Pagliaro, Lance C.

PURPOSE The COSMIC-021 study assessed the safety and efficacy of cabozantinib plus atezolizumab in advanced solid tumors. Presented here are results from the expansion cohorts with advanced urothelial carcinoma (UC). METHODS This phase Ib study (ClinicalTrials.gov identifier: NCT03170960 ) enrolled patients with inoperable locally advanced/metastatic UC into four tumor cohorts: first-line cisplatin-eligible (cis-eligible), first-line cisplatin-ineligible (cis-ineligible), previous platinum-containing chemotherapy (previous chemotherapy-treated), and previous immune checkpoint inhibitor (ICI)–treated. Patients received oral cabozantinib 40 mg once daily and intravenous atezolizumab 1,200 mg once every 3 weeks. The primary end point was objective response rate (ORR), as assessed by the investigator per RECIST v1.1 every 6 weeks for 12 months and every 12 weeks thereafter; the secondary end point was safety. RESULTS A total of 121 patients (previous ICI-treated cohort, n = 31, and each of the other cohorts, n = 30) received study treatment from March 2018 to November 2021. The ORR (95% CI) was 30% (15 to 49) for cis-eligible, 20% (8 to 39) for cis-ineligible, 27% (12 to 46) for previous chemotherapy-treated, and 10% (2 to 26) for previous ICI-treated cohorts. The median progression-free survival (95% CI) was 5.5 (1.6 to 11.6), 5.6 (3.1 to 11.1), 5.4 (1.6 to 7.6), and 3.0 (1.8 to 5.5) months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) were experienced by 43%, 67%, 57%, and 45% of patients, respectively. TRAEs led to discontinuation of all treatment components in 17%, 13%, 3%, and 19%, respectively. No grade 5 TRAEs were reported in any cohort. CONCLUSION The novel combination of cabozantinib plus atezolizumab exhibited clinical activity in advanced UC that is cis-eligible, cis-ineligible, or previously treated with platinum-containing chemotherapy; clinical activity in previous ICI-treated UC was modest. The toxicity profile was consistent with that previously reported for the combination.

524 Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) play a key role in treating renal cell carcinoma and other solid organ malignancies, but TKIs cause bothersome side effects that frequently necessitate dose reductions or treatment holds. Olanzapine has been useful for palliating symptoms from classical chemotherapies and advanced cancer, but its effect on TKI-related symptoms is largely unknown. This retrospective study aimed to estimate the efficacy of olanzapine for TKI-induced nausea, vomiting, anorexia, weight loss, and insomnia. Methods: All patients prescribed olanzapine with lenvatinib, cabozantinib, axitinib, or tivozanib at Mayo Clinic between January 1, 2018, and June 30, 2024 were assessed for inclusion. For baseline symptom assessment, clinical care team notes documenting the presence or absence of symptoms and indication(s) for starting olanzapine were reviewed. For response assessment, clinical notes and patient portal messages from the first three months after starting olanzapine were evaluated for qualitative descriptions of change in symptom burden. Relevant data were extracted as direct quotations, which were reviewed by the research team and categorized as “improved,” “worsened,” “stable,” or “missing data.” Each symptom domain was analyzed independently when olanzapine was prescribed for multiple interrelated symptoms. Results: A total of 60 patients who received olanzapine for the treatment of TKI-related adverse effects were included. The most common documented indication for olanzapine was nausea without vomiting (n=35), followed by anorexia (n=25), nausea with vomiting (n=16), weight loss (n=16), and insomnia (n=11). In 32 cases (53%), olanzapine was prescribed for multiple, simultaneous symptoms. Response rates for each symptom domain are shown in the table. In addition, prior to olanzapine, 34 patients (57%) had documented weight loss. Following olanzapine, 50% (n=17) gained weight (median increase: 6.1 kg; range: 2.0 - 10.7 kg), 26% (n=9) stabilized their weight (±1 kg), and 24% (n=8) continued to lose weight. Clinicians utilized a TKI dose reduction within one week of olanzapine initiation in 5 cases (8.3%), and 3 of these patients could resume the higher dose of TKI after starting olanzapine. Only 4 patients (7%) discontinued olanzapine within 3 months due to perceived side effects. Conclusions: Olanzapine appears to be effective in treating TKI-induced nausea, vomiting, anorexia, insomnia, and weight loss. Prospective randomized placebo-controlled studies are needed to confirm these findings. Improvedn (%) Worsened n (%) Stablen (%) Missing Datan (%) Nausea without emesis 32 (84) 3 (8) 1 (3) 2 (5) Nausea with emesis 13 (93) 0 (0) 0 (0) 1 (7) Anorexia 26 (74) 2 (6) 4 (11) 3 (9) Insomnia 11 (85) 0 (0) 2 (15) 0 (0)

TPS5108 Background: Penile cancer is a devastating malignancy that affects just over 2000 patients per year in the United States and approximately 40,000 worldwide. Metastatic or unresectable penile cancer is rapidly fatal in most cases and there are few effective systemic therapy options.1 There is an urgent need for alternatives to chemotherapy such as immunotherapy or targeted therapy. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 protein on the tumor cell surface and having efficacy in treatment of metastatic urothelial carcinoma.2 Recent studies have demonstrated frequent and strong expression of nectin-4 in penile squamous cell carcinoma (PSCC).3,4 In this setting, Mayo Clinic is leading a phase II trial of EV for advanced PSCC, currently in progress. Methods: This single arm, open-label, two-stage, phase II trial evaluates best overall response rate (BRR) to EV in patients with PSCC regional lymph node involvement or distant metastatic (M1) disease. Participants may have had any prior systemic therapy or be treatment naïve. Previously untreated patients must be ineligible for or have refused surgery or radiotherapy, have N2-N3 disease and are ineligible for or have refused neoadjuvant chemotherapy, or have clinical evidence of M1 disease. Participants will receive treatment with EV until disease progression, withdrawal, death, or limiting toxicity. Participants will receive EV 1.25 mg/kg intravenous on days 1, 8, and 15 of a 28-day cycle, with tumor assessment performed at 8-week intervals. The primary endpoint is the combined BRR of partial and complete responses (whether confirmed or unconfirmed) according to RECIST 1.1. Secondary endpoints are confirmed response rate, duration of response, progression-free survival, overall survival, adverse events, and BRR in HPV related and unrelated subgroups. Stage 1 will consist of 15 participants, and if there are 2 or more responses will proceed to Stage 2 with an additional 10 participants. The trial opened to enrollment in December 2023, and is active at Mayo Clinic sites in Minnesota, Arizona, and Florida. Clinical trial information: Funding and drug supplied by Astellas Pharma Global Development, Inc./Seagen Inc. NCT06104618. 1. Chahoud J, et al., Curr Opin Urol. 2022 Jan 1;32(1):8-16. 2. Powles T, et al. N Engl J Med. 2021 Mar 25;384(12):1125-1135. 3. Tekin B, et al. Hum Pathol. 2023 Dec;142:42-50. 4. Grass GD, et al. Eur Urol Open Sci. 2023 Jan 10;49:1-5. Clinical trial information: NCT06104618 .

Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs.

Abstract Introduction This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking. Methods Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan–Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0. Results A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort. Conclusion Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes.

695 Background: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with limited data informing prognosis. We present a novel prognostic model for disease specific survival (DSS) for patients with non-metastatic (M0) SCCB, derived from the Surveillance, Epidemiology and End Results (SEER) database. Methods: The SEER database (18 registries/November 2020) was queried with the ICD-10 topography codes C67.0-C67.9 (bladder), and the morphologic code 8041 (SCCB). Eligible patients (adults, histologic confirmation, available follow-up/staging data, M0) were randomly divided into a training (TC) and a validation cohort (VC) (7:3 ratio). Variables significantly associated with DSS were identified with multivariate Cox regression and backwards stepwise conditional approach and inserted in the model. Points were assigned to each variable based on the formula: Probability of an event at time t=S0(t)exp(β1x1, β2x2...), (β = regression coefficients, x = observed covariate values, S0(t) = survival function). Cumulative risk points were assigned to each patient and three distinct risk categories for DSS were constructed. Harrel’s C-statistic with bootstrap resampling was used for internal (TC) and external (VC) validation. Model performance was compared to the AJCC 8th edition (likelihood ratio test -LRT). Results: A total of 1039 patients were included (739 TC, 300 VC). No statistically significant differences in baseline characteristics/survival outcomes were identified between TC and VC. Age (years), T/N stage, radical cystectomy, chemotherapy, and radiation were significant variables inserted in the multivariate model (table). Patients were stratified to three risk groups (low, intermediate, high) based on the total cumulative risk points collected. Median DSS was NR (95%CI; NR, NR), 25 (95% CI; 18-32) and 9 months (95% CI; 7-11) for the low, intermediate, and high-risk category, log-rank p<.001. Harrel's C-statistic for the model was 0.70 (95%CI;0.67-0.73) in the TC and 0.66 (95%CI; 0.61-0.71) in the VC. In comparison, C-statistic for the AJCC 8th edition was 0.56 (95% CI; 0.52-0.59) and 0.53 (95% CI; 0.51 to 0.57), respectively. The LRT demonstrated superior performance of the model compared to AJCC (p<.001). Conclusions: We present a novel prognostic model for DSS in patients with locoregional SCCB composed of variables readily available in daily practice, which may serve as a useful tool for individualized risk assessment of patients with this rare malignancy. Further validation in prospective studies/clinical trials is warranted. [Table: see text]

Abstract Background The Surgery in Early Metastatic Seminoma (SEMS) trial examined retroperitoneal lymph node dissection as first-line treatment for patients with isolated 1-3 cm retroperitoneal lymphadenopathy. To date, the standard of care for these patients has been either chemotherapy or radiotherapy. Herein, we evaluated the relative cost-effectiveness of these management strategies. Methods A microsimulation model assessed the cost-effectiveness of retroperitoneal lymph node dissection, chemotherapy, and radiotherapy for stage IIA seminoma. Sensitivity analyses were performed to evaluate model robustness. Retroperitoneal lymph node dissection recurrence probabilities were obtained from the SEMS trial. All other probability and utility values were obtained from published literature. Primary outcomes included costs from a commercial insurer’s perspective, effectiveness (quality adjusted life-years [QALYs]), and incremental cost-effectiveness ratios using a willingness-to-pay threshold of $100 000/QALY. Results At a lifetime horizon, the mean costs per patient for retroperitoneal lymph node dissection, radiotherapy, and chemotherapy were $58 469, $98 783, and $104 096, and the mean QALYs were 40.61, 40.70, and 39.15, respectively. Retroperitoneal lymph node dissection was found to be the most cost-effective approach because of high costs and accrued disutility of chronic toxicities associated with radiotherapy (cost-effectiveness ratios = $433 845/QALY) and chemotherapy (dominated). On 1-way sensitivity analyses, retroperitoneal lymph node dissection was no longer cost-effective if the probabilities of infertility and cardiovascular toxicity after radiotherapy were less than 13% and 16%, respectively, or if the 2-year probability of progression after retroperitoneal lymph node dissection was more than 26%. Conclusions Retroperitoneal lymph node dissection was the most cost-effective treatment approach for stage IIA seminoma. These findings support clinical guideline consideration of including retroperitoneal lymph node dissection as a treatment option for well-selected patients with stage IIA seminoma.

Abstract Background The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy. Methods A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria. Results Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for an MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR). Conclusions Our study highlights that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12. This study further demonstrates the utility of liquid biopsy NGS for identifying MSI-H and/or TMB-H disease.

Zusammenfassung Hintergrund Aktuell wurde mit dem Tetrafecta-Score das erste Instrument zur Beurteilung der Behandlungsqualität in der chirurgischen Primärtherapie des Peniskarzinoms (PECa) publiziert. Eine externe wissenschaftliche Auseinandersetzung mit den ihn definierenden Einzelkriterien steht bislang noch aus und bildet das Studienziel. Material und Methode Es wurde eine internationale Arbeitsgruppe bestehend aus 12 Urologen und einem Onkologen mit klinischer und akademisch-wissenschaftlicher Expertise auf dem Gebiet des Peniskarzinoms gegründet. In einem modifizierten vierstufigen Delphi-Prozess wurden unter Einbeziehung der Tetrafecta-Kriterien insgesamt 13 Kriterien für PECa-Patienten in den klinischen AJCC-Stadien 1–4 (T1–3N0–3, aber M0) definiert, von denen in einer geheimen Abstimmung jeder der Experten 5 auswählen musste, um dadurch einen individuellen Pentafecta-Score zu generieren. Anschließend wurde das Rating der Experten aggregiert ausgewertet und dadurch ein finaler Pentafecta-Score gebildet. Ergebnisse Keines der ursprünglichen Tetrafecta-Kriterien wurde in den finalen Pentafecta-Score übernommen, der sich aus den folgenden Kriterien zusammensetzt: 1.) Organerhalt, sofern immer möglich (≤T2), jedoch stets unter Wahrung eines negativen chirurgischen Schnittrandes, 2.) beidseitige inguinale Lymphadenektomie (ILAE) ab pT1G2N0, 3.) perioperative Chemotherapie sollte erfolgen, sofern durch die Leitlinien indiziert, 4.) ILAE sollte, sofern indiziert, in einem zeitlichen Abstand von maximal 3 Monaten zur Primärtumorresektion erfolgen und 5.) die behandelnde Klinik sollte im Minimum 15 chirurgische Primärtherapien bei PECa-Patienten durchführen. Nur 7 der 13 Experten (54%) zeigten eine starke Korrelation ihres individuellen mit dem finalen Pentafecta-Score (rsp >0.60). Schlussfolgerung Auf der Basis eines moderierten Abstimmungsprozesses unter internationalen PECa-Experten wurde ein Pentafecta-Score als Qualitätssicherungs-Instrument für die chirurgische Primärtherapie gebildet, der nun anhand von patientenrelevanten und patientenberichteten Endpunkten zu validieren ist.