase 4/6− pathway genes were linked to early progression. Absence of a detectable mutation at baseline (n = 150, 57%) was associated with a better prognosis [hazard ratio (HR) = 0.41]. Among patients with a detectable mutation at baseline (n = 104), early clearance (mutation undetectability) was observed in 47.1% at C1D15 and 52.4% at C2D1 and was associated with improved PFS (C1D15, HR = 0.51; C2D1, HR = 0.44). In patients without a detectable mutation at baseline, 22.7% (n = 34) developed new mutations at C1D15, C2D1, or first imaging. Patients without new mutations had a lower risk of progression (HR = 0.45). Conclusions: Pretreatment and early dynamics of ctDNA represent promising prognostic and predictive biomarkers in patients with HR+/HER2− ABC treated with ribociclib/letrozole. Early ctDNA dynamics seem to be a promising surrogate biomarker for treatment. Further studies are warranted to validate their clinical utility.