Imaging of solid tumors using 68Ga-FAP-2286 Hope, Thomas A.; Aggarwal, Rahul Raj; Dhawan, Mallika Sachdev ...
Journal of clinical oncology,
06/2022, Letnik:
40, Številka:
16_suppl
Journal Article
Recenzirano
3059
Background: Fibroblast Activation Protein (FAP) is a transmembrane protein overexpressed on cancer associated fibroblasts (CAFs), and is abundantly present in many epithelial cancers, suggesting ...FAP is an attractive imaging and therapeutic target. FAP-2286 is a cyclic peptide that binds to FAP and is currently being evaluated as a radioligand therapy to treat patients (pts) with FAP-positive solid tumors. The role of 68Ga-FAP-2286 as a diagnostic agent is unknown. We present an interim analysis of the ability of 68Ga-FAP-2286 to detect metastatic disease across multiple cancer types. Methods: This is a first in human Phase I/II study of 68Ga-FAP-2286 (NCT04621435) with a planned total enrollment of 65 pts across 3 cohorts: dosimetry cohort (n = 5), cohort with RECIST measurable disease (n = 30) and a cohort at risk for metastases without measurable disease (n = 30). By the cutoff date of February 12, 2022, 27 pts were enrolled (3 in cohort 1, 15 in cohort 2 and 9 in cohort 3). For each pt, the five largest lesions were included for analysis, and for each lesion, the maximum standardized uptake value (SUVmax) of the 68Ga-FAP-2286 and the size (short axis for lymph nodes) were documented. In pts who had an available FDG PET performed within 8 weeks of 68Ga-FAP-2286 PET, uptake on the two scans was compared. Results: Of the 27 enrolled pts, 9 had bladder cancer, 5 sarcoma, 4 head and neck squamous cell cancer (HNSCCA), 3 breast cancer (BC), and 3 castration resistant prostate cancer (CRPC). Most pts (89%, 24/27) had tumors positive for uptake on 68Ga-FAP-2286 PET, including 30 lesions < 1.5 cm, and 17 less than 1.0 cm. 16 pts had a paired FDG PET. In these pts, the average SUVmax on 68Ga-FAP-2286 PET was 244% higher than on FDG PET. Only two pts had higher uptake on FDG PET than on 68Ga-FAP-2286 PET (HNSCCA and DSRCT). The highest relative uptake was seen in 2 pts with BC (both 3.4 times higher on 68Ga-FAP-2286 PET); the average SUVmax in BC was 16.6. The lowest uptake on 68Ga-FAP-2286 PET was CRPC with an average SUVmax of 7.0. Sarcoma had variable uptake with one pt having an SUVmax of 4.5 (Ewing’s), while two pts had an SUVmax over 30 (both undifferentiated pleomorphic). Although sarcoma had high uptake on 68Ga-FAP-2286 PET, it was similar to FDG PET uptake across the 5 pts (ratio to FDG PET = 1.0). Conclusions: 68Ga-FAP-2286 is a promising imaging agent across cancers, although its benefit is not seen equally. BC had the highest absolute uptake and highest relative uptake compared to FDG PET; prostate cancer had the lowest uptake. Further work should be undertaken to define the settings where 68Ga-FAP-2286 PET may inform clinical decision making, and which pts may benefit from FAP-targeted radioligand therapy. Clinical trial information: NCT04621435.
Cancer is the leading cause of death in older adults aged 60 to 79 years. Older patients with good performance status are able to tolerate commonly used treatment modalities as well as younger ...patients, particularly when adequate supportive care is provided. For older patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. RT can be highly effective and well tolerated in carefully selected patients, and advanced age alone should not preclude the use of RT in older patients with cancer. Judicious application of advanced RT techniques that facilitate normal tissue sparing and reduce RT doses to organs at risk are important for all patients, and may help to assuage concerns about the risks of RT in older adults. These NCCN Guidelines Insights focus on the recent updates to the 2016 NCCN Guidelines for Older Adult Oncology specific to the use of RT in the management of older adults with cancer.
Purpose of Review
Triple negative breast cancer (TNBC) is an aggressive subtype with frequent chemotherapy resistance. In recent years, advances in immunotherapy have yielded promising new ...therapeutic strategies for the treatment of TNBC; studies evaluating immune check point inhibitors (ICIs) in combination with chemotherapy have shown encouraging results in both early and advanced stages of disease.
Recent Findings
Atezolizumab plus nab-paclitaxel resulted in improved progression-free survival (PFS) and overall survival (OS) compared to nab-paclitaxel alone in patients with programmed death-ligand 1-positive (PD-L1+) metastatic TNBC (mTNBC). However, atezolizumab plus paclitaxel did not improve outcomes. Pembrolizumab plus chemotherapy improved PFS compared to chemotherapy alone in patients with PD-L1+ mTNBC, and follow-up for OS is ongoing. The addition of pembrolizumab and atezolizumab to neoadjuvant chemotherapy increased pathologic complete response rates, regardless of PD-L1 status, and event-free survival is pending. Several other combinations of ICIs with targeted agents are under investigation to enhance the host immune response and are discussed in this review.
Summary
TNBC has a poor prognosis with limited treatment options. Recent studies have demonstrated encouraging results by adding ICIs to chemotherapy, although optimal combinations remain to be defined. In this review, we highlight advances in TNBC treatment including ICIs and targeted agents and also discuss future directions.
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TPS1111
Background: Chest wall recurrence is a subtype of breast cancer that is challenging to treat, and associated with a short duration of response to treatment and an increased risk ...of development of distant metastases. Given the inflammatory nature of this disease and the association of chest wall disease with lymphovascular invasion, which is correlated with higher programmed cell death 1 (PD-1) expression, we hypothesized that immunotherapy may be beneficial as treatment. Combinations of immunotherapy and chemotherapy have a synergistic effect and demonstrated efficacy in the treatment of metastatic triple negative breast cancer (TNBC). This study is evaluating the efficacy of pembrolizumab, an anti-PD-1 antibody, in combination with carboplatin, in patients with chest wall infiltration from breast cancer. This drug combination has shown efficacy in advanced lung cancer. Methods: This is a multicenter, 2:1 randomized phase II study of pembrolizumab/carboplatin (Arm A, 56 patients) vs. carboplatin (Arm B, 28 patients) in 84 patients with chest wall disease from breast cancer, with or without distant metastases. Patients may have TNBC, hormone receptor positive/HER2 negative (following receipt of 2 prior hormone therapies), or HER2 positive breast cancer (with option to continue trastuzumab on study). Pembrolizumab is administered as 200 mg IV every 3 weeks, and carboplatin as AUC 5 IV every 3 weeks. Patients on Arm A may continue pembrolizumab +/- carboplatin (Arm Ax) after completion of 6 cycles of treatment, while patients in Arm B can cross-over to pembrolizumab (+/- carboplatin) on progression (Arm Bx). Patients must have adequate organ function, performance status ≤ 2, and may have received any number of lines of prior chemotherapy. Patients undergo serial chest wall photography and imaging (CT chest, abdomen, and pelvis, and bone scan) at baseline and every 6 weeks, as well as blood collection for correlative studies and chest wall biopsies at baseline and after 2 cycles of treatment. The primary endpoint is disease control rate (RECIST 1.1) at 18 weeks of treatment, and the study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, a = 0.10, ß = 0.20). An interim analysis will occur for Arm B after 18 patients are enrolled, with a stopping rule for futility. Secondary endpoints include progression-free survival, toxicity (NCI CTCAE), and response based on irRECIST and tumor programmed death ligand 1 (PD-L1) expression. Exploratory objectives include evaluating changes in soluble PD-L1, tumor and peripheral blood immune composition, circulating tumor cells and cell-free DNA, and MYC oncogene expression. This study (NCT03095352) is open at 7 sites in the Translational Breast Cancer Research Consortium (TBCRC). 52 patients are enrolled. Grant funding is provided by Merck and UCSF. Clinical trial information: NCT03095352 .
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TPS1110
Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies ...demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .
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1092
Background: Response Evaluation Criteria in Solid Tumors (RECIST) criteria are often used to measure tumor response in cancer trials, especially in the stage IV setting. However, ...RECIST requires measurable disease, which is less common in invasive lobular breast carcinoma (ILC) of the breast, a diffusely growing tumor type, compared to invasive ductal carcinoma (IDC). We examined the prevalence of RECIST in breast cancer clinical trials, and whether there are differential trial enrollment rates by histology and stage. Methods: We analyzed the clinicaltrials.gov database to evaluate the proportion of interventional, stage IV clinical trials that require measurable disease as inclusion criteria or outcome measures. We then performed an institutional cohort study comparing the proportion of patients in the University of California, San Francisco (UCSF) OnCore clinical trials management system (CTMS) to the UCSF Cancer Registry between 2000-2018, stratified by histology and stage. We hypothesized that the proportion of patients with ILC in the CTMS would be significantly lower than in the cancer registry. Results: There were 146 actively-recruiting, interventional clinical trials for stage IV breast cancer that were identified in our search on clinicaltrials.gov. Overall, 108 (74%) required measurable disease for study participation. The UCSF Cancer Registry included 8,679 patients, while the UCSF OnCore CTMS included 1,511 patients (Table). In those with early stage disease, where RECIST is not typically used, there was no difference in the proportion of ILC patients enrolled in clinical trials versus in the cancer registry. However, among those with stage IV disease, there was a significantly lower proportion of patients with ILC in the CTMS than in the cancer registry (9.2% versus 17.9%, p = 0.005). In contrast, patients with stage IV IDC were overrepresented in the clinical trials database compared to the cancer registry. Conclusions: Patients with metastatic ILC were significantly less likely to be enrolled in clinical trials than those with metastatic IDC. This decreased enrollment may be due to the widespread use of RECIST, and further investigation is needed to ensure equity in access to clinical trials.Table: see text
Myeloid growth factors (MGFs) are given as supportive care to patients receiving myelosuppressive chemotherapy to reduce the incidence of neutropenia. This selection from the NCCN Guidelines for MGFs ...focuses on the evaluation of regimen- and patient-specific risk factors for the development of febrile neutropenia (FN), the prophylactic use of MGFs for the prevention of chemotherapy-induced FN, and assessing the risks and benefits of MGF use in clinical practice.
LBA501 Background: I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) in the neoadjuvant breast cancer setting that evaluates novel experimental ...regimens as first in a sequence (Block A) followed by standard chemo/targeted therapies (Blocks B/C) if indicated. The goal is to achieve a pCR after novel targeted agents alone or in sequence with standard therapies, with the optimal therapy assigned based on the tumor response predictive subtype (RPS). RPS incorporates expression-based immune, DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to subset patients into 6 subtypes: S1: HR+HER2-Immune-DRD-; S2: HR-HER2-Immune-DRD-; S3: HER2-Immune+; S4: HER2-Immune-DRD+; S5: HER2+/non-Luminal; S6: HER2+/Luminal. Methods: RPS S1, S2, S3, and S4 were eligible for assignment to Dato+Durva in Block A. Patients were followed by MRI during treatment (at 3, 6, and 12 weeks after start of Blocks A and B). Predicted responders by MRI and biopsy at the end of Block A or B have the option of going to surgery early; otherwise, they proceed to next treatment Block (B +/- C). Randomization to Block B includes a taxane-based regimen specific to the RPS, and options include S1: paclitaxel; S2 and S3: paclitaxel + carboplatin + pembrolizumab; S4: paclitaxel + carboplatin vs. paclitaxel + carboplatin + pembrolizumab. Patients who did not go to surgery after Block B proceeded to Block C (AC or AC + Pembrolizumab if HR-HER2-). The primary endpoint is pCR. Efficacy is evaluated within each RPS and HR+HER2- and HR-HER2- signatures. To estimate the arm's efficacy as a stand-alone therapy, we use a Bayesian covariate-adjusted model to estimate the pCR rate and compare the posterior distribution to a subtype-specific fixed threshold. This model uses pCR data when available and MRI data when pCR is not. To estimate pCR rate in the context of a multi-decision treatment regimen, we use a Bayesian model based on if and when a pCR occurred in the trial. The posterior is compared to a subtype-specific dynamic control generated from historical I-SPY data. Results: 106 patients were randomly assigned to the Dato+Durva arm between September 2022 and August 2023. The results for Dato+Durva as a stand-alone therapy are summarized in Table. After completion of Block A, 36 patients proceeded to surgery without completing Blocks B/C. Conclusions: Dato+Durva meets threshold for graduation within the RPS S3 subtype based on estimated pCR rate of 72% and warrants further investigation in a larger randomized controlled trial. Clinical trial information: NCT01042379 . Table: see text
1006 Background: In the primary analysis of the Phase 3 TROPION-Breast01 study (NCT05104866), Dato-DXd showed a statistically significant and clinically meaningful improvement in progression-free ...survival vs investigator’s choice of CT (ICC) (HR 0.63 95% CI 0.52‒0.76; p<0.0001) (Bardia et al, ESMO 2023). Here we report PROs from TROPION-Breast01. Methods: Patients with inoperable or metastatic HR+/HER2‒ BC, with disease progression on endocrine therapy and for whom endocrine therapy was unsuitable and who had received 1‒2 prior lines of systemic CT, were randomized 1:1 to Dato-DXd (6 mg/kg Q3W, n=365) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine, n=367). PROs were measured at prespecified timepoints, including secondary PRO endpoints of time to deterioration (TTD) in global health status (GHS)/QoL, physical functioning, and pain based on EORTC QLQ-C30, and exploratory PRO endpoints based on additional questionnaires. Results: PRO questionnaire compliance was 82.5% at baseline in both arms and remained similar across arms over time. TTD was delayed in Dato-DXd vs ICC arms for all secondary endpoints. In an analysis of time to first deterioration (primary analysis), median TTD (HR 95% CI) in GHS/QoL was 3.4 vs 2.1 months (0.85 0.68–1.06), physical functioning was 5.6 vs 3.5 months (0.77 0.61–0.99), and pain was 3.5 vs 2.8 months (0.85 0.68–1.07); in an analysis of time to confirmed deterioration (sensitivity analysis), median TTD in GHS/QoL was 9.0 vs 4.8 months (0.76 0.58–0.98), physical functioning was 12.5 vs 6.2 months (0.77 0.59–1.01), and pain was 9.0 vs 5.5 months (0.72 0.55–0.94). The Table shows TTD in other selected functioning and symptom scales from EORTC. Patient-reported symptomatic AEs (measured by PRO-CTCAE and EORTC) were generally consistent with clinician-reported safety data, and patient-reported treatment tolerability (measured by PGI-TT) was comparable between arms. Conclusions: In TROPION-Breast01, TTD was delayed in the Dato-DXd vs ICC arms for GHS/QoL, physical functioning, pain, and most other symptoms and functioning scales. PRO data complement the improvement in efficacy and manageable safety profile demonstrated with Dato-DXd vs ICC in the primary analysis, supporting Dato-DXd as a potential new, well tolerated therapeutic option in this setting. Clinical trial information: NCT05104866 . Table: see text
TPS1121 Background: Therapies to manage pts with HER2+ MBC have significantly improved, but better agents are still needed. BDC-1001 (trastuzumab imbotolimod) is being studied for MBC and other HER2+ ...cancers. The ISAC BDC-1001 consists of a trastuzumab biosimilar conjugated to a cell membrane impermeable TLR7/8 agonist via a non-cleavable linker and is given IV every 2 wks. Designed to trigger the innate immune system, BDC-1001 causes a durable tumor-targeted adaptive immune response. Early studies show that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, and tumor regression, in a TLR- and Fc receptor-dependent manner (1). Preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) show better efficacy with trastuzumab-T785 compared to trastuzumab + P. In the BDC-1001 dose-escalation trial (BBI-20201001), 6 PRs and 12 SDs ≥ 24 weeks in 8 tumor types were observed, particularly in 20mg/kg q2w dose cohorts. The most frequent drug-related AE was low grade (grade 1/2) infusion-related reactions (29%) (2). We showed the combination of a surrogate ISAC (trastuzumab-T785) + P significantly enhances efficacy in multiple HER2-expressing tumors, including those with lower HER2 expression (1). The addition of P lowered the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. The combination of P with the ISAC significantly increased the tumor cytokine and chemokine concentration compared to monotherapy or antibody-alone, indicating enhanced tumor myeloid activation suggesting this combination may enhance the clinical activity of trastuzumab-based ISACs. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 patients with HER2-positive (ASCO/CAP 2018) MBC previously treated with 2 or more anti-HER2 therapies including T-DXd. Patients must be > 18 years, have measurable disease, and have ECOG performance status of 0 or 1. Patients will be randomized 1:1 to receive BDC-1001 20mg/kg every 2 weeks with or without P (840mg initial dose, followed by 420mg IV q 3w). Each arm has a Simon 2 stage design. The primary objective is anti-tumor activity of BDC-1001 alone and in combination with P. Secondary objectives will evaluate safety, PK, and immunogenicity of BDC-1001 alone and in combination with P. Exploratory objectives will include PD biomarkers in tumor tissue and in peripheral blood to elucidate the MOA and biomarkers associated with BDC-1001 activity with or without P. This study began accrual in Nov 2023. 1. Ackerman S, et al. Nature Cancer. 2021. 2. Li B, et al. ASCO 2023, Abstract 2538. Clinical trial information: NCT05954143 .
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