Systemic Therapy Regimens Research Articles

Time to Next Treatment Following Sub-Ablative Progression Directed Radiation Therapy for Oligoprogressive Non-Small-Cell Lung Cancer

We aimed to evaluate whether progression-directed radiation therapy (PDRT) can prolong the initiation of a subsequent systemic therapy regimen in a cohort of patients with oligoprogressive NSCLC. A retrospective analysis was conducted on NSCLC patients who underwent PDRT for extracranial oligoprogressive NSCLC, defined as limited (up to five) progressing lesions following initial complete, partial, or stable response to systemic therapy according to REC1ST 1.1 and/or PERCIST 1.0 criteria. Cox proportional hazard regressions were performed to identify factors influencing time to next treatment (TTNT), which was considered the primary endpoint. Forty patients were analyzed. First, second, and ≥3 lines of systemic therapy were administered in 22 (58.2%), 14 (27.2%), and 4 (14.6%) cases, respectively. The median total dose was 36 Gy (range: 12–60) in five fractions (1–10), with a median biological effective dose for tumor control (BED10) of 52 Gy (26.4–151.2). After a median follow-up of 11 months (2–50), PDRT delayed further systemic therapy in 32 (80.0%) treatments. Median TTNT was not reached at 8 months (1–47) with a one-year Kaplan–Meier estimate of 81.4% (95% CI: 75.0% to 87.8%). No >grade 3 adverse event was observed. On multivariate analysis, patients with ≥3 lines of systemic therapy and/or with larger CTV volumes did not benefit from PDRT. Despite the use of sub-ablative doses, our findings show that PDRT represents an effective, safe, and viable option for oligoprogressive NSCLC. Patients irradiated early during their systemic treatment course, with a low volume of disease and nonmetastatic oligoprogression, could derive substantial benefits from PDRT.

Prognostic Role of Specific KRAS Mutations Detected in Aspiration and Liquid Biopsies from Patients with Pancreatic Cancer

Background/Objectives: Although the overall survival prognosis of patients in advanced stages of pancreatic ductal adenocarcinoma (PDAC) is poor, typically ranging from days to months from diagnosis, there are rare cases of patients remaining in therapy for longer periods of time. Early estimations of survival prognosis would allow rational decisions on complex therapy interventions, including radical surgery and robust systemic therapy regimens. Understandably, there is great interest in finding prognostic markers that can be used for patient stratification. We determined the role of various KRAS mutations in the prognosis of PDAC patients using biopsy samples and circulating tumor DNA. Methods: A total of 118 patients with PDAC, clinically confirmed by endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNB), were included in the study. DNA was extracted from cytological slides following a standard cytology evaluation to ensure adequacy (viability and quantity) and to mark the tumor cell fraction. Circulating tumor DNA (ctDNA) was extracted from plasma samples of 45 patients in stage IV of the disease. KRAS mutations in exons 12 and 13 were detected by denaturing capillary electrophoresis (DCE), revealing a minute presence of mutation-specific heteroduplexes. Kaplan–Meier survival curves were calculated for individual KRAS mutation types. Results:KRAS mutations were detected in 90% of tissue (106/118) and 44% of plasma (20/45) samples. All mutations were localized at exon 2, codon 12, with G12D (GGT > GAT) being the most frequent at 44% (47/106) and 65% (13/20), followed by other types including G12V (GGT > GTT) at 31% (33/106) and 10% (2/20), G12R (GGT > CGT) at 17% (18/106) and 10% (2/20), G12C (GGT/TGT) at 5% (5/106) and 0% (0/20) and G12S (GGT/AGT) at 1% (1/106) and 5% (1/20) in tissue and plasma samples, respectively. Two patients had two mutations simultaneously (G12V + G12S and G12D + G12S) in both types of samples (2%, 2/106 and 10%, 2/20 in tissue and plasma samples, respectively). The median survival of patients with the G12D mutation in tissues was less than half that of other patients (median survival 101 days, 95% CI: 80–600 vs. 228 days, 95% CI: 184–602), with a statistically significant overall difference in survival (p = 0.0080, log-rank test), and furthermore it was less than that of all combined patients with other mutation types (101 days, 95% CI: 80–600 vs. 210 days, 95% CI: 161–602, p = 0.0166). For plasma samples, the survival of patients with this mutation was six times shorter than that of patients without the G12D mutation (27 days, 95% CI: 8–334 vs. 161 days, 95% CI: 107–536, p = 0.0200). In contrast, patients with detected KRAS G12R in the tissue survived nearly twice as long as other patients in the aggregate (286 days, 95% CI: 70–602 vs. 162 days, 95% CI: 122–600, p = 0.0374) or patients with other KRAS mutations (286 days, 95% CI: 70–602 vs. 137 days, 95% CI: 107–600, p = 0.0257). Conclusions: Differentiation of specific KRAS mutations in EUS-FNB and ctDNA (above all, the crucial G12D and G12R) is feasible in routine management of PDAC patients and imperative for assessment of prognosis.

The time toxicity efficacy-effectiveness gap: A population-based study of stage III/IV non-small cell lung cancer (NSCLC) in Ontario, Canada.

133 Background: While patients enrolled in clinical trials tend to have superior cancer-specific outcomes relative to those in routine practice (the ‘’efficacy-effectiveness gap’’), it is unknown if this gap extends to time toxicity. While trial protocols can impose additional contact days, trial participants also tend to be healthier, perhaps needing fewer contact days. We sought to evaluate the time toxicity efficacy-effectiveness gap among patients with stage III/IV NSCLC. Methods: We created a population-based, retrospective cohort with health administrative data covering the population of Ontario, Canada (15.5 million), of adults aged ≥20 years diagnosed with stage III/IV NSCLC in 2014-2017 and died in 2014-2019, receiving palliative systemic anti-cancer drug(s) as part of a trial. We matched patients 1:1 to those who received the same drug(s) in the real world (post-approval) in the same line of treatment, and received the same total lines of therapy. We calculated contact days (days with healthcare contact outside the home) from diagnosis to death and measured overall survival. We plotted, normalized, and fitted with cubic splines the weekly percentage of contact days to obtain trajectories over the disease course. Results: We identified and matched 55 trial participants to 55 patients in routine practice. Trial participants were younger (median age, 62 vs 66 years), had fewer co-morbidities (hypertension, 35% vs 53%), and more often had de novo metastatic disease (82% vs 67%). Median lines of therapy were 2. Systemic therapy regimens most commonly included immunotherapy (n=41, 75%). Trial participants initiated systemic therapy sooner than in routine practice (median 2.0 vs 2.4 months). Trial participants had a longer overall survival (median 13.8 vs 11.6 months) and a similar number of contact days (median 79 vs 78 days). The percentage of contact days was lower in trial participants due to longer survival (median 19% vs 22%). Trial participants had similar acute/assisted institutional care contact days (median 19 vs 18 days), but more days with laboratory tests (median 23 vs 17 days), systemic therapy (median 9 vs 6 days), and radiotherapy visits (median 15 vs 11 days). Normalized trajectories for both cohorts followed a ‘’U-shape’’; the difference between the maximal peak and trough was smaller in trial participants. Conclusions: We describe a novel efficacy-effectiveness gap in time toxicity, in addition to the previously established efficacy-effectiveness gap in overall survival. Encouragingly, trial participants did not experience delays in treatment, and initiated treatments sooner than in routine practice. Among trial participants, the higher number of contact days for tests, and the shallower U-shaped curve (indicating frequent visits even when relatively well) indicate potential opportunities to decrease trial-related time toxicity.

Health-related quality of life of Canadian patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

397 Background: The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a validated tool that assesses health utility (HU) as a self-reported measure of health-related quality of life (HRQoL). This study aims to generate Canadian-specific HU data for patients with stable, HER2-positive (HER2+) metastatic breast cancer (mBC) receiving standard therapies. Methods: A cross-sectional study was conducted at McGill University Health Centre in Quebec, Canada. Eligibility criteria included: age ≥18 years, de novo or recurrent mBC, stable disease, and active treatment with a Health Canada-approved systemic therapy regimen (any line/time point on treatment). The EQ-5D-5L questionnaire was administered at every visit and each record was treated as a unique singular data point. The HU values were derived using the Canadian algorithm developed by Xie et al., 2016. The EQ-5D-5L measures HRQoL across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and is scored on 5 levels ranging from one “no problems” to five “extreme problems”. A second part of the questionnaire includes a visual analogue scale (VAS) where respondents rank their overall health on scale of 0-100. The primary outcome was mean HU and standard deviation (SD) for HER2+ patients overall. Secondary outcomes included mean HU by hormone receptor (HR) status and describing patient responses to the questionnaire. Results: Between December 2022 and July 2023, a total of 81 HER2+ HU data points were included for analysis, representing 30 patients. For these patients, the mean age was 54.2 years (SD: 10.6). Most patients (58.3%) were on first line and had an Eastern Cooperative Oncology Group Performance Status of 0 (65.5%). The mean HU value was 0.83 (SD: 0.14, n=81). For patients with HR-positive mBC, the mean HU was 0.81 (SD: 0.14, n=44), while for patients with HR-negative mBC, it was 0.85 (SD: 0.13, n=37). The majority of patients reported “no problems” across all domains: mobility (69.1%), self-care (81.5%), usual activities (46.9%), pain/discomfort (35.8%), and anxiety/depression (58%). The mean VAS score was 77.3 (SD: 17.0). Conclusions: This study provides the first Canadian data on contemporary HU values for patients with HER2+ mBC, which reflects current HRQoL amidst a changing treatment landscape.

Stereotactic radiotherapy for managing ovarian cancer oligoprogression under poly (ADP-ribose) polymerase inhibitors (PARPi)

ObjectivePoly (ADP-ribose) polymerase inhibitors (PARPi) have become a new standard of care for the maintenance treatment of advanced epithelial ovarian cancer. This study aims to evaluate the efficacy and safety...

An Evolving Paradigm in Borderline Resectable and Locally Advanced Pancreatic Cancer: Current Strategies and Opportunities for the Future

Pancreatic ductal adenocarcinoma (PDAC), a cancer of the gastrointestinal tract, has been increasing in incidence, with an estimated doubling worldwide over the past two decades. Despite increases in awareness and innovations in genomics and drug discovery, 5-year survival remains low, at only 10%. This is in part owing to the majority of patients being diagnosed at the advanced stage of the disease, in addition to chemotherapy recalcitrant disease. Surgical resection is necessary for a potential cure, however, this is only possible for the 10% of patients who present with resectable disease and potentially for those with borderline resectable disease. Locally advanced pancreatic cancer accounts for approximately 30% of those with PDAC and most of those patients are often precluded from curative intent surgery due to major vascular invasion and local infiltration into peri-pancreatic soft tissue. In cases of locally advanced disease, induction chemotherapy is often used, identifying the subgroup of patients more suited for local treatments and those who may later develop metastases. The treatment regimens used for patients with locally advanced PDAC are often extrapolated from trials involving patients with metastatic disease. In some cases, responses to neoadjuvant therapy have allowed for surgical resection, albeit these aggressive resections were associated with significant morbidity. There is growing interest in identifying the optimal neoadjuvant treatment for patients with borderline resectable pancreatic cancer (BRPC) and locally advanced PDAC (LAPC) in an effort to improve outcomes. Here we review therapeutic strategies for borderline resectable and locally advanced PDAC, with a focus on novel systemic therapy regimens, chemoradiation, and different radiation modalities.

Prognostic factors in patients with hepatocellular cancer with progression after liver transplantation

Introduction. Hepatocellular cancer is the most frequent primary malignant neoplasm of the liver, developing against the background of viral hepatitis, alcohol abuse, metabolic disorders, cirrhosis. Most often hepatocellular cancer is diagnosed at late stages of the disease, when patients are no longer subject to specific treatment. The priority method of treatment of early stages remains surgical. In the absence of cirrhosis or with compensated cirrhosis the best option is liver resection, in other cases orthotopic liver transplantation is performed. However, when hepatocellular cancer is diagnosed, most patients fall outside the Milan criteria, and the bridge to orthotopic liver transplantation is down-stage therapy. Bridge therapy is used to treat hepatocellular cancer while awaiting liver transplantation and aims to prevent stage progression. The probability of progression of hepatocellular cancer after orthotopic liver transplantation within the first two years is about 75% and about 10% is detected after the fourth year. Progression of hepatocellular cancer remains the main factor limiting the life expectancy of patients after orthotopic liver transplantation.The aim of the study: to evaluate the results of antitumor treatment of patients with hepatocellular cancer progression after liver transplantation.Materials and methods. We evaluated the results of treatment of 50 patients with hepatocellular cancer progression after orthotopic liver transplantation, who were treated on the basis of FGBU NMI Center of Oncology named after N.N. Blokhin. N.N. Blokhin Oncology Center in the period from 2009 to 2020. We analyzed and evaluated overall and recurrence-free survival depending on the bridge therapy, type of treatment, presence of vascular invasion and portal vein thrombosis.Results. According to the results of bridge therapy, hepatocellular cancer stage progression was observed in 9 patients, stabilization - in 17 patients, partial/complete response – in 9 patients. The median recurrence-free survival of patients who received bridge therapy and down-stage therapy was 23.6 months; among patients who did not, it was 35.6 months. The median overall survival with surgical treatment was 79.8 months, whereas with radiation therapy it was 17.2 months. Conclusions. In the studied group of patients the treatment was tolerated satisfactorily. Optimization of immunosuppression protocol and modification of dose regimens of systemic therapy is considered as a condition for treatment, which leads to improvement of long-term treatment results (overall and relapse-free survival).

A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study.

8513 Background: A multinational pivotal study WU-KONG1 (NCT03974022) has been conducted to assess sunvozertinib (DZD9008) in pre-treated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (exon20ins). Here we report the results of primary analysis. Methods: WU-KONG1 Part B is a phase 2, multinational pivotal study to assess the antitumor efficacy of sunvozertinib at two dose levels, 200 mg and 300 mg, in platinum pre-treated NSCLC patients with EGFR exon20ins. Eligible patients were randomized at the ratio of 1:1 to receive 200 mg or 300 mg sunvozertinib once daily until discontinuation criteria were met. Randomization was stratified by brain metastasis at baseline and number of regimens of prior systemic anti-cancer therapy. The primary endpoint was Independent Review Committee (IRC) assessed objective response rate (ORR) (per RECIST v1.1) and key secondary endpoint included IRC assessed duration of response (DoR). Results: As of January 4, 2024, a total of 184 patients were randomized to receive sunvozertinib treatment at 200 mg or 300 mg. Patients who met the predefined criteria for efficacy analysis were included in the primary analysis. The majority of patients (96.0%) had metastatic diseases, 60.7% had ECOG PS of 1, and 23.7% had baseline brain metastasis. All patients received prior platinum-based chemotherapy for advanced NSCLC, and 43.4% and 13.3% had prior onco-immunotherapy or amivantamab treatment. Per IRC assessment, the best ORR was 54.3% (41.0% confirmed and 5.8% pending confirmation). Confirmed complete response (CR) was achieved in 2.9% patients. The disease control rate (including CR, PR and stable disease) was 90.8%. The primary endpoint met its predefined target, with statistical significance. Tumor response was observed in patients with baseline brain metastasis, different demographics and EGFR exon20ins subtypes. With median follow-up time of 5.5 months for responders, the duration of response has not been reached, with 74.6% responders still responding. The PFS data are not mature with approximately 6-month follow-up. Safety findings were similar to previously reported results of sunvozertinib in other clinical studies. The most common drug-related TEAEs included diarrhea, skin rash and CPK increase. The majority of the TEAEs were CTCAE grade 1 or 2 and clinically manageable. Conclusions: In this primary analysis of WU-KONG1 multinational pivotal study, sunvozertinib demonstrated promising antitumor efficacy in platinum pre-treated NSCLC with EGFR exon20ins, with a tolerable safety profile. The updated data will be presented at the meeting. Clinical trial information: NCT03974022 .

Evaluation of the study of control arms in randomized clinical trials of cancer.

11023 Background: Randomized clinical trials (RCTs) in cancer typically compare experimental to control arm regimens. The choice of an appropriate control (ctrl) arm can have a major impact on the expected success of an RCT. The frequency with which cancer RCTs use control arms based on established dosing and scheduling protocols has not been described. Methods: The HemOnc knowledgebase (KB) was used to identify systemic anti-cancer therapy (SACT) regimen variants, defined as regimens with identical components that differ in dosing, scheduling, and/or route. Non-cancer, nonrandomized, and non-SACT studies were excluded. Study publication year was used to define standard variants as those evaluated in the experimental arm of a positive phase 3 RCT >1 year prior to publication as a control arm, regardless of cancer type or context of treatment. Study-variant dyads were evaluated to determine whether the variant was standard. Success rates of RCTs with standard vs non-standard control arms were evaluated with Fisher’s exact test. Results: 5221 studies were associated with ≥1 named variant in the HemOnc KB, as of 2024-02-06. After exclusions, there were 3511 study-variant dyads (2386 studies; 1714 variants). The 9 most common regimens are shown in the Table. The median (IQR) number of variants per regimen was 2 (1-3); carboplatin & paclitaxel (CP) had the most variants (n=33). Across all control arm study-variant dyads, 2228/3492 (64%) utilized non-standard variants. For example, 60/97 studies (62%) of docetaxel as control used the 75 mg/m2 q3wk variant after it was established in 2000, whereas n=27 others used 19 non-standard variants. Trials that used a standard control arm had a numerically higher success rate, 45% vs 42% (OR 1.10, 95% CI 0.92-1.32). Conclusions: Non-standard regimen variants are frequently used in cancer RCTs. Reasons for this could include toxicity, patient convenience, or emerging data from smaller studies that establish comparable efficacy or improved toxicity to standard variants. However, the a priori efficacy of non-standard control arms is less rigorously established, and trials with standard control arms might be more successful. Future directions include quantifying the granular differences between standard and non-standard variants and investigating whether certain types of non-standard variation (e.g. fewer cycles, lower doses) associate with trial success rates. [Table: see text]

Systemic therapy in NF-1 associated malignant peripheral nerve sheath tumors (MPNST).

11583 Background: MPNST are rare sarcomas that have a poor prognosis and are challenging to treat. Around 50% of MPNSTs are associated with NF1, 40% are sporadic, and 10% are radiation-associated. Doxorubicin (D) based chemotherapy (CT) regimens are commonly used in the front-line, and combinations have better response rates than single agents. Response to second-line regimens is not well documented. The objective of this study is to document efficacy of systemic regimens in MPNST as a benchmark for future novel therapeutics in this space. Methods: 72 patients (pts) with NF1-associated MPNSTs in an MD Anderson database were reviewed retrospectively from EMR. Variables collected included demographics, primary MPNST location, localized vs metastatic, and treatments received (+/- radiation, +/-surgery, +/- lines of CT). Responses (progressive disease (PD), stable disease (SD), partial response (PR)) as interpreted by treating physician and radiology reports and time on treatment for 1st and 2nd line chemotherapy regimens were assessed. Cox proportional-hazard regression was used to investigate associations of variables with overall survival (OS: from time of diagnosis to death or last follow-up). Results: Demographic and CT details are provided (Table). The median age at diagnosis was 34.5 yrs (range: 9-71). The most common MPNST location was the trunk (56.94%). D based regimens were the most frequent 1st-line CT (65.7%), and gemcitabine- docetaxel was the most frequent 2nd-line CT (33.3%). In pts with metastases, 74.4% got 1st line, 44.7% 2nd line, 25.5% 3rd line, and 12.7% got 4th line therapy. Median follow-up was 2.46 yrs (IQR 1.24-9.52). The median time on treatment for 1st and 2nd line CT was 110 (IQR 48-153) and 57 (IQR 41-133) days, respectively. In the multivariate COX model for the entire cohort, male sex (HR: 0.35, 95%CI: 0.18-0.68), lower extremity primary (HR: 0.09, 95%CI: 0.02-0.40), and absence of metastases at last follow up (HR: 0.05, 95%CI: 0.02-0.17) were associated with decreased risk of death. Additional analysis on efficacy and survival of the systemic therapy regimens will be presented at the meeting. Conclusions: In this study < 50% pts with advanced NF1 related MPNST made it to 2nd line CT and outcomes were inferior to the predominantly D based 1st line regimens. This highlights an area of high unmet need. [Table: see text]

Clinical efficacy of various regimens of systemic glucocorticoids therapy in COVID-19 patients

Introduction. Systemic glucocorticoids have been successfully used in the treatment of patients with moderate to severe COVID-19. However, the best clinical efficacy dosage regimen and duration of glucocorticoid usage is remained unclear.Aim. To evaluate the results of using different regimens of systemic glucocorticoid therapy in the treatment of patients with moderate and severe COVID-19.Materials and methods. The results of a retrospective study of medical papers of 200 patients who had moderate to severe COVID-19 in the period from May 2020 to December 2021 are presented. The inclusion criterion was the use different regimens of doses and durations systemic glucocorticoid therapy in these patients without the use blockers of Janus kinases. and genetically engineered biological drugs. Clinical effectiveness was assessed by the severity and sufficiency of the anti-inflammatory effect, the frequency and nature of side effects of this therapy.Results. The regimen of glucocorticoids at a dose equivalent to 6 mg/day of dexamethasone for 7 days demonstrated the greatest clinical effectiveness: it significantly reduced C-reactive protein, hematological inflammatory indices,% lung tissue damage, minimally affecting carbohydrate metabolism and hemostasis. Glucocorticoid therapy equivalent to 20 mg/day of dexamethasone for more than 7 days and pulse-therapy for 3 days demonstrated significantly lower clinical effectiveness.Conclusions. In patients with moderate to severe COVID-19, it is reasonable to use a dose of glucocorticoid equivalent to 6 mg/day of dexamethasone for 7 to 10 days, or equivalent to 20 mg/day for no more than 7 days. The use of pulse therapy and the use of glucocorticoids at a dose equivalent to ≥ 20 mg/day of dexamethasone for a duration of 7 days are not recommended. To assess the dynamics of inflammation and monitor the effectiveness of glucorticoid therapy, in addition to routine markers of inflammation, it is recommended to use hematological inflammatory indices.

Abstract PO5-19-05: A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer

Abstract Background: The term oligoprogression (OP) refers to a clinical scenario in which patients with diffuse metastatic disease on systemic therapy have a limited number of metastases that have progressed or are new whereas the majority of metastases are stable or improved. OP disease is increasingly being encountered in clinical practice due to improvements in systemic therapy. Treating OP disease with local ablative therapies may therefore prolong the time to more diffuse progression necessitating a change in systemic therapy and may therefore lead to improved overall survival in these patients. Only one study has evaluated the role of SBRT in patients with OP MBC. This trial accrued 47 patients with OP MBC, with 2/3 having triple negative disease. There was no difference in PFS between patients that received SBRT versus those that did not (4.2 months vs. 4.4 months, p=0.2). Whether ablative therapies are beneficial in subtypes of breast cancer that have many effective systemic therapies available, such as ER+ breast cancer, remains an open question and an unmet clinical need. Design: Phase II study for patients with OP ER+ MBC (1-4 new and/or progressing metastatic lesions). Eligible patients will receive stereotactic body radiation therapy (SBRT) to the OP lesions. SBRT will be delivered to each lesion in 3-5 fractions. Each patient’s systemic therapy regimen will be held during study therapy and will resume upon completion of study therapy. Patients will then be restaged at 12 weeks post-SBSRT. Patients that have at least stable disease at that time point will continue on their systemic therapy and then be re-staged 12 weeks later (24 weeks after SBRT). This study will also study the role of ER-targeted positron emission tomography (PET) imaging with 16α-18F-Fluoro-17β-Fluroestradiol (FES) in the OP ER+ patient population with FES PET scans obtained at baseline, and at each of the 2 follow-up imaging timepoints. A key secondary hypothesis is that the use of FES PET in addition to standard imaging at baseline and in follow-up will help confirm patients have OP disease and will help assess for new lesions on subsequent restaging. Eligibility: Key inclusion criteria: age≥18 yo; histologically confirmed ER+/HER2- metastatic breast cancer; the presence of metastatic breast cancer at the time of study entry with progression in 1-4 lesions (including new lesions); SBRT must be feasible for all progressing lesions. Key Exclusion Criteria: >2 lines of systemic therapy for metastatic disease; intracranial disease progression Objective: To determine whether using SBRT to treat OP lesions allows ER+ breast cancer patients to continue on their current systemic therapy for at least 24 weeks post SBRT. Objective: To assess whether FES-PET increases the number of lesions found prior to SBRT; To determine the impact of SBRT on patient quality of life; time to next line systemic therapy; PFS Statistical Methods Simon 2 stage optimal design with α=0.05 and 1-β=0.80. The null hypothesis is that the proportion of patients that remain on their original systemic therapy ≥24 weeks (2 restaging scans) post-treatment is 20%. The alternative hypothesis is that the proportion of patients that remain on their original systemic therapy after 2 restaging scans is 50%. In stage 1, 8 patients that proceed to SBRT will be enrolled. The study will be terminated if only 0 or 1 subjects remain on original systemic therapy after 2 restaging scans. However, if ≥2 patients remain on original systemic therapy after 2 restaging, then an additional 10 patients would be enrolled for a total of 18 patients. The null hypothesis will be rejected if ≥6 patients remain on their original systemic therapy after 2 restaging scans. Contact Information: Jose G. Bazan (jbazan@coh.org) Funding Source: City of Hope Comprehensive Cancer Center Citation Format: Jose Bazan, Joanne Mortimer, Yun-Rose Li. A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive 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 PO5-19-05.

Abstract ED07-03: Novel Systemic Therapy Strategies for HER2+ Brain Metastases

Abstract More than 1/3 of patients with HER2+ metastatic breast cancer will develop brain metastases. Local therapies such as resection or radiation therapy continue to play a pivotal role in brain metastases treatment. However, receipt of HER2-directed systemic therapies lead to significant survival advances for both stable and active brain metastases and are integral to optimal outcomes. We will review clinical goals for stable and active brain metastases. In the last few years, novel early line systemic therapy regimens have improved outcomes for HER2+ brain metastases which will be reviewed. We will review evolving evidence that Antibody Drug Conjugates targeting HER2 have robust intracranial activity. We will review exciting HER2 directed tyrosine kinase inhibitors and combinations. Citation Format: S. Sammons. Novel Systemic Therapy Strategies for HER2+ Brain Metastases [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 ED07-03.

Abstract ED05-03: Surgical management of Stage I TN and HER2+ breast cancer

Abstract The management of early-stage triple-negative (TN) and HER2-positive (HER2+) breast cancer has evolved significantly with continually improving systemic therapies. The use of neoadjuvant chemotherapy (NAC) has become standard for stage II disease, for both surgical downstaging and assessment of response to treatment, allowing for tailoring of systemic therapy in the adjuvant setting. However, the optimal treatment approach for stage I TN and HER2+ disease remains controversial, given the limited burden of disease at presentation with most patients considered candidates for limited surgery, and the excellent overall outcomes with de-escalated systemic therapy regimens in the adjuvant setting. This presentation will discuss the evolving landscape and current standards for stage I TN and HER2+ disease. Citation Format: A. Mamtani. Surgical management of Stage I TN and HER2+ 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 ED05-03.

Overview of Molecular Diagnostics in Irish Clinical Oncology

Background Molecular diagnostics are critical for informing cancer patient care. In Ireland, the National Cancer Control Programme (NCCP) develops cancer therapy regimens, which include relevant information on molecular indications. Here, we present a collated overview of the current molecular indications of all NCCP systemic anti-cancer therapy regimens and the funding statuses of their associated drugs. Furthermore, we also provide estimates for the scale of required molecular testing in cancer therapy and for the clinical genetic sequencing capacity of Ireland, and provide a summary of current cancer clinical trials in Ireland which have molecular components. Methods Through a combination of web scraping, keyword search, and manual review, we performed a full review of all 757 indications included in the 476 therapy regimens published to date by the NCCP to identify therapy indications with explicit molecular criteria. For all cancer types identified in these indications, we obtained incidence rates in Ireland from National Cancer Registry Ireland to predict the number of patients yearly who stand to benefit from a molecular test. We then applied molecular subtype rates from published literature to estimate the number of patients who would then qualify for a relevant molecularly guided therapy. Results We identified 210 indications for 148 NCCP therapy regimens that include molecular criteria. These 210 molecular indications encompassed 85 genetic criteria, 137 cellular biomarker criteria, 57 molecularly informed drugs, and over 20 cancer types. We estimated that up to approximately 50% of cancer patients in Ireland could qualify for a molecular test and that the majority of tested patients would qualify for a treatment informed by a molecular test. Conclusions As personalised cancer medicine continues to develop in Ireland, this study will provide a baseline understanding of current practices. We anticipate that work such as this will help to inform planning in the healthcare system.

Reconciling the discrepancies in randomized data of combining immunotherapy and radiation therapy: Not all radiotherapy is created equal

It remains highly unclear and debatable whether combining radiotherapy (RT) and immune checkpoint blocker (ICB) therapy yields improved outcomes compared to either modality alone. Whereas some randomized data have shown improved outcomes, others have not. As a result of these conflicting data, it is essential to reconcile differences in the data and postulate reasons thereof. This work seeks to address these discrepancies, and uses the lessons learned from both positive and negative trials, including the most cutting-edge data available, in order to guide future clinical trial design and clarify the ideal/expected role of combinatorial therapy going forward. Because RT offers two distinct contributions (cytoreductive (local) effects & immune-stimulating (systemic) effects), RT should complement immunotherapy by addressing immunotherapy-resistant clones, and immunotherapy should complement RT by addressing RT-resistant or out-of-field clones. RT is not merely a single “drug”, but rather a constellation of diverse “drugs” that can be varied based on dose regimens, previous systemic therapy regimens, number of irradiated sites, treatment intent/location/timing, tumor biology, and individual patient immunological circumstances. These factors are discussed as an important explanation for the discrepancies in results of various randomized trials in heterogeneous populations and clinical settings, and these discrepancies may continue until trials of more uniform circumstances are designed to use particular RT paradigms that meaningfully add value to systemic therapy.

Safety of non-standard regimen of systemic steroid therapy in patients with Graves' orbitopathy: a single-centre experience.

Graves' orbitopathy (GO) is an autoimmune disorder of the orbit and retro-ocular tissues and the primary extrathyroidal manifestation of Graves' disease. In moderate-to-severe and active GO iv glucocorticoids (GCs) are recommended as first-line treatment. The aim was to assess the safety profile of methylprednisolone administered intravenously for three consecutive days at 1g in patients with active, moderate-to-severe or sight-threatening Graves' orbitopathy. We retrospectively evaluated 161 medical records of patients with GO treated with high-dose systemic GCs in the Department of Endocrinology, Metabolic Disorders, and Internal Medicine in Poznań between 2014 and 2021. Clinical data included age, gender, laboratory results, activity and severity of GO, smoking status, disease duration, and presented side effects. The presence of mild side effects was observed during 114 (71%) hospitalizations. The most common complications were hyperglycemia (n = 95) and elevated aminotransferases (n = 31). Increased levels of aminotransferases were more likely observed in smokers and GO duration above 12months. Based on the multivariate logistic regression, higher TRAb and CAS values were significantly associated with lower odds of hyperglycemia. In turn, the increased odds of elevated aminotransferases were significantly correlated with higher initial ALT levels, female gender, and GO duration above 12months. In addition, the multidimensional correspondence analysis (MPA) showed that GO patients who declared smoking and had not L-ornithine L-aspartate applied demonstrated a higher probability of elevated aminotransferases. Active GO treatment with high-dose systemic GCs is not associated with serious side effects. Hyperglycemia is the most common steroid-induced complication.

Understanding the efficacy of frontline therapies for hepatocellular carcinoma through etiologic stratification.

491 Background: Despite significant advancements in recent years, hepatocellular carcinoma (HCC) treatment options remain limited for patients who progress on locoregional therapy. Given increasing interest in personalized cancer care for HCC, analysis was done to understand whether the etiology of HCC influenced the efficacy of four common first-line FDA approved systemic therapy regimens. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 1/1/2003 to 8/1/2021 with 3519 HCC patients who have received either atezolizumab-bevacizumab (AB), nivolumab, sorafenib, or lenvatinib as a first-line systemic therapy. Information on demographics (age, gender, sex race, ethnicity, ECOG, SES Index), cancer stage, and treatment type was collected. In addition, comorbidities of hepatitis B, hepatitis C, alcohol use, diabetes, and obesity were collected as surrogates for disease etiology: viral hepatic disease, alcohol induced hepatic dysfunction or non-alcoholic fatty liver disease (NAFLD). Patients with missing data in any of the population stratifying variables were excluded. Overall survival (OS), Progression-free-survival (PFS) and time to treatment discontinuation (TTTD) were analyzed for each systemic therapy stratified by etiology as endpoints. Kaplan-Meier (KM) univariate analysis was performed along with the log-rank test for the primary outcome. Multivariate analysis (MVA) was conducted on all three endpoints via cox proportional hazard model to adjust for possible covariates in the patient population. Results: After exclusion criteria, 548 patients with complete data were included (AB N=124, Sorafenib N=324, Lenvatinib N=61, Nivolumab N=39) with variable etiologic presence (hepatitis B N=14, hepatitis C N=50, alcohol use N=41, diabetes N=50, Obesity N=44). When comparing patients across all recorded systemic therapies stratified by the etiologic variables, there was no statistically significant difference in OS, PFS, or TTTD. When stratified by presence of Hepatitis B, patients treated with atezolizumab-bevacizumab trended towards improved outcomes but did not reach statistical significance (P = 0.064). Other treatments showed mixed results in relation to specific etiologies, but no clear trend in efficacy emerged. Conclusions: This early retrospective study suggests that systemic therapy for HCC is not significantly impacted by factors associated with the etiology of disease, such as hepatitis C, alcohol use, and obesity. However, small population sizes and potential nonrandom covariate missingness in this study may obscure effects. Future studies are needed to further elucidate this trend along with subpopulation effects of other systemic therapies.

Incidence of Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.

Systemic therapy with or without local intervention for oligometastatic oesophageal squamous cell carcinoma (ESO-Shanghai 13): an open-label, randomised, phase 2 trial

The efficacy of local therapy for patients with oligometastatic oesophageal squamous cell carcinoma is unclear. We aimed to assess the efficacy of local plus systemic therapy compared with systemic therapy alone in patients with oligometastatic oesophageal squamous cell carcinoma. The ESO-Shanghai 13 trial was a randomised, open-label, multicentre, phase 2 trial. Patients (aged ≥18 years) were recruited from six hospitals in China with histological confirmation of oligometastatic oesophageal squamous cell carcinoma with a controlled primary tumour and one to four metastatic lesions. Eligible patients were randomly assigned via a computer-generated schedule in a 1:1 ratio to receive either systemic therapy alone (ie, systemic therapy only group) or combined systemic and local therapy (ie, systemic and local therapy group). The systemic therapy regimens in both groups were at the discretion of the investigator and included chemotherapy alone, anti-PD-1 antibodies alone, or chemotherapy plus anti-PD-1 antibodies. Local therapy-radiotherapy, surgery, or thermal ablation-was delivered to all metastatic lesions for patients in the systemic and local therapy group. Randomisation was balanced dynamically on three factors: the number of disease sites, the lines of systemic therapy, and the location of the metastases. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, defined as the time from randomisation to progression or death from any cause in the intention-to-treat population. The safety population included all patients who had undergone random assignment and at least one of the intended therapies. This trial is registered with ClinicalTrials.gov, NCT03904927. The trial is ongoing but closed to new participants. 116 patients were screened for enrolment between March 5, 2019, and Sept 16, 2021, and 104 patients who met the eligibility criteria were randomly assigned to the systemic and local therapy group (n=53) or the systemic therapy only group (n=51). 20 (38%) patients in the systemic plus local therapy group and 23 (45%) patients in the systemic therapy only group received anti-PD-1 antibody-based systemic therapy; three patients in the systemic and local therapy group did not receive systemic therapy. At a median follow-up of 30·5 months (IQR 24·7-37·8), median progression-free survival was 15·3 months (95% CI 10·1-20·5) in the systemic and local therapy group versus 6·4 months (5·2-7·6) in the systemic therapy only group (stratified hazard ratio 0·26 [95% CI 0·16-0·42]; stratified log rank p<0·0001). Grade 1-2 acute oesophagitis was more common in the systemic and local therapy group than in the systemic therapy only group (10 [19%] vs one [2%] patients; p=0·036). The number of patients who had grade 3 or worse treatment-related adverse events was similar between groups (25 [47%] vs 21 [41%]; p=0·538), with the most common adverse events being leukocytopenia (17 [32%] vs 18 [35%]) and neutropenia (19 [36%] vs 20 [39%]). Treatment-related deaths occurred in two patients in the systemic and local therapy group and one patient in the systemic therapy only group. The addition of local treatment for metastases could significantly improve progression-free survival among patients with oligometastatic oesophageal squamous cell carcinoma being treated with systemic therapy. Our findings suggest that combining local and systemic therapy could be a treatment option for patients with oligometastatic oesophageal squamous cell carcinoma, but further support from phase 3 trials is required. Science and Technology Commission of Shanghai Municipality, National Nature Science Foundation of China, and Shanghai Municipal Health Commission. For the Chinese translation of the abstract see Supplementary Materials section.