This Viewpoint evaluates the present relevance of Response Evaluation Criteria in Solid Tumors (RECIST) as cancer therapeutics have evolved beyond cytotoxic chemotherapy in assessing treatment outcomes.
Importance Very high-risk non–muscle-invasive bladder cancer (VHR NMIBC) includes extensive high-grade T1 (T1HG) disease, T1HG with carcinoma in situ, variant histology, lymphovascular invasion, or bacille Calmette-Guérin (BCG)–unresponsive disease. Transurethrally unresectable disease warrants radical cystectomy, but patients ineligible for or declining cystectomy lack established nonsurgical therapy. Objective To evaluate the efficacy and safety of disitamab vedotin (DV, an anti- ERBB2 [formerly HER2 ] antibody-drug conjugate) plus tislelizumab (an anti–programmed cell death 1 protein immune checkpoint inhibitor) in transurethrally unresectable ERBB2 -positive VHR NMIBC. Design, Setting, and Participants This was an open-label, single-arm, phase 2, nonrandomized clinical trial with a Simon 2-stage design, conducted in an academic hospital from August 2022 to May 2024 with a median follow-up of 29.4 months. The analysis included adults with transurethrally unresectable ERBB2 -positive NMIBC who met the 2019 European Association of Urology VHR criteria and who were ineligible for or declined cystectomy. Intervention Patients received an intravenous injection of DV (120 mg, day 1) plus tislelizumab (200 mg, day 2) every 3 weeks for 3 cycles; patients who responded received up to 8 DV cycles and 17 tislelizumab cycles. Main Outcomes and Measures The primary outcome was complete response (CR) of high-risk disease, defined as no high-grade tumor, T1 disease, carcinoma in situ, or progression. Secondary outcomes were response duration, progression-free survival, overall survival, and safety. Results Among 137 screened patients, 28 participants (median [IQR] age, 72 [67-74] years; 25 male [89%]) were included. Two preassessment withdrawals were counted as nonresponders in the all-treated analysis, which left 26 efficacy-evaluable patients. CR of high-risk disease was achieved in 19 of 26 (73.1%; 95% CI, 54.8%-91.3%), meeting the prespecified 70% alternative-rate goal. Among all 28, 19 responded (67.9%; 95% CI, 49.4%-86.3%), exceeding the 17-response exact binomial threshold. Both analyses met the primary criterion. Among responders, the 24-month sustained response was 83.5% (95% CI, 68.0%-100.0%), and no muscle invasive or metastatic progression occurred. Treatment-related adverse events occurred in 25 patients (89.3%), most commonly paresthesia (12 [42.9%]), alopecia (11 [39.3%]), and pruritus (10 [35.7%]); 4 (14.3%) had grade 3 to 4 events; 2 (7.1%) discontinued treatment; and none had grade 5 events. Conclusions and Relevance Findings of this nonrandomized clinical trial suggest that DV plus tislelizumab may show a high CR rate and durable disease control in patients with transurethrally unresectable ERBB2 -positive VHR NMIBC, supporting randomized clinical trials. Trial Registration ClinicalTrials.gov Identifier: NCT05495724
Importance:In the KEYNOTE-826 study, pembrolizumab (vs placebo) plus platinum-based chemotherapy (with or without bevacizumab) significantly improved progression-free survival and overall survival in participants with previously untreated persistent, recurrent, or metastatic cervical cancer at interim analysis 1 (median follow-up, 22.0 months), with continued benefit at final analysis (median follow-up, 39.1 months). Long-term follow-up is important to further inform the benefit-risk profile of anticancer treatments. Objective:To investigate 5-year efficacy and safety results of pembrolizumab plus chemotherapy (with or without bevacizumab) in previously untreated persistent, recurrent, or metastatic cervical cancer. Design, Setting, and Participants:This ad hoc exploratory analysis of the phase 3, double-blind KEYNOTE-826 randomized clinical trial was conducted in participants with previously untreated persistent, recurrent, or metastatic cervical cancer across 151 sites in 19 countries. Participants were randomly assigned to treatment between November 20, 2018, and January 31, 2020. The median follow-up for this analysis was 59.1 (range, 52.1-66.5) months (approximately 20 months after final analysis). Data were analyzed between November 20, 2018, and June 4, 2024. Interventions:Pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles vs placebo, each combined with platinum-based chemotherapy (with or without bevacizumab). Main Outcomes and Measures:Progression-free survival and overall survival. Results:A total of 617 female patients were randomized. At baseline, the median age of participants was 51.0 (range, 22-82) years, with 303 participants (49.1%) having stage I/II and 190 (30.8%) having IVB disease and 446 (72.3%) having squamous cell/squamous cell carcinoma. At 5 years, the overall survival benefit was sustained with pembrolizumab plus chemotherapy in the programmed cell death ligand 1 combined positive score of at least 1 (median [IQR], 28.6 [12.3 to not reached] vs 16.5 [9.0-40.5] months; hazard ratio [HR], 0.62 [95% CI, 0.50-0.76]) and intention-to-treat (median [IQR], 26.4 [12.0 to not reached] vs 16.8 [9.1-40.1] months; HR, 0.64 [95% CI, 0.53-0.78]) populations. The progression-free survival advantage was similarly maintained (median [IQR], 10.5 [6.2 to not reached] vs 8.2 [4.2-17.1] months; HR, 0.58 [95% CI, 0.48-0.71] and median [IQR], 10.4 [6.2 to not reached] vs 8.2 [4.3-15.5] months; HR, 0.61 [95% CI, 0.51-0.74], respectively). No new safety signals were observed. No additional deaths due to treatment-related adverse events had occurred since the final analysis. Conclusions and Relevance:In this exploratory analysis of the KEYNOTE-826 randomized clinical trial, the 5-year data confirm the durability of benefit and reinforce pembrolizumab plus chemotherapy (with or without bevacizumab) as a first-line standard-of-care option for recurrent and metastatic cervical cancer. Trial Registration:ClinicalTrials.gov Identifier: NCT03635567.
