CUPISCO (ClinicalTrials.gov identifier: NCT03498521) demonstrated longer progression-free survival (PFS) with comprehensive genomic profiling (CGP) and subsequent molecularly guided therapies (MGTs), versus standard platinum-based chemotherapy, in patients with previously untreated, unfavorable cancer of unknown primary (CUP) who reached disease control after induction chemotherapy (three cycles). We report efficacy and safety after >1 year of additional follow-up. Eligible patients were randomly assigned (3:1) to MGT (investigator-chosen after discussion in a molecular tumor board) or three further cycles of chemotherapy. The primary end point was PFS. Secondary end points included overall survival (OS) and safety. At data cutoff (December 6, 2024), 436 patients were randomly assigned (326 to MGT; 110 to chemotherapy). Median follow-up was 37.0 months (range, 0.0-67.8). Updated median PFS was 6.1 months (95% CI, 4.7 to 6.5) with MGT and 4.4 months (95% CI, 4.2 to 6.4) with chemotherapy (hazard ratio [HR], 0.75 [95% CI, 0.59 to 0.95]; P = .017); median OS was 15.2 months (95% CI, 13.9 to 18.4) and 12.8 months (95% CI, 9.8 to 15.4), respectively (HR, 0.79 [95% CI, 0.61 to 1.02]; P = .0689). No new safety signals were identified. These updated results aligned with the primary analysis, demonstrating the benefit of CGP with subsequent MGT and highlighting the importance of incorporating CGP at initial diagnosis to guide treatment decisions for patients with unfavorable CUP.
In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (EFS) and pathologic complete response in patients with resectable non-small cell lung cancer (R-NSCLC), with a safety profile consistent with the individual agents. We report EFS from a second planned interim analysis, interim disease-free survival (DFS) and overall survival (OS), and safety, after all patients completed/discontinued treatment. In this phase III, double-blind, placebo-controlled study, patients with treatment-naïve R-NSCLC (stage II-IIIB [N2]) were randomly assigned (1:1) to neoadjuvant platinum-based chemotherapy plus durvalumab/placebo (once every 3 weeks, four cycles) presurgery and then adjuvant durvalumab/placebo (once every 4 weeks, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (n = 740; for DFS, its resected subpopulation), which excluded patients with documented EGFR/ALK aberrations. As of May 10, 2024 (median follow-up, 25.9 months [censored patients]), EFS benefit favoring the durvalumab arm remained consistent (hazard ratio [HR], 0.69 [95% CI, 0.55 to 0.88]). Numerical improvement in DFS (HR, 0.66 [95% CI, 0.47 to 0.92]) and OS (HR, 0.89 [95% CI, 0.70 to 1.14]) favored the durvalumab arm. Maximum grade 3/4 adverse events occurred in 15.4% and 10.6% of the durvalumab and placebo arms, respectively, during adjuvant treatment. These results further support perioperative durvalumab plus neoadjuvant chemotherapy as a new treatment option.
PURPOSE:EA1181 (ClinicalTrials.gov identifier: NCT04266249) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point-3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)-will be reported when data mature. METHODS:Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS:A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER-]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER- tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION:Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER- and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.
[Box: see text]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 I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website.
PURPOSE:Chemoimmunotherapy has been the standard approach for untreated indolent B-cell lymphoma. We hypothesized that initial use of the CD3/CD20 bispecific mosunetuzumab followed by response-adapted polatuzumab vedotin and obinutuzumab would yield an optimized chemotherapy-free approach. METHODS:Previously untreated patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) with indication for treatment received eight cycles of mosunetuzumab. Those not achieving a complete response (CR) by positron emission tomography-computed tomography (PET-CT) following mosunetuzumab could go on to receive six cycles of polatuzumab vedotin and obinutuzumab. The primary end point was best overall response rate (ORR) of CR by fluorodeoxyglucose-PET-CT. RESULTS:The 42 enrolled patients had a median age of 60 years (range, 36-83), 39 were stage III to IV (93%), 37 (88%) had FL, and 13 (31%) had bulk >7 cm. The end-of-treatment ORR and CR rates were 100% and 86%, respectively. The ORR and CR to mosunetuzumab alone were 100% and 71%, respectively. With a median follow-up of 34 months, the 2-year progression-free survival (PFS) was 89% (95% CI, 80 to 100) and the 2-year overall survival was 100%. The four progression events included CD20 loss (2) and histologic transformation (2). Cytokine release syndrome occurred in 27 patients (64%), but all were grade 1. No patients required tocilizumab. CONCLUSION:Single-agent mosunetuzumab as well as response-adapted polatuzumab vedotin and obinutuzumab yield encouraging CR rates and PFS with limited toxicity among previously untreated patients with FL and MZL. This chemotherapy-free strategy may provide a template for larger study designs for personalized approaches in this population that balances efficacy with safety.
The COMBI-I trial (ClinicalTrials.gov identifier: NCT02967692) evaluating spartalizumab plus dabrafenib and trametinib (sparta-DabTram, n = 267) versus placebo plus dabrafenib and trametinib (placebo-DabTram, n = 265) for BRAF V600-mutant unresectable or metastatic melanoma failed to reach its primary end point of progression-free survival at 24 months. This final analysis reports overall survival (OS) during at least 5 years of extended follow-up. At the end of the trial (August 21, 2024), the median duration of follow-up was 76.9 months (range, 73.7-83.3 months). The median OS was 61.5 months (95% CI, 41.6 to not evaluable) for the sparta-DabTram arm and 41.6 months (95% CI, 30.6 to 56.9) for the placebo-DabTram arm (hazard ratio, 0.760 [95% CI, 0.598 to 0.966]). The safety findings were consistent with the known safety profile for sparta-DabTram. The most common treatment-related adverse event (TRAE) was pyrexia (65.9% v 46.2%, respectively, in the two study arms). Grade ≥3 TRAEs were reported in 57.3% and 36.7% of patients in the two arms, respectively. The combination of sparta-DabTram appears to improve OS compared with dabrafenib and trametinib alone in patients with BRAF V600-mutant metastatic melanoma.
PURPOSE:Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS:The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 (IDH1/2) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS:We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH-mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], Pinteraction < .001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/-10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH-mutant glioma. CONCLUSION:In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.
PURPOSE:Systemic treatment options for advanced salivary gland carcinoma (SGC) are limited, and prospective data for human epidermal growth factor receptor 2 (HER2)-directed therapy remain sparse, particularly in HER2-low disease. We evaluated trastuzumab rezetecan (SHR-A1811), a HER2-directed antibody-drug conjugate, in prospectively defined HER2-high and HER2-low cohorts. PATIENTS AND METHODS:In this phase II trial, patients with unresectable locally advanced or recurrent/metastatic SGC were enrolled in separate HER2-high (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) and HER2-low (IHC 1+ or IHC 2+/ISH-) cohorts. Each cohort was independently evaluated using Simon's optimal two-stage design. SHR-A1811 was administered intravenously once every 3 weeks at a recommended starting dose of 4.8 mg/kg. The primary end point was confirmed objective response rate (ORR) per RECIST version 1.1. RESULTS:Forty-six patients were enrolled and treated, including 24 in the HER2-high cohort and 22 in the HER2-low cohort. The median follow-up was 21.9 months (95% CI, 16.9 to 26.9) and 11.3 months (95% CI, 6.9 to 15.7), respectively. The confirmed ORR was 91.7% (95% CI, 73.0 to 99.0), including four complete responses, in the HER2-high cohort and 45.5% (95% CI, 24.4 to 67.8) in the HER2-low cohort. Median progression-free survival (PFS) and overall survival (OS) were not reached in the HER2-high cohort. In the HER2-low cohort, the median PFS was 12.7 months and the median OS was 21.3 months. Grade 3 or higher treatment-related adverse events occurred in 41.3% of patients, most commonly neutrophil count decreased (32.6%). Interstitial lung disease occurred in 6.5% of patients, all grade 1. No treatment-related deaths occurred. CONCLUSION:SHR-A1811 showed high antitumor activity in HER2-high SGC and promising activity in HER2-low SGC, with a manageable safety profile.
Daromun (L19IL2/L19TNF) was investigated as a neoadjuvant, intralesional therapy for patients with fully resectable stage III melanoma in the phase III PIVOTAL trial (ClinicalTrials.gov identifier: NCT02938299). The trial enrolled 256 patients in the European Union and met its primary end point, demonstrating a statistically significant improvement in recurrence-free survival (RFS; hazard ratio, 0.59; P = .005) for daromun followed by surgery versus up-front surgery, at a median follow-up (FU) of 21 months from random assignment. PIVOTAL included two clinically distinct subgroups, namely, patients with de novo diagnosed metastatic disease (n = 34; 13%) and patients with recurrence(s) after surgery with or without radiotherapy and/or adjuvant systemic therapies (n = 222; 87%). Here, we present an updated analysis of the primary and secondary end points, including safety data, at a median FU of 36.8 months from random assignment (database cutoff: November 28, 2025), alongside new sensitivity analyses of event-free survival (EFS). The updated analysis confirms the clinically and statistically meaningful improvements in RFS and distant metastasis-free survival recorded in the neoadjuvant daromun versus control arm. The EFS post hoc analysis, conducted in both the overall population and the recurrent patient subgroups (with or without prior systemic therapies), provides consistency and robustness to the benefit of neoadjuvant daromun observed for the primary efficacy end point. No new safety signals of concern were recorded.
Relapsed or refractory (RR) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presents increasing therapeutic complexity in the era of targeted agents. Frontline use of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax-based fixed-duration (FD) or minimal residual disease-guided regimens has led to deeper remissions, yet many patients will eventually require subsequent therapy. Management of first relapse should integrate clinical status, prior therapy, progression kinetics, and assessment for Richter transformation, along with genomic re-evaluation (particularly acquired resistance mutations and TP53 aberrations).Multiple effective options exist for relapsing disease. Second-generation cBTKi (acalabrutinib, zanubrutinib) continuous therapy provides durable disease control with improved tolerability over ibrutinib, whereas continuous venetoclax monotherapy or FD venetoclax-rituximab achieves high response rates and prolonged remission, with retreatment feasible for selected patients. Noncovalent BTKis (ncBTKis) such as pirtobrutinib offer meaningful activity in patients previously exposed to cBTKi. Cellular therapies, particularly lisocabtagene maraleucel, have demonstrated substantial efficacy in heavily pretreated patients, and allogeneic hematopoietic cell transplantation remains an option for select individuals with double-class refractory disease. Emerging therapies-including BTK degraders, next-generation BCL2 inhibitors, and bispecific antibodies-will likely reshape the therapeutic landscape for RR CLL/SLL. With broadening treatment options for RR CLL/SLL, optimal sequencing requires consideration of disease biology, depth and duration of prior response, comorbidities, toxicity profiles, patient preferences, and logistical factors. As therapeutic options expand, individualized treatment planning and clinical trial participation remain essential for improving outcomes in RR CLL/SLL.
