Journal of Clinical Oncology最新文献

The randomized phase III FALCON trial demonstrated significant improvement in progression-free survival (PFS) with fulvestrant versus anastrozole in postmenopausal women with endocrine therapy-naïve, hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Herein, the prespecified final overall survival (OS) analysis is reported. After the primary PFS analysis, data were collected on survival, serious adverse events, and health-related quality of life. The final OS analysis was triggered at ≥65% maturity and ≥8 years since the last patient was enrolled. Analyses were descriptive with nominal P values (one-sided α threshold .01845). At the data cutoff (July 11, 2022), 314 (68.0%) of 462 patients had died (fulvestrant, 157/230 [68.3%], anastrozole, 157/232 [67.7%]). The final OS analysis of FALCON demonstrated no significant difference between fulvestrant and anastrozole (medians, 44.8 and 42.7 months, respectively; hazard ratio [HR], 0.97 [95% CI, 0.77 to 1.21]; P = .7579). Among patients with nonvisceral disease (n = 208), a trend showed a 15% reduction in the relative risk of death with fulvestrant versus anastrozole (median OS, 65.2 v 47.8 months; HR, 0.85 [95% CI, 0.60 to 1.20]). Data from FALCON are consistent with published evidence of long-term clinical benefit with fulvestrant and other endocrine therapies in the subset of patients with nonvisceral disease.

Purpose: ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC.

Methods: Patients with RAS/BRAF-WT mCRC after central confirmation of HER2 positivity (immunohistochemistry 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]) were assigned (1:1) to either trastuzumab plus pertuzumab (TP; trastuzumab 6 mg/kg and pertuzumab 420 mg once every 3 weeks) or cetuximab plus irinotecan (CETIRI; cetuximab 500 mg/m² and irinotecan 180 mg/m² once every 2 weeks) until progression or unacceptable toxicity. Crossover to TP was allowed after progression on CETIRI. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, safety, and HER2 gene copy number (GCN ≥20/<20) as a predictive factor.

Results: Between October 2017 and March 2022, 54 participants were assigned to TP (n = 26) and CETIRI (n = 28). Median PFS did not vary significantly by treatment: 4.7 (95% CI, 1.9 to 7.6) and 3.7 (95% CI, 1.6 to 6.7) months in the TP and CETIRI groups, respectively. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN ≥20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; P interaction = .003). On TP, ORR was 34.6% (57.1% with GCN ≥20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively (P = .004). Grade ≥3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively.

Conclusion: TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with RAS/BRAF-WT, HER2-positive mCRC. Higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP vis-à-vis CETIRI.

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.

The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant. PRO scores were compared between the arms using inverse probability weighted-independent estimating equation models. The PTCy arm had significantly lower scores on the Lee Chronic GVHD Symptom Scale (P = .01), indicating lower GVHD symptom burden. Lee Scale nutrition and mouth subscores were also better in the PTCy arm compared with the Tac/MTX arm (P < .01 for both). Older participants (age >65 years) reported better Lee Scale psychological subscores than younger participants (P = .003). No significant differences were identified in hemorrhagic cystitis or in the PROMIS subscales between treatment arms. The updated clinical end points at 2 years for the parent trial confirmed that PTCy/Tac/MMF maintained a significant advantage over Tac/MTX in GRFS (42.4% v 28.8%, P = .001). In addition to improved GRFS, patients randomly assigned to the PTCy arm reported lower symptom burden during the first year after transplant.

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.

Purpose: The effects of metronomic chemotherapy plus endocrine therapy have yet to be elucidated through a randomized phase III clinical trial.

Methods: Randomized clinical trials were conducted at 12 centers in China from August 22, 2017, to September 24, 2021, and the final follow-up date was August 25, 2023. Patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) who had no previous systemic therapy in the metastatic setting were enrolled. Participants were 1:1 assigned to receive either metronomic capecitabine plus an aromatase inhibitor (AI) or AI alone. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate, disease control rate (defined as disease controlled for ≥24 weeks), and safety.

Results: A total of 263 patients were randomly assigned, among which 254 patients formed the full analysis set. At the median follow-up time of 50.7 months, 203 PFS events occurred. The metronomic capecitabine plus AI arm exhibited a median PFS of 20.9 months compared with 11.9 months in the AI arm (hazard ratio [HR], 0.58 [95% CI, 0.43 to 0.76]). The median OS was not reached in the combination arm and was 45.1 months in the AI arm (HR, 0.58 [95% CI, 0.37 to 0.93]). The most common adverse events were palmar-plantar erythrodysesthesia and peripheral neuropathy; grade 3 events occurred in 15.1% of the patients receiving combination treatment.

Conclusion: The MECCA trial demonstrated a significant improvement in PFS and OS with first-line metronomic capecitabine plus AI compared with AI alone in patients with hormone receptor-positive+/HER2-negative MBC. Both treatment arms exhibited tolerable safety profiles consistent with previous reports.

Purpose: To determine the optimal daunorubicin dose and number of 7 + 3 induction cycles in newly diagnosed AML, this randomized controlled trial compared a once daily dose of 60 mg/m² with 90 mg/m² daunorubicin in the first 7 + 3 induction and one versus two cycles of 7 + 3 induction.

Patients and methods: Patients age 18-65 years with newly diagnosed AML were randomly assigned to 60 versus 90 mg/m² daunorubicin once daily plus cytarabine. Patients with marrow blasts below 5% on day 15 after first induction were randomly assigned to receive a second induction cycle or no second induction cycle.

Results: Eight hundred and sixty-four patients with a median age of 52 years were randomly assigned. After a preplanned interim analysis showing no significant difference in response between 60 and 90 mg/m², all consecutive patients received 60 mg/m² daunorubicin once daily. The proportion of good early responders was 44% versus 48% (P = .983) with a composite complete remission (CRc) rate of 90% versus 89% after induction (P = .691); the 3-year relapse-free survival (RFS) after 60 versus 90 mg/m² once daily was 54% versus 50% (P = .561), and the 3-year overall survival (OS) was 65% versus 58% (P = .242). Among 389 good responders, CRc rates at the end of induction were 87% after single induction and 85% after double induction. The 3-year RFS was 51% versus 60% (hazard ratio [HR], 1.3; P = .091), and the 3-year OS was 76% versus 75% after single versus double induction (HR, 1.0; P = .937).

Conclusion: The use of 90 mg/m² daunorubicin once daily in the context of classical 7 + 3 induction does not significantly improve early response and does not lead to higher remission rates or longer survival than 60 mg/m² once daily. In patients with a good early response after first induction, a second induction has only a limited impact on RFS and does not result in an OS benefit.

@JCO_ASCO paper focuses on racialized approaches to OUD and opioid misuse as underappreciated drivers of disparities in cancer and recs a path forward.