Evidence Of Disease Progression Research Articles

INNV-31. THE USE OF IVOSIDENIB IN PATIENTS WITH ENHANCING IDH1 MUTANT GLIOMAS

Abstract Ivosidenib offers a novel targeted therapy for non-enhancing IDH1 mutated gliomas following initial resection. Potential effects of IDH inhibitors on enhancing disease in clinical settings are not well established. This study characterizes a cohort of patients with IDH1 mutated gliomas with enhancing disease, who were initiated on monotherapy, off-label ivosidenib between October, 2020 to August, 2023. The cohort included 21 patients ages 29 to 73 years, 11 female and 10 male. Diagnoses represented were astrocytoma IDH1 mutant, grade 2-4 (N=9) and oligodendrogliomas IDH1 mutant, grade 2-3 (N=12). Prior treatment exposures included radiation therapy (N=11), temozolomide (N=15), bevacizumab (N=3), and treatment naïve (N=6). Time from diagnosis to ivosidenib initiation was 9.1±2.7 years. Although all patients had enhancing disease, ivosidenib was initiated due to non-enhancing disease progression (N=7), enhancing disease progression (N=13), and temozolomide intolerance (N=1). Size of enhancement by cross-section measured >1cm (N=15) and <1cm (N=6). Best radiographic responses per RANO criteria were partial response (N=3), stable disease (N=11), and progressive disease (N=7). At last contact, eleven patients were maintained on ivosidenib with no evidence of disease progression since initiation with an average treatment duration of 25.5±6.4 months and overall survival of 11.7±3.1 years. Ten patients had disease progression at median 5.2±3.1 months following ivosidenib initiation, three of whom died 16.7 (range 6.8-34.4) months after treatment initiation with an overall survival of 9.4 years (range 4.6-13.6). Adverse events from therapy included diarrhea (N=2), CK elevation (N=4), and QTc prolongation (N=2). No patients discontinued ivosidenib due to adverse events. No significant difference was detected between patients with and without disease progression due to size of enhancement (p=0.4) or prior treatment exposure (p=0.3). Future studies should include biopsies to understand the role of enhancing lesions in treatment response of IDH inhibitors.

Initial results of the Paul Ahmed Comparison (PAC) study in refractory childhood glaucoma

PurposeTo compare the effectiveness and safety of the Paul Glaucoma Implant (PGI) to the Ahmed Glaucoma Valve (AGV) in managing refractory childhood glaucoma. DesignRandomized controlled trial. SettingTwo clinical centers. MethodsAn ongoing randomized controlled trial including patients ≤18 years with refractory childhood glaucoma in whom glaucoma drainage implant surgery was planned. Patients were randomized to receive either PGI or AGV. The primary outcome was the intraocular pressure (IOP) reduction. Secondary outcomes included glaucoma medication reduction, success rate, and complications rate. The success rate was defined as achieving a postoperative IOP between 6-21 mmHg without or with glaucoma medications (up to three topical glaucoma medications), without the need for additional glaucoma surgeries, and without the occurrence of vision-threatening complications or evidence of disease progression. The use of oral glaucoma medications, such as acetazolamide, was considered a failure. ResultsThe current report included 44 patients (44 eyes) who completed the one-year postoperative follow-up (25 in the PGI group versus 19 in the AGV group). The mean age at the time of surgery was 96.9±59.1 months (90.5±60.04 months in the PGI group and 105.4±58.5 months in the AGV group. Preoperatively, the mean IOP was 32.6±6.1 mmHg with a mean of 3.6±0.6 glaucoma medications in the PGI group, compared with 29.8±6.1 mmHg (p=0.1) with a mean of 3.4±0.7 glaucoma medications (p=0.35) in the AGV group. At one year, there were no statistically significant differences in the mean IOP (14.9±4.1 mmHg in the PGI group versus 15.5±3.5 in the AGV group, p=0.6) and number of glaucoma medications (1.1±1 in the PGI group versus 1.6±1.03 in the AGV group, p=0.1). The success rate of PGI was 80% vs. 73.6% in the AGV (p=0.2). The postoperative complications rate was comparable in both groups (three eyes in each group). Conclusion/RelevanceAt one year postoperatively, the IOP reduction, reduction of glaucoma medications, success rates, and rate of complications were comparable between both groups.

Renal Oncocytoma: A Systematic Review of Its Metastatic Features.

Oncocytomas are referred to as benign kidney neoplasms. They primarily affect adults, with patients over 70 years old being the most affected. Renal oncocytomas (ROs) are frequently detected by excision, biopsy, or scan. Hematuria, flank pain, and a palpable mass are the traditional trio of symptoms. Oncocytomas appear as well-circumscribed, tanor mahogany-coloured masses with a central scar that is stellate. Histological features include well-circumscribed lesions, bland cytology, eosinophilic cytoplasm, regular nuclei with prominent central nucleoli, and nested architecture. ROs are rarely linked to an aggressive clinical course and have an excellent prognosis. There is proof that the disease can spread to the liver and bones.Some literature has also reported oncocytoma metastases to the lung and liver. This systematic review of the literature examines and evaluates the malignant potential of oncocytoma. The purpose of the study was to determine whether ROs can be diagnosed as a benign condition or if malignancy needs to be considered and investigated. Seventeen studies were analysed which had a total of 412 ROs. Four patients (one percent) died as a result of their illness. There was evidence of disease progression in every patient who passed away from their illness. Six patients (1.5%) experienced disease progression in total. Three hundred and seventeen patients (80%) underwent radical nephrectomy, while 81 patients (20%) underwent partial nephrectomy. Liver, bone, lung, lymphadenopathy, and local recurrence were among the metastasis sites. Perinephric fat invasion, renal sinus fat invasion, renal capsular invasion, and vascular invasion are characteristics of metastatic behavior that have been found. Despite this, the small number of patients who experienced disease progression and/or death as a result of ROs implies that aggressive malignant behavior is not always correlated with the presence of metastatic features or disease. Oncocytomas should be viewed as having a low potential for malignancy rather than as benign. Individuals who exhibit aggressive characteristics, such as vascular invasion and/or perinephric fat invasion, have an atypically good prognosis. Despite advancements in imaging and immunochemical techniques, it is indisputable that ROs, which were first classified as renal tumours in 1976, continue to pose a diagnostic challenge for multidisciplinary teams.There is considerable variation in practice across the globe due to difficulties in confirming ROs, especially when it comes to metastatic disease. There is even more variation in the management of follow-up care that follows. This will remain the MDT's current state until randomised controlled trials, long-term results, and a better comprehension of the behavior of this tumour are obtained.

7856 In Pursuit of Solutions: Exploring Novel Therapeutic Strategies in the Treatment of a Rare, Aggressive Macroprolactinoma Post-Temozolomide: A Case Report

Abstract Disclosure: N. Konindala: None. H. Darapu: None. K. Ruddiman: None. Introduction: Prolactinomas comprise 40-60% of all pituitary tumors. Most prolactinomas respond well to dopamine agonist treatment. About 10% of these tumors are aggressive prolactinomas (APRL). Although rare, APRLs pose a significant challenge in clinical practice as treatment beyond dopamine agonists, surgery and radiotherapy is limited. A fourth-line therapy called temozolomide may be needed. After temozolomide failure, treatment options are minimal, as there are no evidence-based therapies available for such aggressive pituitary tumors. The efficacy of novel treatment agents remains to be explored. Notably, our case is one of the few where investigational agents, including Pembrolizumab and Pazopanib have been used. We present a case report that contributes to the evolving understanding of potential therapeutic options and highlights the ongoing challenges in refractory prolactinoma management. Case Presentation: A 77-year-old male was diagnosed with a macroprolactinoma in 2001 and was started on cabergoline with a good therapeutic response. In 2011, there was hormonal and imaging evidence of progression, and the patient underwent transsphenoidal hypophysectomy with gross resection followed by gamma knife radiation. The patient was found to have a recurrence of his tumor five years later and underwent repeat transsphenoidal resection. He continued to show evidence of recurrence and was recommended for chemoradiation and adjunct temozolomide (TMZ). After 12 cycles of TMZ, a repeat MRI was done, which showed radiographic recurrence. The patient had a third transsphenoidal surgery done in August 2022, followed by the initiation of a PARP-1 inhibitor, Olaparib. The development of adverse effects complicated this, and treatment was transitioned to capecitabine and TMZ in Jan 2023. The patient had persistent tumor burden symptoms, and a VEGF inhibitor Avastin was initiated. His symptoms initially improved, but unfortunately, his prolactin levels rose from 895 mg/dL to 1,547mg/dL, indicating evidence of disease progression. Immunotherapy with pembrolizumab was started on 6/2023, and he was given three doses before a follow-up MRI showed continued progression of the disease. He was recommended to start pazopanib, a kinase inhibitor. Discussion: Aggressive Prolactinomas present a rare and intricate management challenge, necessitating a multidisciplinary approach. Despite standard therapies, achieving remission can be elusive. While Pembrolizumab showed promise in reported cases, our patient remained refractory. Literature indicates favorable responses to Pazopanib in a small number of refractory cases. A reassessment in a few months will evaluate our patient's response to Pazopanib. This case emphasizes the need for further research to refine refractory prolactinoma management and develop response indicators for investigational agents. Presentation: 6/3/2024

Liver transplantation for unresectable Klatskin tumor: experience of two centers, first distant results

Aim. Evaluation of the first distant results of the combined experience of liver transplantation for unresectable portal cholangiocarcinoma from two large specialized clinical centers.Materials and methods. In total, 23 attempts at liver transplantation for unresectable Klatskin tumor were undertaken. Out of them, 10 were conducted at the A.M. Granov Russian Research Center for Radiology and Surgical Technologies (Granov Center), and 13 were conducted at the Minsk Scientific and Practical Center for Surgery, Transplantology, and Hematology (Minsk Center). The maximum tumor size was 5 and 3 cm in patients operated at the Granov and Minsk Centers, respectively. In the Granov Center, neoadjuvant therapy included a combination of endobiliary photodynamic therapy, regional and systemic chemotherapy. Patients were included in the waiting list only in cases of decreased tumor marker levels and in the absence of disease progression and acute cholangitis. In the Minsk Center, stereotactic radiotherapy was used for neoadjuvant treatment in the absence of active cholangitis; the first 3 patients underwent liver transplantation without prior neoadjuvant treatment.Results. Due to disease progression, six patients were excluded. In three patients at the Mink Center, the diagnosis was not morphologically confirmed after liver transplantation. A total of 14 liver transplantations were performed for unresectable hilar cholangiocarcinoma. After neoadjuvant treatment at the Granov Center, normalization of the CA19-9 marker was observed in four patients, its decrease by 3–4 times was observed in two patients. Liver transplantation was performed in six patients. The average time from the onset of treatment to transplantation was 9.1 months (6–14). Out of the six patients, one was alive for 34 months, with the median overall survival being 22.2 months. Progression was the cause of death in only one patient. Out of the three patients without neoadjuvant treatment at the Minsk Center, two were alive at 16 and 134 months without progression. One patient died after transplantation from disease progression at 24 months. Stereotactic radiotherapy achieved normalization of CA19-9 in four patients; its twofold reduction was observed in one patient. The average time from the onset of treatment to transplantation was six months (3–12). The average CA19-9 tumor marker level by the time of transplantation was 11.3 IU/mL. At 20–26 months, three patients were alive without evidence of disease progression; two patients died of progression after 9 and 59 months.Conclusion. Liver transplantation for unresectable portal cholangiocarcinoma after neoadjuvant treatment regardless of the methods used is highly promising in carefully selected recipients.

Longitudinal assessment of systolic anterior motion of the mitral valve in cats with hypertrophic cardiomyopathy.

The proportion of cats with hypertrophic cardiomyopathy (HCM) that lose systolic anterior motion of the mitral valve (SAM) in the long term is unknown. Cats with HCM will lose SAM in the long term. Loss of SAM will be associated with greater age, longer scan-interval, and alteredleft ventricular (LV) dimensions. Sixty unsedated cats with HCM, not receiving beta blockers or pimobendan. A retrospective cohort study from 2 referral centers. Cats were eligible if they had been diagnosed with HCM and had a repeat echocardiogram ≥1 year later. Clinical and echocardiographic data of the left heart variables were collected. Thirty-eight cats had SAM at the initial scan. After a median follow-up time of 2.1 years (range: 1.0-5.9), 7 cats had lost SAM (18%) and 5 cats (23%) gained SAM. On follow-up, cats with SAM at the initial scan had a larger left atrium (P = .037), lower left atrial fractional shortening (P = .014), greater LV internal diameter in end-systole (P = .002), and lower LV fractional shortening (P < .001). Four cats with SAM developed congestive heart failure. There were no new cases of congestive heart failure or change in left heart variables in cats without SAM at the initial scan. The gain or loss of SAM was not associated with age or time between scans. Similar proportions of cats gained or lost SAM. Cats with SAM at baseline had more evidence of disease progression than cats without SAM.

Exercise as part of survivorship care in metastatic breast cancer: protocol for the randomized EMBody trial

BackgroundExercise is associated with improved survival, physical functioning, treatment tolerability, and quality of life in early-stage breast cancer. These same endpoints matter in metastatic breast cancer (MBC). Prior trials in MBC have found exercise to be not feasible or of limited benefit, possibly due to inclusion of patients with heterogeneous disease trajectories. Patients with MBC have variable disease trajectories and supportive care needs; those with indolent MBC have longer life expectancy, lower symptom burden and distinct priorities, and are well-positioned to participate in and benefit from an exercise program. The EMBody trial aims to determine the impact of a multimodal exercise intervention on cardiorespiratory fitness, physical function, body composition, and patient-reported outcomes, specifically in patients with stable, indolent MBC.MethodsEligible patients have MBC with no evidence of disease progression on current therapy in the prior 12 months and cannot be receiving cytotoxic chemotherapy. The trial aims to enroll 100 patients, randomized 1:1 to the exercise intervention versus usual care, stratified by baseline function. The virtually-delivered exercise intervention arm achieves moderate intensity exercise with exercise physiologists 3 days/week for 16 weeks. The 60-minute sessions include aerobic, resistance, balance and stretching exercises. The exercise arm receives informational sessions on the role of exercise in cancer and principles of habit and self-efficacy. The primary endpoint is 16 week change in fitness on a ramp treadmill test between the exercise and control arms. Secondary endpoints include change in a physical function, muscle mass assessed by CT scans, and PROs of fatigue and quality of life. Exploratory analysis includes behavioral modifiers of exercise adherence and effectiveness and serologic measures of inflammatory, metabolic, and immune pathway biomarkers.DiscussionThe EMBody trial evaluates exercise in a unique patient population with indolent, non-progressive MBC. Patients living with MBC experience similar symptom burden to those undergoing therapy for early-stage disease and the benefits achieved with exercise could be similarly impactful. This trial will contribute evidence to support expansion of exercise recommendations, among other survivorship care efforts, to those living with metastatic disease. Clinical trial information: NCT05468034.Trial registrationNCT05468034. Date of registration: 7/12/2022.

Successful surgical treatment of metachronous carcinoma of the appulla of Vater and ductal carcinoma of the distal parts of the pancreas

Background. Currently, there is a steady trend towards an increase in the incidence of both synchronous and metachronous multiple primary malignant tumors (MPMT). However, metachronous polyneoplasia of the pancreatobiliary tract is relatively rare, and there have been very few reports on successful treatment of this malignancy. Case presentation. In September 2014, the patient K. was diagnosed with adenocarcinoma of the ampulla of Vater (T2N0M0, stage Ib) and underwent gastropancreatoduodenal resection with the creation of pancreatic-gastric anastomosis at the Abdominal Department of Cancer Research Institute of Tomsk National Research Medical Center. There were no complications in the postoperative period. At a 6.5-year followup, no evidence of disease progression was found. In April 2021, a follow-up examination conducted at the Cancer Research Institute revealed a large lesion on the distal part of the pancreatic stump with no clinically significant manifestations. Diagnosis of MPMT was confirmed by transgastric endoscopic ultrasound-guided biopsy. Histological and immunohistochemical examinations revealed undifferentiated ductal carcinoma of the pancreas. Considering the metachronous tumor localization, pancreatic stump extirpation with resection of the posterior wall of the stomach and splenectomy was performed. No complications occurred in the postoperative period. The patient received replacement therapy for exocrine pancreatic insufficiency and individual correction of carbohydrate metabolism. At a 15-month follow-up, liver metastases were detected, and palliative chemotherapy was administered. The patient died 6 months later due to disease progression. The survival time was 99 months after the first surgery and 21 months after the second surgery. Conclusion. We report a rare case of metachronous cancers of the ampulla of Vater and pancreatic stump developed with an interval of 6.5 years. The patient underwent successful curative resections consecutively. The overall survival time from the date of diagnosis was 99 months.

A randomized, multi-center, phase 2 study of ivaltinostat (Ival) plus capecitabine (Cape) versus capecitabine alone in the maintenance setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

TPS4206 Background: Front-line chemotherapy for patients (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/cape in mouse models. RP2D of the Phase 1b combination study of ival and cape in advanced pancreatic cancer was ival 250mg/m2 IV on days 1 and 8 with cape 1000mg/m2 po days 1-14 of a 21-day cycle. Both ival and cape treatment-related AEs &gt;15% were fatigue, nausea, diarrhea, and decreased appetite. Palmar-plantar erythrodysaesthesia syndrome was also commonly observed; all events were attributed to cape. PK and PD demonstrated dose proportionality. Overall and progression-free survival (PFS) were immature, but 70% of pts who enrolled with measurable disease had stable disease as best response. Several pts remained on study with the longest duration of response about 10 months, as of the data cut off for ASCO GI 2024. Based on this data, a randomized phase 2 study is being conducted comparing the combination of ival and cape versus cape alone in the maintenance setting for pts with mPDAC after first line FOLFIRINOX, mFOLFIRINOX or NALFIRINOX therapy. Methods: Key eligibility criteria for the randomized Phase 2 study include: mPDAC; no evidence of disease progression following at least 16 weeks of front-line FOLFIRINOX or NALIRIFOX at full or modified doses; ECOG PS 0-1; and no known germline BRCA1/2 mutation. A total of 52 pts will be randomized 1:1 to receive cape with or without ival until disease progression, with tumor assessments occurring at 6-week intervals. The primary endpoint is investigator-adjudicated PFS, and the primary analysis will compare PFS distributions in the ival/cape and cape alone arms using a one-sided log rank test with an alpha=0.10. The assumed 6-mo PFS rates are 35% (cape), based on historic data, and 60% (ival/cape), corresponding to an HR of 0.487. Enrollment in the phase 2 study began in January 2024 across multiple sites in the US. Accrual is anticipated to complete 4Q2024. Clinical trial information: NCT05249101 .

Phase 2 randomized study of rintatolimod following FOLFIRINOX in patients with locally advanced pancreatic adenocarcinoma.

TPS4214 Background: The immunosuppressive microenvironment of pancreatic ductal adenocarcinoma (PDAC) is a driver of its lethality and resistance to immunotherapy. Strategies which modulate the immunosuppressive milieu have the potential to improve the anti-tumor response and improve outcomes in patients with PDAC. Rintatolimod is a synthetic double-stranded RNA molecule that activates the toll-like receptor 3 (TLR3) present on dendritic cells, B-cells, natural killer cells and pancreatic epithelial cells. TLR3 stimulation may increase cytotoxic T-cell activity in PDAC through dendritic cell maturation, antigen priming and downstream proliferation of cytotoxic T-cells. Twenty-seven patients were treated with rintatolimod in a single center Named Patient Program at Erasmus University Medical Center in Rotterdam between January 2017 and February 2019. All had locally advanced or metastatic PDAC which had not progressed on FOLFIRINOX (median 8 cycles). Maintenance rintatolimod, administered intravenously twice weekly for up to 18 weeks, was generally well tolerated. The most common toxicities were grade 1-2 myalgia (30%), chills (52%) and fatigue (30%); no toxicities ≥ grade 3 were observed. Progression-free and overall survival (from cycle 1 FOLFIRINOX) were 13 and 19 months. Methods: This is a phase 2 randomized, open-label, multicenter clinical trial. The primary objective is to assess the efficacy of rintatolimod compared to observation in subjects with locally advanced PDAC which has not progressed after FOLFIRINOX. Eligible patients have completed at least 4 months of FOLFIRINOX, have no evidence of progressive disease, have measurable disease by RECIST v1.1, Karnofsky Performance Status ≥80 and have adequate organ function. Subjects with resected PDAC or metastatic disease are not eligible. Subjects are randomized 2:1 to rintatolimod vs. observation. Rintatolimod is administered intravenously twice weekly until disease progression in the experimental arm. Cross-sectional imaging is performed every 8 weeks in both arms. The primary endpoint is progression-free survival, as assessed by the investigator. Secondary endpoints include overall survival, objective response rate, duration of response and safety, as assessed by CTCAE v5.0. Exploratory endpoints include quality of life and changes in immune cell composition and T-cell response in the peripheral blood to characterize the immunomodulatory effects of rintatolimod. The planned sample size is 90 subjects. The final analysis will be performed after 64 events (disease progression or death) have been observed. The study is powered to detect a hazard ratio of 0.47 for median PFS with 80% power and significance level of 5%. Clinical trial information: NCT05494697 .

High dose bolus (HDB) interleukin-2 (IL2) and concurrent low dose ipilimumab followed sequentially by nivolumab in patients with advanced melanoma after failure of anti-PD1-based immunotherapy and BRAF-MEK inhibition.

9543 Background: Options are limited for patients with advanced metastatic melanoma who have disease progression following anti-PD1-based immunotherapy and BRAF-MEK inhibition (if BRAF V600 mutant). Evidence supports synergism between IL2 and CTLA4 blockade in enhancing the immunogenicity of the tumor microenvironment and therapeutic susceptibility to PD1 blockade. Methods: We conducted a phase II study of HDB IL2 in combination with LD ipilimumab followed sequentially by nivolumab in patients with advanced inoperable stage III or stage IV melanoma with progression after anti-PD1-based immunotherapy and BRAF-MEK inhibitors. Treatment consisted of up to 3 courses (One cycle is 21 days and one course is 4 cycles). HDB IL2 and concurrent ipilimumab 1 mg/kg were given during week 1 of the initial 2 cycles of each course. Nivolumab was given during week one of the 3rd cycle of each course. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities (CTCAE v.5) were offered additional courses of treatment. A Simon two-stage minimax design (Simon, 1989) was followed. We report the outcomes for Stage I. Results: 12 pts (5 female, 7 male) with metastatic melanoma (2M1a, 1M1b, 6M1c, 3M1d) were treated. Median age 53 years (33 – 69), 11 cutaneous (including 1 acral) and 1 mucosal primary. Tumor mutation status: 4BRAF (V600E), 2NRAS (p.Q61K), 1NF1. The median number of prior regimens for metastatic melanoma was 3 (range 1 - 5). Eight patients previously received ipilimumab as monotherapy or in combination with anti-PD1. On study, the median number of doses of IL2 was 9 during cycle 1 and 7 during cycle 2. A median of 2 doses of ipilimumab and 1 dose of nivolumab were given as part of the combination regimen. Among the 11 evaluable patients (completed 1 course of systemic therapy), the response rate was 2/11 (18.2 %; 95% CI: 2.3% – 51.8%); 1CR, 1 PR, 5 SD, 4 PD and 1 NE as best response. After a median follow up of 39 months, both responses are ongoing (at 10+ and 37+ months), median progression free survival (PFS) was 3 months and median overall survival (OS) was 18.8 months. One-year PFS and OS were 17% (95% CI: 4.7% - 59%) and 83% (95% CI: 65% - 100%), respectively. The adverse event profile was consistent with the expected toxicity profile for each agent with no increase in frequency with the combination. Conclusions: Our combination regimen was relatively safe and well tolerated and demonstrated promising efficacy in a heavily pretreated patient population passing the prespecified efficacy criteria for Simon Stage I. The study has moved into Stage II testing. Clinical trial information: NCT04562129 .

A pilot study of post-consolidation chemoimmunotherapy for high-risk neuroblastoma (ANBL19P1): A report from the Children’s Oncology Group.

10004 Background: Post-consolidation anti-GD2 antibody-based immunotherapy has improved survival for newly diagnosed patients (pts) with high-risk neuroblastoma (HRNBL). However, nearly half of newly diagnosed pts relapse. Based upon the efficacy of anti-GD2 antibody dinutuximab given with chemotherapy (chemoimmunotherapy) in the relapse setting, we hypothesized that post-consolidation chemoimmunotherapy may further improve frontline outcomes. ANBL19P1 first assessed the feasibility of delivering chemoimmunotherapy after tandem high-dose chemotherapy with autologous stem cell transplant (ASCT). Methods: Pts &lt;31 years old with HRNBL who received 4-6 cycles of Induction chemotherapy +/- up to 4 cycles of post-Induction chemotherapy or chemoimmunotherapy, underwent tandem ASCT, had no evidence of progressive disease (PD), and met organ function criteria were eligible. Therapy, administered every 28 days, consisted of temozolomide and irinotecan on Days 1-5, dinutuximab on Days 2-5, and sargramostim on Days 6-12 during Cycles 1-5; isotretinoin on Days 8-21 during Cycles 1-6. Therapy was deemed feasible if the 95% confidence interval (CI) placed on the percentage of pts that completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks contained 75%, and if the interim monitoring rules for feasibility and excessive toxicity were not triggered. Event-free (EFS) and overall survival (OS) were determined from time of enrollment. Results: From 11/30/20-6/30/23, 40 eligible pts enrolled and started protocol therapy. 87.5% (n=35) were ≥18 months old and 97.5% (n=39) had INRG Stage M disease, at diagnosis. 87.5% (95% CI 73.9%, 94.5%) completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks, exceeding the feasibility benchmark of 75%. Feasibility and monitoring rules were not triggered. Five pts were removed from protocol therapy prior to Cycle 4 [physician determination (n=2), pt/parent refusal of further therapy (n=2), and PD (n=1)]. No unacceptable toxicities or deaths on protocol therapy were reported. Toxicities of interest are summarized (Table). One-year EFS and OS were 90.0±5.0% and 97.5±2.7%, respectively (median follow-up time for pts without event=1.2 years). Conclusions: Administration of post-consolidation chemoimmunotherapy in pts who underwent tandem ASCT is tolerable and met pre-defined feasibility criteria. The impact of this approach on survival outcomes will be studied in a future COG trial. Clinical trial information: NCT04385277 . [Table: see text]

Novel RNA-nanoparticle vaccine for the treatment of early melanoma recurrence following adjuvant anti-PD-1 antibody therapy.

TPS9609 Background: Melanoma is a major public health concern with an anticipated increase in prevalence and incidence in the coming years. Early detection and surgical management remain the mainstay of treatment of early-stage disease and use of adjuvant immunotherapy has improved outcomes for patients with more aggressive (IIB-IIC) local disease or those with lymph node involvement (IIIA-IIID). Based on the tolerability and efficacy across subjects with both BRAF mutated and wildtype melanoma anti-PD1 (aPD1) therapy with either nivolumab or pembrolizumab are considered first line treatment in this setting. Adjuvant aPD1 therapy has significant improvement in relapse free survival (RFS) yet 25-30% of subjects will have disease recurrence within 1 year of surgery. When disease recurs, the response rate to immunotherapy is significantly reduced, re-challenged with aPD1 therapy has shown an Objective Response Rate (ORR) of zero and a marginally better response to CTLA-4 blockade. Novel strategies are needed for this at-risk population with early aPD1 resistance. To address this need we have developed a novel multi-lamellar lipid-nanoparticle complexed with total-tumor derived mRNA administered intravenously to restore responsiveness to aPD1 through reprogramming the tumor microenvironment (TME) bridging an innate and adaptive immune response. We have designed a clinical trial in which patients who progress on while on aPD1 therapy or within 6 months of therapy will have tumor sampled and a personalized lipid-nanoparticle vaccine generated. This vaccine is then administered IV for a total of 3 doses spanning 6 weeks to reprogram the TME and restore response to aPD1 which will be resumed on completion of vaccine series. This phase I study will assess initial feasibility and safety of vaccine generation, utilize ctDNA surveillance as early detection of adjuvant failure, and provide essential biologic information on immunotherapy resistance to aPD1 therapy. Methods: We have designed a modified 3+3 phase I clinical trial that will enroll subjects who have evidence of progressive disease (PD) by ctDNA and/or RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or those who progress within 6 months of completion of treatment for stage IIB-IIID melanoma. The goal of this study is to assess safety, tolerability, and feasibility of tumor specific RNA-LPs. Important biological correlates will also be collected and analyzed including tumor tissue sampling at initial time of checkpoint resistance and following vaccination series to identify key changes to the TME and tumor induced by lipid-nanoparticle vaccine administration. Clinical trial information: NCT05264974 .

A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.

e15077 Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m2) plus LV (400 mg/m2f) and 5-FU (2400 mg/m2) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.

Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32.

TPS7576 Background: Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit. Methods: MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator’s choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]). Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti–CD38 antibody–containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd. The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575 .

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P&amp;lt; 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P&amp;lt; 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [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 PO4-17-02.

Abstract PO1-19-09: Integrating gene signatures to guide HR+ MBC therapy in a diverse cohort (INSIGHT)

Abstract Background: Black women with breast cancer (BC) have a 40% higher mortality rate compared to Non-Hispanic White (NHW) women. Among women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) BC, Black women have worse outcomes than NHW despite comparable systemic therapies. Gene expression profiling assays have been used in early-stage BC to provide prognostic and sometimes predictive information beyond standard immunohistochemical classifications. The 80-gene molecular subtype signature (BluePrint) with the 70-gene risk of distant recurrence signature (MammaPrint®) (Agendia, Irvine, CA) further classify HR+/HER2- BC into luminal A-type, luminal B-type, HER2-type, and basal-type tumors. Luminal B, HER2, and basal-type tumors (non-luminal A) are more aggressive with worse survival outcomes and are overrepresented among Black women. In the metastatic setting, the role of molecular subtype signatures in guiding therapeutic decisions has not yet been determined. We hypothesize that patients with metastatic HR+/HER2- non-luminal A-type BC post-progression on endocrine therapy +/- CKD4/6 inhibition will derive more benefit from chemotherapy than standard-of-care endocrine therapy in the second line setting. We also hypothesize that the impact of the intervention will be more pronounced in Black women compared to NHW women. Methods: This is a randomized phase II study that will evaluate the anti-tumor effect of capecitabine compared to physician’s choice endocrine therapy as second line therapy for adult ( &amp;gt;18 years) patients with non-Luminal A HR+/HER2- metastatic or unresectable locoregional invasive carcinoma (NCT 05693766). The study plans to enroll up to 62 patients. This trial enriches for racial/ethnic minority patients through collaborations with the University of Texas Southwestern and the University of Alabama at Birmingham, two health systems that serve a large minority population. Eligible patients who have received prior endocrine therapy with a CDK4/6 inhibitor will have their tumor tissue analyzed using the MammaPrint® and BluePrint assays. Patients with Luminal A tumors will receive standard of care and will be followed for survival only. Patients with non-Luminal A tumors will be randomized (1:1) to receive physician’s choice endocrine therapy versus capecitabine (dosed at 2000mg twice daily for 7 days on, 7 days off) with stratifications by molecular subtype and race. Patients will be evaluated for response every three cycles using the Response Evaluation Criteria in Solid Tumors. Therapy will be continued until evidence of disease progression or unacceptable major toxicity. The primary endpoint is progression free survival; secondary endpoints are overall response rate, clinical benefit rate, overall survival, and patient reported outcomes. The study will have 80% power to detect a minimal hazard ratio of 0.5 at one-sided significance level of 0.05. Cell-free DNA will be collected at baseline and at three times post-baseline to investigate potential genetic markers of disease response and resistance. Enrollment opened on June 1, 2023. We anticipate opening the trial at the external sites before the end of 2023. Citation Format: Moriah Forster, Jennifer Whisenant, Ben Park, Erica Stringer-Reasor, William Audeh, Andrea Menicucci, Fei Ye, Heather McArthur, Sonya Reid. Integrating gene signatures to guide HR+ MBC therapy in a diverse cohort (INSIGHT) [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 PO1-19-09.

Abstract PO2-20-01: The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062)

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [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 PO2-20-01.

Abstract PO2-04-01: Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer

Abstract Background HER2-targeted therapies have transformed the trajectory of HER2-positive (HER2+) metastatic breast cancer (MBC), with a subgroup of responders remaining on first line (1L) therapy for many years (yrs). Despite these promising outcomes, the paradigm remains palliative, with some patients (pts) receiving therapy indefinitely. Opportunities to interrupt therapy are controversial and anecdotal in the setting of a limited understanding of long-term responders and lack of predictive biomarkers. Methods We identified prevalent pts with HER2+ MBC seen and consented at Dana-Farber Cancer Institute between 2010 and 2023, regardless of the original date of MBC diagnosis. Exceptional responders (ExRes) were pts without evidence of progressive disease (PD) 3 yrs from initiation of 1L therapy for MBC. Conventional responders (ConRes) were pts who experienced PD within 3 yrs of 1L treatment initiation. We compared clinicopathological characteristics and treatment patterns between ExRes and ConRes using Chi-square or Wilcoxon test. We analyzed median time to treatment switch due to PD (TTS-PD) – i.e., time from metastatic diagnosis to 1L treatment end due to PD - and overall survival, via the Kaplan-Meier method and with a landmark analysis at year 3 (Y3). Our primary aim was to identify predictors of exceptional response to 1L anti-HER2 therapy. Results Of 635 pts with HER2+ MBC, we identified 147 ExRes and 370 ConRes and excluded 118 pts due to follow up ≤ 3 yrs and no PD events. Median follow up was 7.1 yrs (IQR 5.5-11.0) for ExRes and 7.1 yrs (IQR 4.0-11.4) for ConRes. Median age at MBC diagnosis was 50.7 yrs (range 21.9-91.9) for ExRes and 49.8 yrs (26.9-82.3) for ConRes. ExRes presented more often with de novo MBC than ConRes (52.1 vs 30.6%, p&amp;lt; 0.0001). On metastatic samples, more ExRes than ConRes had HER2 3+ tumors by immunohistochemistry (IHC) (93.7 vs 81.0%, p=0.002), whereas the proportion of ER-positive disease was similar between the two groups (45.6 vs 53.4%, p=0.1). Most pts received (neo)adjuvant anti-HER2 agents in both groups (62.5 vs 72.7%, p=0.1). More ExRes than ConRes (55.8 vs 42.7% p=0.007) received 1L chemotherapy (CT) plus trastuzumab (H)/pertuzumab (P). Alternative 1L treatments were CT plus H (26.5 vs 25.7%), H +/- P +/- endocrine therapy (8.2 vs 10.5%), T-DM1 (2 vs 9.2%), tyrosine kinase inhibitors-based regimens (7.5 vs 10.8%). For pts with recurrent MBC, disease-free interval was longer for ExRes than ConRes (median 4.7 vs 3.4 yrs, p=0.01). Visceral involvement at MBC relapse was similar for ExRes and ConRes (78.2 vs 77.8%, p=0.9). Brain metastases at any timepoint were less frequent among ExRes than ConRes (42.9 vs 55.1%, p=0.01). Among ExRes, 70 (47.6%) pts experienced PD after Y3, with a median TTS-PD of 4.6 (4.1-5.1) yrs. In a landmark analysis at Y3, the 2-year TTS-PD was 68.5% (95% CI: 59.8%-75.7%) (5 yrs from treatment start), and 4-year overall survival was 86.5% (95% CI: 78.1%-91.9%) (7 yrs from treatment start). ConRes received a median of 5 (1-19) treatment regimens for MBC, with a median 1L TTS-PD of 12 (10.8-13) mo. A total of 89 (60.5%) ExRes and 214 (57.8%) ConRes underwent tumor sequencing. Data comparing genomic features between ExRes and ConRes will be presented. Conclusions In this prospective cohort, 28% of pts with HER2+ MBC had exceptional response to 1L anti-HER2 therapy. Consistent with prior data, ExRes present more frequently with de novo disease and HER2 IHC 3+ tumors. In our cohort, ExRes had a median follow-up of 7.1 years and 52.4% never experienced PD. Although a significant proportion of pts with HER2+ MBC derive long-term benefit from anti-HER2 therapy, the treatment paradigm remains palliative, and it is unknown whether biomarkers may reliably predict exceptional response and guide future treatment. Ongoing work will explore whether genomic features vary between ExRes and ConRes. Citation Format: Stefania Morganti, Tianyu Li, Katheryn Santos, Melissa Hughes, Nolan Priedigkeit, Yvonne Li, Marla Lipsyc-Sharf, Gregory Kirkner, Janet Files, Julie Kasparian, Elizabeth Grant, Gunjan Gupta, Giuseppe Curigliano, Sara Tolaney, Andrew Cherniack, Nabihah Tayob, Nancy Lin, Heather Parsons. Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer [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 PO2-04-01.

When less is more: Updates in active surveillance and watchful waiting in the management of prostate cancer.

Prostate cancer is the second most common cancer among men globally. A range of management options are available for prostate cancer, including surgery, radiation therapy, hormone therapy, chemotherapy, or surveillance. Conservative strategies include active surveillance and watchful waiting, which differ in their intent. We provide a targeted instructive management algorithm for improving understanding of conservative strategies inprostate cancer. Active surveillance involves close monitoring with curative intent when there is evidence of disease progression. Incontrast, watchful waiting is palliative in intent and focuses on delaying treatment until symptoms or complications develop. Conservative approaches have demonstrated similar long-term oncological outcomes toradical treatment, while reducing harm from overtreatment, and maintaining quality of life by avoiding potential side effects such as urinary incontinence and erectile dysfunction. The decision to employ a conservative approach is determined by both patient and disease factors. Conservative management strategies play a vital role in the management of prostate cancer.