Hoppenworth, Jenna

Abstract Background: Fatty Acid Synthase (FASN) is a key lipogenic enzyme co-regulated with HER2 and highly expressed in ER+ and HER2+ BC. Its targeting downregulates HER2 expression. Our preclinical studies revealed that FASN inhibition can sensitize or restore sensitivity to trastuzumab, paclitaxel and ET in HER2+ BC models. Denifanstat (deni, formerly TVB-2640) is a novel FASN inhibitor that demonstrated promising clinical activity and safety in a prior phase I trial as either monotherapy or in combination with paclitaxel. The primary objective of this study was to evaluate the objective tumor response rate (ORR) of deni plus trastuzumab (H) in combination with paclitaxel (T) or ET. Methods: Two independent, phase II clinical trials were initiated to assess the efficacy and safety of deni plus H in combination with T (Cohort A) or ET (Cohort B). Key inclusion criteria included HER2+ MBC resistant to HER2-directed therapy, measurable disease, unlimited ET, ≤6 prior chemotherapy or antibody drug conjugate regimens, and confirmation of HER2+ MBC on a pre-registration biopsy. Deni was administered 100 mg/m2 orally once daily. HP or H plus ET (fulvestrant or aromatase inhibitor) was administered at standard dose and schedule. Blood was collected on Cycle 1 Day 1 (C1D1), C1D8 and C2D1 for serum FASN analysis. An additional MBC tumor biopsy was collected on C2D1 for correlative studies. A 2-stage Simon design with a safety-run in was used to test the null hypothesis that the true ORR is at most 5% against the alternative it is at least 20%. With a sample size of 32 patients (pts) per cohort, if ≥4 responses are seen, this design has a 90% chance of rejecting the true ORR is <5% when the true ORR is ≥20% at a 0.10 level of significance. The decision to close both trials to enrollment early was multifactorial. Results: From August 2017 - February 2024, 33 pts with HER2+ MBC pre-registered, among which 17 were eligible and 16 were evaluable (15 pts in Cohort A and 1 pt in Cohort B). The most common reason for ineligibility was HER2-negative status on central review of the pre-registration biopsy. Median age was 57 years (range 35-80). All pts were non-Hispanic and 13 (81.3%) were White. Median prior lines of therapy was 5 (range 0 - 11). In Cohort A, there were 5 partial responses; thus, the primary endpoint was met with the ORR estimated to be 33.3% (90% CI: 14.2-57.7%). The median PFS time was 7.0 months (95 %CI: 3.7 - 11.3), and median OS was 25.7 months (95%CI: 10.2 - NE). No dose limiting toxicities were observed during the C1 safety run-in (6 pts). In Cohort A, 7 (46.7%) developed a grade 3 or 4 adverse event (AE) attributed to combination therapy. Grade ≥2 AEs regardless of attribution occurring in ≥20% of all pts included anemia, fatigue, neutropenia, palmar plantar erythrodysesthesia (PPE), and peripheral neuropathy. Treatment was discontinued due to progression (12; 80%) or AE (3; 20% - pneumonitis; neuropathy; PPE). In Cohort B, the pt maintained stable disease through 8 cycles with grade 3 ALT increase, and she remained alive 31.2 months post-registration. Median C1D1 FASN level was 32.7 ng/mL (IQR: 18.7 - 49.6 ng/mL). There was minimal association between C1D8 and C2D1 FASN levels and time to disease progression (C1D8 n=9, Spearman rank correlation coefficient (r s) = 0.040; C2D1 n=13, r s = -0.019). Analyses of changes in MBC tumor expression of FASN, phospho-AKT, and phospho-S6 are in progress. Conclusion: Deni combined with HP provided clinical antitumor activity in pts with HER2+ MBC resistant to trastuzumab. Expected paclitaxel-associated AEs were observed. Nearly half of pts experienced a grade 3 or 4 AE attributed to the combination therapy, and 20% stopped treatment due to AE. Further study of deni, H plus ET is necessary to draw safety and efficacy conclusions. Citation Format: T. C. Haddad, V. J. Suman, R. R. Roa, B. J. Ernst, R. Lupu, T. Vander Steen, M. H. Solanki, M. Keeney, D. W. Northfelt, K. S. Anderson, T. J. Hobday, S. Chumsri, J. E. Hoppenworth, J. L. Carroll, K. V. Giridhar, C. C. O’Sullivan, R. A. Leon-Ferre, M. P. Goetz. Phase II Trial of the FASN Inhibitor, Denifanstat (TVB-2640), Plus Trastuzumab in Combination with Paclitaxel or Endocrine Therapy (ET) in Patients with HER2+ Metastatic Breast Cancer (MBC) Resistant to Trastuzumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-16.

Abstract Introduction: An Our Practice Advisory (OPA), formerly known as Best Practice Advisory (BPA), is an electronic health record (EHR) tool. OPAs identify key parameters to alert providers of potential interventions that could enhance quality of care. Such functionality is increasingly relevant given the rapid pace of new drug approvals. Within the Mayo Clinic system, we previously identified that amongst Mayo Clinic patients (pts) meeting the MonarchE criteria, 28% of pts did not undergo a documented discussion with their provider regarding the role of adjuvant abemaciclib (Premji, SABCS 2024). Further, a Flatiron study identified that only 40% of eligible pts received abemaciclib (Sandoval, Miami Breast 2025). To address this practice gap, in 2024 we began to implement EHR clinical decision support by creating an OPA trigger for pts eligible for an adjuvant CDK 4/6 inhibitor (CDK 4/6i). Here we report on ‘action taken’ versus not for the OPA and the most common reasons for re-prompts. Methods: The Mayo Breast Disease Group designed an OPA including pts who are within 14 months of a clinical or pathologic diagnosis of high-risk early-stage breast cancer. We leveraged structured data captured in the Epic staging forms (Epic Systems) to identify pts with clinical or pathologic T-stage, N-stage, grade, ± Ki-67/ multigene signature to identify ER+/HER2- pts eligible for adjuvant ribociclib or abemaciclib based on FDA approvals. The OPA was triggered by a patient encounter in oncology when endocrine therapy (but not CDK4/6i) was on the active medication list resulting in a hard stop. The OPA gathered limited details about whether adjuvant CDK4/6 inhibitors were discussed and whether the provider followed a link that resulted in prescribing one—considered an indicator of action taken. In this IRB-exempt quality improvement project, we describe the responses captured in the OPA trigger utilizing Epic tools. Results: The OPA went live on 1/10/2025. Over a 5-month period post OPA initiation, we identified 517 OPA alerts among 332 unique pts. Their median age was 62.5 years, and the majority were female (97%). The median time to resolve the OPA was 17.5 seconds (range 2-567 seconds). 12.6% (65/517) of the time there was ‘action taken’ by selecting the hyperlink to potentially start a treatment plan. Providers selected the following OPA pre-set responses: ‘re-prompt in one month’ 248 (48%), ‘patient not a candidate for therapy’ 48 (9%), ‘patient declines’ 69 (13%), ‘outside oncologist will prescribe’ 36 (7%), ‘not discussed’ 44 (9%), and unknown 72 (14%). The most common free text comments among the 517 OPA alerts (summarized) included: ‘revisit in future’ 108 (21%), ‘too early’ 65 (13%), ‘patient declines’ 66 (13%), ‘outside oncologist will start’ 31 (6%), ‘not a candidate’ 26 (5%), and ‘co-morbidities’ 18 (3%). Erroneous OPA prompting occurred in 14 (3%) who previously failed a CDK4/6i due to toxicity and in 18 (3%) for pts currently on a CDK4/6i. 30 (6%) OPA comments noted that they discussed or started therapy that day. Conclusion: The OPA offered clinical decision support and ensured that clinicians considered prescribing CDK 4/6i in all pts identified as eligible, and captured deferrals. Refinements are needed to ensure appropriate timing of OPA and minimize erroneous firing. The OPA remains active and captures the reason for deferral of adjuvant CDK 4/6i prescription. This data pairs real world decision making to better understand clinically meaningful application of improved invasive disease-free survival (iDFS). Citation Format: S. Premji, P. Advani, S. Chumsri, L. Mina, J. Taraba, J. Carroll, J. Hoppenworth, E. Cathcart-Rake, T. Haddad, B. Rudder, G. Choong, D. Idossa, C. O’Sullivan, S. Yadav, K. Ruddy, P. Peethambaram, T. Hobday, M. Goetz, R. Rao, B. Ernst, F. Batalini, R. Leon-Ferre, A. Tevaarwerk, K. Giridhar. Implementing an Our Practice Advisory (OPA) to provide clinical decision support for adjuvant CDK4/6 inhibitors in early-stage hormone receptor positive breast cancer: The Mayo Clinic Experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-11-10.

Abstract Introduction Serial assessments of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) provide independent prognostic significance for progression free survival and overall survival. A low CTC burden (<5 CTCs / 7.5mL blood) at baseline is favorable prognostically, and reduction of CTCs during treatment indicates response to treatment (Janni, CCR 2025). Despite increasing evidence supporting its clinical validity, real-time serial CTC enumeration has not been utilized broadly in clinical practice in the U.S. The ACT-MBC study is a prospective observational study to evaluate the impact of serial CTC testing on treatment decisions and response assessment (NCT05662345). Provider (physician or advanced practitioner) perception of CTC testing is measured with questionnaires at baseline (PQ1), and for each pt during the first restaging visit (PQ2), and at the end of the study (PQ3). We previously reported PQ1 results (Giridhar, SABCS 2024). Here, we report on results of PQ2. Methods ACT-MBC prospectively enrolled patients (pts) at Mayo Clinic Rochester and Mayo Clinic Health Systems sites (Mankato, Albert Lea and Eau Claire). Pts with MBC were enrolled at time of progressive disease during any line of therapy (TNBC) or ≥2nd line metastatic therapy for ER+/HER2- disease. Pts were tested for CTCs using the FDA-cleared CellSearch® assay which included enumeration and biomarker testing on CTCs for ER, HER2, and PD-L1. The treating clinician determined the regimen and timing of restaging scans. CTC testing was performed once per cycle (every 3-4 weeks) with results returned to the treating provider within 7 days. We descriptively summarized PQ2 responses from providers who had at least one on-treatment CTC result available by the first restaging visit. We report the proportion (90% CI) of providers who agreed or strongly agreed that assessing CTCs enhanced their ability to determine response to therapy and that the CTC results helped guide their decision to continue or change therapy (co-primary endpoints) while accounting for within provider correlation. Results As of June 25, 2025, 15 providers enrolled a median of 2 pts each (range: 1 to 15 pts) and completed PQ2 surveys on 40 pts. 7 providers (47%) practiced in the community setting and 4 (27%) were nurse practitioners. Most pts were female (98%), White (98%), and had ER+/HER2- MBC (80%). Baseline (C1) CTC results were elevated (≥5 CTCs) in 24 (60%) pts (CTC range 0-609). At C2 (n=39), CTC values remained undetected in 7 pts, decreased in 21 pts, increased in 8 pts, and remained unchanged in 3 pts. At PQ2 (n=40), based on clinician interpretation of radiographic findings, results showed 2.5% of pts with complete response, 20% with partial response, 25% with stable disease, 17.5% with mixed response, and 35% with progressive disease. Clinicians reported that CTC results were concordant with imaging results in 34 (85%) responses, discordant with imaging in 7.5% of responses, and unclear in the remaining 7.5% of responses. Most clinicians (82.5%) agreed or strongly agreed that assessing CTCs enhanced their ability to determine response to therapy (90% CI: 68.3%, 96.7%). Further, 70% of providers agreed or strongly agreed that the CTC results helped guide their decision to continue or change therapy (90% CI: 50.8%, 89.2%). 32.5% of the time, CTCs results influenced the timing of the first restaging scans. In 11/25 pts without progressing disease, CTC results influenced the timing of future scans. In the 7/8 pts with a mixed response at first restaging scans with decreasing CTCs, 4 remained on the same systemic therapy. Conclusions Oncologists in academic and community practice responded that serial CTC assessments enhance ability to determine response of therapy, guide decisions to continue or change treatments, and influence timing of radiographic assessments. Citation Format: K. V. Giridhar, D. Zahrieh, M. Hanna, A. Singh, E. Al-Hattab, P. Schumacher, J. Carroll, J. Hoppenworth, T. Haddad, A. Tevaarwerk, B. Rudder, G. M. Choong, S. Basu, R. A. Leon-Ferre, T. O'Brien, A. Lewis, F. de Snoo, L. Stork-Sloots, F. K. Kuhr, S. Lazaro, R. Prendergast, D. S. Spinner, M. P. Goetz. Assessing the impact of real-time serial circulating tumor cell results on the management of patients with metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-03-10.

431 Background: The National Adult and Influenza Immunization Summit (NAIIS) promoted clinical subspecialist efforts toward vaccination assessment and recommendation as one strategy to increase adult vaccination rates. Problem Statement: Between August 1, 2022, and May 31, 2023, 0% (n=0/100) of patients seen in medical oncology at Mayo Clinic (Rochester, MN) and receiving chemotherapy for breast cancer had a documented comprehensive vaccination status assessment by breast medical oncology staff. Aim Statements: (1) To increase the rate of comprehensive vaccination status assessment performed by breast medical oncology staff from 0% to 75% of patients receiving chemotherapy for breast cancer by September 2024. (2) To increase the rate of documented vaccination recommendation for patients who were not up to date with recommended vaccinations from 0% to 50% by September 2024. Methods: We deployed multiple interventions including physician and nurse education; development of patient education materials; and a standard operating procedure (SOP) for vaccination status assessment, vaccination recommendation, and vaccine-related documentation. Our SOP utilized an Epic SmartPhrase with following elements: (1) SmartLink that autopopulated overdue vaccinations, (2) hidden tip text permitting the use to hyperlink to Health Maintenance, (3) SmartLists that captured nurse actions (e.g., provided education) and encounter outcomes (e.g., patient endorsed plans to receive vaccinations), and (4) scripting for immunization education. Results: Multi-faceted interventions were associated with an improvement in the documented rate of comprehensive vaccination status assessment from 0% (n=0/100) to 82.8% (n=101/122). Most patients (77.2%, n=78/101) were not up to date with recommended vaccinations. Recommendations for appropriate vaccinations were made for 80.8% (n=63/78) of patients who were not up to date. Only 19.2% (n=15/78) of patients who were not up to date endorsed intention to receive missing/recommended vaccines. Counterbalance: Nurses were able to assess vaccination status and make appropriate recommendations in less than 5 minutes per patient. There was no difference in nurse-reported workflow burden related to vaccination status assessment, recommendation, or documentation after intervention. Conclusions: This quality project aligned our breast medical oncology practice with vaccination-related care promoted by NAIIS. We increased rates of vaccination status assessment and vaccination recommendations without impacting nurse-reported workflow burden. Medical subspecialty clinic engagement in vaccination efforts is feasible.

1089 Background: T-DXd has become an important treatment option in mBC and other malignancies. Interstitial lung disease/pneumonitis (ILD) occurred in 10-14% of pts in the DESTINY-Breast trials (0-2% G5 ILD), and with potential lower incidence/severity in earlier line settings (Krop et al, ASCO 2023). We previously reported the Mayo Clinic Rochester, MN experience with T-DXd related ILD in mBC (Hoppenworth et al, ASCO 2024). Here, we expand the data to include patients treated at all locations of the Mayo Clinic Enterprise. Methods: We retrospectively identified pts with mBC who received ≥1 dose of T-DXd across the Mayo Clinic enterprise (Rochester, MN; Mayo Clinic Health System locations in MN/WI; Scottsdale, AZ; and Jacksonville, FL) between July 2022-December 2023. Demographic, mBC characteristics, and pulmonary clinical variables were abstracted from the clinical records. Data were summarized using descriptive statistics. Diagnosis of ILD was determined by treating clinicians, and severity was approximated to CTCAE V5 based on clinical documentation. Results: 252 pts with mBC received T-DXd during the study period. The majority were Caucasian (86%) and female (99%) with a median age of 63. 91 pts (36%) were current/formers smokers and 97 (39%) had prior pulmonary comorbidities. The majority had HER2 low (155, 62%) and HR positive (164, 65%) mBC. 35 (14%) developed any grade ILD [G1: 6 (17%), G2: 13 (37%), G3: 3 (8.6%), G4: 3 (8.6%), G5: 10 (29%)], with 15 (43%) presenting with ≥G3. 29 (83%) presented with at least 1 symptom (cough or SOB). Among those with previous pulmonary toxicity, 4 (33%) had previous pneumonitis in the ILD cohort. The median prior lines of all therapies (including endocrine therapy) were 5, with a median of 3 prior lines of chemotherapy in both the ILD (range 1-13) and non-ILD cohorts (range 1-13). Median onset to any grade ILD was 7 cycles. 20 pts (57%) received steroids for ILD. 14 (40%) had a bronchoscopy, all had a CT chest, 16 (46%) were hospitalized, 7 (20%) were intubated and 1 (3%) had a lung biopsy. Pts with G5 ILD had a median of 3 lines of chemo and a median of 8 cycles prior to onset of ILD, compared to 3 lines of chemo and a median of 7 cycles for those with G1-4 ILD. G5 pts were all Caucasian females, 5 were former smokers, 5 were non-smokers, 1 had a history of pneumonitis. T-DXd was rechallenged in 4 pts (G1-2 ILD) without ILD recurrence. Conclusions: In this retrospective case series,14% of pts treated with T-DXd experienced any grade ILD (4% G5) which is in alignment with the rate observed in the pivotal DESTINY-Breast trials, though with higher rates of G5 toxicity. Among those with ILD, increased lines of therapy were not associated with increased risk. Further research is needed to correlate risk.

1015 Background: T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low breast cancer and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For > grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) if imaging findings resolve. Limited data exist on outcomes of RC after ILD in diverse real-world patients (pts). Methods: In this multi-center retrospective study, we analyzed pts with T-DXd related ILD treated from 2017-2024. Pts with ILD were identified via chart/ICD code review. Adjudication of T-DXd related ILD was based on treating providers’ assessment and graded via CTCAE v5. We collected pt demographics, T-DXd and steroid dosing, imaging results, and outcomes after RC. Statistical analysis was performed using Wilcoxon rank sum and Fisher’s exact tests. Results: Four centers treated 712 pts with T-DXd, with a 9.1% rate of any grade ILD (n=65). One other center reported only RC data in 18 pts with ILD. In total, 47 pts were RC; 38 after G1 ILD (81%), 9 after G2. Median (med) time to initial ILD was 145 days (d) after 1st dose (interquartile range [IQR] 78-205). Demographics for pts RC are shown in the table. Among 50 pts with G1 ILD, including pts not RC, 28/50 (56%) received steroids for a med of 36d (IQR 27-79). Radiographic improvement was seen at a med of 24d (IQR 19-63) for pts treated with steroids vs 82d (IQR 48-94) without (p<0.01); and a med of 35d (IQR 22-82) for pts RC vs 81d (IQR 68-105) for pts not RC (p=0.01). Among pts with G1 ILD, 38/50 (76%) were RC at a med of 42d (IQR 36-57) from last dose; 23/38 (61%) were dose reduced. After RC, pts remained on T-DXd for a med of 215d (IQR 60-334); 10/38 (26%) developed recurrent ILD (7-G1, 2-G2, 1-G3) at a med of 211d (IQR 47-273) from RC. No statistically significant differences were seen between ILD onset, time to RC, or demographics for pts with recurrent ILD vs not. Of the 9 pts RC after G2 ILD, T-DXd was continued for a med of 129d (IQR 49-171); 2/9 (22%) developed recurrent ILD (1-G2, 1-G3). No G5 toxicity was seen with RC. Conclusions: In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Pts treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously. Our large cohort data further supports the safety of T-DXd RC in diverse real-world settings. RC Pt Characteristics (n=47) n (%) or Median (IQR) Cancer typeBreastGIGyn 43 (91)3 (6)1 (2) Age (yrs) 57 (52-68) Prior # therapy lines in the advanced/metastatic setting 3 (1-5) Renal impairment (CrCl < 60 mL/min) 8 (17)

1083 Background: T-DXd and SG are both FDA-approved treatments for patients (pts) with HER2-low MBC, but little data exists on the sequential use of these ADCs. Methods: In this multicenter retrospective cohort study, we identified pts with HER2-low MBC treated sequentially with both T-DXd and SG in either order, with or without intervening therapies (IntTx), at 5 academic centers between 2020-2023. We previously reported real-world progression free survival (rwPFS) and real-world overall survival (rwOS) by HR-status and ADC sequence order. Here we provide updated rwPFS and rwOS data, as well as new subgroup analyses by age, sites of disease, and use of IntTx between ADCs for HR- and HR+ disease. Results: 84 pts with HER2-low MBC treated with both T-DXd and SG were included, including 56 pts with HR+/HER2-low MBC (66.7%) and 28 pts with HR-/HER2-low MBC (33.3%). Prior to the start of ADC1, median age was 58 yrs and 22 pts were >65 yrs (26.2%), 65 pts (77.4%) had visceral disease, and 14 pts (16.7%) had central nervous system (CNS) disease. 36 pts (42.9%) had an IntTx between ADCs. Table 1 shows updated rwPFS and rwOS data by HR-status and ADC sequence order. For pts with HR+ and HR- MBC, there was no difference in ADC1 rwPFS or ADC2 rwPFS by age ≤65 vs. >65 yr or by presence vs. absence of visceral disease. For pts with HR- MBC, ADC1 rwPFS and rwOS was shorter for pts with CNS disease vs. pts without CNS disease (rwPFS 5.4 mo (n=6) vs. 8.5 mo (n=22), p=0.03; rwOS 11.6 mo vs. 21.1 mo, p<0.01 respectively). For pts with HR+ and HR- MBC, there was no difference in ADC2 rwPFS with or without receipt of IntTx. There was no difference in time to treatment failure for first IntTx vs. ADC2 if no InTx was given. Conclusions: This is one of the largest multicenter cohorts of pts treated with sequential ADCs for HER2-low MBC. Median rwPFS was longer for ADC1 than ADC2 in all subgroups, regardless of HR-status, ADC sequence order, age ≤65 or >65 yr, presence of visceral disease, or use of IntTx. Among pts with HR-/HER2-low MBC, pts with CNS disease had shorter ADC1 rwPFS and rwOS than pts without CNS disease. [Table: see text]

11145 Background: T-DXd is increasingly used in mBC. A T-DXd toxicity of special interest is interstitial lung disease/pneumonitis (ILD), occurring in 10-15% of pts in the DESTINY-Breast trials, and with potential lower incidence/severity in earlier line settings [Krop et al, ASCO 2023]. However, in routine practice, T-DXd may be used in pts with more heavily pre-treated mBC and previously exposed to other antibody-drug conjugates (ADC) [Premji et al SABCS 2023]. We evaluated the incidence/severity of T-DXd related ILD in mBC at Mayo Clinic. Methods: We retrospectively identified pts with mBC who received ≥1 dose of T-DXd at Mayo Clinic, Rochester, MN, between July 2022-December 2023. Demographic, mBC, and pulmonary clinical variables were abstracted from the clinical records. Data was summarized using descriptive statistics. Diagnosis of ILD was determined by treating clinicians, and severity to CTCAE V5 based on clinical documentation. Results: 77 pts with mBC received T-DXd during the study period. All were female, the majority (70, 91%) were Caucasian, and median age was 58. 53 (69%) had HER2-low mBC (37 HR+, 16 HR-) and 24 (31%) had HER2+ mBC (17 HR+, 7 HR-). 31 (40%) were active or former smokers. 11 (14%) had pulmonary comorbidities, including 6 (7.8%) with asthma, 2 (2.6%) with prior pneumonitis, and 3 (3.9%) with other pulmonary comorbidities. They had previously received a median of 1 line of endocrine therapy, and 4 lines of chemotherapy, with 20 (26%) having received another ADC. 17 (22%) developed any grade ILD [G1: 3 (4%), G2: 7 (9%), G3: 2 (3%), G4: 1 (1%), G5: 4 (5%)]. Among pts with ILD of any grade, 13 (76.5%) presented with at least 1 symptom (cough/SOB). The median number of T-DXd cycles prior to onset of any grade ILD was 6 (range 2-13), or 18 (range 6-39) weeks. 5 (29%) pts with any grade ILD received a prior ADC. Of pts with ≥G3 ILD (n=7), all were Caucasian, 2 (30%) were prior smokers, none had prior lung disease, and had received a median of 5 prior lines of chemo, with 4 (57%) having received a prior ADC. All grade ≥2 ILDs were treated with systemic steroids, and 1 also received IVIG. CT chest was used for diagnosis of all ILD. 7 pts (41%) required hospitalization, all of whom had bronchoscopy, with 5 (29%) requiring intubation. All pts with G1 ILD (3, 18%) restarted T-DXd without ILD recurrence. Conclusions: In this case series,22% of ps treated with T-DXd experienced ILD (5% G5), higher than the rate observed in the pivotal DESTINY-Breast trials, possibly due to real-world use of T-DXd in more heavily pre-treated pts and in pts with pulmonary comorbidities.

Abstract Introduction: Interstitial Lung Disease (ILD) is a known adverse event associated with Antibody Drug Conjugates (ADCs), causing fibrosis of the lung. In the DESTINY-Breast 04, TROPICS-02, and ASCENT trials the rate of ILD/Pneumonitis was 12.1%, 0.4%, and 0% respectively. In these studies, the time to first cross-sectional imaging after initiation of ADC was 6 weeks. However, prior treatment with a topoisomerase-1 inhibitor ADC was not permitted in these studies, so the influence of sequential ADC treatments remains unknown. Here, we aimed to characterize the frequency and management of ILD in sequential use of ADCs in a multi-institution retrospective analysis. Methods: We identified patients (pts) with HR+/HER2-low and HR-/HER2-low MBC who had received both Trastuzumab-deruxtecan (T-DXd) and Sacituzumab govitecan (SG) monotherapy (in either order, with or without intervening therapies) who were treated at five academic centers between 2020-2023. Patients had received treatment with the ADC in either routine clinical treatment or as a prior participant on a clinical trial with ADC monotherapy. Information regarding ILD diagnosis, imaging, timing of onset, peak and resolution along with management information was collected and analyzed. Retrospective assessment of ILD toxicity was graded using CTCAE v5.0, based on available clinical and radiographic reports. Results: 10/60 pts who received ADC therapy in this multi-institutional cohort were diagnosed with ILD (all grades). No differences in age or BMI were observed in those who developed ILD versus those who did not, and 9/10 pts were White, 1 was Asian, with a median age of 59 years (47-79 years). Pertinent history in these pts included 3/10 had a prior smoking history, 8/10 had a prior cardiac or pulmonary comorbidity (including sleep apnea, lung cancer, hypertension, hyperlipidemia, thrombosis, or stroke). Prior to receiving their first ADC, 7/10 patients had metastatic disease to the lung. All 10 patients were diagnosed with ILD during treatment with T-DXd. 4 pts initially received T-DXd, then developed ILD and then upon recovery, subsequently received SG. The remaining 6 pts initially received SG (with no reports of ILD), and then received T-DXd and subsequently developed ILD. In the entire cohort, the median time from ADC initiation to first CT scan was 8 weeks (range 1-22 weeks). Within the cohort that developed ILD, the median time from initiation of T-DXd to first CT scan was also 8 weeks (range 6-13 weeks). The median time to diagnoses of ILD was 3 months after initiation of T-DXd (range 0.4-14.5 months). Dyspnea was the most common presenting symptom in 9/10 pts and at diagnosis of ILD, dyspnea was graded as III in 6/10 pts, II in 3/10 pts, and I in 1/10 pts. Diagnostic evaluation included CT chest (9/10), pulmonary consultation (8/10), pulmonary function testing (2/10), and bronchoscopy (1/10). 4/10 patients presented at their highest-grade toxicity at diagnosis. All patients stopped T-DXd treatment, 7 were hospitalized, 7 required supplemental oxygen, and 8 were prescribed steroids for treatment. Of those receiving steroids, the most common starting dose was prednisone 1 mg/kg and doses ranged from 0.5 mg/kg to 9mg/kg prednisone equivalents. No patient received a secondary immunosuppressive agent. The steroid treatment duration ranged from 1-4 months. None of the 10 pts underwent re-challenge with T-DXd and 3/10 developed grade V ILD (death). Conclusion: We observed a 16.6% incidence of all grade ILD (5% grade V ILD) with T-DXd and 0% with SG. In this small cohort study, we did not observe a clear increased risk for ILD with sequential treatment of ADCs. Practice patterns were consistent with recommended diagnostic evaluation and steroid management. Additional strategies are needed to characterize pts most at risk for developing ILD and to identify situations where re-challenge may be safe. Citation Format: Sarah Premji, Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Hope Rugo, Karthik Giridhar. Interstitial Lung Disease (ILD) in Sequential Antibody Drug Conjugate (ADC) use in patients with Metastatic Breast Cancer (MBC): A Multi-Institutional experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-06.

Abstract Introduction. T-DXd is FDA-approved for patients (pts) with hormone receptor positive (HR+) or HR- HER2-low (IHC 1+ or 2+, ISH-) MBC and SG is FDA-approved for pts with HR+/HER2- and triple negative MBC. However, several outstanding questions impact the use of these drugs in clinic, including: 1) what is the efficacy and safety of these agents in real-world populations with diverse pt characteristics not well represented in the pivotal phase III trials, and 2) what is the impact of sequential treatment with ADCs on the efficacy and safety of these agents. Methods. In this multicenter retrospective cohort study, we identified pts with HR+/HER2-low and HR-/HER2-low MBC who had received both T-DXd and SG monotherapy (in either order, with or without intervening therapies) treated at 5 academic centers between 2020-2023. Pts received treatment per standard of care or on a clinical trial with ADC monotherapy. We describe pt demographic and clinical characteristics, treatment history, key safety parameters, and response and survival data by HR+ status and ADC sequence order. Results. Sixty pts with MBC treated sequentially with T-DXd and SG were included in this analysis, including 45 pts with HR+/HER2-low MBC (75.0%) and 15 pts with HR-/HER2-low MBC (25.0%). Most pts were female (n=59; 98.3%), non-Hispanic (n=49, 81.7%), and white (n=43, 71.7%). Median age at start of ADC #1 was 56.6 years (range 23-82). Prior to treatment with ADC #1, most pts had visceral disease (n=45, 75.0%) and 16 (26.7%) had central nervous system metastases. Among pts with HR+/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 49.0 months, with 4 median lines of prior therapy in the metastatic setting (2 endocrine, 2 chemo). Approximately half of the HR+ pts received T-DXd prior to SG (n=22, 48.9%; median 3.0 prior lines of therapy for MBC, range 1-9) while the other half received SG prior to T-DXd (n=23, 51.1%; median 4.5 prior lines of therapy for MBC, range 1-10). 44% (n=20) received an intervening therapy between ADCs. For HR+ pts who received T-DXd prior to SG, response and survival data is as follows for T-DXd and SG respectively: Overall response rate (ORR) [54.5% and 21.1%], time to next treatment (TTNT) [4.3 mo and 1.6 mo], and real-world overall survival (rwOS) [19.8 mo and 4.9 mo]. For HR+ pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [78.3% and 42.9%], TTNT [8.6 mo and 2.8 mo], and rwOS [22.3 mo and 7.3 mo]. Among pts with HR-/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 8.2 months with 2 median lines of prior therapy in the metastatic setting (2 chemotherapy); 66.7% (n=10) received prior immunotherapy. Most HR- pts received SG prior to T-DXD (n=14, 93.3%) and 40.0% (n=6) received an intervening therapy between ADCs. For HR- pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [64.3% and 38.5%], TTNT [6.2 mo and 2.7 mo, and rwOS [15.7 mo and 6.5 mo]. In terms of key safety parameters during treatment with T-DXd, 13.3% of pts (8/60) required a dose reduction. 16.7% (10/60) were diagnosed with interstitial lung disease (ILD)/pneumonitis of any grade including 3 pts with grade 3-4 ILD (5.0%) and 3 pts with grade 5 ILD (5.0%). During treatment with SG, 40.0% of pts (24/60) required a dose reduction. 83.3% (50/60) received growth factor support (24 pts primary prophylaxis; 26 pts secondary prophylaxis); 9 pts (15%) required treatment delay due to neutropenia. Conclusion. This study represents the largest multicenter series to date of pts treated with sequential ADCs for HR+/HER2-low or HR-/HER2-low. ORR was higher and TTNT was longer for ADC #1 than ADC #2 in all subgroups, regardless of HR+ status and ADC sequence order. An additional ~30 pts will be reported at time of final analysis. Future prospective studies are planned to further clarify the efficacy and safety of sequential ADC use and to identify biomarkers of response and resistance. Key demographic, clinical and treatment characteristics in pts with HR+ and HR- HER2-low MBC treated sequentially with T-DXd and SG (in either order, with or without intervening therapies) Abbreviations: T-DXd (trastuzumab deruxtecan), SG (sacituzumab govitecan), MBC (metastatic breast cancer), ADC (antibody drug conjugate), HR (hormone receptor), HER2 (human epidermal growth factor receptor 2), CNS (central nervous system), ET (endocrine therapy), ORR (overall response rate), TTNT (time to next treatment), rwOS (real world overall survival), CI (confidence interval) * Several pts on ADC #2 with ongoing treatment and first scan pending, hence smaller denominator for response assessment Citation Format: Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Sarah Premji, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Karthik Giridhar, Hope Rugo. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-04.