Cisplatin-ineligible Patients Research Articles

Neoadjuvant nivolumab (N) + ipilimumab (I) in cisplatin-ineligible patients with upper tract urothelial cancer (UTUC): Updated results.

645 Background: Perioperative platinum-based chemotherapy for UTUC improves pathologic responses and disease-free survival (DFS). We report the updated results from our on-going phase II neoadjuvant trial of N+I for cisplatin-ineligible patients (pts) with UTUC (NCT03520491). Methods: Cisplatin-ineligible pts with histologically confirmed high-grade UTUC and/or radiographically invasive UTUC with positive selective urine cytology were eligible. Pts were treated with I 3mg/kg + N 1mg/kg (weeks 0, 6), and “N” 3mg/kg (week 3) prior to radical nephroureterectomy (NU). The primary endpoint (EP) was pathologic complete response (pCR, ypT0pN0) and secondary EPs included <ypT2pN0 rate, DFS, and toxicity. Next generation sequencing of pre-treatment tumors was correlated with pathologic response. Results: Seventeen pts (76% male) were enrolled between 2/2021-6/2023 with median age 73 (range 59-85). Primary sites included ureter in 10 pts, renal pelvis in 5 and both in 2. Median tumor diameter was 3.0 cm, (range: 1.5 - 4.2 cm), with 8 pts (47%) having hydronephrosis. To date, 11 pts (65%) have received all planned treatment, 6 pts had N+/-I stopped early due to treatment-related toxicities, 2 pts are pending NU, 13 pts have undergone NU, 1 declined surgery, and another progressed on N+I. A pCR was seen in 4/15 pts (27%) and <ypT2pN0 in 9/15 (60%). Median time from last treatment to NU was 1.6 months (range 0.5-4.9). Three pts developed metastatic recurrence at 3.9, 10.3 and 15.6 months after treatment initiation. CTCAE grade ≥3 treatment-related adverse events occurred in 5 pts (29%). Four pts died during follow up: two of metastatic disease, one of complications related to a bowel leak (7.2 months after N+I initiation and 4.7 months after NU), and one from complications of a fall unrelated to disease or treatment (9.2 months after N+I initiation and 4.7 months after NU). Median tumor mutational burden (TMB) in 9 pts with pre-treatment sequencing was 13.2 mutations/mb (range 4.1-106.3), with 4/5 pts with TMB>10 <ypT2pN0 at NU. Pathogenic germline variants in mismatch repair genes were confirmed in 4 pts (MSH2 in 3, MLH1 in 1) and MSI-high tumors without germline alterations in 2 pts, with 5 of 6 completing NU (1 pending surgery); all 5 achieved pCR (n=3) or ypTaN0 (n=2) and remain alive and disease-free at last follow-up (6, 13.4, 17, 17.9 and 31 months). Conclusions: Updated findings from an on-going phase II trial of cisplatin-ineligible pts with UTUC receiving neoadjuvant N+I shows clinical activity in line with our initial results. All pts with pathogenic germline variants in mismatch repair genes or MSI-high tumors without germline alteration who underwent NU achieved <ypT2pN0 and remain free of disease. Clinical trial information: NCT03520491 .

Phase I/II study of ipilimumab plus nivolumab (IPI-NIVO) combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma.

TPS713 Background: Treatment options are suboptimal and limited for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Sacituzumab govitecan (SG) is a Trop-2 directed antibody-drug conjugate (ADC) coupled with SN-38 through a hydrolysable linker. In the phase II TROPHY-U-01 study, SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in mUC patients who progressed after platinum-based chemotherapy and immune checkpoint inhibitors (ICI), receiving accelerated approval by the US FDA. In CheckMate 032 study, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1+I3) every 3 weeks (Q3W) x 4 cycles followed by nivolumab monotherapy 3mg/kg Q2W showed promising activity post-platinum that led to the ongoing phase III trial in the first-line setting (NCT03036098). Given potential synergism between immunogenic cell death induced by ADC and ICI, we hypothesized that the combination of SG and IPI-NIVO would benefit patients with manageable toxicities. We designed this study to assess the safety and clinical activity of IPI-NIVO with SG as first-line therapy for cisplatin-ineligible mUC patients. Methods: This is an ongoing phase I/II, single arm, multicenter study for cisplatin-ineligible mUC. The Phase I portion enrolled 9 patients using a 3+3 design with safety and RP2D as primary endpoints. In this part, patients received fixed doses of IPI-NIVO (N1+I3) IV Q3Wx 4 cycles combined with SG (DL1 8 mg/kg or DL2 10mg/kg) IV on days 1, 8 Q3W x 4 cycles. This was followed by maintenance nivolumab 360 mg IV Q3W with SG on days 1, 8 Q3W. The RP2D of SG was determined as 8 mg/kg and combination was deemed safe and tolerable. ORR is the primary endpoint in the ongoing phase II portion of the study using Simon 2 stage design (n=34) with a futility interim analysis after 13 patients. The null hypothesis of ORR ≤ 38% will be tested with a desirable ORR of >60% under a statistical power of 80% and a one-sided type I error rate of 5%. Thirteen of the 34 patients have been enrolled and the study has passed the predefined interim analysis for futility. We aim to continue accrual. Exploratory biomarker analyses will be conducted using tumor and blood samples collected during screening and at progression. Clinical trial (NCT04863885). Clinical trial information: NCT04863885 .

Clinical efficacy of enfortumab-pembrolizumab combination therapy in locally advanced/metastatic urothelial carcinoma (UC): A real-world experience.

643 Background: The FDA approval of enfortumab (EV) and pembrolizumab (Pembro) combination therapy as a first-line treatment for cisplatin-ineligible patients with locally advanced/metastatic urothelial carcinoma (la/mUC) was based on the EV-103 trial. We aim to assess the clinical response rate of this combination therapy in our institution's patients with locally advanced and metastatic UC. Methods: This retrospective cohort study included 20 patients diagnosed with locally advanced/metastatic UC(la/mUC) who were treated with EV-Pembro combination for at least 2 cycles, from June 2022 to August 2023 at the Mayo Clinic. Patients who were treatment naïve or who progressed one or more lines of therapy were included in the study cohort. Main outcome of interest included imaging-based best overall response rate in terms of complete (CR) and partial (PR) response, stable disease (SD), and progressive disease (PD). Results: Out of 20 patients, the number of males and females were 16 (80%) and 4 (20%) respectively; the median age was 77 years (IQR: 51-92). 3 (15%) of patients had involvement of upper urinary tract disease along with bladder cancer. The common sites of visceral metastasis at the time of initial presentation include liver 2(10%), lung 6(30%) and lymph nodes12(60%). Common toxicities of this regimen included rash, pruritis, peripheral neuropathy, fatigue, transaminitis, dysgeusia, and diarrhea. The treatment was stopped in 10 (50%) patients due to completion of planned therapy (achieved CR or proceeded with resection of residual disease) (30%), 5 patients due to progression (50%), 1 patient due to therapy side effects (10%) and in 1 patient due to death (10%). The objective response was 45% (N =9); 5 (25%) had PR, and 4 (20%) had CR. A total of 2 (10%) had SD while 2 (10%) experienced PD. Histological correlation with clinical benefit is shown in the table. Conclusions: EV-Pembro combination therapy shows promising responses in patients who have progressed after previous lines of therapy, consistent with previously published data on EV 201 in small cohorts. However, ongoing expansion of this cohort and data from larger studies will help further elucidate survival benefits and their correlation with genetic testing. [Table: see text]

Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).

625 Background: Erdafitinib (E) is a treatment option in mUCpatients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved as a single agent to treat mUC patients following prior PBC and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients. Retrospective studies suggest that the activity of EV is not compromised by FGFR2/3 GAs. E and EV have different mechanisms of activity, and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination E + EV, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR2/3 GAs. Methods: This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination E + EV evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after PBC and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of EV at dose levels of 1 mg/kg and 1.25 mg/kg in combination with E at 8 mg/day as shown in the table. Preliminary safety, PK, and efficacy data for Dose Level (DL) 1 and 2 are presented in this abstract. Results: As of data cutoff, based on 3+3 design, total 8 patients are enrolled and finished dose limiting toxicity (DLT) period (1st cycle). Six patients were enrolled in DL1 with 1 DLT (skin rash) and 2 patients in DL2. The most common treatment-related adverse events (TRAE) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAE included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 subjects in DL1. The average steady-state Cmin of E and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 8 patients are evaluable for response, and best response is partial response in all. Detailed safety and additional efficacy data will be presented. Conclusions: Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153 . [Table: see text]

Comparative Effectiveness of Neoadjuvant Pembrolizumab Versus Cisplatin-based Chemotherapy or Upfront Radical Cystectomy in Patients with Muscle-invasive Urothelial Bladder Cancer

BackgroundRecent progresses in the use of immune checkpoint inhibitor (ICI) have challenged the therapeutic standards in patients with muscle-invasive urothelial bladder carcinoma (MIBC). ObjectiveTo compare neoadjuvant pembrolizumab followed by radical cystectomy (RC) versus neoadjuvant chemotherapy (NAC) and RC or upfront RC, according to cisplatin eligibility. Design, setting, and participantsWe conducted two separate analyses for cisplatin-eligible and cisplatin-ineligible cT2-4N0M0 MIBC patients. We used a propensity score adjustment that relied on inverse probability of treatment-weighting (IPTW). InterventionPembrolizumab within the PURE-01 trial, and NAC and RC or upfront RC from a high-volume tertiary care referral center. Outcome measurements and statistical analysisThe primary endpoint in both analyses was event-free survival (EFS), defined as freedom from recurrence, and/or death from any cause indexed from the date of treatment initiation or RC. The secondary endpoints included EFS in propensity score–matched patients, pathologic response rate, and recurrence-free survival (RFS) after RC. Results and limitationsA total of 458 patients who underwent RC, with or without NAC, at Moffitt Cancer Center between October 2005 and October 2020, and 146 patients enrolled in PURE-01 were analyzed. In cisplatin-ineligible patients, EFS was superior in those receiving pembrolizumab (p < 0.001). The estimated 3-yr EFS was 77.8% (95% confidence interval [CI]: 63.5–95.2) for pembrolizumab and RC, and 36.1% (95% CI: 28.6–45.5) for upfront RC. EFS remained superior in those receiving neoadjuvant ICI (NICI) following IPTW (p < 0.001). In cisplatin-eligible patients, EFS was superior in those receiving pembrolizumab and RC (p < 0.001). The estimated 3-yr EFS was 86.9% (95% CI: 80.9–93.3) for pembrolizumab and 63.5% (95% CI: 56.5–71.4) for NAC. EFS remained superior in those receiving NICI following IPTW (p < 0.001). Pathologic responses and RFS in pembrolizumab-treated patients were also superior to those in NAC-treated patients. Results are limited by the retrospective nature of the study. ConclusionsIn the first ever reported comprehensive comparison of outcomes between neoadjuvant ICI and NAC, followed by RC, or upfront RC, we report increased responses and improved oncologic outcomes with neoadjuvant ICI in patients with MIBC. Patient summaryWe compared the results obtained from the use of pembrolizumab and radical cystectomy with standard-of-care treatments in patients with bladder carcinoma infiltrating the muscle layer. We reported increased response and survival rates possibilities with the use of immunotherapy, anticipating the possibility to set new therapeutic standards in these patients, pending the results of ongoing randomized studies.

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy

Background and objectiveNeoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. MethodsPatients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, <ypT2N0 rates, 2-yr recurrence-free survival (RFS), and OS. Key findings and limitationsAmong 43 patients enrolled (n = 13, cohort 1; n = 30, cohort 2), 13 and 29 completed intended neoadjuvant therapy, respectively, in cohorts 1 and 2, and 41 underwent RC. The median time from the last dose to RC was 4 wk. The G3 TRAEs occurred in 0% (90% confidence interval [CI] 0–21%) of patients in cohort 1 and 7% (90% CI 1–20%) in cohort 2; all these TRAEs resolved and no G4/5 TRAEs occurred. No patient had delayed RC for >6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, <ypT2N0 rates were 25% and 32%, 2-yr RFS rates were 73% and 71%, and 2-yr OS rates were 82% and 89%, respectively. CD8+ T-cell density increased significantly from TURBT to RC in cohort 2. Conclusions and clinical implicationsNeoadjuvant nivolumab-based immunotherapy was safe, feasible, and well tolerated in cisplatin-ineligible patients with MIBC. Although ypT0N0 rates were lower than expected, 2-yr survival rates seem to be comparable with those of other neoadjuvant immunotherapy trials. Nivolumab is being evaluated in the CA-017-078 trial (NCT03661320). Patient summaryFor patients with muscle-invasive bladder cancer unable to receive cisplatin-based chemotherapy, treatment with nivolumab without and with lirilumab prior to radical cystectomy was safe, feasible, and well tolerated. Nivolumab-based immunotherapy showed lower pathologic response rates than but similar survival rates to other neoadjuvant immunotherapy trials.

Enfortumab vedotin and pembrolizumab as new first-line standard for metastatic urothelial cancer

Treatment options for patients with metastatic urothelial carcinoma ineligible for cisplatin-based chemotherapy have historically been limited. O'Donnell etal. recently reported the results of EV-103 Cohort K,1 leading to accelerated approval of enfortumab vedotin and pembrolizumab for cisplatin-ineligible patients and raising additional questions of how to best utilize this effective regimen.

Healthcare costs associated with first-line (1L) treatment of patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in the United States (US).

11 Background: In 2023 in the US, 82,290 new cases of bladder cancer and 16,670 related deaths were estimated. Prior analyses assessing the economic burden of la/mUC in the current and evolving treatment landscape have been limited. This study aimed to estimate the direct medical costs of treating patients with la/mUC, from US Medicare and commercial perspectives. Methods: A cost model was developed to estimate annual direct medical care costs in patients with la/mUC eligible for 1L platinum-based chemotherapy (PBC) in 2023. Costs (2023 USD)—including drug acquisition and administration, disease management and adverse event (AE) management—were calculated, including subsequent therapy costs. Inputs included estimated number of treated patients per year, treatment duration, progression-free survival and overall survival with various therapies, AEs incidence, and market shares. Efficacy and safety data were sourced from product prescribing information, epidemiology data from Surveillance, Epidemiology, and End Results (SEER) database and published literature. Market share assumptions were based on market research data. Results: For a hypothetical health plan with 1,000,000 members, 108 and 22 patients with la/mUC from Medicare and commercial perspectives, respectively, were estimated to be eligible for 1L PBC in 2023. Estimated total annual costs per treated patient are shown in the Table below. With market share data comprising 1L PBC, with and without avelumab (AVE) 1L maintenance (61% and 25%) and enfortumab vedotin (EV) + pembrolizumab (PEM) (for cisplatin-ineligible patients, 14%), annual costs of $16,673,645 ($12,861 per treated member per month) and $4,637,226 ($17,852 per treated member per month) were estimated for Medicare and commercial perspectives, respectively. Drug acquisition costs in 1L represented most of the total costs (Medicare, 75%; commercial, 64%). Conclusions: Understanding the economic burden associated with la/mUC treatments may facilitate informed decision making on treatment choice and optimal sequencing. Further real-world studies are needed to assess the impact of these innovative treatments on disease and AE management costs of la/mUC. [Table: see text]

Overview, Diagnosis, and Perioperative Systemic Therapy of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma comprises 5-10% of all urothelial carcinoma cases. This disease tends to have a more aggressive course than its lower urinary tract counterpart, with 60% of patients presenting with invasive disease and 30% of patients presenting with metastatic disease at diagnosis. The diagnostic workup of UTUC involves imaging with CT urogram, urine cytology, and direct visualization and biopsy of suspected lesions via ureteroscopy. Standard treatment of high-grade UTUC involves radical nephroureterectomy (RNU) and excision of the ipsilateral bladder cuff. Both the NCCN and EAU Guidelines include neoadjuvant chemotherapy as a treatment option for select patients with UTUC; however, there are no strict guidelines. Much of the rationale for neoadjuvant chemotherapy is based on extrapolation from data from muscle-invasive bladder cancer, which has demonstrated a 5-year OS benefit of 5-8%. Retrospective studies evaluating the use of NACT in urothelial carcinoma have yielded pathologic objective response rates of 48% in UTUC cohorts. The randomized Phase III POUT study noted a DFS advantage with adjuvant platinum-based chemotherapy, compared with surveillance in UTUC, of 70% vs. 51% at 2 years. Though not the standard of care, multiple studies have explored the use of perioperative immunotherapy or chemoimmunotherapy in the management of invasive urothelial carcinoma. The PURE-02 study explored the use of neoadjuvant pembrolizumab in patients with high-risk UTUC. A small study of 10 patients, it showed no significant signals of activity with neoadjuvant pembrolizumab. Another Phase II study of neoadjuvant ipilimumab and nivolumab in cisplatin-ineligible UTUC yielded more promising findings, with 3/9 patients attaining a pathologic CR and the remaining six pathologically downstaged. The ABACUS trial found a 31% pathologic complete response rate amongst cisplatin-ineligible MIBC patients treated with neoadjuvant atezolizumab. The use of adjuvant immunotherapy has been explored over three phase III trials. The CheckMate-274 trial found a DFS benefit with the addition of one year of adjuvant nivolumab in patients with high-risk urothelial carcinoma. The IMvigor-010 study of adjuvant atezolizumab was a negative study. The AMBASSADOR trial of adjuvant pembrolizumab is pending results. With the FDA approval of erdafitinib in metastatic urothelial carcinoma, similar targets have been explored for use in perioperative use in invasive urothelial carcinoma, as with adjuvant infigratinib in the PROOF-302 trial. As the treatment paradigm for urothelial carcinoma evolves, further prospective studies are needed to expand the perioperative treatment landscape of UTUC.

Outcomes after Contemporary Definitive Radiotherapy Alone in Patients with TNM-7 Stage III/IV Head and Neck Squamous Cell Carcinoma

This study was undertaken to determine outcomes and prognostic factors of definitive intensity-modulated radiotherapy (IMRT) alone for patients with TNM-7 stage III/IV HNSCC who did not receive concurrent chemotherapy. We evaluated TNM-7 stage III/IV HNSCC patients treated with definitive IMRT alone in our institution from 2004-2019. Patients were reclassified according to TNM-8 staging. Stage II HPV+ oropharyngeal cancers (OPC) were subdivided into T1-2N2 and T3N0-2 for analysis. The rationale for chemotherapy omission was obtained retrospectively from clinical documentation. Recurrence-free survival (RFS) and overall survival (OS) were estimated stratified by HPV status (determined by p16 staining, sometimes supplemented by HPV DNA testing). Multivariable analysis (MVA) identified prognostic factors for RFS and OS, taking into account stage and IMRT regimen. Age, performance status, and smoking were also examined for OS. A total of 1083 patients were included (460 HPV+ and 623 HPV-). Reasons for omission of chemotherapy were: age >70 years or frailty (n = 551, 51%), cisplatin contraindication (n = 241, 22%), patient refusal (n = 106, 10%), and clinician's decision (n = 185, 17%). Median age was 67 years for HPV+ and 70 years for HPV- cohorts. IMRT mostly utilized altered fractionation regimens (n = 1016, 94%): moderately accelerated (Acc) (70 Gy/35 fractions [f]/6 weeks [w], 55%), hypofractionated (Hypo) (60 Gy/25f/5w, 14%), and hyperfractionated-accelerated (Hyper) (64 Gy/40f/4w, 25%). Median follow-up was 5 years. Five-year RFS and OS for HPV+ TNM-8 stage I/T1-2N2/T3N0-N2/III were 89%/86%/76%/52% and 83%/80%/64%/33% respectively (p<0.01). The same outcomes for HPV- TNM-8 stage III/IVA/IVB were 58%/52%/39% and 47%/27%/13%, respectively (p<0.01). MVA confirmed that HPV+ T3N0-2 subset within stage II and stage III (vs stage I) had lower RFS, and HPV- stage IVA and IVB (vs stage III) carried worse RFS and OS (Table). Despite the retrospective nature and inherent selection bias, this large single institutional study shows that altered fractionated IMRT alone is an acceptable alternative for elderly, frail or cisplatin ineligible patients with HPV+ stage I/IIA (T1-2N2) OPC. Patients with HPV+ T3N0-2/stage III OPC and HPV- stage III/IV HNSCC have poor outcomes with IMRT alone and may benefit from alternative strategies.

PD-L1 mRNA Detection in Immunohistochemically Negative Patients: A Complementary Method for a Better Treatment Selection?

PD-L1 inhibitors have been approved for cisplatin-ineligible urothelial cancer patients relapsing after radical cystectomy. A prerequisite for therapy is a positive PD-L1 expression in the tumor tissue, whereas no options are available for patients with negative PD-L1 status. However, studies revealed that many PD-L1-negative patients also responded to PD-L1 therapy. This study investigated the feasibility of PD-L1 mRNA complementary RNA in situ hybridization (RNAish) analysis to detect PD-L1-responders independent of PD-L1 protein status. Immunohistochemistry and RNA in situ hybridization were used to assess PD-L1 protein and mRNA in radical cystectomy tissue from patients with advanced and metastasized urothelial cancer. In this study, PD-L1 protein and mRNA were detected in ≥90% of the examined tissue. Positive PD-L1 mRNA expression (≥1%) on TC and IC could be evaluated in 77% and 31% of the cases, respectively. Moreover, scatterplot analysis revealed a PD-L1 mRNA positive and PD-L1 protein negative subpopulation. According to the CPS score, positive PD-L1 protein expression could be evaluated in 88% and positive PD-L1 mRNA expression in 71% of the cases. Scatterplot analysis of the CPS scores revealed a CPS protein negative but CPS mRNA positive small subpopulation. The feasibility of RNAish on formalin-fixed tissue could be proven. Moreover, complementary PD-L1 RNAish identified a sub-population of PD-L1 protein-negative and PD-L1 mRNA-positive patients, which may benefit from PD-L1 therapy.

Long-Term Outcomes of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma

To report long-term oncologic outcomes among patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive de-intensified chemoradiotherapy. Major criteria for de-intensification were (1) AJCC 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) pathologically confirmed p16 positive, and (3) no or minimal/remote smoking history (non-mutated p53 if ≥30 pack-years). Treatment was 60 Gy intensity-modulated radiotherapy with first-choice concurrent cisplatin 30 mg/m2 once per week (alternative regimens permissible for cisplatin ineligible patients). Patients with T0-T2 N0-1 (AJCC 7th edition) were recommended 60 Gy radiation alone. Systemic therapy received included: cisplatin 30 mg/m2 (n = 122), cetuximab (n = 15), cisplatin 40 mg/m2 (n = 12), carboplatin/paclitaxel (n = 2), and radiation alone (n = 25). Kaplan Meier estimates for overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated. Cox regression models were used for comparisons among subgroups. A total 176 patients received de-intensified treatment (n = 153 prospective protocol, n = 23 off-protocol). Median follow-up was 52.6 months (range 5.3 - 102.0, 90.8% with minimum 2-year follow-up); 56.8% (n = 100) were never smokers and 43.2% (n = 76) former smokers; former smokers had median 9 pack-years smoking history (range 0.25 - 50) with 46% ≥10 pack-years. Outcomes were as follows: 2-year OS 99.4% and 5-year OS 91.8%; 2-year PFS 94.1% and 5-year PFS 84.3%; 2-year LRC 98.3% and 5-year LRC 95.8%; 2-year FFDM 95.8% and 5-year FFDM 93.2%. Median time to progression events were 21.1 months (range, 7.2 - 54.1) with 37.5% (6 of 16) of recurrences occurring after 24 months. Six total locoregional events occurred (five recurrences and one site of persistent disease), within the 60 Gy planning target volume. Twenty-three patients with T0-T2 N0-1 disease received radiation alone with 2-year PFS 92.9% (5-year 83.8%) and 2-year LRC 100% (5-year 95.2%). Outcomes for former smokers with ≥10 pack-years were comparable to patients with less or no smoking history (2-year PFS 94.1% vs 94.1%; 5-year PFS 90.6% vs 82.7%; HR 0.58, p = 0.38). Early results suggest similar oncologic outcomes among those treated off-protocol (median follow-up 25.6 months) with 1 of 23 patients experiencing locoregional recurrence. Dose de-intensification of 60 Gy radiotherapy with weekly cisplatin results in favorable long-term tumor control in patients with HPV-associated OPSCC. De-intensified 60 Gy alone may be efficacious in carefully selected patients with T0-T2 N0-1 (AJCC 7th edition) disease. Inclusion of biologically favorable patients with more extensive former smoking history in de-intensification clinical trials may be warranted.

Abstract PO-050: Preliminary results from an early-phase, open-label study of tolinapant and radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer

Abstract Background: Genomic alterations in NF-kB and inhibitor of apoptosis protein (IAP) pathways are common in head and neck cancer (HNC). IAP antagonists have shown activity in HNC, especially when paired with radiation therapy (RT), in both preclinical and early clinical studies. Our preclinical studies suggest that the combination of tolinapant and RT works in part by enhancing T cell activation, dendritic cell maturation, immunogenic cell death, and other aspects of the anti-tumor immune response. However, the safety and efficacy of IAPi combined with definitive RT, without platinum chemotherapy, has not been explored clinically. Methods: This is an open-label, early-phase study to determine the safety of the IAPi tolinapant combined with definitive or adjuvant RT. Eligible patients have previously untreated, locally advanced HNC, ECOG ≤1, with plan for definitive or adjuvant RT but are ineligible for treatment with cisplatin. Patients are treated with intensity-modulated radiation therapy (IMRT) or proton therapy (IMPT) to 60-70 Gy with tolinapant 180 mg (the single-agent recommended phase 2 dose) daily by mouth or feeding tube for 7 days during weeks 1, 3, 5, and 7 of RT, with the option of tolinapant dose reduction to 90 mg daily for toxicity. In the adjuvant setting, patients are treated for 6 weeks with 3 cycles of tolinapant. Blood is collected for research at baseline and during weeks 2 and 7. Tissue biopsies at baseline and during week 2 are optional. Results: Eight patients have been consented, including 3 screen failures and 5 enrolled (accrual target = 10 enrolled). All enrolled patients to date received definitive RT; four patients were treated with IMPT. Tumor sites included nasopharynx (1), oropharynx (one HPV+, one HPV-), and larynx (2). The most common reason for cisplatin ineligibility was hearing loss. The median age was 70 (range, 64-81). One patient had a grade 2 rash with pruritis that persisted for several weeks after treatment; other AEs included one treatment interruption during week 1, attributed to RT. Dose reduction of tolinapant was not required for any patients. Three patients have been evaluated by imaging and clinical exam 3 months after treatment, with no evidence of residual disease. Flow cytometry of peripheral blood samples showed a decrease in the proportion of CD4+CD25+ T cells (3/5 patients) and increase of differentiation markers on CD8+ T cells (4/5 patients) from baseline to week 2; these trends were more pronounced at week 7. The one patient who experienced a persistent grade 2 rash with pruritis had a &amp;gt;10-fold increase in activated (HLA-DR+CD38+) CD8+ T cells by week 7. Conclusions: Based on preliminary safety and tolerability data reviewed at this interim analysis, tolinapant at 180 mg appears to be a safe dose for combination with definitive RT. Additional studies will further characterize the dynamics of the peripheral immune response and provide longer follow up on a larger cohort of patients. This study was supported by Astex Pharmaceuticals, Inc. with a research grant to NCS and NFS. Citation Format: Nicole C. Schmitt, William A. Stokes, James E. Bates, Madison Stallings, Brendan L. C. Kinney, Mark W. McDonald, Soumon Rudra, Jill Remick, Zachary S. Buchwald, Dong M. Shin, Azeem S. Kaka, Mihir R. Patel, Nabil F. Saba. Preliminary results from an early-phase, open-label study of tolinapant and radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-050.

Clinical outcomes of immune checkpoint inhibitor plus nab-paclitaxel in metastatic upper tract urothelial carcinoma.

Metastatic upper tract urothelial carcinoma (mUTUC) is a malignant cancer associated with poor prognosis. Few studies have investigated the clinical outcome of a recently developed combination regimen of programmed cell death 1 (PD-1) inhibitor plus nab-paclitaxel in mUTUC. We retrospectively retrieved data from the electronic medical records of cisplatin-ineligible or cisplatin-refractory mUTUC patients from five participating Chinese centers, who received treatment of PD-1 inhibitor plus nab-paclitaxel between April 2018 and January 2022. Clinical response was assessed according to Response Evaluation Criteria in Solid Tumors criteria version 1.1 (RECIST 1.1). Duration of response (DOR), overall survival (OS), and progression-free survival (PFS) were evaluated by the Kaplan-Meier method. The confirmed overall response rate (ORR) was 14/34 (41.2%), and the disease control rate (DCR) was 24/34 (70.6%). Complete response (CR) was achieved in one case, partial response (PR) in 13 cases (38.2%), stable disease (SD) in 10 cases (29.4%), and progressive disease (PD) occurred in 10 cases (29.4%). After a median follow-up period of 16.0 months [95% confidence interval (CI): 9.9-22.1], 14 deaths were reported, with a median OS of 15.0 months (95% CI: 9.9-20.1); 22 progressions were reported, with a median PFS of 6.0 months (95% CI: 2.4-9.6). Patients with visceral metastasis had a similar PFS [hazard ratio (HR): 1.28, 95% CI: 0.53-3.09, P=0.574) and OS (HR: 1.94, 95% CI: 0.64-5.83, P=0.279] to patients with lymph node metastasis only. This real-world study suggests that PD-1 inhibitor plus nab-paclitaxel is effective in cisplatin-ineligible and cisplatin-refractory mUTUC patients with acceptable toxicity, especially for patients with visceral metastasis.

Avelumab as First-Line Maintenance Treatment in Locally Advanced or Metastatic Urothelial Carcinoma.

This work provides a summary of guideline recommendations and an expert position on the use of maintenance avelumab therapy based on a review of current international clinical practice guidelines for locally advanced or metastatic urothelial carcinoma (UC). A PubMed literature search was conducted in March 2022 (updated in July 2023) to identify guidelines for locally advanced or metastatic UC. An expert panel (four oncologists and one urologist) reviewed the guidelines and clinical evidence, and discussed practical questions regarding the use of avelumab maintenance therapy in this clinical setting. The National Comprehensive Cancer Network, European Association of Urology and European Society for Medical Oncology guidelines recommend first-line cisplatin-containing chemotherapy for cisplatin-eligible patients, carboplatin-gemcitabine for cisplatin-ineligible patients who are fit for carboplatin, or immunotherapy with programmed death ligand-1 (PD-L1) inhibitors (e.g. atezolizumab) in platinum-ineligible patients. Maintenance avelumab is recommended in patients with response/stable disease following chemotherapy (regardless of PD-L1 status). In patients who relapse after/during chemotherapy, options include immunotherapy, erdafitinib [in those with fibroblast growth factor receptor (FGFR) mutations], enfortumab vedotin or further chemotherapy. The expert panel provided the following practical guidance: (1) consider maintenance avelumab in all eligible patients; (2) continue avelumab until disease progression/unacceptable toxicity; (3) ideally, administer six cycles of platinum-based chemotherapy prior to maintenance avelumab; (4) perform radiological evaluation after four chemotherapy cycles and prior to maintenance avelumab; (5) carboplatin-gemcitabine followed by maintenance avelumab is preferred in cisplatin-ineligible patients (regardless of PD-L1 expression), but consider first-line immunotherapy in PD-L1-positive patients and platinum-ineligible patients (regardless of PD-L1 status); and (6) for patients who relapse on avelumab, second-line options include enfortumab vedotin, FGFR inhibitors (in those with FGFR mutations) or clinical trial inclusion. In conclusion, avelumab maintenance therapy is recommended following platinum-based chemotherapy in all eligible patients with locally advanced or metastatic UC, continued until disease progression or unacceptable toxicity.

Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer.

We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel. We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m2 , respectively. At a median follow-up of 29 (range 5-91) months, the 2-year rates of LRR, DM, PFS, and OS were 8.8%, 9.4%, 72.2%, and 88.7%, respectively. In total, there were 5 LRR, 7 DM, and 12 deaths. Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.

Physicianreported treatment patterns and outcomes in metastatic bladder cancer in the USA: the CancerMPact® Survey 2020.

Aim: This study assessed physician-reported treatment patterns for metastatic bladder cancer. Materials & methods: A total of106 USA-based physicians were surveyed in 2020 using the CancerMPact® online survey. Results: Among cisplatin-eligible patients, 86.1% received first-line (1L) platinum-containing chemotherapy, most commonly cisplatin plus gemcitabine, and 9.8% received immune checkpoint inhibitor monotherapy. Among cisplatin-ineligible patients, 46.5% received 1L platinum-containing chemotherapy, most commonly carboplatin plus gemcitabine and 46.2% received 1L immune checkpoint inhibitor therapy. Approximately 44% of patients who received 1L treatment received second-line (2L) therapy after progression. Conclusion: Platinum-containing chemotherapy was the most widely reported 1L treatment approach. A high proportion of patients received no 2L therapy. Validation in an updated dataset is warranted following the practice-changing approvals of avelumab 1L maintenance and additional 2L options.

XRay Vision: A phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

TPS6101 Background: The current standard of care for patients with resected LA SCCHN who are at high-risk of disease recurrence and are cisplatin eligible is chemoradiotherapy (CRT; cisplatin + RT). For patients at high risk of disease recurrence who cannot receive cisplatin, treatment options are limited, and there is currently no treatment specifically recommended by international guidelines. Xevinapant is a first-in-class, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that has been shown to restore cancer cell sensitivity to apoptosis, thereby enhancing the effects of chemotherapy and RT. In a randomized phase 2 study in patients with unresected LA SCCHN, treatment with xevinapant + CRT was associated with a 53% lower risk of death after 5 years of follow-up and reduced the risk of death or disease progression by 67% after 3 years of follow-up vs placebo + CRT. In preclinical SCCHN models, xevinapant + RT alone also demonstrated antitumor activity. These promising clinical and preclinical data provide a strong rationale for combining xevinapant and RT in cisplatin-ineligible patients with LA SCCHN. Methods: XRay Vision (NCT05386550) is a randomized, double-blind, placebo-controlled, phase 3 study comparing xevinapant or placebo in combination with intensity-modulated RT (IMRT) in patients with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse. Eligible patients must have histologically confirmed cancer of the oral cavity, oropharynx, hypopharynx, or larynx; undergone surgery with curative intent 4 to 8 weeks before the start of treatment; high risk of relapse; no residual disease by computed tomography scan; and ineligible for cisplatin (meeting ≥1 of the following criteria: estimated glomerular filtration rate &lt;60 mL/min/1.73 m2; hearing loss [grade ≥2 audiometric hearing loss or grade ≥2 tinnitus]; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14]). Other eligibility criteria include ECOG performance status of 0 or 1 and adequate hematologic and hepatic function. Approximately 700 eligible patients will be randomized to oral xevinapant (200 mg/day on days 1-14 of a 3-week cycle) or placebo for 3 cycles + standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy per fraction, 5 days per week) followed by 3 cycles of xevinapant or placebo. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, time to subsequent cancer treatments, safety, and health-related quality of life. Patients will be followed up for a minimum of 60 months. Enrollment is planned in 27 countries, including the US, and countries in South America, Europe, and Asia. The study started in October 2022, and recruitment is ongoing. Clinical trial information: NCT05386550 .

Impact of pre-treatment anemia on survival in locally advanced head neck squamous cell carcinomas treated with radiation with or without concurrent chemotherapy.

e18079 Background: Locally advanced head neck squamous cell carcinomas (LAHNSCCs) are treated either with surgery followed by radiation (RT) alone, surgery followed by concurrent chemoradiation (CTRT) or definitive CTRT. Patients receiving RT need to have an optimal hemoglobin (Hb) level, however there is limited data on what is an optimal pre-treatment Hb level required during RT/CTRT in these patients. Hence we performed this analysis. Methods: This data is a pooled analysis of 3 major randomized studies (RCT) performed in the field of chemoradiation over the last decade. These include, a RCT comparing weekly versus (vs) 3 weekly cisplatin in LAHNSCC‘s, weekly cisplatin vs weekly cisplatin plus nimotuzumab in the definitive setting in LAHNSCC‘s and in cisplatin ineligible patients, a comparison of radiation vs docetaxel plus radiation. The baseline demographics, Hb levels, and outcomes were collected and used for analysis. To ensure unanimity, anemia was defined as &lt; 12g/dL in both males and females. Univariate (UVA) and multivariate analysis (MVA) evaluated the factors affecting anemia. The impact of anemia on locoregional control (LRC), disease free survival (DFS) and overall survival (OS) was studied. Kaplan meier analysis was used for estimation of time to event parameters and log rank test was used for comparison. Cox proportional hazards model was used to test the importance of anemia in presence of other important parameters like age, gender, T and N stage, concurrent chemotherapy including its pattern (weekly vs 3 weekly) and site of disease. Results: We studied 1192 patients. Anemia of any grade was seen in 417 patients (35.0%), with the median Hb levels of the entire cohort being 12.8g/dL (IQR 11.6-13.9). Grade 3 or higher anemia (Hb &lt; / = 8g/dL) was seen in only 2 patients (0.2%). Female gender, oral cavity disease, patients with stage IV disease and those receiving adjuvant CTRT significantly impacted anaemia on UVA (p = 0.000 for all). MVA confirmed advancing age (p = 0.001), female gender (p = 0.000), patients with stage III and IV disease (p = 0.009) and those treated with adjuvant CTRT (p = 0.011) to significantly impact anemia. The LRC in patients with or without anaemia was 12.9 months (95%CI 7.8-18.0) and 23.5 months (95%CI 17.8-29.2) respectively (p = 0.000). Similarly the DFS and OS in anemic and non anemic patients were 9.6months (95%CI 6.0-13.2) vs 18.5months (95%CI 12.4-24.7, p = 0.022) and 21.5months (95%CI 16.3-26.8) vs 39.9months (95%CI 31.0-48.9, p = 0.000) respectively. Conclusions: Pre-treatment anemia in LAHNSCC‘s leads to a decrement in treatment outcomes (LRC, DFS and OS) and is an independent prognostic factor.

Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients (pts) with muscle invasive bladder cancer (MIBC): Updated results for Cohort H.

4595 Background: Cisplatin-ineligible pts with MIBC have no established neoadjuvant treatment options known to prolong survival before undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. In a phase 3 study, EV showed improved overall survival vs standard chemotherapy and a tolerable safety profile in pts with advanced urothelial cancer previously treated with a platinum agent and a PD-1/L1 inhibitor (Powles NEJM 2021). In Cohort H of the EV-103 phase 1b/2 study, preliminary results, including pathological complete response (pCR) and pathological downstaging (pDS) rates, showed antitumor activity in cisplatin-ineligible pts with MIBC who received neoadjuvant EV treatment (Petrylak ASCO GU 2022). Here we report updated results, including event-free survival (EFS) and subsequent cancer-related therapy. Methods: Cohort H of the EV-103 phase 1b/2 study (NCT03288545) enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), EFS based on investigator assessment, and safety. Results: 22 pts (median age 74.5 yr, range 56-81) were enrolled and treated; 17 pts (77.3%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had transitional cell carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV treatment; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2, 59.3) and the pDS rate was 50.0% (95% CI, 28.2, 71.8). Median EFS has not been reached. The EFS rate at 12 months was 76.4% (95% CI, 52.2, 89.4). All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs and 31.8% pts had grade ≥3 surgery-related TEAEs. The most common surgery-related TEAEs were procedural pain (18.2%), anaemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment; in 2 pts the AEs occurred &gt;30 days after RC+PLND. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905, KN-B15). Clinical trial information: NCT03288545 .