Publications

5548 Background: The aim of this international multicenter retrospective analysis was to identify prognostic markers for the clinical outcome in late-stage mCRPC patients treated with 177 Lutetium-prostate-specific membrane antigen (LuPSMA) radionuclide treatment. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA, and Australia were considered for inclusion. Eligible patients had 24 predefined, pretherapeutic covariates (demographics, prior mCRPC treatments, and PSMA PET/CT derived parameters) and survival data available. Endpoints included overall survival (OS) and PSA progression-free survival (PSA-PFS). Covariates were tested using univariate and mulitvariate proportional hazards regression Cox models. Results: 267/414 (64%) patients met inclusion criteria and were analyzed. 113 patients participated in clinical trials (ACTRN12615000912583, NCT03042312), while 154 were enrolled in compassionate-access programs. After a median follow-up of 22.5 months, median OS was 13.0 months (95%CI 11.6-14.4); 83% of the patients died. Median PSA-PFS was 4.0 months (95%CI 3.2-4.7). In the multivariate analysis, factors associated with shorter OS were: shorter time since diagnosis of prostate cancer (HR=2.04; p=0.002), lower number of prior systemic therapies (≤3; HR=1.56; p=0.006), prior exposure to chemotherapy (HR=1.42; p=0.05), lower hemoglobin levels (HR=1.13; p=0.002), higher number of lesions (≥20: HR=1.53; p=0.009), multiple sites of metastases (bone/LN only vs. bone + LN; HR=1.39; p=0.03) and visceral involvement (M1c) (HR=1.45; p=0.01). Factors associated with longer PSA-PFS were: longer time since diagnosis of prostate cancer (HR=0.44; p<0.001), higher hemoglobin levels (HR=0.32; p=0.03), presence of pelvic lymph nodes (LN) metastasis (N1) (HR=0.68; p=0.01), no distant lymph node metastases (M1a) (HR=0.66; p=0.01), no skeleton involvement (HR=0.44; p=0.01), no visceral metastases (M1c) (HR=0.51; p<0.001), higher PSMA-positive tumor volume (HR=0.87; p=0.04), and higher SUVmean (HR=0.94; p=0.002). Conclusions: This retrospective analysis identified prognostic factors for survival and treatment response to LuPSMA. Along with the conventional risk factors in mCRPC, PSMA PET/CT can be a useful tool for stratifying patients and guide patient’s selection for LuPSMA radionuclide treatment.

9545 Background: Combination ipi and nivolumab is approved for advanced melanoma and is in trials across oncology. Toxicity (tox) most often occurs 6-10 wks into treatment. Whether early tox is harder to manage or influences treatment efficacy is unknown. Methods: Consecutive metastatic melanoma patients (pts) who developed hyperacute (HA) tox, defined as grade (G) 2 or higher (2+) tox within 21 d of receiving combination immunotherapy (ipi + PD1), were retrospectively identified from 9 centres. Demographics, disease characteristics, tox and outcome data were examined. Results: 80 pts developed HA tox, at a median (med) 10 d (range 1-21). Pts had med age 55y, 66% were stage IV M1c/d, 49% had elevated LDH, 14% were ECOG 2. 61 (76%) pts were treatment naïve, 9 had received prior BRAF inhibitors, 4 ipi, 2 PD1 antibodies. Most frequent HA tox was colitis (n = 23), rash (n = 17), hepatitis (n = 9), endocrine (n = 9), pneumonitis (n = 6), and neurotoxicity (n = 4). 39% were G2, 54% G3, 8% G4. 48% required treatment beyond oral steroids, including IV steroids (21%), infliximab (18%), and other immunosuppression (9%) including mycophenolate and IVIG. Pts required a med 45 days on > 10mg prednisone equivalent. 83% of HA colitis pts required treatment beyond oral steroids (22% IV steroids, 61% infliximab), with a med 75 d on > 10mg prednisone. 20% pts received further combination therapy, 48% permanently discontinued all immunotherapy. 48% pts developed additional tox (10% had 3+ further tox), and 31% with G3-4 HA tox developed another G3-4 tox without further therapy. The overall response rate (ORR) was 54%, and after a med 11.6 mo follow-up, med PFS was 8.74 mo. Patients with G2 tox had a similar ORR but greater PFS than those with G3-4 tox (65% vs 47%, p = 0.19; 10.2 vs 2.8 mo, p = 0.01). There was no difference in ORR and PFS by type or duration of immunosuppression. Conclusions: Hyperacute toxicities from combination immunotherapy are varied. Many pts require treatment beyond oral steroids and for a prolonged duration, and pts are at risk of further severe tox. Efficacy in such pts appears similar to trial populations, although severe tox may correlate with worse outcomes. The degree and duration of immunosuppression does not appear to influence the efficacy of immunotherapy.

<p>Sample list and sequencing metrics for samples used in this study.</p>

<div>AbstractPurpose:<p>Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer with poor prognosis and limited treatment options. As NEPC aberrantly expresses delta-like ligand 3 (DLL3), the activity of tarlatamab, a bispecific T-cell engager that directs cytotoxic T cells to DLL3-positive (DLL3+) cells, was evaluated in the DeLLpro-300 study (NCT04702737).</p>Patients and Methods:<p>This was a phase 1b, open-label study evaluating tarlatamab monotherapy in patients with metastatic <i>de novo</i> or treatment-emergent NEPC defined by histologic, genomic, or IHC criteria. Tarlatamab was administered intravenously every 2 weeks at a dose of 100 mg with a 1-mg step dose. The primary objective was safety, and a secondary objective was objective response rate (ORR) per RECIST v.1.1; DLL3 expression was retrospectively assessed by IHC.</p>Results:<p>Forty patients were enrolled (DLL3+ tumors, <i>n</i> = 18; DLL3− tumors, <i>n</i> = 14; and DLL3 unknown tumors, <i>n</i> = 8). The most common treatment-related adverse events were cytokine release syndrome (82.5%), dysgeusia (42.5%), and decreased appetite (40.0%). Cytokine release syndrome was predominantly of low grade (grade 1/2/3/4+, 62.5%/15%/5%/0%), occurred exclusively in cycle 1, and was transient in duration (median duration, 3 days). The ORR was 10.5% [95% confidence interval (CI), 2.9–24.8]; the median duration of response was 7.3 months in the overall cohort. Patients with DLL3+ tumors (vs. patients with DLL3−/DLL3 unknown tumors) achieved a higher ORR [22.2% (95% CI, 6.4–47.6) vs. 0% (95% CI, 0–15.4)] and radiographic progression-free survival rate at 6 months [27.7% (95% CI, 8.7–50.9) vs. 0%].</p>Conclusions:<p>The DeLLpro-300 study provides preliminary evidence for the safety and antitumor activity of tarlatamab in DLL3+ NEPC.</p></div>

TB embedded for histopathological examination in neoadjuvant stage IIIB/C/D melanoma specimens can be reduced without significantly compromising accuracy of %RVT calculation. We recommend an updated pathological assessment protocol: lymph nodes ≤3 cm examined in entirety; macroscopically involved lymph nodes >3 cm should have a modified examination protocol of at least a full cross-sectional transverse slice. Capping TB slides examined at 20 appears reasonable. This refined approach results in high accuracy and significant reduction in the slides examined.

Background Metastatic Merkel cell carcinoma (mMCC) is an aggressive neuroendocrine malignancy of the skin with a poor prognosis. Immune checkpoint inhibitors (ICIs) have shown substantial efficacy and favorable safety in clinical trials. Methods Medical records of patients (pts) with mMCC treated with ICIs from August 2015 to December 2018 at Peter MacCallum Cancer Centre in Australia were analyzed. Response was assessed with serial imaging, the majority with FDG-PET/CT scans. RNA sequencing and immunohistochemistry for PD-L1, CD3 and Merkel cell polyomavirus (MCPyV) on tumor samples was performed. Results 23 pts with mMCC were treated with ICIs. A median of 8 cycles (range 1 to 47) were administered, with treatment ongoing in 6 pts. Objective responses (OR) were observed in 14 pts (61%): 10 (44%) complete responses (CR) and 4 (17%) partial responses (PR). Median time to response was 8 weeks (range 6 to 12) and 12-month progression-free survival rate was 39%. Increased OR were seen in pts aged less than 75 (OR 80% vs 46%), no prior history of chemotherapy (OR 64% vs 50%), patients with an immune-related adverse event (OR 100% vs 43%) and in MCPyV-negative tumors (OR 69% vs 43%). Pts with a CR had lower mean metabolic tumor volume on baseline FDG-PET/CT scan (CR: 35.7 mL, no CR: 187.8 mL, p=0.05). There was no correlation between PD-L1 positivity and MCPyV status (p=0.764) or OR (p=0.245). 10 pts received radiation therapy (RT) during ICI: 4 pts started RT concurrently (OR 75%, CR 50%), 3 pts had isolated ICI-resistant lesions successfully treated with RT and 3 pts with multisite progression continued to progress despite RT. Overall, 6 pts (26%) had grade 1–2 immune-related adverse events. Conclusion ICIs showed efficacy and safety in mMCC consistent with trial data. Clinical and imaging predictors of response were identified.

Age alone was not associated with safety outcomes in phase 1 clinical trials for metastatic solid malignancies. Instead, comorbidity burden and ECOG performance status were predictors of adverse events in our cohort of patients.

TPS5091 Background: The median overall survival for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) is short. Available agents may offer limited therapeutic benefit, but no molecularly stratified treatment has yet been approved for this heterogeneous disease. A sizable percentage of pts with mCRPC has loss of function aberrations in genes involved in homologous recombination repair (HRR) in tumor tissue, such as BRCA1/2 and ATM. These aberrations can confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition. A Phase II study indicated that the oral PARP inhibitor olaparib (Lynparza) had antitumor activity in 33% of mCRPC pts who had progressed after new hormonal agent (NHA) treatment and chemotherapy, with a strikingly higher composite response rate in pts with a deleterious HRR gene aberration (HRRa) (88%; 14/16) vs pts without a HRRa (6%; 2/33) (Mateo et al.2015). The PROfound study evaluates olaparib efficacy and safety versus physician’s choice of either abiraterone acetate or enzalutamide, in pts with mCRPC and a HRRa (NCT02987543). Methods: To be eligible for this multinational, open-label, Phase III study, mCRPC pts must have progressed on prior NHA treatment and have a tumor HRRa in one of 15 genes, as confirmed by an HRR Assay (Foundation Medicine, Inc.). Cohort A (n = 240 approx) includes pts with mutations in BRCA1, BRCA2 or ATM, while pts with a mutation in 12 other HRR genes will be assigned to Cohort B (n = 100 approx). Pts will be randomized (2:1) to olaparib tablets (300 mg orally bid) or physician’s choice of either enzalutamide (160 mg orally od) or abiraterone acetate (1000 mg orally od with 5 mg bid prednisone) and treatment continued until radiographic progression (as assessed by blinded independent central review) or lack of treatment tolerability. The primary endpoint of radiographic progression-free survival (rPFS) will be assessed in Cohort A using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. Key secondary efficacy endpoints include confirmed objective response rate, time to pain progression, overall survival (all Cohort A) and rPFS (both cohorts combined). Clinical trial information: NCT02987543.

Abstract Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas. Patients and Methods: Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks. Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity. Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.