Journal of Clinical Oncology最新文献

Purpose: Despite limited RCTs, neoadjuvant chemotherapy (NAC) shows promise for resectable pancreatic adenocarcinoma (rPAC). Few prospective results are available on completing the full therapeutic sequence and oncologic outcomes with NAC.

Methods: The PANACHE01-PRODIGE48 phase II trial randomly assigned 153 patients with rPAC (2:2:1) to four cycles of NAC (modified leucovorin, fluorouracil, irinotecan, and oxaliplatin [mFOLFIRINOX], arm 1; leucovorin, fluorouracil, and oxaliplatin [FOLFOX], arm 2) or up-front surgery (control) across 28 French centers (February 2017-July 2020). The primary objective was to evaluate the feasibility and efficacy of these NAC regimens. Two binary primary end points included 1-year overall survival (OS) postrandomization and the rate of patients completing the full therapeutic sequence. Event-free survival (EFS) assessed time to failure, defined as progression before surgery, unresectable/metastatic disease at surgery, recurrence, or death.

Results: The primary objective was achieved for arm 1. In the intention-to-treat population, 70.8% (90% CI, 60.8 to 79.6) and 68% (90% CI, 55.5 to 78.8) completed the therapeutic sequence in arm 1 and arm 2, respectively. Within 12 months postrandomization, 84.3% (90% CI, 75.3 to 90.9) and 71.4% (90% CI, 59.0 to 81.8) of the patients were alive in arm 1 and arm 2, respectively. Treatment was safe and well-tolerated in both NAC arms. Arm 2 was stopped after interim analysis for lack of efficacy (H0 rejection for 1-year OS). One-year EFS rates were 51.4% (95% CI, 41.0 to 64.3), 43.1% (95% CI, 31.3 to 59.5), and 38.7% (95% CI, 24.1 to 62.0) in arm 1, arm 2, and control arm, respectively.

Conclusion: The feasibility and efficacy of mFOLFIRINOX in the perioperative setting are confirmed concerning therapeutic sequence completion and oncologic outcomes, supporting ongoing trials (PREOPANC3, Alliance AO21806). Further research is needed to identify patients who benefit from NAC (ClinicalTrials.gov identifier: NCT02959879; EudraCT: 2015-001851-65).

Purpose: Taletrectinib is an oral, potent, CNS-active, selective, next-generation ROS1 tyrosine kinase inhibitor (TKI). We report integrated efficacy and safety from registrational taletrectinib studies in ROS1+ non-small cell lung cancer.

Methods: TRUST-I and TRUST-II were phase II, single-arm, open-label, nonrandomized, multicenter trials. Efficacy outcomes were pooled from TRUST-I and TRUST-II pivotal cohorts. The safety population comprised all patients treated with once-daily oral taletrectinib 600 mg pooled across the taletrectinib clinical program. The primary end point was independent review committee-assessed confirmed objective response rate (cORR). Secondary outcomes included intracranial (IC)-ORR, progression-free survival (PFS), duration of response (DOR), and safety.

Results: As of June 7, 2024, the efficacy-evaluable population included 273 patients in TRUST-I and TRUST-II. Among TKI-naïve patients (n = 160), the cORR was 88.8% and the IC-cORR was 76.5%; in TKI-pretreated patients (n = 113), the cORR was 55.8% and the IC-cORR was 65.6%. In TKI-naïve patients, the median DOR and median PFS were 44.2 and 45.6 months, respectively. In TKI-pretreated patients, the median DOR and median PFS were 16.6 and 9.7 months. The cORR in patients with G2032R mutation was 61.5% (8 of 13). Among 352 patients treated with taletrectinib 600 mg once daily, the most frequent treatment-emergent adverse events (TEAEs) were GI events (88%) and elevated AST (72%) and ALT (68%); most were grade 1. Neurologic TEAEs were infrequent (dizziness, 21%; dysgeusia, 15%) and mostly grade 1. TEAEs leading to discontinuations (6.5%) were low.

Conclusion: Taletrectinib showed a high response rate with durable responses, robust IC activity, prolonged PFS, favorable safety, and low rates of neurologic adverse events in TKI-naïve and pretreated patients.

Purpose: Although multiple agents targeting PD-1 have been approved as second-line treatment for esophageal squamous cell carcinoma (ESCC), only a fraction of patients derive long-term survival. Hence, reliable predictive biomarkers are urgently needed.

Methods: Comprehensive tumor genomic profiling and transcriptome sequencing were performed on samples from the RATIONALE-302 study. We also conducted single-cell RNA sequencing analysis on Notch1 knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti-PD-1 benefit.

Results: We identified NOTCH1 mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months v 5.3 months; hazard ratio, 0.35 [95% CI, 0.17 to 0.71]). At the transcriptional level, type I IFN (IFN-I)/toll-like receptor expression signatures were positively associated with OS benefit of tislelizumab, whereas B-cell and neutrophil signatures predicted unfavorable OS. Exploratory analyses showed that the presence of NOTCH1 mutation correlated with enrichment of IFN-I signatures and reduced infiltration of B cells and neutrophils. In murine models, comparative single-cell transcriptome analyses further revealed that Notch1 deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti-PD-1 treatment.

Conclusion: Our data provide novel insights for anti-PD-1 treatment selection using NOTCH1 mutations and may provide a rationale for combination therapy in ESCC.

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.