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Mantle cell lymphoma (MCL) is a rare lymphoma with a median age at diagnosis of 60-70 years. Front line therapy has traditionally been bendamustine-rituximab (BR) in older patients and then Bruton Tyrosine kinase inhibitors (BTKi) for relapsed disease. Due to their efficacy, BTKi are now being combined with chemotherapy as induction treatment. The TRIANGLE trial of R-CHOP/R-DHAP +/- ibrutinib +/- transplant showed the benefit of adding a BTKi in young patients (Dreyling M, 2022). The SHINE trial, a phase III trial of BR +/- ibrutinib in patients >65 years, showed a significant improvement in median PFS (81 months vs. 53 months) (Wang M, 2022). However, this came with an increase in toxicity with more treatment related deaths in the ibrutinib arm (11% vs. 6%) and no difference in overall survival. Therefore, a better tolerated approach is still needed in older patients. A phase II study of rituximab + indefinite ibrutinib in 50 patients >65 years demonstrated efficacy of frontline BTKi with a 96% ORR and 71% CR (Jain P, 2021). However, a disadvantage of BTKi therapy is continuous treatment until disease progression or intolerance. In this study half of patients required dose reductions and almost a third of patients stopped treatment due to drug toxicity, most frequently atrial fibrillation or bleeding. If front line intermittent BTKi therapy is as effective as continuous therapy, it could minimize cumulative toxicity. A052101 (NCT05976763), an Alliance for Clinical Trials in Oncology trial, is a randomized phase 3 multicenter trial of upfront zanubrutinib that asks the question “in older patients with previously untreated MCL who obtain a CR with zanubrutinib-rituximab, is it safe and equally effective to stop treatment and restart it upon disease progression rather than continuing indefinitely?” The A052101 trial is enrolling pts with previously untreated MCL who are either >70 years old or 60-69 years old but are not transplant candidates due to cardiac ejection fraction <45%, DLCO <60% of predicted, creatinine clearance <70, Eastern Cooperative Oncology Group (ECOG) performance status of >2, or a Cumulative Illness Rating Scales score of >6. Key exclusion criteria include: history of a severe bleeding disorder or clinically significant cardiac arrhythmias. Patients will take zanubrutinib 320 mg daily and rituximab/rituximab biosimilar once monthly for 6 cycles. Patients with less than partial response after 6 cycles will go off study treatment. Patients with a complete remission will be randomized in a 1:1 manner to intermittent treatment versus continuous treatment. Randomization will be stratified by age (60-69 years vs ≥70 years) and MIPI score. Those randomized to the continuous arm will receive zanubrutinib until intolerance or disease progression. Those randomized to the intermittent arm will stop all study drugs after those initial 6 cycles and will restart zanubrutinib at first disease progression and continue it until intolerance or second disease progression. In order to make the study results generalizable to clinical practice, disease progression will be defined by clinical parameters rather than minimal residual disease testing. The primary objective of this study is to compare time from randomization to first progression or death (PFS1) in the continuous treatment arm to the time to second progression or death (PFS2) in the intermittent treatment arm. The primary evaluation will be to determine whether, for patients in a CR, active monitoring followed by retreatment with zanubrutinib therapy upon disease progression will result in non-inferior clinical outcomes compared to indefinite zanubrutinib. Serial quality of life testing and adverse event monitoring will be performed throughout the study to gain a full understanding of the impact of continuous vs intermittent zanubrutinib on patients' lives. A052101 has the potential to change management of older patients with previously untreated MCL. If our study demonstrates that the time to second progression/death when using the stop and retreat strategy is non-inferior to time to first progression/death when using continuous BTK therapy, then it might lead to a new standard of care in this patient population. This could result in decreased health care costs, decreased toxicity and improved quality of life for older patients with mantle cell lymphoma. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org

Background: Myxoid liposarcoma predominantly affects young and middle-aged individuals, and little is known regarding treatment tolerability and outcomes in older patients. This study aims to better understand this older patient population. Methods: This single institution retrospective study included patients aged 70 years and older with localized (non-metastatic) myxoid liposarcoma. Results: Sixteen patients were included. The median age was 75 years, and 9 (56%) were female. Fourteen (88%) were extremity tumors and two (12%) were trunk. The median tumor size was 10.4 cm (range, 3.6 to 28 cm). Five (31%) tumors had a round cell component. All patients had surgery. Fourteen (88%) had perioperative radiation, and three (19%) had perioperative chemotherapy. One patient had postoperative infection, and one patient had neutropenic fever from preoperative chemotherapy. The median follow up from surgery was 6.3 years. Eight (50%) patients died from MLPS. The median relapse-free survival and overall survival were 34 months and 75 months, respectively. Conclusions: Most older patients with localized MLPS received perioperative radiation therapy with surgery, and few serious toxicities were reported. Even with treatment, half of the patients relapsed.

Background: Synovial sarcoma is rare and may present as a small, slow-growing mass. These tumors are often mistaken as benign and are therefore prone to unplanned and/or non-oncologic excision. We sought to identify the rate of unplanned excision of synovial sarcoma and risk factors for recurrence and survival among this cohort. Methods: The medical records of 246 patients evaluated at a single institution for synovial sarcoma between 1997 and 2022 were retrospectively reviewed. Of these, 87 (35%) underwent unplanned, non-oncologic excision. The mean age of the cohort was 49 years. Primary tumors were located in the extremity (n = 63), abdomen (n = 6), thorax (n = 7), head/neck (n = 8), and paraspinal region (n = 3). The median maximum pre-treatment dimension of the primary tumor was 4.8 cm (IQR 7–2.4). Seventy-seven (86%) patients underwent re-excision of the tumor bed, 39 (45%) received chemotherapy, and 63 (72%) received radiation therapy. Results: Among patients who underwent unplanned excision, local recurrence-free survival (LRFS) was 98% at 1 year and 82% at 5 years. Metastasis-free survival (MFS) was 91% at 1 year and 72% at 5 years. Disease-specific survival (DSS) was 98% at 1 year and 72% at 5 years. When adjusting for tumor size, tumors which underwent unplanned excision did not have worse recurrence or survival compared to those which had planned excision (p > 0.10). Size > 5 cm, monophasic subtype, and axial location were associated with increased risk of disease recurrence. Forty-six patients had residual tumor following re-excision, which was associated with worse MFS (HR 8.17, 95% CI [1.89, 35.2], p < 0.01) and DSS (HR 7.66, 95% CI [1.76, 33.4], p < 0.01). Patients who received radiotherapy had improved MFS (HR 6.4, 95% CI [1.42, 29.0], p = 0.02) and DSS (HR 5.86, 95% CI [1.27, 26.9], p = 0.02). Conclusions: One-third of patients presenting with synovial sarcoma were diagnosed after unplanned, non-oncologic excision. Patients with large, axial tumors had worse survival. Approximately half of patients who underwent unplanned excision had no residual tumor after pre-operative radiation. The use of radiation was associated with decreased rates of recurrence and improved disease-specific survival. Our results suggest that margin-negative re-resection and radiotherapy should be considered when feasible following unplanned excision of synovial sarcoma.

11514 Background: The role of immunotherapy remains uncertain in most sarcomas. We recently showed significant antitumor benefit for cabozantinib (C) with N in AS previously treated with a taxane. Since chemotherapy-immunotherapy combinations may synergize, and paclitaxel remains a standard of care option for advanced AS, we hypothesized that P+N would be more effective than P alone. Methods: We report Arm 1 (P+N) and Arm 2 (P) of this open label, multi-arm, phase II study. Pts all had locally advanced/metastatic AS, and no prior taxane (including adjuvant) or checkpoint inhibitor prior to entry. Pts were randomized 1:1 (stratified scalp/face vs other) to receive P 80 mg/m2 on days 1, 8, 15 every 4 weeks (wks), with (Arm 1) or without (Arm 2) N (480 mg intravenously every 4 wks). A pt could remain on study beyond disease progression (PD), after the initial 12 wk evaluation (4 wk confirmatory scan required), but responses were censored at 12 wks. Primary endpoint was progression-free survival (PFS) comparing P+N to P, with an assumed improvement from a median of 4 to 7 months with N added to P (power = 85.3%, alpha = 0.148, and one interim analysis (Wieand rule) for futility planned after 30 events). Secondary endpoints were overall response rate (ORR), adverse events (AEs), overall survival (OS), and pt reported outcomes (PRO). At PD, Arm 2 (P) pts were permitted to receive C+N. Results: 62 evaluable pts (P+N = 30, P = 32 pts) were balanced for age, race, ECOG PS 0 vs. 1, site of disease (including radiation related vs. not), while P+N had more females (60%) and P had more males (63%). Median PFS for P+N was 7.2 mo (5.3-17 mo), and 8.3 mo (4.0-18 mo) for P (hazard ratio (HR) 1.01 (95%CI: 0.55-1.9), p = 0.96). Median PFS for scalp/face was 16 mo (95%CI: 10-NR) for P+N and 8.3 mo (95%CI: 3.7-NR) for P. Median PFS for all others was 5.5 mo (95%CI 4.3-16) for P+N, and 6.0 mo (95%CI 4.1-NR) for P. Median OS was 18 mo (13-NR) in P+N, and 23 mo (15-NR) in P (HR 1.3 (95%CI: 0.63-2.7), p = 0.48). Overall confirmed ORR: P+N = 33% (10/30 pts, with 4 partial responses (PR) and 6 complete responses (CR) with scalp/face ORR = 73%, all others ORR = 11%). Overall ORR for P = 34% (11/32 pts, with 7 PR and 4 CR, with scalp/face ORR = 38%, all others ORR = 26%). Grade 3-4 AEs regardless of attribution occurred in 57% of P+N, and 44% of P, most commonly ( > 10%) fatigue, AST increase, and dyspnea for P+N (n = 3 each), and anemia (n = 4) for P. Conclusions: P alone can be an effective therapy in a subset of pts with AS. The combination of P+N failed to demonstrate improvement in median PFS over P alone, but may show benefit in scalp/face AS. OS trended better with P alone. No new safety signals were observed. The impact of weekly steroid premedication prior to P+N on these outcomes remains to be determined. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; NCT04339738. https://acknowledgments.alliancefound.org . Clinical trial information: NCT04339738 .

Abstract Background Radiation‐associated soft tissue sarcomas (RA‐STS) are rare complications of patients receiving radiation therapy (RT) and are generally associated with a poor prognosis. Most of the literature surrounding RA‐STS of the chest is centered on angiosarcoma. Therefore, we aim to document the management and outcome of patients with non‐angiosarcoma RA‐STS of the chest. Methods We reviewed 17 patients (all female, median age 65 years) diagnosed with RA‐STS. The most common primary malignancy was breast carcinoma ( n = 15), with a median RT dose of 57.9 Gy. All patients underwent surgical resection; five patients (29%) received radiotherapy; and five patients (29%) received peri‐operative chemotherapy. Results The 5‐year local recurrence and metastatic‐free survival were 61% and 60%, while the 5‐year disease‐specific survival was 53%. Local recurrence was associated with death due to disease (HR 9.06, p = 0.01). Complications occurred in nine of patients, most commonly due to a wound complication ( n = 7). At the most recent follow‐up, the median Musculoskeletal Tumor Society Score was 63%. Conclusion RA‐STS involving the chest wall are aggressive tumors with a high risk of local relapse and death due to disease. Local recurrence was associated with death due to disease; as such, we recommend aggressive surgical management with evaluation for adjuvant therapies.

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

AbstractIntroductionIncreasingly, early‐stage non–small cell lung cancer (NSCLC) is treated with stereotactic body radiation therapy (SBRT). Although treatment is generally effective, a small subset of tumors will recur because of radioresistance. Preclinical studies suggested PI3K‐AKT‐mTOR activation mediates radioresistance. This study sought to validate this finding in tumor samples from patients who underwent SBRT for NSCLC.MethodsPatients with T1‐3N0 NSCLC treated with SBRT at our institution were included. Total RNA of formalin‐fixed paraffin‐embedded tumor biopsy specimens (pretherapy) was isolated and analyzed using the Clariom D assay. Risk scores from a PI3K activity signature and four published NSCLC signatures were generated and dichotomized by the median. Kaplan–Meier curves and Cox regressions were used to analyze their association with recurrence and overall survival (OS). The PI3K signature was also tested in a data set of resected NSCLC for additional validation.ResultsA total of 92 patients were included, with a median follow‐up of 18.3 months for living patients. There was no association of any of the four published gene expression signatures with recurrence or OS. However, high PI3K risk score was associated with higher local recurrence (hazard ratio [HR], 11.72; 95% CI, 1.40–98.0; p = .023) and worse disease‐free survival (DFS) (HR, 3.98; 95% CI, 1.57–10.09; p = .0035), but not OS (p = .49), regional recurrence (p = .15), or distant recurrence (p = .85). In the resected NSCLC data set (n = 361), high PI3K risk score was associated with decreased OS (log‐rank p = .013) but not DFS (p = 0.54).ConclusionsThis study validates that higher PI3K activity, measured by gene expression, is associated with local recurrence and worse DFS in early‐stage NSCLC patients treated with SBRT. This may be useful in prognostication and/or tailoring treatment, and merits further validation.

11503 Background: Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes. Methods: This open-label multi-arm study enrolled pts with locally advanced/metastatic AS. Arm 3, reported here, enrolled pts who had received a taxane for AS (including adjuvant) prior to study enrollment. Pts were not restricted on number of prior lines, but prior anti-VEGF and immunotherapies were not allowed. Eligible pts received C (40 mg po daily) with N (480 mg IV every 4 wks). Treatment was permitted beyond progressive disease (PD) in the 1st 12 wks (4 wk confirmatory scan), but PD response was censored at 12 wks. The Simon 2-stage design (null and alternative overall response rate (ORR) were 10% and 35%, respectively) required ≥1 confirmed response in 9 pts in the 1st stage, and >4 of 18 pts (91.4% power, alpha 0.095) for the primary endpoint. Secondary endpoints were adverse events (AEs), progression free, overall survival (PFS, OS), and pt-reported outcomes (PRO). Results: 21 eligible pts [median age 66 yrs (32-92), 10 female] received ≥1 dose of C+N. Primary disease sites: 12 cutaneous (scalp/face), 1 liver, 2 breast, 6 other. All pts received prior taxanes (11/21 = 52% as adjuvant therapy) and 5/21 (24%) had also received prior anthracycline (all relapsed AS). Primary endpoint: 13 of the first 18 evaluable patients (72%) experienced objective response (OR, 95%CI: 47%-90%). After a median follow-up of 11.2 mo, 13 of 21 pts achieved OR (11 partial response, 2 complete), for ORR 62% (95%CI: 38-82%). Responses were seen in pts with primary cutaneous disease 7/12 (58%) and noncutaneous disease 6/9 (67%). Median PFS was 9.6 mo (5.3-NR), and OS 20.5 mo (14.4-NR). Off treatment reasons include: progressive disease (14), comorbid condition unrelated to AS or study (1); 6 pts remain on study. Grade (G) 3 hypertension was the only possibly treatment related AE (TRAE) occurring in ³10%. No G 4/5 TRAE were reported. Conclusions: C + N demonstrated significant antitumor activity in taxane-pretreated AS and was well tolerated without new safety concerns. Activity of the combination was seen across AS subtypes. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; U10CA180820; https://acknowledgments.alliancefound.org . U10CA180868; U10CA180888. NCT04339738. Clinical trial information: NCT04339738 .

Introduction Carfilzomib dosing as a single agent or in combination with dexamethasone (Kd) has evolved from the initial 27 mg/m 2 twice-weekly (legacy dose), to more recently approved doses of 56 mg/m 2 twice-weekly and 70 mg/m 2 once-weekly (optimized doses). The objective of this study was to evaluate the overall survival (OS), and time to next treatment (TTNT) among multiple myeloma patients treated with Kd optimized vs legacy doses. Methods A retrospective analysis of patients receiving Kd between 01/01/2013–07/31/2017 was conducted using IQVIA’s oncology electronic medical records database. Kd dose was estimated based on body surface area. OS was measured from the Kd-initiation date until death. TTNT was defined as the time from Kd-initiation until the start of subsequent treatment. Kaplan-Meier analysis and Cox models were used to evaluate OS and TTNT. Results Of the 1,469 patients evaluated, 129 (8.8%) received optimized dose and 1,340 (91.2%) received legacy dose. Risk of mortality was 64% lower for patients receiving the optimized doses (HR: 0.36, 95% CI: 0.178–0.745). Patients receiving the optimized doses had significantly longer TTNT compared to patients receiving the legacy dose (median TTNT: 17.5 months [95% CI: 14.8-NE] and 13.2 months, [95% CI: 12.4–14.4], respectively; p = 0.023), and 33% lower risk of progressing to the subsequent treatment (HR: 0.67, 95% CI: 0.48–0.93). Conclusions Patient outcomes could be improved if eligible MM patients are treated with the optimized, recently approved Kd doses (56 mg/m 2 twice-weekly and 70 mg/m 2 once-weekly).