Curti, Brendan D.

PURPOSE Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981 ). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

Background SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. Methods SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. Results A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10–30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. Conclusions SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. Trial registration number NCT02376699.

Abstract Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Abstract Background: NL-201 is a selective and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors, which share beta and gamma signaling subunits. NL-201 is being developed as a potent activator of CD8+ T cells and NK cells for cancer immunotherapy. Binding to the beta and gamma subunits stimulates dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and NK cells, thereby enhancing the immune response in the tumor. The absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. As such, NL-201 is designed to promote the desired immunomodulatory anti-tumor effects of IL-2 with an improved safety profile. Methods: NL201-101 is a Phase 1 first-in-human, open-label, dose-escalation and cohort expansion study consisting of two parts. Part 1 is a monotherapy dose-escalation study in up to 60 adult patients with advanced and/or refractory solid tumors to define the safety profile and the recommended Phase 2 dose (RP2D) and schedule of NL-201. During dose escalation, two different schedules will be evaluated: dosing every 21 days (Schedule A), or on days 1 and 8 of each 21-day cycle (Schedule B). Tumor response will be assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and/or RECIST for use in cancer immunotherapy trials (iRECIST). In Part 2, patients with pathologically proven diagnosis of melanoma and renal cell carcinoma (up to N=30/cohort), who have advanced and/or refractory measurable disease and have failed at least one line of treatment, which may include checkpoint inhibitors, will be enrolled. Key exclusion criteria include history of brain cancer or active brain metastases, carcinomatous meningitis, neurologic autoimmune disease; patients previously receiving CAR-T or IL-2-based therapies are not eligible. Recruitment of Part 1 began in April 2021, and the trial is actively enrolling. Clinicaltrials.gov identifier: NCT04659629. Citation Format: Aung Naing, Margaret Callahan, Brian A. Costello, Brendan Curti, Evan Hall, Aaron Hansen, Georgina V. Long, Anthony M. Joshua, Cynthia Wetmore, Andrew Weickhardt. A first-in-human phase 1 study of NL-201 in patients with relapsed or refractory cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT250.

9573 Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection <90 days prior to registration, and no prior systemic therapy (adjuvant radiation allowed), ECOG 0/1, no uncontrolled significant autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From 9/17 to 8/21, 44 patients were approached at 6 centers. Of these 9 were ineligible, and 35 were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) had adjuvant radiation prior to enrollment. As of Dec 2021, 31 patients have completed the treatment phase. Of the 35 patients treated on study, 20 patients have recurred (7 local, 5 distant, 3 regional, 5 sites unconfirmed), 6 stopped therapy due to adverse effects, and 8 have died. The mean age of patients was 65.8 years and 21 (60.0%) were female. The primary site of disease was vulvovaginal N=12 (32.4%) patients, sinonasal N= 11 (29.7%), anorectal N= 9 (24.3%) and other site N= 5 (13.5%). Adjuvant radiation had been given in 7 pts. Driver mutations were rare, with only 3 (8.6%) patients having a KIT mutation, and one patient (2.9%) each having a NRAS or BRAF mutation. RFS rates at 1 and 2 years were 50% (95% CI 31-66%) and 37% (95% CI 19-55%), with OS rates at 1 and 2 years of 87% (95% CI 68-95%) and 68% (95% CI 46-83%). Median RFS was 10.3 m (95% CI5.7-25.8). Most common grade 3 adverse events were diarrhea (14%), hypertension (14%), hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip dose ipilimumab and nivolumab after resection is associated with outcomes improved over previously reported outcomes in the absence of therapy. Long term follow up is ongoing as are subgroup analyses and correlative studies. Clinical trial information: NCT03241186.

Background Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. Methods Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. Results For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). Conclusions Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. Trial registration number NCT01546571.

Abstract CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5535.

4521 Background: Expression of PDL1 by RCC has been associated with aggressive histology and poor survival. Tissue obtained from the patients enrolled in the IL-2 Select Trial, a prospective, single arm, multicenter CWG study, was analyzed by IHC to determine if PDL1or PDL3 expression predicted for response to initial or subsequent therapy. Methods: Paraffin embedded tumor tissue was stained for PDL1 and PDL3 expression, and results were correlated with RECIST defined response to IL2 treatment. Tumor tissue was considered positive for PDL1 if >5% of the tumor membranes stained for the marker. A cutoff of 10% was used for PDL3. Duration of subsequent VEGFR/mTOR inhibitor therapy was also correlated with tissue PDL1/3 expression. Results: 120 eligible pts were enrolled; 115 had clear cell histology. The overall response rate (ORR) to IL2 was 25% (30/120) with a median OS of 40.6 months. 113 tumors were stained. 18 (16%) were PDL1+. ORR was 19% and 50% in the patients PDL1- and PDL1+ tumors, respectively (p=0.012). 85 (75%) tumors were PDL3+. ORR was 10.7% and 29.4% in the PDL3- and PDL3+ tumors, respectively (p=0.075). In the 17 patients who were positive for both PDL1 and PDL3, ORR was 52.9%. In the 27 pts who were negative for both PDL1 and PDL3, ORR was 11.1%. 69 patients received at least 1 dose of a VEGFR TKI as next therapy following IL2 treatment. 66 tumors were stained. Pts who were PDL1+/PDL3+ had a shorter duration on VEGFR TKI therapy compared to pts who were PDL1-/PDL3- (see Table). Conclusions: This small, retrospective analysis suggests that PDL1 and PDL3 tissue expression may predict for better response to IL2. PDL1 expression has been suggested as a possible predictor of response to anti-PD1 therapy. The current data suggests that its expression may predict for benefit to other immune therapies. PDL3 (+/- PDL1) expression appears to correlate to less benefit from subsequent VEGFR TKI therapy. Funded by NCI SPORE Grant # 5 P50 CA101942-08. [Table: see text]

TPS65 Background: Mucosal melanoma is a rare and, therefore, poorly studied malignancy. Patients with resected primary tumors have a median time to recurrence of 5.5 months. While no one adjuvant therapy is of proven benefit for patients, immunotherapy has shown activity in metastatic mucosal melanoma. Methods: We are performing a single arm, phase II clinical trial through the Midwest Melanoma Partnership/Hoosier Cancer Research Network (6 sites) for resected mucosal melanoma. The primary endpoint is recurrence free survival (RFS), and it will include 36 subjects. Patients must have had an R0 or R1 resection of a mucosal melanoma (sinonasal, anorectal, vulvar, or other), and register within 90 days of surgery. Adjuvant radiation is allowed prior to registration but not required. Therapy consists of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) IV q3w x 4, then 480 mg nivolumab x 1 year. Statistical power is calculated to be 85% to detect a change in RFS from 5.5 months to 9.5 months, with a one sided alpha of 0.05. Enrollment began Sept 2017, with current participation from 6 large volume centers in the United States, with 17 patients enrolled as of Sept 2019. Full accrual is anticipated to complete by year end 2020. Patients will be followed for RFS and OS. Translational studies will include mutational burden, c-kit, BRAF, NRAS status, and serum markers of immunity -- including soluble PD-L1 and Bim. Clinical trial information: NCT03241186.