Annals of Oncology最新文献

Background: Circulating tumor DNA (ctDNA) analysis has emerged as a minimally invasive tool for detecting minimal residual disease (MRD) in colorectal cancer (CRC) patients. This enables dynamic risk stratification, earlier recurrence detection and optimized post-surgical treatment. Two primary methodologies have been developed for ctDNA-based MRD detection: tumor-informed strategies, which identify tumor-specific mutations through initial tissue sequencing to guide ctDNA monitoring, and tumor-agnostic approaches, which utilize predefined panels to detect common cancer-associated genomic or epigenomic alterations directly from plasma without prior tissue analysis. The debate over which is superior in terms of sensitivity, specificity, cost-effectiveness and clinical feasibility remains unsolved.

Design: This review summarizes studies published up to November 2024, exploring the utility and performance of tumor-informed and tumor-agnostic approaches for ctDNA analysis in CRC. We evaluate the strengths and limitations of each methodology, focusing on sensitivity, specificity and clinical outcomes.

Results: Both strategies demonstrate clinical utility in post-operative risk stratification and guiding adjuvant chemotherapy decisions in CRC patients. Tumor-informed approaches generally exhibit superior sensitivity and specificity for recurrence prediction, attributed to their personalized tumor profile designs. However, these methods are limited by the need for prior tissue sequencing and higher associated costs. In contrast, tumor-agnostic approaches offer broader applicability due to their reliance on plasma-only analysis, although with relatively lower sensitivity. Technological advancements, including fragmentomics and multi-omic integrations, are expanding the capabilities of ctDNA-based MRD detection, enhancing the performance of both approaches.

Conclusions: While tumor-informed strategies currently offer higher precision in MRD detection, tumor-agnostic approaches are gaining traction due to their convenience and improving performance metrics. The integration of novel technologies in ongoing clinical trials may redefine the optimal approach for MRD detection in CRC, paving the way for more personalized and adaptive patient management strategies.

Background: Futibatinib is the only covalent inhibitor of FGFR1-4 to gain regulatory approval in oncology. In this article, we present genomic analyses of tissue biopsies and circulating tumor DNA (ctDNA) from patients with 1 of nearly 20 tumor types treated with futibatinib in the phase I/II FOENIX study.

Patients and methods: Eligible patients included those with ctDNA samples collected per protocol at baseline and/or progression on futibatinib in the phase Ib portion of the study for FGF/FGFR-altered advanced solid tumors or the phase II portion of the study for FGFR2 fusion/rearrangement-positive cholangiocarcinoma. Assessments included analytical concordance between tumor and ctDNA analyses for detection of FGFR alterations, association of ctDNA-detected co-occurring genomic alterations with response to futibatinib, and determination of patterns of acquired resistance following progression on futibatinib.

Results: Among 300 patients treated with futibatinib, 226 were eligible for this analysis, including 139 (62%) with cholangiocarcinoma. Among patients with known FGFR2 fusions/rearrangements, FGFR1 fusions, FGFR3 fusions, or FGFR2 amplifications per tissue analysis, detection rates in ctDNA for these aberrations were 84%, 0%, 11%, and 59%, respectively. Objective response rates on futibatinib were not significantly different between patients with TP53-altered versus -unaltered solid tumors; progression-free survival was reduced in patients with CDKN2B-altered versus -unaltered cholangiocarcinoma (median 4.8 versus 11.0 months; P = 0.03). Acquired resistance to futibatinib was frequently polyclonal and driven by an array of mutations within the relevant FGFR kinase domain, predominantly V565L, V565F, and N550K variants.

Conclusions: In this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis shows clinically relevant potential as a noninvasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms.

Background: In CLEAR, lenvatinib + pembrolizumab (L + P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (aRCC). We report results from CLEAR biomarker analyses.

Patients and methods: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA sequencing) were carried out on archival tumor specimens. For IHC-derived/RNA sequencing analyses, a continuous analysis was carried out adjusting by Karnofsky performance status (KPS) score for: PD-L1 combined positive score (CPS) versus best overall response (BOR)/progression-free survival (PFS); and each gene signature score [T-cell inflamed gene expression profile (Tcell_infGEP)/non-Tcell_infGEP signatures including proliferation and angiogenesis] versus BOR/PFS. Association between mutation status of RCC driver genes and PFS were analyzed for genes for which ≥20 patients per arm had oncogenic alterations. Association of molecular subtypes with outcome was evaluated with baseline KPS adjustments. The set of biomarkers evaluated and statistical significance criteria for PD-L1 CPS, gene signature scores, and molecular subtypes were prespecified.

Results: Within-arm analyses using continuous values showed no association between PD-L1 levels and BOR/PFS for either treatment. PFS hazard ratios between arms were similar regardless of the mutant or wild-type subgroups of RCC driver genes (VHL, PBRM1, SETD2, BAP1, KDM5C). No associations between PFS and gene signature scores were observed for L + P. With sunitinib, high proliferation and MYC signature scores showed shorter PFS; high angiogenesis and microvessel density signature scores showed longer PFS. Six new molecular subtypes were defined. Tumors of patients with favorable/intermediate risk were enriched in angiogenesis and angiogenesis/stromal clusters; those with poor risk were enriched in proliferative and unclassified (low-Tcell_infGEP/low-angiogenesis/low-proliferation) clusters. No association between molecular subtypes and PFS for L + P/sunitinib was observed (after adjustment for KPS and gene signatures that were individually associated with PFS).

Conclusions: Improvements in objective response rate and PFS for L + P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.

Background: HER2-targeted antibody-drug conjugates (ADCs) such as disitamab vedotin (DV) and trastuzumab deruxtecan (T-Dxd) have emerged as effective treatment options and received regulatory approvals for HER2 expressing locally advanced or metastatic urothelial carcinoma (la/mUC). In addition, ADCs in combination with immunotherapy have demonstrated anti-tumor activity. The current study aimed to evaluate the combination of DV and toripalimab in patients with la/mUC.

Patients and methods: This open-label phase 1b/2 study enrolled patients with untreated or chemo-refractory la/mUC. During the dose escalation phase, DV was administered at escalating doses of 1.5 and 2.0 mg/kg in combination with toripalimab 3.0 mg/kg once every two weeks. Primary endpoints were safety and the recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results: From August 2020 to December 2021, a total of forty-one patients were enrolled, including six in the dose-escalation phase, and thirty-five in the dose-expansion phase. Sixty-one percent of patients were treatment naïve. No dose-limiting toxicity was observed. The RP2D was determined as DV (2.0 mg/kg) plus toripalimab (3.0 mg/kg). By the data cutoff date of March 1, 2024, the confirmed ORR was 73.2%. The median PFS was 9.3 months, and the median OS was 33.1 months. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (65.9%), alanine aminotransferase increased (63.4%), and peripheral sensory neuropathy (63.4%). Grade 3 or higher TRAEs occurred in 51.2% of patients, with the most common being gamma-glutamyltransferase increased (12.2%), asthenia (9.8%), and alanine aminotransferase increased (7.3%). One treatment-related death (due to pneumonitis) was reported.

Conclusions: The combination of DV and toripalimab demonstrated promising response rate and overall survival results with a manageable safety profile in HER2 unselected la/mUC patients. This combination represents a promising first-line option for la/mUC. Randomized phase III study is currently ongoing.

Background: In resectable gastric/gastroesophageal junction adenocarcinoma, microsatellite instability-high (MSI-H) confers improved survival, but limited benefit from chemotherapy. Immunotherapy may eliminate the need for chemotherapy or surgery.

Patients and methods: INFINITY is a multicenter, multicohort phase II trial (NCT04817826) investigating in cohort 1 the activity and safety of tremelimumab + durvalumab (T300/D) as neoadjuvant treatment of mismatch repair deficient/MSI-H, resectable gastric/gastroesophageal junction adenocarcinoma. Primary endpoint was pathologic complete response (pCR) rate; Secondary endpoints: progression-free survival (PFS), overall survival (OS), quality of life, and translational analyses. In cohort 2, the activity and safety of T300/D was explored as definitive treatment in patients achieving clinical complete response (cCR). Primary endpoint was 2-year cCR rate, and secondary endpoints were PFS, OS, quality of life, gastrectomy-free survival and translational analyses.

Results: In cohort 1, 18 patients were recruited and 15 evaluable. pCR and major pathologic response-pCR were 60% and 80%, respectively. Since pCR rate in T4 tumors was 17%, this subgroup of patients was excluded from enrollment in cohort 2. At 28.1 months median follow-up, 24-month gastric cancer-specific PFS and OS rates were 85% and 92%, respectively. In cohort 2, 18 patients were enrolled and 17 assessable, and 13 had cCR and started non-operative management. At 11.5 months median follow-up, one patient had local regrowth and underwent salvage surgery; 12-month gastrectomy-free survival was 64.2%.

Conclusions: The INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as preoperative treatment in mismatch repair deficient/MSI gastric/gastroesophageal junction adenocarcinoma and the first available feasibility results of a non-operative management strategy in this disease setting, worthy of further validation in larger cohorts.

Background: Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUAD^Muc), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUAD^Muc by comparing it with LUAD without mucinous histology (LUAD^non-muc) and determine the relative benefit of current treatments.

Patients and methods: Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUAD^Muc or LUAD^non-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUAD^Muc and LUAD^non-muc.

Results: Of 4082 patients with LUAD, 9.9% had LUAD^Muc. Compared with LUAD^non-muc, patients with LUAD^Muc had a lighter smoking history (median 15 versus 20 pack-years; P = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, P < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, P < 0.0001). Mutations in KRAS, NKX2-1 [thyroid transcription factor 1 (TTF-1)], STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in LUAD^Muc, while TP53, EGFR, BRAF, and MET mutations were enriched in LUAD^non-muc. At stage IV diagnosis, LUAD^Muc was more likely to have contralateral lung metastasis (55.2% versus 36.9%, P < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, P < 0.0001). Compared with LUAD^non-muc, LUAD^Muc cases showed lower intratumor CD8⁺, PD-1⁺, CD8⁺PD-1⁺, and FOXP3⁺ cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUAD^non-muc (n = 1511), LUAD^Muc (n = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, P < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, P < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, P < 0.0001). Similarly, patients with LUAD^Muc had worse outcomes to chemoimmunotherapy. LUAD^Muc (n = 18) and LUAD^non-muc (n = 150) had similar ORR (16.7% versus 34.9%, P = 0.12) and mPFS (4.6 versus 5.6 months, P = 0.17) to treatment with KRAS^G12C inhibitors, but LUAD^Muc had shorter mOS (6.8 versus 10.8 months, P = 0.018).

Conclusions: LUAD^Muc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.