BACKGROUND:The randomized phase III study KEYNOTE-564 (NCT03142334) established pembrolizumab after surgery as the standard of care for patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence. Prior analyses showed significantly improved disease-free survival (DFS) and overall survival (OS) with adjuvant pembrolizumab versus placebo. We present results from the fourth prespecified interim analysis, with a minimum follow-up of five years. PATIENTS AND METHODS:Eligible adults with ccRCC at increased risk of recurrence were randomly assigned 1:1 to adjuvant pembrolizumab 200 mg or placebo every 3 weeks following nephrectomy or following nephrectomy and metastasectomy. Study treatment continued for ≤17 cycles (∼1 year), until recurrence, or until treatment discontinuation criteria were met. The primary endpoint was DFS per investigator assessment, and the key secondary endpoint was OS. Safety was a secondary endpoint. RESULTS:Overall, 994 participants were randomized to pembrolizumab (n = 496) or placebo (n = 498). Median time from randomization to data cutoff (September 25, 2024) was 70 months (range, 60-87). Pembrolizumab improved DFS versus placebo (hazard ratio [HR] 0.71, 95% CI 0.59-0.86); median DFS was not reached (NR) versus 68 months, and estimated 5-year DFS rates were 60.9% versus 52.2%, respectively. OS was improved with pembrolizumab over placebo (HR 0.66, 95% CI 0.48-0.90); median OS was NR for both arms with an estimated 5-year OS rate of 87.7% and 82.3%, respectively. DFS and OS benefits were consistent across key subgroups. Safety was largely unchanged since last analysis. CONCLUSIONS:After a median follow-up of 70 months, adjuvant pembrolizumab demonstrated sustained DFS and OS benefit and a safety profile consistent with prior analyses. These findings continue to support the use of adjuvant pembrolizumab in ccRCC at increased risk of recurrence.
BACKGROUND:Adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved survival outcomes compared with neoadjuvant chemotherapy and surgery alone in participants with early-stage non-small-cell lung cancer (NSCLC) in the phase 3, randomized KEYNOTE-671 study. We report results from KEYNOTE-671 after 5 years of follow-up. PATIENTS AND METHODS:Eligible participants with previously untreated, resectable stage II, IIIA, or IIIB (N2) NSCLC were randomized 1:1 to 4 cycles of pembrolizumab 200 mg or placebo every 3 weeks, plus platinum-doublet chemotherapy, followed by surgery then adjuvant pembrolizumab or placebo every 3 weeks for up to 13 cycles. Dual primary endpoints were event-free survival (EFS) per RECIST v1.1 by investigator assessment and overall survival (OS). RESULTS:797 participants were randomized to pembrolizumab (n=397) or placebo (n=400). Median time from randomization to data cutoff (July 3, 2025) was 60.4 (range, 42.6‒85.8) months. Five-year EFS was 49.9% (95% CI, 44.6‒55.0) in the pembrolizumab arm and 26.5% (95% CI, 21.7‒31.5) in the placebo arm (HR, 0.58; 95% CI, 0.48‒0.69); 5-year OS was 64.6% (95% CI, 59.5‒69.2) and 53.6% (95% CI, 48.3‒58.6), respectively (HR, 0.74; 95% CI, 0.59‒0.92). No detriment to health-related quality of life was identified in the pembrolizumab versus placebo arm with longer follow-up. Safety was consistent with the known profiles of each treatment. CONCLUSIONS:After 5 years of follow-up, EFS was nearly double with perioperative pembrolizumab plus neoadjuvant chemotherapy, along with continued improvement in OS compared with neoadjuvant chemotherapy and surgery alone. The durable and clinically meaningful benefits observed support use of this treatment as a standard of care for patients with resectable early-stage NSCLC (ClinicalTrials.gov, NCT03425643).
BACKGROUND:New therapies are needed to improve survival in unresectable esophageal squamous cell carcinoma (ESCC) following definitive chemoradiotherapy (dCRT). We investigated the efficacy and safety of atezolizumab ± tiragolumab versus placebo in this setting. PATIENTS AND METHODS:SKYSCRAPER-07 (ClinicalTrials.gov: NCT04543617) is a global, randomised, placebo-controlled, phase III trial performed at 166 centres in 28 countries. Adult patients with stage II-IVA locally advanced and selected stage IVB ESCC who had received dCRT were randomised (1:1:1) to receive atezolizumab 1200 mg plus tiragolumab 600 mg, atezolizumab 1200 mg plus placebo, or placebo plus placebo (hereafter placebo) intravenously every 3 weeks for 17 cycles. Hierarchically tested primary endpoints are investigator-assessed progression-free survival (INV-PFS) then overall survival (OS) with atezolizumab plus tiragolumab versus placebo, followed by OS with atezolizumab plus placebo versus placebo. RESULTS:Between 28 September 2020 and 31 August 2023, 760 patients were assigned to atezolizumab plus tiragolumab (n=257), atezolizumab plus placebo (n=250), or placebo (n=253). Overall, 564 (74.2%) patients were male and 477 (62.8%) were Asian. At a median survival follow-up of 25.0 months, atezolizumab plus tiragolumab versus placebo did not statistically improve INV-PFS (hazard ratio [HR] 0.82, 95% CI 0.65-1.03; p=0.0947) or OS (HR 0.91, 95% CI 0.70-1.18; descriptive p=0.4772). However, OS was significantly improved with atezolizumab plus placebo versus placebo (HR 0.69, 95% CI 0.52-0.91; descriptive p=0.0085) as was INV-PFS (HR 0.74, 95% CI 0.58-0.93). Treatment-related adverse events occurred in 74.8%, 65.2%, and 55.4% of patients in the atezolizumab plus tiragolumab, atezolizumab plus placebo, and placebo groups, respectively, with treatment-related deaths occurring in 1.2%, 0.8%, and 1.6%. CONCLUSIONS:The SKYSCRAPER-07 study did not meet the primary endpoint. Clinically meaningful improvements in OS and PFS were demonstrated with atezolizumab plus placebo versus placebo following dCRT for patients with unresectable ESCC. CLINICAL TRIAL NUMBER:NCT04543617.
BACKGROUND:Despite the dramatic activity of next generation targeted therapies, most patients with oncogene-driven lung cancers eventually relapse. Novel inhibitors are particularly active against on-target resistance, fostering the emergence of off-target resistance mechanisms. The current clinical development of RAS inhibitors hints at their potential role in overcoming off-target resistance mediated by RAS alterations. PATIENTS AND METHODS:Using tissue and liquid biopsies, we assessed resistance mechanisms to first-line osimertinib in patients with EGFR-mutant lung cancer, and to ALK-, MET-, ROS1-, and RET- inhibitors, for a total of 590 patients. We established two patient-derived models with acquired KRAS mutations obtained at osimertinib progression, enabling in vitro and in vivo functional experiments. RESULTS:Among 312 patients progressing on first-line osimertinib, we observed a major complementary role of tissue and liquid biopsies in identifying resistance mechanisms. We identified RAS alterations in 35 of 312 patients (11.2%), with an enrichment in KRAS G12D (n = 10) and a paucity of KRAS G12C (n = 1) mutations. In patients with ALK-positive disease (n = 148), RAS alterations were more common at resistance to lorlatinib compared to second-generation inhibitors (14.7% vs 5%, p = 0.0444). Across MET-, ROS1-, and RET-driven lung cancers at progression to targeted agents, RAS alterations were detected in 7-16% of the cases. In the two patient-derived models established at osimertinib resistance with acquired KRAS mutations (G12D and G12R, respectively), we tested the combinatorial effect of osimertinib with either the selective KRAS G12D inhibitor zoldonrasib or the pan-RAS inhibitor daraxonrasib. Both combinations demonstrated marked synergistic activity in vitro and in vivo. CONCLUSIONS:RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer. Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.
BACKGROUND:We previously reported that, at median follow-ups of 34 and 68 months, enzalutamide improved overall survival (OS) compared with a first-generation non-steroidal anti-androgen (NSAA) when added to testosterone suppression for metastatic hormone-sensitive prostate cancer (mHSPC). We now report longer-term outcomes, with a focus on adverse events and causes of death. PATIENTS AND METHODS:Participants with mHSPC were randomly assigned (1:1) to daily enzalutamide or NSAA in addition to testosterone suppression; concurrent early docetaxel was permitted at clinician discretion. OS was the primary endpoint; secondary endpoints included progression-free survival (PFS), cause-specific survival, duration of treatment, and adverse events (AE). RESULTS:At a median follow-up of 8.1 years (97 months), deaths occurred in 285/563 (51%) participants assigned enzalutamide versus 337/562 (60%) assigned NSAA. OS was longer with enzalutamide than NSAA (median years 7.9 vs 5.8; OS at 8 years 50% vs 40%; HR 0.73, 95% CI 0.63 to 0.86; p=0.0001). Clinical PFS at 8 years also favoured enzalutamide (43% vs 20%; HR=0.49, 95% CI 0.42 to 0.57; p<0.0001). Of 622 deaths, 468 were attributed to prostate cancer and were fewer with enzalutamide than NSAA (207 vs 261), whereas deaths attributed to other causes occurred with similar frequency in the two groups (78 vs 76). Median treatment duration was 4.8 years with enzalutamide and 1.9 years with NSAA group. Of 185/563 (33%) participants still receiving enzalutamide at data-cut-off, most (163/185, 88%) remain on the full 160mg dose. Rates of grade 3-5 AEs per 100 person-years were similar between groups for cardiac (2.2 vs 2.2) and nervous system disorders (2.3 vs 2.0), with more falls observed with enzalutamide (0.70 vs 0.24). CONCLUSION:Enzalutamide continues to provide substantial long-term OS benefit at 8 years, with sustained efficacy, maintenance of full dose in most participants, and no increase in non-prostate cancer mortality. CLINICALTRIALS:gov Identifier: NCT02446405.
BACKGROUND:Nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit compared with chemotherapy for patients with previously untreated advanced esophageal squamous cell carcinoma (ESCC). We report OS and additional analyses at a minimum follow-up of 5 years. PATIENTS AND METHODS:The open-label, phase III CheckMate 648 trial (NCT03143153) enrolled patients with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. The primary endpoints were OS and progression-free survival (PFS) by blinded independent central review (BICR) in patients with tumor cell programmed death ligand 1 (PD-L1) expression ≥1%. Key secondary endpoints included OS and PFS by BICR in all randomized patients. RESULTS:In total, 970 patients were randomized. At the 5-year minimum follow-up, OS improvement continued to be observed with nivolumab plus chemotherapy versus chemotherapy (HR 0.62, 95% CI 0.48-0.79) and nivolumab plus ipilimumab versus chemotherapy (HR 0.62, 95% CI 0.48-0.80) in patients with tumor cell PD-L1 ≥1%. OS benefit was also observed in all randomized patients (HR 0.77, 95% CI 0.65-0.92 for both nivolumab plus chemotherapy and nivolumab plus ipilimumab versus chemotherapy). PFS benefit was observed with nivolumab plus chemotherapy versus chemotherapy in the tumor cell PD-L1 ≥1% (HR 0.67, 95% CI 0.51-0.88) population, but not with nivolumab plus ipilimumab versus chemotherapy (HR 1.03, 95% CI 0.78-1.35). Among all treated patients, grade 3/4 treatment-related adverse events were observed in 49% of patients in the nivolumab plus chemotherapy group, 33% in the nivolumab plus ipilimumab group, and 37% in the chemotherapy group. CONCLUSIONS:Nivolumab-containing treatment regimens continued to demonstrate clinically meaningful OS benefit versus chemotherapy at the 5-year follow-up, with no new safety signals. These data further support nivolumab in combination with chemotherapy or ipilimumab as first-line treatment for patients with advanced ESCC.
BACKGROUND:SKYSCRAPER-03 (NCT04513925) was a phase III, open-label, randomized, study that evaluated consolidation therapy with tiragolumab plus atezolizumab versus durvalumab in patients with locally advanced, unresectable, stage III, non-small cell lung cancer (NSCLC) after platinum-based concurrent chemoradiation. PATIENTS AND METHODS:Eligible patients were randomized (1:1) to receive either atezolizumab (1680 mg every 4 weeks [Q4W]) plus tiragolumab (840 mg Q4W) on day 1 of each cycle, or durvalumab (10 mg/kg every 2 weeks or 1500 mg Q4W for those ≥30 kg body weight) on days 1 and 15 of each cycle, for 13 x 28-day cycles. The primary endpoint was Independent Review Facility (IRF)-assessed progression-free survival (PFS) in patients with programmed cell death ligand-1-positive (PD-L1+; tumor cells [TC] ≥1%) NSCLC. Key secondary endpoints were overall survival (OS) and safety. RESULTS:The PD-L1 all-comers population included 413 patients randomly assigned to tiragolumab plus atezolizumab and 416 to durvalumab; the PD-L1+ population included 209 and 210 patients in each arm, respectively. After a median follow-up of 33.0 months, median IRF-assessed PFS in PD-L1+ patients was 19.4 months with tiragolumab plus atezolizumab versus 16.6 months with durvalumab (stratified hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.75-1.23; p = 0.76); median PFS in PD-L1 all-comers was 14.2 versus 13.8 months, respectively (stratified HR 1.00; 95% CI, 0.84-1.19). Median OS in PD-L1+ patients was not estimable with tiragolumab plus atezolizumab versus 54.8 months with durvalumab (stratified HR 0.99; 95% CI 0.73-1.34); in PD-L1 all-comers, median OS was 45.6 versus 45.8 months, respectively (stratified HR 0.98; 95% CI 0.80-1.20). The safety profile of the combination was consistent with prior observations, and there were no new or unexpected findings. CONCLUSIONS:The primary endpoint of the SKYSCRAPER-03 study was not met. Tiragolumab plus atezolizumab was tolerated but did not offer additional benefit over durvalumab.
BACKGROUND:Clavien-Dindo (CD) grade ≥II complications occur in approximately one in five patients after curative gastrectomy for gastric cancer and independently shorten overall survival (OS) by compromising adjuvant therapy delivery. Current nutritional, inflammatory, and global surgical-risk scores identify only a minority of affected patients. We developed and validated a multimodal deep learning framework for simultaneous preoperative prediction of CD grade ≥II complications and long-term survival. PATIENTS AND METHODS:This multicenter study analyzed 5237 patients with gastric adenocarcinoma from 11 Chinese centers and additionally validated the model using prospectively collected data from six registered clinical trials covering three neoadjuvant treatment settings (chemotherapy, chemoradiation, and immunochemotherapy). DeepComp integrates clinical variables with foundation-model image features from the target lesion region, 5-mm peritumoral region, and L3 body composition compartments through a tabular dual-task architecture to jointly predict CD grade ≥II complications and OS. RESULTS:DeepComp achieved an area under the receiver operating characteristic curve of 0.888 [95% confidence interval (CI) 0.854-0.921] in the merged internal validation set and 0.824-0.869 across nine external cohorts, outperforming the best clinical baseline by 15.3 percentage points (P < 0.001) and all nine established clinical scores (all P < 0.001). With DeepComp assistance, the mean sensitivity of 10 surgeons increased from 47.1% to 87.9% (P < 0.001). Through target-trial emulation, DeepComp-guided prophylactic intensive care unit monitoring, preoperative nutritional support with delayed surgery, and minimally invasive triage yielded absolute CD grade ≥II risk reductions of 5.9%, 20.6%, and 11.7%, respectively (all P < 0.01; E-values 1.90-5.73). DeepComp independently predicted OS (adjusted hazard ratio 3.08 per standard deviation, 95% CI 2.91-3.25; pooled C-index 0.766), with 5-year survival ranging from 97.5% in quintile 1 to 2.4% in quintile 5. CONCLUSIONS:DeepComp showed consistent performance across validation cohorts for preoperative risk stratification of post-operative complications and long-term survival and may support individualized perioperative management.
