Faculty Bibliography

Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3 weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39 months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239 .

PURPOSE/UNASSIGNED:Screening colonoscopies (CS) performed before prostate stereotactic body radiation therapy (SBRT) allow for identifying synchronous malignancies and comorbid gastrointestinal (GI) conditions. Performing these procedures prior to radiation precludes the necessity of post-SBRT pelvic instrumentation, which may lead to severe toxicity and fistulization. We review compliance of CSs, incidence of GI pathology, and the impact of pretreatment CS findings on subsequent physician-reported toxicity and patient-reported quality of life (QoL). METHODS AND MATERIALS/UNASSIGNED:We reviewed an institutional database of patients treated for prostate cancer with SBRT including toxicity and QoL outcomes. A detailed review of pretreatment CS findings was reviewed including identification of diverticulosis, location of polyp resection, and presence of hemorrhoids. Pretreatment CS findings were then correlated with outcomes following SBRT. RESULTS/UNASSIGNED:Identification of comorbid GI conditions was a common event, with the presence of diverticulosis in 49.5% (n = 100), hemorrhoids in 67% (n = 136), and polyps in 48% (n = 98). More than half of patients with polyps removed had at least 1 removed from the rectosigmoid. Pretreatment CS did not introduce a delay in SBRT start date. Grade 1 toxicity was significantly lower in patients who underwent CS closer to the initiation of SBRT. There was no increased risk of physician-graded toxicity in the presence of diverticulosis, hemorrhoids, or polyps. Patient-reported GI QoL pattern in our screening cohort mimicked that seen in the previously published nonscreened population. There was no overt QoL detriment observed in patients who had GI pathology identified before SBRT. CONCLUSIONS/UNASSIGNED:GI pathology identified in our elderly patient population was commonly identified on pretreatment CS. Screening CS may optimize bowel health for patients heading into radiation therapy. Toxicity and QoL for patients with GI pathologies identified on pretreatment CS do not preclude the delivery of prostate SBRT. We advocate for pretreatment CS in patients eligible prior to SBRT.

Small cell carcinoma of the bladder is a rare, aggressive malignancy accounting for less than 1% of all bladder malignancies. Treatment regimens are drawn from the small cell lung cancer (SCLC) literature, with platinum and etoposide commonly used in the first-line setting. Unfortunately, responses are generally short-lived, and most patients relapse. There is little evidence to guide selection of later lines of therapy. Lurbinectedin is an alkylating agent with accelerated US FDA approval for use in patients with SCLC. Immune checkpoint inhibitors have also been approved for SCLC, improving survival when added to chemotherapy. This article describes the design and rationale behind LASER, an open-label phase II trial of lurbinectedin with or without avelumab.Clinical trial registration: NCT06228066 (ClinicalTrial.gov).

BACKGROUND:The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. METHODS:KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS/RESULTS:Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. INTERPRETATION/CONCLUSIONS:Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. FUNDING/BACKGROUND:Merck Sharp & Dohme.

PURPOSE OF REVIEW/OBJECTIVE:The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies. RECENT FINDINGS/RESULTS:Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy. SUMMARY/CONCLUSIONS:MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.

BACKGROUND:Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS:This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS:Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS:Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.