Search

PURPOSE To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

PURPOSE Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

130 Background: The field of targeted radionuclide therapy (RNT) for prostate cancer (PC) is growing rapidly with recent FDA approval of the first lutetium-177-PSMA-ligand. Commonly used patient-reported outcome (PRO) measures were originally designed to assess the impacts of traditional therapies (e.g., chemotherapy, surgery). We aimed to develop the first PRO measure for PC patients receiving RNT. Methods: We used a multi-step approach based on input from experts and patients. We identified symptoms and toxicities potentially relevant in the context of RNT for PC from a literature review of published trials and interviews with PC patients who had received RNT, caregivers of RNT recipients, and clinicians. We identified items to include in the measure from the Functional Assessment of Chronic Illness Therapy (FACIT) item library. Finally, we reviewed, refined, and finalized the new measure. Results: Potentially relevant symptoms/toxicities were identified by reviewing published trials (e.g., xerostomia, nausea). Interviews with PC patients who received RNT (n=29), caregivers (n=14), and clinicians (n=11) yielded additional symptoms/toxicities (e.g., fatigue, constipation). After selecting a broad and comprehensive list of items from the FACIT item library, we refined the list based on input from 9 experts in the field of RNTs and PROs from 5 institutions. Patients who received RNT for PC (n=11) reviewed the draft measure and confirmed items were relevant to RNT recipients and comprehensible. This resulted in a brief 15-item measure deemed by key stakeholders to be relevant and useful in the context of RNT for PC. Conclusions: The FACT-RNT (Functional Assessment of Cancer Therapy – Radionuclide Therapy) is a PRO new measure for RNT recipients developed through multi-step collaboration with patients, caregivers, clinicians, and international experts. The FACT-RNT can be used in RNT clinical trials and real-world settings.

TPS817 Background: Metastatic disease remains a consistent challenge for patients with gastrointestinal (GI) malignancies. Multiple immune checkpoint inhibitors (ICI) have been FDA approved for several GI indications. Still, patients will progress on these therapies, either immediately or after initial response. Palliative radiation therapy (RT) is an effective treatment that can be delivered to symptomatic metastases. It also has been reported to lead to an abscopal effect, which is an induction of response in a distant tumor. This is thought to result from increased tumor immunogenicity, tumor microenvironment modulation, and immune cell recruitment. Thus, palliative RT could not only relieve symptoms, but also potentially reinvigorate the immune response, prolong ICI efficacy, and delay next-line systemic therapy that carries risks of unknown efficacy and tolerability. Ongoing studies seek to elucidate prognostic and predictive biomarkers of the abscopal effect. However, cohorts of patients with GI malignancies are limited, so there remains a need for research in combining RT and immunotherapy in the context of metastatic GI cancer. ARM-GI aims to study the radiation-augmented immune response in patients with metastatic GI cancers progressing on immunotherapy. Methods: ARM-GI is a phase 2, single arm study. Key eligibility criteria include confirmed metastatic GI malignancy, progressive disease per RECIST v1.1 on any ICI, and at least 2 metastases, one of which can be safely left unirradiated. The target prescription dose is 30 Gy in 5 fractions to symptomatic sites through intensity modulated RT or stereotactic body RT. Patients will continue the same immunotherapy after RT and be evaluated per RECIST v1.1 longitudinally. The primary endpoint is overall response rate (ORR) per RECIST v1.1. Secondary endpoints include ORR per iRECIST, progression free survival, overall survival, local control in radiated lesion(s), effect of distant radiation on unirradiated target lesions, incidence of new metastatic lesions, safety by CTCAE v5.0, and time to new systemic therapy. The study will enroll 28 patients, with recruitment ongoing. Serial peripheral blood samples are collected for exploratory studies that will analyze for association with disease response and quantification of changes in circulating immune cell subsets after RT compared to baseline. Clinical trial information: NCT04221893 .

2570 Background: TIGIT is a promising emerging immunotherapeutic target. However, the specific sources of TIGIT expression within the tumor microenvironment are largely unknown. Here, we present an AI-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer, Lunit SCOPE IO, to integrate image analysis from whole slide images with single-cell molecular profiling. Methods: We used The Cancer Genome Atlas (TCGA) RNA expression data across 23 cancer types (n=6,930). Lunit SCOPE IO was developed, trained, and validated based on >17k H&E whole-slide images, to segment cancer area (CA) and cancer-associated stroma (CS) and to detect tumor cells and TILs. The intra-tumoral TIL, stromal TIL, and tumor cell purity (TCP) in the CA+CS area were calculated. The public spatial transcriptomics (ST) dataset for breast cancer was downloaded from the 10X Visium web page. Lunit SCOPE IO was applied to the associated H&E WSIs to match distinct TIGIT expression to single cells identified in the WSIs. Results: TIGIT was highly expressed in TGCT (3.45±0.11; median±SEM), LUAD (3.07±0.05), and HNSC (2.89±0.06), and was highly enriched in samples with microsatellite instability-high or tumor mutational burden-high (≥ 10/Mb) compared to those without them (fold change = 1.30, p < 0.001). At a macroscopic, bulk-level in the TCGA dataset, TIGIT expression was positively correlated with intra-tumoral TIL density (R=0.37, p

8060 Background: Belantamab mafodotin (belamaf) is a BCMA antibody drug conjugate approved for the treatment of relapsed refractory multiple myeloma (RRMM) patients (pts) based on the pivotal phase 2 DREAMM-2 study (Lonial et al, Lancet Oncology, 2019), which demonstrated an overall response rate (ORR) of 32%, median progression free survival (PFS) of 2.8 months, and overall survival (OS) of 13.7 months in triple class (proteasome inhibitor, IMiD, and anti-CD38) refractory (TCR) MM. In this single-center retrospective study, we report the efficacy and safety of belamaf in RRMM pts administered in a real-world, standard of care (SOC) setting. Methods: All MM pts who initiated therapy with SOC belamaf, either as monotherapy or in combination, between 11/1/2020 and 11/30/2021 at MD Anderson were included in this study. Response and progression were evaluated using International Myeloma Working Group standard criteria. Keratopathy and best corrected visual acuity (BCVA) adverse events (AEs) were graded per the Keratopathy and Visual Acuity (KVA) scale. The Kaplan-Meier method was used to estimate time to event endpoints. Results: A total of 39 consecutive pts with a median of 7 prior lines of therapy were included in the analysis, of whom 37 pts (95%) received single agent belamaf. Median age was 66 years (range 39-89), 14 of 37 (38%) pts with available FISH had high risk disease (del 17p, t(4;14, and/or t(14;16)), 14 pts (36%) had extramedullary disease, 37 (95%) pts were TCR, 32 (82%) pts were TCR and alkylator-refractory, and 8 pts (21%) were BCMA-refractory. Notably, the majority (69%) of pts in this analysis would have been ineligible for the DREAMM-2 trial based on key eligibility criteria. Median number of belamaf doses administered was 2 (range 1-9). Among 37 pts with measurable, response evaluable baseline disease, the best ORR (≥ PR) was 27% with ≥ VGPR of 3%. The clinical benefit rate (≥ MR) was 35%. Among 8 BCMA-refractory pts, there was 1 PR and 1 MR. Median PFS was 1.8 months and median OS was 9.2 months with a median follow-up of 10.1 months. Median duration of response has not been reached among 10 responding pts. Among 33 pts with a post-treatment ocular exam, 25 pts (76%) developed any grade keratopathy (Grade 1/2/3/4, 9%/55%/12%/0%, respectively) and BCVA changes (Grade 1/2/3/4, 42%/27%/6%/0%, respectively). Median time to first keratopathy or BCVA AE was 1.3 months. The most common reasons for treatment discontinuation were disease progression (75%) and AEs (9%). Conclusions: Our current study in heavily pretreated RRMM pts, of whom the majority would have been ineligible for the DREAMM-2 study, demonstrates an ORR, PFS, and ocular AE profile with SOC belamaf therapy comparable to outcomes reported in the pivotal registration study. Future studies are needed to further define the optimal use and sequencing of belamaf in MM pts, particularly in context of other BCMA-targeting modalities.

8517 Background: TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes. Methods: This is a phase 2, open-label, single-arm study of the safety and efficacy of TALA plus TMZ in patients with ES-SCLC, relapsed or refractory to a first-line platinum-based regimen. Participants receive TALA 0.75 mg (or 0.5 mg if creatinine clearance < 60 mL/min) po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria, versus a historical control of 15% ORR in second-line topotecan, with the null hypothesis rejected for 8 or more confirmed responses among 28 evaluable subjects (29% ORR). Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient reported outcomes. A Simon two-stage design was utilized to reach a total accrual of 28 evaluable patients. Results: Thirty-one subjects were enrolled, of which 3 were non-evaluable due to ineligibility (1) or early withdrawal of consent prior to first disease assessment (2). Eleven of 28 evaluable subjects (39.3%) achieved a confirmed partial response. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and -sensitive subgroups (4/13). The median time to response was 1.8 months (m), duration of response 5.8 m, progression free survival 4.5 m, and overall survival 11.9 m. Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (61.3%), anemia (54.8%), neutropenia (41.9%), and atypical pneumonia (3.2%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed. Cell free DNA and tissue analysis demonstrated no germline DDR mutations among the trial subjects, but somatic DDR mutations at baseline and acquired during treatment were common. Three subjects remain on study treatment. Conclusions: The study exceeded its target response rate. This is the second trial to demonstrate a benefit of PARP inhibition with low-dose TMZ in SCLC (see Farago Cancer Discovery 2019). A phase 3 study is appropriate to confirm the benefit of this approach compared to currently approved options. Clinical trial information: NCT03672773.

10541 Background: It is well known that estrogen exposure is a major risk factor for breast cancer (BC). Estrogen levels can be affected by the gut microbiome through enterohepatic circulation. No studies regarding gut microbiome changes in BC have examined the colonic mucosal microbiome; and there is no data on which types of gut microbiome studies would be most relevant to the study of the microbiome in BC. Methods: We examined differences in the gut microbiome composition in BC and control subjects using the following sample types: Home-collected stool, endoscopically collected stool, and colonic biopsy samples (for all groups, n=48 total, n=24 BC, n=24 controls). Here, we used both operational taxonomic unit (OTU) and amplicon sequence variant (ASV) based approaches in QIIME2 for 16S rDNA sequencing analysis. Alpha diversity metrics (Chao1, Pielou’s Evenness, Faith PD, Shannon, and Simpson) and beta diversity metrics (Bray-Curtis, Weighted and Unweighted Unifrac) were calculated. LefSe was used to analyze differences in the abundance of various taxa between sample types. Results: Alpha and beta diversity metrics were different between the three sample types when using both OTU or ASV-based analysis, however there were some minor differences between analysis types in these samples. Comparing the 3 sample types, Actinobacteria and Firmicutes (Log10 LDA score >4) were the predominant phyla in home stool samples, while Bacteroidetes and Proteobacteria (Log10 LDA score >4) were higher in abundance in the colonic biopsy samples. Conclusions: Our data shows that alpha and beta diversity metrics differ between sampling methods (home-collected stool, endoscopically collected stool, and colonic biopsies) when looking at the composition of the gut microbiome in BC. Results remained the same regardless of ASV or OTU-based analysis. [Table: see text]

6501 Background: Effective cancer screening leads to a substantial increase in the detection of earlier stages of cancer, while decreasing the incidence of later stage cancer diagnoses. Timely screening programs are critical in reducing cancer-related mortality in both breast and colorectal cancer by detecting tumors at an early, curable stage. The COVID-19 pandemic resulted in the postponement or cancellation of many screening procedures, due to both patient fears of exposures within the healthcare system as well as the cancellation of some elective procedures. We sought to identify how the COVID-19 pandemic has impacted the incidence of early and late stage breast and colorectal cancer diagnoses at our institution. Methods: We examined staging for all patients presenting to UCSD at first presentation for a new diagnosis of malignancy or second opinion in 2019 and 2020. Treating clinicians determined the stage at presentation for all patients using an AJCC staging module (8th edition) in the electronic medical record (Epic). We compared stage distribution at presentation in 2019 vs 2020, both for cancers overall and for colorectal and breast cancer, because these cancers are frequently detected by screening. Results: Total numbers of new patient visits for malignancy were similar in 2019 and 2020 (1894 vs 1915 pts), and stage distribution for all cancer patients was similar (stage I 32% in 2019 vs 29% in 2020; stage IV 26% in both 2019 and 2020). For patients with breast cancer, we saw a lower number of patients presenting with stage I disease (64% in 2019 vs 51% in 2020) and a higher number presenting with stage IV (2% vs 6%). Similar findings were seen in colorectal cancer (stage I: 22% vs 16%; stage IV: 6% vs 18%). Conclusions: Since the COVID-19 pandemic, there has been an increase in incidence of late stage presentation of colorectal and breast cancer, corresponding with a decrease in early stage presentation of these cancers at our institution. Cancer screening is integral to cancer prevention and control, specifically in colorectal and breast cancers which are often detected by screening, and the disruption of screening services has had a significant impact on our patients. We plan to continue following these numbers closely, and will present data from the first half of 2021 as it becomes available.

e13062 Background: The PIK3R1 gene is genetically altered in ̃3% of breast cancers in the Western and ̃17% in the Eastern worlds. We recently reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. To better understand whether MEK inhibition is a therapeutic option for breast cancer patients with mutated PIK3R1, we tested the newer generation MEK inhibitor, binimetinib, in a PDX mouse model. Methods: Two PDx models (table) were tested in athymic nude-foxn1nu (immune-compromised) mice. Both patients had had metastatic, grade 3 breast cancer and expressed moderate RNA levels of PIK3R1. Results: Body weights of treatment arms were unchanged throughout the experiment. The TNBC PDx study was halted early at 13 days because tumors reached the predefined maximum size of 1500 mm2. The binimetinib treated mice experienced slowed tumor growth (522.8 +/- 172.8%) compared to the vehicle control (720.7 +/- 229.1%), (p=0.0693). In the HR+ PDx model, the combination of binimetinib plus tamoxifen resulted in a statistically significant decrease (371.5 +/- 108.1%) in tumor volume compared to tamoxifen alone (525.0 +/- 154.1%; p = 0.0302). Conclusions: Our previous and current results suggest that mutation in PIK3R1 sensitizes cells to MEK inhibitors. Binimetinib inhibited growth in both models. This inhibition was of borderline significance in the TNBC model and was statistically significant in the ER+, HER2- model. To the best of our knowledge, these results provide the first evidence of binimetinib efficacy in PIK3R1-mutant, HR+, HER2- PDX immunodeficient mice. Plans for a phase II trial in patients with PIK3R1-mutant, HR+, HER2- breast cancer are underway.[Table: see text]

e18678 Background: Older adults over the age of 65 represent the majority of patients diagnosed with (60%), among them, 15-30% have a pre-existing Alzheimer’s disease or related dementia (ADRD) that puts them at higher risk for over and under treatment. Studying the role of pre-existing ADRD in cancer patients is vital to understanding treatment planning behavior, patterns of health care utilization, and adverse treatment outcomes. Massive administrative datasets, or “big data” represent the information rich environment that is useful for this endeavor. Methods: Our study utilized a clinically validated algorithm to assess the prevalence of pre-existing ADRD and cancer across six cancer types. We utilized the SEER-Medicare dataset for analyzing the study years 2004-2015 (N = 337 932). We extracted ICD-9 codes to identify ADRD using the Centers for Medicaid Services Chronic Conditions Warehouse (CCW) algorithm. In sensitivity analysis we compared the prevalence of ADRD+Cancer using the NCI (2014) and CCW algorithms. Results: We found a significant difference between the two algorithms (p < .0001) and a higher overall prevalence of comorbid ADRD+Cancer using the CCW (6.6%). Additionally, we found ADRD+Cancer prevalence was significantly higher among racial and ethnic subgroups compared to White and unstaged tumors compared with any numbered American Joint Committee on Cancer (AJCC) stages (p < .0001). Conclusions: Using a clinically validated algorithm we were able to identify more cases of ADRD+Cancer in big data. This figure remains underestimated for ADRD+cancer compared to clinically-validated studies. Further research into the validation approach and codes that are used for ADRD classification can improve how we identify ADRD in massive administrative data. This is critical given the growing population of diverse older adults in the U.S.