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Background: Atezolizumab (atezo; anti–PD-L1) + bevacizumab (bev; anti-VEGF) showed first-line (1L) anti-tumor activity with a manageable safety profile in PD-L1+ mRCC pts in a Phase ...II study (McDermott ASCO-GU 2017). Here we describe the first randomized Phase III trial of a PD-L1/PD-1 pathway inhibitor combined with an anti-VEGF agent in 1L mRCC. Methods: IMmotion151 (NCT02420821) enrolled treatment-naïve pts regardless of prognostic risk group randomized 1:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sunitinib (sun) 50 mg PO QD 4 wk on/2 wk off. Pts were stratified by PD-L1 status (< 1% vs ≥ 1% PD-L1 expression on tumor-infiltrating immune cells IC; SP142 IHC assay). Coprimary endpoints: progression-free survival (PFS; by investigator per RECIST v1.1) in PD-L1+ pts (≥ 1% IC) and overall survival (OS) in intent-to-treat (ITT) pts. Secondary endpoints included PFS in ITT pts, ORR and DOR. Results: Baseline characteristics were comparable between arms within PD-L1+ (40% of ITT) and ITT pts. Median survival follow-up was 15 mo. PFS HR for atezo + bev vs sun was 0.74 (95% CI 0.57, 0.96) in PD-L1+ pts and 0.83 (95% CI 0.70, 0.97) in ITT pts. OS was immature at first interim analysis. PFS benefit was consistent across analyzed subgroups, including MSKCC risk, liver metastases and sarcomatoid histology. In PD-L1+ pts, ORR was 43% and DOR was not reached for atezo + bev vs 35% and 12.9 mo for sun. 40% of atezo + bev–treated pts and 54% of sun-treated pts had treatment-related Gr 3-4 AEs; 12% and 8% of treatment-related all-Gr AEs led to discontinuation, respectively. Conclusions: The study showed longer PFS for atezo + bev vs sun in PD-L1+ pts. Improved PFS was also observed in ITT pts. Safety was consistent with that of the individual agents. These results support the use of atezo + bev as a 1L treatment option in mRCC. Clinical trial information: NCT02420821. Table: see text
576
Background: Standard of care for patients with metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin has been gemcitabine and carboplatin (gem/carbo), and more recently ...followed by maintenance therapy with avelumab. Combination pembrolizumab (pembro) and the antibody-drug conjugate enfortumab vedotin (EV) has shown very promising results and is now approved for first-line therapy in cisplatin-ineligible patients based on the phase Ib/II EV-103 trial. We were interested in assessing providers’ decision-making between gem/carbo and EV/pembro based on perceived comparative response rates and toxicity profiles, as well as the nationwide platinum chemotherapy shortage in 2023. Methods: We sent a 10-question encrypted electronic survey centered on a scenario of a mUC case to 150 oncologists via email listservs and social media. Results: We received 45 responses: 7 oncologists (15.6%) chose gem/carbo, 15 (33.3%) chose EV/pembro, and a majority, 23 (51.5%) chose to discuss both options with patients. 40 (88.9%) were academic or disease focused and 5 (11.1%) described their practice as general oncology. Of oncologists who chose gem/carbo, the most common reasons were: gem/carbo has more long-term data (86.6%) and lack of phase 3 data for EV/pembro (71.4%). Of oncologists who chose EV/pembro, the most common reasons were: higher response rates (86.7%) followed by the carboplatin shortage (40%). Only 6.7% chose the carboplatin shortage as the main reason while 73.3% chose higher response rates as the main reason. Of oncologists who chose to discuss both, the most common reasons why they would consider EV/pembro were: higher response rates (82.6%), followed by patient preference (56.5%), followed by the carboplatin shortage (43.5%). 60.9% chose higher response rates as the main reason why they would consider EV/pembro. Conclusions: This questionnaire-based study of predominantly academic genitourinary oncologists suggests that the majority would consider EV/pembro as a first-line treatment for cisplatin-ineligible patients with mUC. The primary reason for this choice was the belief that it has higher response rates, as opposed to the national shortage of carboplatin or concerns regarding toxicity. We anticipate that the awaited results of the EV-302 trial in the coming months will also change the treatment landscape of mUC. However, similar issues may be relevant in the future for other treatment decisions in which incomplete information is available or with ongoing chemotherapy shortages.
113
Background: mCSPC pts experience adverse outcomes (AOs) with intensified androgen deprivation, resulting in treatment discontinuation; however, there is limited data to identify those at risk. ...The IRONMAN registry is a global initiative to enroll advanced prostate cancer patients worldwide, and survey data on AOs, patient-reported outcomes (PROs), and clinico-epidemiologic (demographic, cancer, and treatment) details. We report the prevalence and predictors of AOs from baseline demographic, clinical, and PRO information with the onset of AOs and present a risk prediction model for clinical use. Methods: We analyzed data from 553 mCSPC patients in the IRONMAN registry from inception to March 2023 who received ADT+ alone (Abiraterone 47.6%, Enzalutamide 26.9%, Apalutamide 22.6%, Darolutamide 2.9%) and had completed baseline PROs. We defined AOs, reported by 60 global sites, as non-progression-related clinically significant serious adverse events (csSAE), treatment discontinuation, and dose reductions (DR/DC), delineated as a composite outcome based on first event. We processed baseline variable groups: Demographics (race, ethnicity, marital status, study site), Clinical Factors (age, ECOG score, metastatic sites, ADT+, concurrent medications, labs ALP, Hb, LDH, and PSA), Concurrent therapies (steroid use within 30 days d & steroid dose, radiation/surgery prior or planned in 6months) and PROs (EORTC QLQ-C30 and EPIC-23). We developed a multifactorial logistic regression model to predict adverse outcomes (AOs) within two years of initiating ADT+ therapy. All variables with less than 25-30% missing data were included. Variable selection was conducted in two layers: intra-group stepwise selection followed by an inter-group selection of variables retained from the first layer. The model's discriminatory ability was evaluated using the area under curve (AUC). Results: 553 pts met inclusion (51.6% North America, 72% White, mean age: 71 years range, 40 to 96 years, and 62.9% confirmed bone-metastatic mCSPC). 119 pts (21.5%) developed AOs (61 csSAEs 18 dead; Median: 140 d; IQR 81-360 d, 58 DR/DC Median: 122 d; IQR 43-262 d). <5% went off study. The multifactorial model (n=314 pts) performed well at predicting AOs (AUC 0.77 0.70-0.84), with significant factors being more self-reported pain, greater urinary frequency, prednisone>5mg within 30d, more self-reported weakness and poor sexual function within 3 months of ADT+ initiation. Conclusions: 1 in 5 mCSPC patients on ADT+ experienced non-progression-related AOs at 2 years. Significant, easily assessed predictive factors are identified and may be utilized in their clinical management. A novel multifactorial model is presented to predict AOs at 2 years. Further validation, assessment of missingness bias, and imputation are planned.
407
Background: It has been hypothesized that the rarity of molecular inclusion criteria hampers trial accrual. In this study, we attempted to address this challenge in the context of a ...SETD2-mutation targeted trial. Methods: Patients who received molecular sequencing services from Tempus were analyzed for the presence of SETD2 molecular variants that matched trial enrollment criteria, and resided within 50 miles from the treatment center or were receiving treatment at clinical sites with strong referral histories. A written notification was issued to the ordering physician whenever a likely match was identified, and additional phone and email outreach follow up, including reasons for not pursuing the clinical trial, was conducted. Results: Over one year, 38 eligible patients were identified, none of which were enrolled. The most common reason for not being enrolled was cohort closure following initial identification and outreach. More specifically, cohort closure occurred < 2 months, 2-4 months, 4-6 months and > 6 months following identification of the mutation in 5, 8, 2 and 7 patients, respectively. Physicians for additional potential patients cited trial consideration as a future option, presence of prohibitive comorbidities, lack of interest, and patient death in 6, 3, 2 and 1 patients, respectively. Physicians for 4 patients did not respond to multiple follow up attempts. In regards to individual follow up, physicians received 0-1, 2-3, and 4 or more follow up outreach notifications regarding trial availability for 14, 19, and 5 patients respectively. Conclusions: Despite identification of a large number of potential trial candidates for a molecular targeted therapeutic trial through use of matching algorithms and extensive treating physician follow up, no patients were enrolled. This raises the hypothesis that the biggest barrier to enrollment, as in other settings, is treating physician motivation and that AI algorithms for identifying potential subjects are insufficient. Larger target populations than anticipated, better coordination between outreach efforts and enrollment status, and directed patient outreach may be necessary.
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TPS2663
Background: Immune checkpoint blockade (ICB) antibodies have made a major impact in a wide range of cancers. However, only subsets of patients across all malignancies benefit ...from ICB. In particular, metastatic castrate-resistant prostate cancer (mCRPC) and advanced endometrial cancers (EC) have shown very limited responses to ICB. The central hypothesis of this trial is that the combination of PARP inhibitor (rucaparib) with PD-1 inhibitor (nivolumab) will enhance ICB efficacy in mCRPC and mEC patients. Given that PTEN loss has also been associated with poor response to ICB, a secondary hypothesis of this study is that the combination therapy will have differing efficacy based on the PTEN mutation status of the tumor. Methods: This is an investigator-initiated Phase 1b/IIa clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC and mEC patients. Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms will switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in immune infiltrates by Nanostring RNA sequencing, multiplex immunofluorescence, 3D mapping, IHC, and flow cytometry. Secondary objectives are to assess clinical response, and correlate changes in TME with PTEN status. We have currently enrolled 4 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study presents an opportunity for in-depth TME analysis that will enable the delineation of the effects of PARP inhibition singly and in combination with PD-1 blockade, on immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immunooncology combinations for specific molecular subsets of prostate and endometrial cancers. Clinical trial information: NCT03572478.
5062
Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR ...signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I study of the combination of rela and enz in patients with mCRPC. Methods: The study used a 6+3 design to assess safety and pharmacokinetics (PK) of the 2-drug combination. The starting dose of rela 100mg/day was chosen based on current clinical studies indicating this dose was both safe for daily dosing and pharmacologically active and the starting dose for Enz was 120mg based on anticipated drug-drug interactions. Escalating doses of rela were combined with Enz 120 using pre-specified dose escalation rules. An additional 12 patients were to be assessed at the MTD to refine safety and PK profiles. Primary endpoint was safety of the combination and to establish safe and pharmacologically active doses of both agents. Key secondary endpoints were tumor response per RECIST 1.1 criteria and progression-free survival (PFS; defined as either PSA progression, radiographic progression or death). PSA was measured after 12 weeks or at the last time at which PSA data was available, including times <12 weeks. Results: 35 pts were enrolled. Pts had a median age of 74 (range 62-85) and baseline PSA of 89.5 (range 7.3-2391). 100% had prior potent AR signaling inhibitor (abi or enz) with 89% receiving prior enz, 94% prior abi, 83% prior both. 69% of pts received prior docetaxel. Median PSA change was 0.1%. Enz 120mg + Rela 100mg and Enz 120+Rela 150 were found to be safe and tolerable and achieved desirable Enz PK. DLTs were noted in 3 pts at the 200mg Rela dose, which was deemed to have exceeded the MTD, which was thus defined as 150mg Rela+120mg Enz. Most common ≥ grade 3 treatment related adverse events (TRAEs) were fatigue (11% of pts), anemia (9%), abdominal pain (6%) and pericardial effusion (6%). Median PFS was 2.5 months for 21 of 35 evaluable pts. Best response per RECIST 1.1 were Not Evaluable (40%), SD (34%) & PD (26%). No CR or PR were noted. Most common reasons for discontinuation from trial included progressive disease/hospice (82%), AEs (12%), physician discretion (3%) & death (3%). 2 pts remain on trial as of data cutoff (12/31/22). Conclusions: The combination of enzalutamide and relacorilant was safe & largely well tolerated. The majority of pts were discontinued from trial due to progressive disease or hospice. Further analyses of secondary & correlative endpoints such as translational/endocrine biomarkers, GR target gene expression and circulating tumor cells are ongoing. Clinical trial information: NCT03674814 .
Utilizing the teaching value of real-world case discussions, Cancer Biology Review presents the principles of cancer biology in a clear and memorable manner, allowing the clinician to relate the ...cases shown in the book to those seen in practice. Focusing on ten topics in cancer biology for which there have been major changes in fundamental understanding, the authors provide a concise overview of the principles of each topic, followed by presentation of clinical cases illuminating the topic and detailed discussions. Summaries and key teaching points are highlighted at the end of each chapter to facilitate quick recall and review. The chapter authors are established translational experts in the biology being discussed as well practicing master clinicians.Cancer Biology Review is a useful tool for any oncology clinician in training or preparing for boards, and for the oncology practitioner preparing for recertification or who sees the need to be more fully conversant in the current science of the field as clinically applied.
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Background: Zoledronic acid (ZA) and denosumab are both bone-modifying agents (BMAs) approved for use in patients with bone metastases with breast or prostate cancer as well as ...patients who are receiving aromatase inhibitors (breast cancer) or androgen deprivation therapy (prostate cancer). There are various frequencies of administration, doses, and duration of these agents depending on indication and extent of disease. Currently there is data to show that ZA can be given every 3 months in patients with metastatic breast and prostate cancer, however, there is no data that clearly indicates that denosumab every 3 months is non-inferior to every 28 days. This study aimed to analyze current prescribing patterns of ZA and denosumab in metastatic breast cancer and metastatic castration resistant prostate cancer patients at The University of Chicago Medicine (UCM). Methods: This was a retrospective study of 80 patients who received at least one dose of ZA or denosumab between July 1
st
2018 to June 30
th
2019 from UCM outpatient oncology clinic for the purpose of treating metastatic breast cancer or metastatic castration resistant prostate cancer in conjunction with standard antineoplastic therapy. All included patients must have bone metastases. Patients were divided into four groups by disease state (breast or prostate cancer) and BMA agent (ZA or denosumab). The primary outcome was BMA therapy adherence rate, which was defined by those who received greater than or equal to 80% of appropriately scheduled doses. Descriptive statistics were used for skeletal-related events (SREs) and BMA associated adverse effects. Results: Patients who received ZA achieved higher adherence rates (100% breast, 86% prostate) compared to patients that received denosumab (63% breast, 23% prostate). The most common reason for the lower adherence rate in denosumab groups was scheduling convenience. During the study period, there were 3, 0, 2 and 5 patients had SREs in the above four groups respectively. The predominant adverse event across all groups was hypocalcemia and two patients with prostate cancer on denosumab developed osteonecrosis of the jaw. The cost analysis showed using ZA as primary BMA agent might save up to 2.5 million dollars per year at UCM. Conclusions: The use ofZA was associated with higher adherence rates compared to denosumab. Implementing a pharmacy driven protocol for ZA use for patients with metastatic breast and prostate cancer may improve BMA regimen adherence rates and significantly reduce costs.
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Background: Prostate stem cell antigen (PSCA) is expressed in >80% of metastatic prostate cancers. BPX-601 is an autologous PSCA-directed chimeric antigen receptor (CAR)-T cell immunotherapy ...engineered to express a rimiducid-inducible MyD88/CD40 costimulation switch to enhance T cell potency and persistence. Safety and activity of BPX-601 with rimiducid in mCRPC and pancreatic cancer is being assessed in an ongoing, phase 1/2 clinical trial (NCT02744287). Results from the first two prostate cancer cohorts are reported. Methods: Eligible mCRPC patients (pts) had progressed on ≥ 2 prior therapies including an androgen receptor antagonist and taxane. Using a 3+3 design, pts received lymphodepleting chemotherapy followed by a single-dose of 5 x 10
6
BPX-601 cells/kg and single or weekly doses of 0.4 mg/kg rimiducid infused over 2 hours beginning 7 days following cell infusion. Primary objective of phase 1 is to determine safety, tolerability and MTD or RP2D. Secondary objectives include characterization of clinical efficacy, PK of rimiducid and long-term safety. Biomarkers indicative of GoCAR-T cell expansion in blood, immune cell activity, and infiltration to tumor are being monitored. Results: As of Sept 2022, 8 pts received BPX-601 5x10
6
cells/kg; 3 and 5 pts received a single or weekly (range: 1-30) doses of rimiducid. Most common ≥ grade 3 adverse events were myelosuppression, attributed to lymphodepletion. All patients developed cytokine release syndrome (6 G1, 2 G3). Immune-effector cell associated neurotoxicity syndrome occurred and resolved in 2 pts (1 G1, 1 G4). One pt experienced a DLT of neutropenic sepsis (G5) with possible hemophagocytic lymphohistiocytosis (eg, IL-18, ferritin, M-CSF, fractalkine, MIP-1β and IL-1RA levels were elevated). Of 7 evaluable pts, PSA50 response was observed in 3 pts at Day 28. Preliminary RECIST-based results demonstrated partial response in 1, stable disease in 3, 1 progressive disease; at data cut off 2 had not reached imaging timepoint. One patient continues on study with SD after >9 months, with persistent evidence of rimiducid responsiveness. Peripheral blood BPX-601 cells expanded to an average of 3466 vector copies / μg DNA +/- 3109 during the first week with continued re-expansion to an average of 30234 copies/ug DNA +/- 67031) following rimiducid treatment. Serum IFN-γ, GM-CSF and IL-6 rapidly increased over 24 hours following rimiducid treatment (mean IFN-γ increase 26.9-fold ± 14.2) and subsequently diminished over 2 days. Conclusions: BPX-601, a PSCA-directed GoCAR-T cell product, has preliminary evidence of biologic activity with toxicity characteristic of previously reported CAR-T studies. Markers of rimiducid-induced GoCAR-T cell activation and proliferation were observed. Exploration of escalating weekly rimiducid doses > 0.4 mg/kg and BPX-601 cell doses is planned. Clinical trial information: NCT02744287 .
5012 Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from ...adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years y) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . Table: see text
