Journal of Clinical Oncology最新文献

Purpose: The ESPAC4 trial showed that adjuvant chemotherapy with gemcitabine plus capecitabine (GemCap) produced longer overall survival (OS) than gemcitabine monotherapy. Subsequently, the PRODIGE24-CCTG PA.6 trial showed even longer survival for modified fluorouracil, folinic acid, irinotecan, and oxaliplatin (mFOLFIRINOX) than gemcitabine but had more restrictive eligibility criteria. Our aim was to analyze the ESPAC4 survival on long-term follow-up.

Methods: The OS of 732 ESPAC4 patients comparing 367 randomly assigned to gemcitabine and 365 to GemCap was previously reported after a median follow-up time of 43.2 months (95% CI, 39.7 to 45.5) and 458 deaths. Analysis was now carried out after a median follow-up of 104 months (101-108) and 566 deaths.

Results: The median OS was 29.5 months (27.5-32.1) for all patients, 28.4 months (25.2-32.0) in the gemcitabine group and 31.6 months (26.5-38.0) in the GemCap group (hazard ratio [HR], 0.83 [0.71 to 0.98]; P = .031). R0 patients given gemcitabine had a median survival of 32.2 months (27.9-41.6) compared with 49.9 months (39.0-82.3) for those given GemCap (HR, 0.63 [0.47 to 0.84]; P = .002). Lymph node-negative patients had significantly higher 5 year OS rates on GemCap (59% [49%-71%]) than gemcitabine (53% [42%-66%]; HR, 0.63 [0.41 to 0.98]; P = .04) but not those with positive lymph nodes (P = .225). The OS advantage for GemCap was retained in the PRODIGE24 subgroup of 193 (26.4%) ESPAC4 patients not eligible for PRODIGE24 with a median survival of 20.7 (16.2-27.3) months in patients allocated to gemcitabine compared with 25.9 (22.3-30.2) months for ineligible patients allocated to GemCap (HR, 0.71 [95% CI, 0.52 to 0.98]; χ²_log-rank-1df = 4.31; P = .038).

Conclusion: GemCap is a standard option for patients not eligible for mFOLFIRINOX. Exploratory evidence suggests that GemCap may be particularly efficacious in R0 patients and also in lymph node-negative patients.

Purpose: The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion-positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion-positive solid tumors with response-adapted duration of therapy and local control.

Methods: Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS).

Results: Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities.

Conclusion: Larotrectinib is highly active in patients with newly diagnosed NTRK fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Purpose: In light of evolving evidence that some patients with node-positive estrogen receptor-positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy.

Methods: In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers.

Results: Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not.

Conclusion: At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and 2). Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline.

Purpose: Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy.

Patients and methods: Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival.

Results: Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event.

Conclusion: Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.

Purpose: Melanoma as a subsequent malignant neoplasm has been described among childhood cancer survivors; however, the risk factors and long-term survival are not well understood.

Methods: We assessed incidence, risk factors, and outcomes for melanoma among participants in the Childhood Cancer Survivor Study cohort. Cumulative incidence and standardized incidence ratios (SIRs) were calculated, and multivariable Cox models were used to determine hazard ratios (HRs) and associated 95% CI for melanoma risk factors. Radiation exposure to seven body regions and melanoma status for each of eight regions per survivor were integrated into the Cox model.

Results: Among 25,716 participants, 177 melanomas developed in 160 survivors (110 invasive, 62 in situ cutaneous, five ocular). The 40-year melanoma cumulative incidence was 1.1% (95% CI, 0.9 to 1.4) for all participants and 1.5% (95% CI, 1.0 to 2.1) among those receiving a cumulative radiation dose of ≥40 Gy. Compared with the general population, the SIR for invasive skin or ocular melanoma was 2.0 (95% CI, 1.6 to 2.4). A cumulative radiation dose of ≥40 Gy to the corresponding body region(s) of the melanoma (HR, 2.0 [95% CI, 1.1 to 3.7]), a cumulative cyclophosphamide equivalent dose of ≥20,000 mg/m² (HR, 1.9 [95% CI, 1.1 to 3.6]), and bleomycin exposure (HR, 2.2 [95% CI, 1.2 to 4.1]) were associated with increased cutaneous melanoma. Invasive melanoma at any site was associated with an increased risk of death (HR, 2.4 [95% CI, 1.7 to 3.3]).

Conclusion: Childhood cancer survivors have more than a two-fold increased risk of melanoma compared with the general population, and those with an invasive melanoma have more than a two-fold risk of death. High-dose radiation and alkylating agent exposure, and bleomycin are important risk factors for melanoma and should be considered in future patient guidance and screening.

Purpose: In CheckMate 204, nivolumab + ipilimumab showed high intracranial (IC) objective response rates (icORRs) in patients with melanoma brain metastases (MBMs). Using icORR as a surrogate for overall survival (OS) has prompted use of alternate response criteria. To set the stage for harmonized MBM trials, the aim of this exploratory analysis was to determine icORR using several response criteria and examine correlations of response with survival.

Methods: Patients (N = 119) with ≥one unirradiated MBMs received nivolumab + ipilimumab every 3 weeks (four doses), followed by nivolumab every 2 weeks for ≤24 months. Blinded review icORR was assessed with modified RECIST (mRECIST), Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM; 5 mm and 10 mm cutoffs), and volumetric criteria (5 mm and 10 mm). Using a 6-week response landmark, IC progression-free survival (icPFS) and OS were compared for responders versus nonresponders.

Results: icORR was higher with mRECIST and volumetric criteria than with RANO-BM or RECIST. mRECIST and volumetric response also showed stronger correlations with icPFS and OS. mRECIST responders who were RANO-BM 5 mm nonresponders (n = 14) had similar OS to RANO-BM 5 mm responders (n = 41). Clinical deterioration affected RANO-BM icORR; however, when assessed only radiographically without deterioration, RANO-BM 5 mm performed similarly to mRECIST. Among 41 patients with target lesions all <10 mm, responder icPFS and OS were similar to those of responders in the total population, indicating that response could be accurately determined in these patients.

Conclusion: This analysis supports mRECIST or radiographic-only RANO-BM 5 mm as reliable assessment scales in MBM trials. Volumetric response correlated with survival, supporting its application in future trials. Response could be accurately determined in patients with MBMs all <10 mm, supporting the inclusion of patients with MBMs ≥5 mm in future trials.

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma. This cohort included 91 patients (younger than 18 years) from two clinical trials: infantile fibrosarcoma (49), other soft tissue sarcomas or related mesenchymal tumors (41), and bone sarcoma (1). Treatment-related adverse events were of maximum grade 1 or 2 in 25% and 25% of patients, respectively. The overall response rate was 87% (95% CI, 78 to 93). In the wait-and-see analysis, 47 patients discontinued larotrectinib. Median time from discontinuation to disease progression was not reached. Sixteen patients had tumor progression during the wait-and-see period. All 16 patients resumed larotrectinib, and 15 (94%) achieved disease control, with 11 objective responses. Larotrectinib continues to demonstrate durable responses with favorable safety in children with TRK fusion sarcomas. Treatment discontinuation is feasible in select patients with objective response and clinical benefit noted in those who have disease progression after elective treatment discontinuation.