Radiographic Progression Research Articles

Incidence and Progression of Foot Osteoarthritis in a Longitudinal Cohort: The Johnston County Osteoarthritis Project

Introduction: The aim of this study was to examine the incidence and progression of foot osteoarthritis (OA), as well as associated factors, in a community-based cohort. Methods: Baseline (2013–2015) and follow-up (2016–2018) foot radiographs were available for 541 participants (71% women, mean age 69 years; 35% black, 53% with obesity). The LaTrobe Foot Atlas was used to examine osteophytes (OPs, score 0–3) and joint space narrowing (JSN, score 0–3) at 5 joint sites. Incident foot radiographic OA (rOA) was a baseline score <2 OP and JSN in all 5 joints with ≥2 OP or JSN at follow-up in any of the joints. Progression was a worsening OP or JSN score in a joint with baseline foot rOA. At baseline and follow-up, participants reported the presence/absence of foot symptoms and completed the Foot and Ankle Outcome Score (FAOS) for each foot. Joint-based logistic regression models with generalized estimating equations were used to examine associations (adjusted odds ratio [aOR], 95% confidence interval [CI]) of foot rOA incidence and progression and with covariates. Results: Among 928 feet without baseline rOA, 4% developed incident foot rOA (2% of those developed symptoms). Among 154 feet with baseline foot rOA, 55% had radiographic progression (16% of those had symptoms). Women and those with higher body mass index (BMI) were more likely to have incident foot rOA (aOR [95% CI] = 4.10 [1.22, 13.8] and 1.60 [1.31, 1.97], respectively); history of gout was associated with incidence or progression of foot rOA (2.75 [1.24, 6.07]). BMI was associated with worse scores on all FAOS subscales (aORs range 1.21–1.40). Conclusion: Progression of foot rOA is common but not necessarily related to worsening symptoms. BMI may be a modifiable risk factor for foot OA.

GCT-24. ISOLATED PITUITARY STALK THICKENING

Abstract BACKGROUND Few studies have examined predictive factors and outcome of isolated pituitary stalk thickening (iPST) in children. We aim to describe our institutional cohort to determine predictors of future proliferative disease. METHODS A search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with iPST diagnosed between January 2000 and June 2019. Clinical data was collected along with detailed radiology review of MRIs in a blinded fashion. RESULTS Forty-seven patients were identified, with 40 meeting criteria for inclusion. Median age of baseline MRI was 9.6 years (range 0.9-17.5). Twenty-five (63%) were female. Median follow up time was 5.2 years (range 0.3-18.6). Indication for MRI was symptoms of diabetes insipidus (DI) in 29 patients followed by concerns for anterior endocrine disturbance (6), headache (1) or visual impairment (1). Thirty-four (85%) subjects had pituitary dysfunction, including 31 with DI however DI was not predictive of future development of proliferative disease (69% with presumed hypophysitis vs 93% with proliferative disease, p=0.12). Fourteen (35%) patients developed proliferative disease, with germinoma (8), Langerhans cell histiocytosis (5) and lymphoma (1) at median of 1.3 years (range 0.3-4.0), 2.2 years (range 0.3-9.4) and 1.1 years after initial MRI respectively. Lumbar puncture was performed in 24 patients with elevated white blood cell count (&amp;gt;5 x 106/L) found in 6 (75%) patients with germinoma, 1 (100%) patient with lymphoma, 0 patients with LCH and 3 of 11 (27%) patients with presumed hypophysitis (p=0.015). Thickening of the entire stalk at time of diagnosis and radiographic progression were more likely to be seen in those that developed proliferative disease. CONCLUSION In this cohort 35% of children with PST were eventually diagnosed with a proliferative disease. Importantly, central DI was not associated with risk of proliferative disease. Several radiographic features and elevated CSF WBC were predictive of this outcome.

GCT-25. THE IMPACT OF RESIDUAL DISEASE ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMAS – A MULTICENTER INSTITUTION EXPERIENCE

Abstract BACKGROUND Germinomas make up about two-thirds of central nervous system (CNS) germ cell tumors and are highly radio-sensitive with excellent survival rate of more than 90%. Current standard of care involves the combination of chemotherapy with reduced-dose radiotherapy. Typically, patients with residual disease receive a higher dose of radiotherapy. However, recent clinical trials showed that there were no differences in the outcomes between those who had complete response (CR) versus partial response (PR) to initial chemotherapy. Hence, we aimed to assess the outcomes of germinoma patients based on the responses to both chemotherapy and radiotherapy. METHODS A multicenter retrospective chart review of patients with germinoma from four large academic institutions was conducted. RESULTS Data from 41 germinoma patients treated between 2011 and 2022 were analyzed. Thirty-two patients had stable disease (SD)(2), PR(28), or CR(2) to chemotherapy. At the end of radiotherapy, 12 had CR, 5 had PR, and 13 had SD. All patients were alive at the time of review, with a median duration of survival from diagnosis of 78.85 months (range 3.90-278.67). One patient experienced radiographic progression following chemotherapy with SD noted following radiotherapy. CONCLUSION Relapses are extremely rare in patients who have residual disease at the end of therapy for germinoma. Future prospective clinical trials are needed to test the possibility of treating germinoma patients who have residual disease with a dose of radiotherapy comparable to that used in patients who achieve complete response.

Assessment of serum tumor markers CEA, CA-125, and CA19-9 as adjuncts in non-small cell lung cancer management.

Conventional tumor markers may serve as adjuncts in non-small cell lung cancer (NSCLC) management. This study analyzed whether three tumor markers (CEA, CA19-9, and CA-125) held associations with radiographic and clinical outcomes in NSCLC. It constituted a single-center study of NSCLC patients treated with systemic therapy at the London Regional Cancer Program. Serum tumor markers were analyzed for differences in radiographic responses (RECIST v1.1 or iRECIST), associations with clinical characteristics, and all-cause mortality. A total of 533 NSCLC patients were screened, of which 165 met inclusion criteria. A subset of 92 patients had paired tumor markers and radiographic scans. From the latter population, median (IQR) fold-change from nadir to progression was 2.13 (IQR 1.24-3.02; p < 0.001) for CEA, 1.46 (IQR 1.13-2.18; p < 0.001) for CA19-9, and 1.53 (IQR 0.96-2.12; p < 0.001) for CA-125. Median (IQR) fold-change from baseline to radiographic response was 0.50 (IQR 0.27, 0.95; p < 0.001) for CEA, 1.08 (IQR 0.74, 1.61; p = 0.99) for CA19-9, and 0.47 (IQR 0.18, 1.26; p = 0.008) for CA-125. In conclusion, tumor markers are positioned to be used as adjunct tools in clinical decision making, especially for their associations with radiographic response (CEA/CA-125) or progression (CEA/CA-125/CA-19-9).

Ultrasonographic Synovitis Is Associated with the Development of Joint Destruction in Patients with Psoriatic Arthritis.

Psoriatic arthritis (PsA) is characterized by enthesitis. As persistent inflammation around joints results in bone and cartilage destruction and physical impairment, a detailed assessment of inflammation is essential. We previously reported the difference between clinical assessment (tenderness) and ultrasound (US) assessment (inflammation) of entheses. Herein, we investigated whether clinical or US assessment of joints and entheses can predict the progression of joint destruction in Japanese patients with PsA. Thirty joints and 14 entheses in 47 patients were assessed using US and clinical examination. The US greyscale (GS) and power Doppler (PD) scores at the ultrasonographic synovitis, the US active enthesitis count, and the clinical tender joint/entheses count were assessed. Additionally, the yearly radiographic progression of the Sharp-van der Heijde scoring method for PsA was assessed. Their correlations were investigated. About half of the patients with PsA experienced joint destruction during a follow-up period of 20.4 months. Progression of joint destruction in patients with PsA only correlated with joint GS and PD scores, reflecting the severity of ultrasonographic synovitis, not with the tender joint/entheses count. US examinations are essential for preventing joint destruction and physical impairment in patients with PsA.

Effect of using the Simple Erosion Narrowing Score or Sharp/van der Heijde score on power of rheumatoid arthritis clinical trials to detect differences in radiographic progression.

The Simple Erosion Narrowing Score (SENS) is a simplification of the Sharp/van der Heijde score (SHS). Previous studies found SENS and SHS to have very similar measurement properties, but suggest that SENS has a lower discriminative ability that may result in reduced power. Therefore, we aimed to quantify the effect of using SENS rather than SHS on the power to show between-group differences in radiographic progression. Using data from two clinical trials in rheumatoid arthritis (DRESS and BeSt), SENS was derived from the SHS. Criterion validity of the SENS in relation to the SHS was assessed by calculating the Spearman correlation. The power of both scores to show a difference between groups was compared using bootstrapping to generate 10.000 replications of each study. Then, the number of replications with a significant difference in progression (using ANCOVA adjusted for baseline scores) were compared. Correlations between SENS and SHS were all >0.9, indicating high criterion validity of SENS compared with SHS as a reference standard. There was one exception, the DRESS study showed a somewhat lower correlation for the change score at 18 months (0.787). The loss in power of SENS over SHS was limited to at most 19% (BeSt year 5). In addition, the difference in power between SENS and SHS is smaller at higher levels of power. SENS appears to be a reasonable alternative to SHS, with only a limited loss of power to show between-group differences in radiographic progression.

Comparison of the Efficacy of Different Combined Therapies Based on Modified Core Decompression for the Treatment of Early-stage Nontraumatic Osteonecrosis of the Femoral Head: A Retrospective Clinical Study.

Osteonecrosis of the femoral head (ONFH) is a severe orthopedic disease, which may cause severe hip dysfunction in later stage. Therefore, it is necessary to treat nontraumatic ONFH during the early stages. The aim of this study was to evaluate the clinical efficacy and survival rates of different combined therapies based on modified core decompression (CD) for early-stage nontraumatic ONFH. This retrospective cohort study assessed 397 hips with ONFH who underwent different combined therapies based on modified CD in our institution between January 2010 and December 2017. Patients were classified into six groups based on treatment modalities, and were followed up at 1 year and 5 years postoperatively. Clinical outcomes, including Harris hip score (HHS) and Western Ontario and McMaster Universities osteoarthritis index (WOMAC), were compared to evaluate the hip function and quick rehabilitation effect. Radiographic progression of ONFH and the incidence of total hip arthroplasty were analyzed to evaluate the survival rate of ONFH postoperatively. Statistical analyses were mainly performed with Kruskal-Wallis test, chi-square test and Kaplan-Meier method. HHS increased significantly in all groups but showed no significant differences among the six groups in the first years. The nonvascularized allogeneic fibula with bone grafting (NVAF + BG) and percutaneous femoral neck-head fenestration with bone grafting via the direct anterior approach (DAA + BG) groups had significantly higher HHS (p = 0.010; p = 0.025) and WOMAC function score (p < 0.001; p = 0.012) than the CD group 5 years postoperatively. Compared with the CD group, all the other groups showed statistically significant differences in radiographic progression (p < 0.001) and a higher survival rate with no significant difference (p = 0.569). Our study demonstrates the potential use of NVAF + BG and DAA + BG, may serve as a promising combined therapy for the treatment of early-stage nontraumatic ONFH.

Prostate-specific membrane antigen PET/CT-guided, metastasis-directed radiotherapy for oligometastatic castration-resistant prostate cancer.

e17057 Background: Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPIs), chemotherapy, and radiopharmaceutical therapy, all of which have associated toxicity. We hypothesized that prostate-specific membrane antigen (PSMA) PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastatic sites. Methods: We retrospectively screened 7 prospective databases of PSMA PET/CT scans conducted between 1/2016-2/2023 for patients with mCRPC who had ≤5 sites of oligorecurrent or oligoprogressive disease and received metastasis-directed radiotherapy to all sites of disease. Castration resistance was defined as either radiographic progression or biochemical progression (two consecutive prostate-specific antigen [PSA] increases ≥3 weeks apart) while on ADT with serum testosterone &lt;50 ng/dL. Progression-free survival (PFS), freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Progression was defined as the first instance of biochemical progression (PSA increase of 25% and 2 ng/mL above nadir, confirmed by repeat measurement ≥3 weeks later), radiographic progression, biopsy-proven recurrence, new systemic or local therapy, or death. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 5. Results: Twenty-six patients met inclusion criteria with a median follow-up of 34.6 months (interquartile range, 28.1-47.2 months). All patients previously received ADT, 20 (77%) received ARPIs, and 3 (12%) had prior chemotherapy. Median PSA was 1.2 ng/mL, median time from initial diagnosis was 6.2 years, and median time from castration resistance was 1.8 years. Between 10/2017-4/2023, 12 patients (46.2%) had one treated metastatic site, 11 patients (42.3%) had two, and 3 patients (11.5%) had three. Twenty-four patients (92.3%) received concurrent systemic therapy. Median PFS was 16.4 months (95% confidence interval [CI], 11.4-21.4 months). Four-year PFS was 26.7% (95% CI, 8.9-44.5%). Median time to initiation of a new line of systemic therapy was 18.0 months (95% CI, 0-36.2 months). Four-year freedom from new lines of systemic therapy was 36.1% (95% CI, 15.5-56.7%). Median OS was not reached. Four-year OS was 72.5% (95% CI, 51.1-93.9%). Grade 2 and ≥3 toxicity rates were 3.8% and 0%, respectively. Conclusions: For patients with oligometastatic CRPC, PSMA PET/CT-guided metastasis-directed radiotherapy appears to offer durable disease control with low toxicity. Further prospective studies are needed to compare PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

Glioma monitoring via longitudinal intracranial cerebrospinal fluid cell-free DNA.

2053 Background: Current methods for glioma treatment response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using intracranial CSF from patients with gliomas during their disease course. Methods: Adults with gliomas were recruited for longitudinal intracranial CSF collection using 1) Ommaya reservoirs, from which CSF would be sampled on at least two separate occasions, or 2) CSF collection from other clinically indicated CSF access devices, such as ventriculoperitoneal (VP) shunts. Patients were followed until their last visit or present time for ongoing participants. For this initial cfDNA feasibility study, CSF was collected from Ommaya reservoirs in four patients and from an existing VP shunt in one patient. cfDNA was then extracted and analyzed using two sequencing platforms, PredicineCARE for cancer variant profiling and PredicineSCORE for low-pass whole genome sequencing (LP-WGS). This analysis generated genomic aberration profiles and genome-wide copy number burden (CNB) score. Results: Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, thirty-five CSF samples were obtained (median volume: 3.80 mL; 0.5-5 mL), with 30 samples (85.7%) yielding sufficient cfDNA for variant profiling and LP-WGS. Our initial findings suggest that tumor fraction increased by 6.28x and 2.87x with radiographic progression in two patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased in the patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. Conclusions: Longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course. Ongoing studies will evaluate hypotheses generated in this case series regarding how longitudinal CSF cfDNA could be utilized to sensitively detect changes in disease burden. Clinical trial information: NCT04692337 ; NCT04692324 .

Prognostic value of circulating tumor DNA testing in surgically resected pancreatic cancer.

4134 Background: The majority of patients with pancreatic cancer who undergo curative intent resection have recurrence, but optimal surveillance is unknown. Circulating tumor DNA (ctDNA) tests, custom-designed multiplex-PCR tumor assays unique to each patient’s tumor, may assist in monitoring for recurrence. Methods: We performed a single center retrospective review of patients with surgically resected pancreatic cancer who had at least 1 ctDNA test performed post-operatively between 8/1/21 and 11/13/23 with Natera Inc.’s Signatera assay. Primary outcomes were documented radiographic progression and death. Results: 74 patients were identified, of whom 36 were positive for ctDNA at any point during the study (median follow up from surgery 19.1 months) while 38 remained negative for ctDNA (15.3 months). There was no difference in age (≥ or &lt; 70), sex, or race. Positive ctDNA at any time point was associated with advanced stage disease (p=0.013), positive resection margins (p=0.008), and having received neoadjuvant therapy (p=0.005). Those with any positive ctDNA were more likely to have radiographic progression (p&lt;0.0001) or death (p=0.0005) by the end of the study. These differences remained when the population was examined in subgroups of first post-operative ctDNA positive, first ctDNA negative but at least one subsequent ctDNA positive, and all ctDNA negative. In Cox proportional hazard models, both any positive ctDNA test and positive first ctDNA test (first ctDNA limited to ≤120 days post-op) were associated with higher risk of radiographic progression and/or death compared to never testing positive for ctDNA and negative first ctDNA test, respectively (HR 12.6 (3.0-51.9), p=0.0005; HR 5.6 (1.4-22.8), p=0.02). Conclusions: Positive ctDNA tests, both in the immediate post-operative and subsequent settings, are associated with higher risk of radiographic progression or death in patients with resected pancreatic cancer. These data suggest that ctDNA testing provides independent, meaningful prognostic information superior to traditional pathologic risk factors and CA19-9 testing alone. These findings have implications for future clinical study design and decisions about surveillance and treatment. [Table: see text]

Final results of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC (MOUNTAINEER).

3509 Background: HER2 overexpression/amplification (HER2+) occurs in ~3%-5% of pts with metastatic colorectal cancer (mCRC) and up to ~10% of pts with RAS/BRAF wild-type (WT) mCRC. The primary results of the MOUNTAINEER study (NCT03043313) demonstrated that the combination of tucatinib (TUC), a highly selective HER2-directed TKI, and trastuzumab (Tras) was well tolerated with clinically meaningful activity in pts with chemo-refractory HER2+ mCRC. Confirmed ORR was 38.1%, median DOR was 12.4 months, and median OS was 24.1 months. Here, we present results from the final analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomized, phase 2 trial. Eligible pts had HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy. Previous HER2-directed therapies were not permitted. The trial consisted of Cohort A, comprising pts treated with TUC (300 mg PO BID) + Tras (8 mg/kg IV then 6 mg/kg IV Q3W), as well as pts randomized 4:3 to receive TUC+Tras (Cohort B) or TUC monotherapy (Cohort C). Pts randomized to Cohort C were allowed to crossover and receive TUC+Tras on radiographic progression or if they did not achieve a complete or partial response by Week 12. Study endpoints evaluated at final analysis include DOR per BICR, PFS per BICR, OS, and safety. Results: The median duration of follow-up was 32.4 months (IQR, 25.1-46.7), with an additional 16.1 months of follow-up since the primary analysis (data cutoff, 02-Nov-2023). A total of 116 pts received at least 1 dose of study treatment (Cohorts A+B, N = 86; Cohort C, N = 30). In Cohorts A+B, median DOR per BICR was 15.2 months (95% CI, 8.9-20.5), median PFS per BICR was 8.1 months (95% CI, 4.2-10.2), and median OS was 23.9 months (95% CI, 18.7-28.3). In Cohort C post-crossover (N = 28), median DOR was not reached (95% CI, 2.8 months-NE). Median OS in Cohort C was 21.1 months (95% CI, 17.0-NE). The most common TEAEs in Cohorts A+B were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). The majority of TEAEs were low grade, and rates were stable with longer follow-up. The most common grade ≥3 TEAE was hypertension (7.0%). TEAEs leading to TUC discontinuation in Cohorts A+B occurred in 5.8% of pts, which was unchanged from the primary analysis. In Cohort C, the most common TEAEs post-crossover were diarrhea (39.3%), back pain (21.4%), and pyrexia (21.4%); the most common grade ≥3 TEAE was AST increase (10.7%). No deaths resulted from TEAEs in any cohort and no new safety signals were identified. Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating clinically meaningful activity of the combination on longer follow-up. TUC+Tras is an important chemotherapy-free treatment option in HER2+ mCRC. TUC+Tras is being further evaluated in the first-line setting in combination with chemotherapy in the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) for pts with HER2+ mCRC. Clinical trial information: NCT03043313 .

Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with advanced germ cell tumors.

e17022 Background: Germ cell malignancies, commonly manifesting as testicular cancer, is one of the most common malignancies in men 15 to 45 years of age, with the incidence doubling over the past 40 years. When identified promptly and treated with a multidisciplinary approach, germ cell tumors have an excellent prognosis with cure rate &gt;90% and 5-year survival rate &gt;95%. Treatment involves radical orchiectomy for diagnostic and therapeutic purposes. Further management includes active surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection (RLND), and radiation therapy. While AFP, B-HCG, and LDH are good biomarkers, they are not sensitive or specific for detecting molecular residual disease (MRD). B-HCG is detected in &lt;30% of individuals with seminoma and B-HCG and AFP are detected in 50–60% of patients with non-seminomatous tumors. We describe the use of circulating tumor DNA (ctDNA) for detection of MRD in advanced germ cell malignancy, especially when baseline biomarkers are negative. Methods: This is a retrospective analysis of 20 patients with testicular cancer treated at Rush University Medical Center who monitored closely for MRD. Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at MRD (1-12 weeks post-orchiectomy) and regular intervals thereafter, regardless of treatment modality. Event free survival (EFS) was determined, defined as the period from radical orchiectomy to date of radiographic progression of disease. Results: There was a total of 20 patients (35% seminoma, 65% non-seminoma) with 2 of the patients having extragonadal disease. The mean age was 32.2 years old with IQR (28-36). Post operatively, 20% underwent RLND, 10% were on surveillance, 53% received post-orchiectomy chemotherapy, 6.7% of patients underwent autologous stem cell transplant. The median follow up time is 1.14 years. Two patients had positive ctDNA despite negative baseline traditional biomarkers. There were 23.3% (7/30) of patients that had evidence of radiographic progression. Of the patients with progression, serial ctDNA monitoring had high rates of concordance (85%, 6/7) of ctDNA positivity with biomarker positivity and radiographic progression. Conclusions: Overall, ctDNA correlated with, and sometimes even preceded, traditional biomarkers and radiographic findings of disease progression. The ctDNA positivity of 2 patients in this cohort despite negative baseline AFP, B-HCG, and LDH, highlights the sensitivity and specificity of ctDNA for MRD compared to more traditional biomarkers. Serial monitoring of ctDNA offers valuable insights into germ cell tumor disease status, including presence of MRD, and there is a need for prospective studies to guide treatment escalation and de-escalation in germ cell tumors.

Evaluating metrics of circulating tumor DNA response and progression using a high sensitivity tumor-agnostic assay in metastatic HR+/HER2- breast cancer receiving endocrine therapy and a CDK4/6-inhibitor.

1043 Background: CDK4/6-inhibitors (-i) and endocrine therapy (ET) are first-line treatment for HR+/HER2- metastatic breast cancer (mBC). Clinical evaluation and cross-sectional imaging are used for treatment response assessment. The relationship between clinical/radiographic response and ctDNA dynamics using a high sensitivity tumor-agnostic assay is unknown in HR+/HER2- mBC. ctDNA monitoring in mBC may support clinical decision-making, enable new strategies for response assessment in clinical trials, and facilitate enrolment of patients lacking measurable disease (bone-only). Methods: Patients (pts) with HR+/HER2- mBC receiving ET and CDK4/6i were enrolled in a prospective cohort study. Plasma samples were collected at baseline (BL) and regularly on-treatment. Samples were analyzed using Guardant Infinity, a tumor-agnostic genomic and epigenomic platform. ctDNA-response (-R) was defined as a ≥50% decrease (dec) in methylation tumor fraction (mTF) from BL. ctDNA-progression (-P) was defined as a &lt;50% dec in mTF from BL or any subsequent increase in mTF above an absolute mTF of 0.001% (cohort specific definition). Imaging outcomes and dates of treatment discontinuation (TD) were collected. Results: 57 pts with 350 clinical timepoints were evaluated. Median follow up was 28.2m (range: 1.6-66.0m). 42/57 (74%) pts received palbociclib and 40/57 (70%) received an aromatase inhibitor. ctDNA-R/-P was evaluable in 49/57 patients. ctDNA-P identified within the first 90d on CDK4/6i was not prognostic of TD (p=0.7972); when assessed between 90-180d it was prognostic of early TD (med: 6.3m vs. not reached; HR: 5.17, 95%CI: 1.04-25.7; p=0.0003). 156 matched radiographic and ctDNA assessments (blood collected within 30d of CT) were evaluable for ctDNA-R/-P and imaging concordance. Excluding those with clinician-identified sclerotic bone changes suggestive of treatment effect (n=5 events), adjudicated radiographic progression did not occur in the setting of ctDNA-R (NPV: 100%, sensitivity: 100%); no pts had clinical progression in the presence of ctDNA-R. ctDNA rise in the absence of radiographic progression occurred in 13 pts; 7/13 had TD (med: 10.1m, range: 3.0-21.9m) in the follow up period reflecting a molecular lead time. Blood first monitoring, using these metrics, could have avoided 104/150 (69%) staging CT scans in this cohort. Conclusions: ctDNA dynamics are associated with clinical outcomes in HR+/HER2- mBC. The use of a high sensitivity assay permits assessment of response in nearly all patients and suggests the possibility that radiographic surveillance could be reduced in patients with ctDNA-R. Prospective validation of these findings are required. Additional ctDNA-R/-P definitions and relationship with RECIST 1.1 criteria will be presented at the meeting.

CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer.

5001 Background: Oncogenic addiction to androgen receptor (AR) signaling drives mCRPC progression, highlighting the unmet need for novel treatment strategies to maximize AR-directed therapy. Preclinical evidence suggests a key role for CDK4/6 in sustained AR signaling, uncontrolled proliferation, and hormonal resistance in prostate cancer. Abemaciclib (ABEMA) is a potent CDK4/6 oral inhibitor that significantly augments the efficacy of endocrine therapy in hormonally driven (ER+) high-risk early-stage and metastatic breast cancer. ABEMA also showed single-agent activity in heavily pretreated mCRPC. Here, we report the primary results of CYCLONE 2, a Phase 3 study of ABEMA plus abiraterone (ABI) in pts with 1L mCRPC. Methods: CYCLONE 2 was a seamless Phase 2/3 adaptive trial with a dose-finding safety lead-in. Randomization to the ABEMA or placebo (PBO) plus ABI and predniso(lo)ne was stratified by prior docetaxel receipt for mHSPC, measurable disease, and radiographic progression at study entry. Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. The study was powered at ~90%, assuming a HR of 0.55 for rPFS, at a cumulative 2-sided alpha level of 0.05. Results: Between Nov 2018 and Jul 2022, 393 pts were randomized. Baseline characteristics were balanced across arms. Primary endpoint of rPFS was not met (HR 0.829; 95% CI, 0.619–1.111; p=0.2123), medians were 21.96 months for the ABEMA plus ABI group vs 20.28 months for the PBO plus ABI group. rPFS by blinded independent central review was consistent with investigator assessment (HR 0.842; 95% CI, 0.611–1.160). OS was a gated secondary endpoint and not inferentially tested (HR 0.927; 95% CI, 0.669–1.285; 38.9% maturity). Other secondary endpoints included time to PSA progression (HR 0.637; 95% CI, 0.474–0.856), time to symptomatic progression (HR 0.768; 95% CI, 0.522–1.131), and time to worst pain progression (HR 0.935; 95% CI 0.665–1.314). The most common grade ≥3 adverse events (AEs) reported in the ABEMA plus ABI group were anemia (13.6% vs 4.3% in the PBO plus ABI group), neutropenia (12.6% vs 0.5%) and ALT increased (8.7% vs 6.5%). Discontinuations of all study treatments due to AEs were 13.1% vs 4.3% in ABEMA plus ABI vs PBO plus ABI groups, while discontinuations of ABEMA or PBO alone due to AEs were 5.8% vs 1.6%, respectively. Conclusions: In patients with mCRPC, adding abemaciclib to abiraterone did not significantly increase rPFS. While no OS detriment was observed, secondary endpoints were not meaningfully improved. Overall, the combination was well tolerated, and safety was consistent with the known profiles of the individual medicines. Clinical trial information: NCT03706365 Clinical trial information: NCT03706365 .

Circulating metabolic profiling as a biomarker for immune checkpoint blockade efficacy.

2564 Background: Immune checkpoint blockade (ICB) has changed the treatment landscape of non-small cell lung cancer (NSCLC). Despite being the mainstay of treatment for advanced NSCLC, the development of resistance to ICB is common. Hence, identifying biomarkers that can be used to select patients (pts) who will benefit from ICB is crucial. Here, we interrogate the circulating metabolome to identify the metabolic parameters associated with ICB effectiveness. Methods: This single-center retrospective analysis used a mass-spectrometry (MS) targeted metabolomics approach to assess the relative abundance of 115 metabolites in baseline (pre-ICB) plasma of 55 pts with advanced NSCLC. Pts treated with ICB at the Princess Margaret Cancer Centre from 2018-2020 were included. Electronic medical records were reviewed to collect clinicopathological and treatment data. All pts had tumour next-generation sequencing (NGS) by a targeted gene panel. Descriptive statistics were used to summarize the patient characteristics, treatment modalities, and outcomes. Time-to-event outcomes were analyzed using the Kaplan-Meier method. Progression-free survival (rwPFS) and overall survival (rwOS) were defined as the time from the first treatment dose to radiographic or clinical progression or death from any cause and time from the first dose of treatment to death from any cause, respectively. The response rate was assessed using RECIST 1.1. Statistical significance was determined as a p-value &lt;0.05. Results: Amongst the 55 pts profiled, 42 (76.3%) had adenocarcinoma. The most common molecular alterations included KRAS (n=15), BRAF non-V600 (n=5), and METex14 (n=3). The median PD-L1 score was 65% (IQR 22.5 – 59%). All pts were treated with a single-agent PD-1 inhibitor, and 67.2% of pts received ICB as the first line of treatment. Metabolomic analysis of the pre-ICB initiation plasma samples identified 8 metabolites whose relative abundance significantly differed between responding (CR/PR) and non-responding pts (SD/PD). Amongst these metabolites was the endogenous danger signal Glucosylceramide (d 18:1/24:0), whose abundance was increased in the plasma of the responding pts. When we stratified pts by circulating levels of glucosylceramide, we found a statistically significant higher rwPFS (8.5 vs. 1.6 months, p=0.0001) and rwOS (13.5 vs. 6.1 months, p=0.0001) in pts who had high baseline plasma levels of Glucosylceramide (d 18:1/24:0) (top 50%) versus those with lower levels (bottom 50%). Conclusions: Utilizing a targeted metabolomics approach, we identified the metabolite and endogenous danger signal glucosylceramide (d 18:1/24:0) as a potential metabolic biomarker of response to ICB therapy. Future work will aim to validate this finding in a larger cohort and to understand the biological mechanism underpinning this correlation.

Stereotactic radiosurgery in patients with small cell lung cancer and 1-10 brain metastases: A multi-institutional, phase II, prospective clinical trial.

2020 Background: Stereotactic radiosurgery (SRS) as opposed to whole brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases. Brain metastases from small cell lung cancer (SCLC), however, represent an exception to this dogma, given that prior trials evaluating SRS in lieu of WBRT excluded patients with SCLC due to the historical role of prophylactic cranial irradiation (PCI) and concerns relating to neurologic decline and death when WBRT is omitted from upfront management. We conducted a prospective, multi-center, phase II trial of SRS in patients with SCLC and 1-10 brain metastases to determine how rates of neurologic death compared to historical controls managed with WBRT. Methods: Following approval from the Dana-Farber/Harvard Cancer Center IRB, we opened a single-arm, multi-center, phase II trial to investigate SRS in patients with SCLC and 1-10 brain metastases naïve to prior brain-directed radiation including PCI (NCT03391362). Prior resection of a brain metastasis was permitted. Patients with leptomeningeal disease were excluded. Metastases &lt;2cm in maximal size were generally managed with SRS to 20 Gy; larger tumors, or those near sensitive structures, were dose reduced to 16-19 Gy or managed with fractioned SRS (SRT) to 30 Gy in 5 fractions. Gross totally resected brain metastases received SRT to 25 Gy in 5 fractions. We sought to determine, as the primary endpoint, whether or not use of SRS in lieu of WBRT would lead to meaningfully higher rates of neurologic death (HR 1.61, corresponding to a 1-year event rate of 26.7% relative to a historical 1-year rate of 17.5% in patients previously managed with WBRT at our center), with 90% power and a one-sided alpha error of 5%. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression / systemic symptoms of a life-threatening nature and was assessed by a panel of 2-3 neuro-radiation oncologists. Results: Between 3/2018 – 4/2023, 100 patients were enrolled across 4 centers. The median age was 68 years (IQR 63 – 74 years). The median number of brain metastases was 2 (IQR 1 – 3); 16 (16%) of patients underwent prior neurosurgical resection. On study, 66 (66%) patients were treated with SRS alone while 32 (32%) were treated with SRT to at least 1 site; 2 patients died of systemic disease progression before study treatment. The median overall survival was 10.3 months. In total, 19 neurologic deaths were observed, relative to 62 systemic deaths. The neurologic death rate at 1 year was 11.0% (95% CI 4.8% – 17.2%). Conclusions: Our prospective, multi-institutional study demonstrated modest rates of neurologic death when SRS as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases and represents the largest prospective experience to date. Clinical trial information: NCT03391362 .

Sequential use of PI3K/AKT/mTOR pathway inhibitors alpelisib and everolimus in patients with hormone receptor-positive (HR+) metastatic breast cancer.

1057 Background: Alpelisib (A), a PI3K inhibitor, is FDA-approved with fulvestrant for patients with PIK3CA-mutated HR+/HER2- MBC. Everolimus (E), an mTOR inhibitor, is FDA-approved with endocrine therapy (ET) regardless of PI3K/AKT/mTOR pathway mutation status. The efficacy and safety of sequential treatment with these pathway inhibitors is not well described. Methods: This single-center retrospective cohort study identified patients with HR+/HER2- MBC treated with both A and E sequentially, each in combination with ET, in either order from 2012-2023. We collected information on patient demographics, clinical and pathologic characteristics, treatment history, treatment adverse effects, and dates of disease progression (defined as radiographic or clinical progression leading to treatment change) from medical records. Patients treated first with E then A were categorized as Group 1 and those first with A then E as Group 2. Rates of prior CDK4/6i use were compared between groups with the chi-square test; differences in prior lines of therapy were assessed with the Wilcoxon rank sum test. Median PFS1 (PFS on 1st pathway inhibitor) and PFS2 (PFS on 2nd pathway inhibitor) were computed using the Kaplan-Meier method and the impact of prior treatment on PFS2 between groups was compared using Cox proportional hazards analysis. Results: 115 patients with HR+/HER2- MBC were included in this study. There were 62 (54%) patients in Group 1 and 53 (46%) patients in Group 2. Median prior lines of therapy in the metastatic setting for Group 1 was 4 (range 1-13) and for Group 2 was 3 (range 1-8; p=0.08). Median number of intervening therapies between E and A in Group 1 was 2 (range 0-8) and between A and E in Group 2 was 0 (range 0-4; p&lt;0.001). 34/62 (55%) patients in Group 1 and 45/53 (85%) in Group 2 received prior CDK4/6i ( p&lt;0.001). In Group 1, 49/62 (79%) of patients discontinued E for progression and 13 (21%) discontinued for toxicity. Median PFS1 was 9.2 months (95%CI 5.5-13.0) and PFS2 was 5.0 months (95%CI 4.6-7.9). In Group 2, 34/53 (64%) of patients discontinued A for progression and 19 (36%) discontinued for toxicity. Median PFS1 was 9.3 months (95%CI 7.0-14.0) and PFS2 was 3.5 months (95%CI 3.0-4.1). After adjusting for prior CDK4/6i use and prior lines of therapy (total and intervening), PFS2 was not significantly different between the groups. Genomic information will be included at the time of presentation. Conclusions: This is the largest retrospective study to-date of patients treated sequentially with PI3K/AKT/mTOR pathway inhibitors. PFS was longer with the 1st pathway inhibitor than with the 2nd regardless of sequence. This has implications for optimal integration of capivasertib, an AKT inhibitor, into HR+ MBC treatment. Prospective studies testing optimal sequencing are needed.

A phase 1/2, open label study of amivantamab in combination with tyrosine kinase inhibitors among participants with advanced NSCLC harboring ALK, ROS1, and RET gene fusions.

TPS8661 Background: Patients with ALK, ROS1, or RET rearranged NSCLC demonstrate dramatic and sustained responses to tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance remains a major clinical challenge. The EGFR and MET pathways have been reported as important escape mechanisms for cancer cells treated with highly potent TKIs. Combining amivantamab with ALK, ROS1, or RET TKIs upon radiographic progression represents a rational combination strategy in addressing TKI mediated resistance. Methods: This is an open-label, multicenter, Phase 1b / 2 study of amivantamab in combination with TKIs among participants with advanced NSCLC harboring ALK, ROS1, and RETgene fusions progressing on FDA-approved TKIs for their respective oncogene. Participants must be on their TKI at the same dose for at least 3 months prior to enrolling in the study. A pre-treatment biopsy is required to rule out neuroendocrine transformation and for translational objectives. Local confirmation of an ALK, ROS1, or RET gene fusion through tissue or circulating tumor DNA (ctDNA) assessment is allowed. Plasma collection for ctDNA assessments will occur prior to treatment, on C3D1, and post-treatment. This study will have both a safety lead-in cohort and a dose expansion cohort. A safety lead-in cohort will be treated with amivantamab at the RP2D in combination with their ALK, ROS1, or RET TKI. The primary endpoint will be dose-limiting toxicity (DLT) within the first cycle of dosing at a given dose level. A Bayesian optimal interval (BOIN) design will be employed as a safety lead-in using a dose de-escalation design to find the maximum tolerated dose (MTD) of amivantamab in combination with a standard fixed dose of common ALK, ROS1, and RET TKIs. The RP2D dose for amivantamab was previously set at 1050mg (for patients &lt; 80kg) and 1400mg (for patients ≥ 80kg). Patients will be treated in cohorts of size 3, and the maximum sample size for the dose escalation portion of the trial is 12 patients. The dose expansion cohort will evaluate the safety and efficacy of amivantamab (at the RP2D dose) in combination with standard FDA-approved doses of ALK, ROS1, and RET TKIs. The primary endpoint will be objective response rate (ORR). All patients enrolled at the RP2D level will be included in the phase II efficacy analysis, including patients enrolled in the safety lead-in cohort. A total of 16 to 35 evaluable patients, depending on the safety of the tested treatments in the dose escalation phase, are expected to be accrued to this study. Relevant exclusion criteria include: (1) prior EGFR directed therapy, (2) prior receipt of a MET monoclonal antibody or MET-ADC, (3) crizotinib use as immediate prior line of therapy, (4) small cell transformation, and (5) active, untreated, CNS metastases. The study has initiated enrollment without DLT and is ongoing. Clinical trial information: NCT05845671 .

Impact of maintenance pemetrexed cessation on clinical outcomes of patients with metastatic non-squamous NSCLC.

8568 Background: Combination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first line systemic approach for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on progression free survival (PFS) and overall survival (OS). Methods: 121 patients with stage IV or recurrent, metastatic non-squamous NSCLC treated at VUMC were included in this retrospective analysis. Patients diagnosed between 7/2017- 9/2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. PFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively, and compared with the Kaplan Meier method. Results: Among patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n=68), the median PFS was 11.7 months (95% CI, 7.47-NA) compared to 24.3 months (95% CI, 19.4-NA) among patients who stopped maintenance pemetrexed (n=53; p=0.1). The median OS in the same patient groups was 25.8 months (95% CI, 13.8-NA) compared to 36.4 months (95% CI, 26.9-NA) (p=0.15), respectively. Among patients with stage IV disease at diagnosis (n = 97), the median PFS among patients who did not stop pemetrexed was 8.7 months (95% CI, 7.2–NA) compared to 24.3 months (95% CI, 17.3-NA) for patients who stopped pemetrexed (p=0.089). The median OS in these groups were 21 months (95% CI, 13.6-NA) and 38.6 months (95%, 28.0-NA) (p=0.054), respectively. Conclusions: In this study of patients with metastatic non-squamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The necessity of continuation of maintenance chemotherapy should be further evaluated in the immunotherapy era. [Table: see text]

Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC)—2-year event-free survival and safety data for Cohort H.

4564 Background: For patients (pts) with MIBC who are cisplatin-ineligible and undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), no neoadjuvant treatment options have been shown to improve survival. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. EV, alone and in combination w/ pembrolizumab, has been shown to improve OS vs chemotherapy in pts with previously treated and untreated locally advanced or metastatic urothelial cancer, respectively (Powles NEJM 2021; Powles ESMO 2023). In Cohort H of the EV-103 phase 1b/2 study, promising results for 1-year EFS and antitumor activity, including pathological complete response (pCR) and pathological downstaging (pDS) rates, were achieved in cisplatin-ineligible pts with MIBC after neoadjuvant monotherapy EV treatment (Petrylak ASCO GU 2022; Flaig ASCO 2023). Here we report updated results, including 2-year EFS. Methods: Cohort H of the EV-103 study enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), safety, and EFS per investigator assessment (radiographic progression prior to RC, failure to undergo RC, gross residual disease at time of RC, recurrence, or death). Results: 22 pts (median age 74.5 years) were enrolled and treated; 15 pts (68.2%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had urothelial carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2-59.3) and the pDS rate was 50.0% (95% CI, 28.2-71.8). The EFS rate at 24 months was 62.0% (95% CI, 38.2-78.9). Median EFS has not been reached. All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs: the most common were procedural pain (18.2%), anemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and 2-year EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905/EV-303, KN-B15/EV-304). Clinical trial information: NCT03288545 .