Background: Anti-programmed death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 antibodies are efficacious in various malignancies. The potential role of dual checkpoint inhibitors in many rare solid tumors is not established. Objectives: This study presents the results of ipilimumab–nivolumab in salivary gland neoplasm cohorts of the SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) trial. Design: DART is a prospective, open-label, multicenter (1016 US sites), multi-cohort phase II trial of ipilimumab (1 mg/kg intravenously (IV) every 6 weeks) plus nivolumab (240 mg IV every 2 weeks). Methods: We performed a prospective, multicenter phase II clinical trial of ipilimumab (1 mg/kg IV every 6 weeks) plus nivolumab (240 mg IV every 2 weeks) in three salivary gland neoplasm cohorts: major and minor salivary gland and adenoid cystic cancers. Patients with adenoid cystic salivary gland tumors ( N = 26) and other salivary gland neoplasms ( N = 34) were evaluable. The most common site of origin was the parotid (31%, N = 8 adenoid cystic group; 68%, N = 23 remaining histologies). Results: In the adenoid cystic group, objective response rate (ORR), 4% (complete response (CR) 0%, N = 0; partial response (PR) 4%, N = 1); 6-month progression-free survival (PFS) and overall survival (OS), 32% (95% confidence interval (CI) 18%–57%) and 84% (95% CI 71%–100%), respectively. In the remaining histologic subtypes, the confirmed ORR was 9% (CR, 0%, N = 0; PR, 9%, N = 3); stable disease (SD) >6 months/PR/unconfirmed PR = 35%; 6-month PFS and OS, 34% (95% CI 21%–55%) and 88% (95% CI 78%–100%), respectively. The most common toxicities were fatigue (39%) and diarrhea (26%); diarrhea (8%) was the most common grade 3–4 immune-related adverse event. Conclusion: In salivary gland tumors, combined ipilimumab plus nivolumab resulted in only a 4% ORR in adenoid cystic carcinoma and 9% in all other histologies combined, though the latter showed clinical benefit (included SD >6 months) in 35% of patients. Trial registration: ClinicalTrials.gov registry: NCT02834013.

Treatment of sarcoma often leads to serious long-term health consequences, including decreased physical functioning. Supervised progressive resistance training (PRT) has been shown to improve physical functioning in survivors of carcinomas. We conducted a single-arm, pre-post study to assess the feasibility of remote delivery of a supervised, individualized resistance training program in sarcoma survivors. Survivors of extremity sarcomas who were more than 2 years from final sarcoma treatment with no evidence of recurrent disease were eligible. Participants followed a PRT program of exercises that were tailored to each patient’s exercise capacity. Each week for 12 weeks, participants engaged in one unsupervised session and one supervised session delivered remotely by videoconferencing. Feasibility was measured by retention rate, session completion rate, and safety. Changes in self-reported physical function, health-related quality of life, and fatigue were assessed with patient reported outcome measures, while objective physical function was assessed by the short physical performance battery (SPPB). The COVID pandemic emerged during the accrual period, requiring protocol modification to objective assessments. Ten participants aged 27–69 enrolled in the study; the majority had a lower extremity tumor (70

LBA5003 Background: Circulating miR371 has been reported in retrospective studies as a biomarker with high accuracy for predicting aGCM. However, large prospective data of miR371 in identifying early stage disease are missing. S1823/GCC.1 (NCT04435756) is an international prospective cohort study designed to define the operating characteristics of plasma miR371 in detecting tumor relapse in pts with early stage aGCM managed with active surveillance (AS). Methods: Serial plasma samples for miR371 assessment were obtained within 56 days from new diagnosis of GCM (baseline) and every 6-12 months (according to risk of relapse) during AS, for maximum 3 years or until relapse. Samples most proximate to relapse were analyzed. Control pts were histology-matched 2:1 to cases. miR371 was measured by RT-PCR and expression was analyzed both qualitatively and quantitatively. Sensitivity, specificity, positive and negative predictive value (PPV and NPV) were evaluated to define miR371 operating characteristics. Results: 948 eligible pts were enrolled from June 2020 to May 2024 (median f/u= 32.7 months). The CSI and IIA pts managed with AS (n=630) formed the cohort of interest. At the time of data cutoff, 103 pts (16.3% overall; 14.7% of seminoma; 19.3% of nonseminoma) had relapsed. Results are from the 224 pts selected for the pre-specified interim analysis. PPV/NPV for the whole cohort was 0.66 (95% CI: 0.51, 0.80)/0.90 (95% CI: 0.88, 0.92), for seminoma 0.58 (95% CI: 0.36, 0.80)/ 0.92 (95% CI: 0.90, 0.94), for nonseminoma 0.75 (95%CI: 0.58, 0.92)/0.86 (95% CI: 0.83, 0.89). Sensitivity increased with stage at relapse (IIA,IIB, IIC/III) (p = 0.07) (Table). Conclusions: S1823 achieved the primary objective of defining the operating characteristics of plasma miR371 during AS. In aggregate, S1823 results showed high specificity and NPV suggesting potential clinical utilities of miR371 in managing pts with germ cell tumors. Future miR371-informed interventional trials to integrate miR371 in clinical practice are either underway or planned. Clinical trial information: NCT04435756 . Operating characteristics of miR371. Group N (Cases; Controls) Sensitivity (95% CI) Specificity (95% CI) Median time to relapse (mo) 1 Median miR371 at relapse (log RQ) 2 Overall 224 (69; 155) 0.54 (0.42, 0.65) 0.94 (0.90, 0.97) 5.8 17.17 Seminoma 108 (33; 75) 0.52 (0.35, 0.69) 0.93 (0.88, 0.99) 7.4 16.89 Nonseminoma 116 (36; 80) 0.56 (0.39, 0.72) 0.94 (0.88, 0.99) 5.3 17.50 Low-risk 184 (48; 136) 0.52 (0.38, 0.66) 0.93 (0.89, 0.98) 6.6 17.15 Moderate-risk 40 (21, 19) 0.57 (0.36, 0.78) 0.95 (0.85, 1.00) 4.1 17.27 Stage at Relapse 3 IIA 23 0.39 (0.19, 0.59) — 6.8 16.89 IIB 28 0.57 (0.39, 0.76) — 5.7 17.32 IIC/III 16 0.69 (0.46, 0.92) — 5.3 17.37 1 From orchiectomy; 2 Amongst miR371+ cases; RQ: relative expression; 3 Stage at relapse unavailable for 2 pts whose relapse was identified by STM only.

BACKGROUND:Management of retroperitoneal liposarcoma (RPLPS) is challenging and recurrence rates remain high despite aggressive surgical resections. Preoperative radiation alone lacks definitive benefit, thus we sought to evaluate combined chemoradiotherapy with the potential to enhance local efficacy of radiation as well as control micrometastatic disease. We assessed the safety and tolerability of preoperative eribulin, a cytotoxic microtubule inhibitor approved for the treatment of advanced liposarcoma, in combination with radiation in patients with RPLPS. METHODS:In this open-label dose-finding study, patients with primary or recurrent resectable RPLPS received preoperative intensity-modulated radiation therapy (IMRT) with escalating doses of eribulin. Eribulin was administered for three 21-day cycles at a starting dose of 1.1 mg/m2. Concurrent radiation to 50.4 Gy began during cycle 1. Surgical resection occurred 3-10 weeks after completion of chemoradiation. The primary endpoint was determination of the recommended phase 2 doses (RP2D) of concurrent eribulin and radiation. RESULTS:Between 2018-2023, fifteen patients were enrolled. Thirteen patients were evaluable for dose-determination. Four patients treated at starting dose level had no dose-limiting toxicities (DLTs). Two of nine patients treated with escalated eribulin dose had DLTs. The RP2D was established as eribulin 1.4 mg/m2 and IMRT 50.4 Gy. Eleven patients were evaluable for secondary efficacy endpoints. The median recurrence-free survival was 30.4 months (95% CI 12.0-NR) and the median overall survival was 54.1 months (95% CI 9.5-NR). Patient reported outcome data did not show any significant changes over the study period. CONCLUSION:A preoperative chemoradiation protocol of eribulin in combination with IMRT showed a manageable safety profile and warrants additional prospective evaluation for treatment of resectable RPLPS.

OBJECTIVE:The SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial is the first basket study to include a sub-cohort assessing ipilimumab and nivolumab in patients with primary vaginal cancers with differing histology. METHODS:DART is a prospective, open-label, multicenter, multi-cohort phase II clinical trial of ipilimumab (1 mg/kg intravenously) 6 weekly plus nivolumab (240 mg intravenously) 2 weekly across multiple rare tumor cohorts, with the vagina cohort (any vaginal histology) reported here. The primary endpoint was objective response rate (ORR) per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease [SD] ≥6 months), and toxicity are secondary endpoints. RESULTS:Seven evaluable patients (median age, 60 years; performance status 0-1; no prior exposure to immunotherapy) were analyzed, of whom 3 had adenocarcinoma, 2 had squamous cell carcinoma (SCC), one had small-cell carcinoma and one had undifferentiated histology. The ORR was 29%, with 1 patient (14%) with undifferentiated histology achieving complete response (lasting 14.8 months) and 1 patient with SCC histology (14%) attaining a partial response (lasting 45.2 months). The CBR was 43%. The 6-month PFS rate was 43% and the median OS was 11.7 months. Five patients (71.4%) experienced an adverse event (AE) with 4 (57.1%) having grade 3-4 AE's. CONCLUSION:Ipilimumab plus nivolumab showed efficacy (ORR was 29% and CBR of 43%) and durability (one patient with prolonged SD >6 months) in a sub cohort of patients with vaginal cancer of differing histology without new safety signals. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02834013.

BACKGROUND:Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene. Patients report substantial pain, stiffness, and declining physical function; those whose disease is not amenable to surgery require systemic therapy. Vimseltinib is an oral, switch-control kinase inhibitor of the CSF1 receptor (CSF1R). Here, the authors report safety and efficacy of vimseltinib in patients with TGCT based on prior treatment. Cohort A included patients who did not receive prior specific anti-CSF1/CSF1R agents (n = 46; prior imatinib/nilotinib allowed), and cohort B included patients who received prior specific agents (n = 20). METHODS:The phase 2 (expansion) portion of this ongoing, multicenter, open-label, phase 1/2 study (NCT03069469) enrolled adults (≥18 years) with histologically-confirmed TGCT not amenable to surgery. Patients received vimseltinib 30 mg twice weekly (recommended phase 2 dose). The primary objectives were to assess safety and antitumor activity; secondary objectives included assessment of active range of motion (ROM) and patient-reported outcomes. RESULTS:Most treatment-emergent adverse events were grade 1/2, and there was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. Best overall response rates were 64% (29 of 45) and 37% (7 of 19) for cohorts A and B after mean follow-up of 23 and 19 months, respectively. Most patients experienced meaningful improvements in active ROM and patient-reported physical function, stiffness, health status, and pain. CONCLUSIONS:Vimseltinib had a manageable safety profile, demonstrated durable antitumor activity, and provided functional and symptomatic improvements in patients with TGCT, offering an effective treatment option regardless of previous treatment with anti-CSF1/CSF1R agents.

Background Dual anti-CTLA-4/PD-1 inhibitors show efficacy in numerous malignancies. We are the first to report on the efficacy of ipilimumab-nivolumab immunotherapy in a dedicated cohort of patients with gynecologic clear cell carcinomas (CCCs), which are rare, aggressive cancers.Methods DART is a multicenter, multicohort phase II trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks), with primary objective as Response Evaluation Criteria in Solid Tumors (RECIST)-based overall response rate (ORR). Secondary objectives were ORR by immune RECIST (iRECIST), progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease (SD) ≥6 months), and toxicity.Results Overall, in this cohort of 32 patients with gynecologic CCC (N=19 ovarian, N=8 endometrial, N=5 cervical; 1–8 prior therapies; 3 had prior PD-1 inhibitor exposure), an ORR of 9.38% was seen. This included two complete responses (CRs) (both ovarian origin) that are ongoing at >3 years and one partial response (PR). Overall ORR increased to 12.5% when including one PR by iRECIST criteria for a patient with cervical CCC lasting 26 months, with an OS of 32.0 months. The CBR was 21.88% overall for all 32 (7/32) evaluable patients with gynecologic CCC. This included two CR, one PR, and two patients with SD >6 months with ovarian CCC and one PR by iRECIST and one SD >6 months in two patients with cervical CCC. PFS for the seven patients with CBR was 63.6+, 47.8+, 40.5+, 50.8+, 7.4, 26, and 58.1+ months. Median OS was 21.7 months for all 32 evaluable patients. Seven of 32 patients (21.9%) discontinued therapy because of toxicity; there were no treatment-related deaths.Conclusions Ipilimumab plus nivolumab demonstrated durable antitumor activity in certain patients with CCC of gynecological origin, particularly in those with CCC of ovarian origin. Safety is consistent with the known profile of ipilimumab and nivolumab. Correlative studies to better identify which patients will respond to combined ipilimumab and nivolumab are ongoing.Trial registration number NCT02834013.

BACKGROUND:The combined use of anti-programmed cell death protein 1 (PD-1)/anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint inhibitors has been effective in various cancer types. The Southwest Oncology Group (SWOG) Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The purpose of the study was to evaluate the potential clinical benefit of ipilimumab and nivolumab in patients with SCCOHT. METHODS:DART was a prospective, open-labeled, multicenter (>1,000 US sites), multi-cohort phase II clinical trial of intravenous administration of ipilimumab (1 mg/kg, every 6 weeks) plus nivolumab (240 mg, every 2 weeks). The primary endpoint was overall response rate [ORR, confirmed complete response (CR) and partial response (PR)] per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease ≥6 months), and toxicity. Immune responses were also evaluated. RESULTS:Six patients (median age, 30.5 years; median, 2 prior therapies; no prior immunotherapy exposure) with advanced/metastatic SCCOHT were evaluable. ORR and CBR were both 16.7% (1/6) with one patient having a confirmed CR lasting 46.2+ months. However, another patient had a confirmed immune CR (iCR) with immune PFS (iPFS) of 53+ months [ORR/iORR, 33.3% (2/6)]. Notably, the latter patient had a progressing lesion at 24 weeks after initial response, but with renewed regression with ongoing therapy, suggesting delayed pseudo-progression. At 12-months, 3 patients remained alive. Median PFS was 1.4 months (range, 0.9 months-not reached); median OS was 14.2 months (2 months-not reached). No adverse events caused treatment discontinuation. CONCLUSION:Two of 6 patients (33.3%) with SCCOHT achieved durable CR/iCR and long-term survival with ipilimumab plus nivolumab. Correlative studies to determine response and resistance markers are ongoing.

BackgroundPexidartinib is effective in patients with tenosynovial giant cell tumor (TGCT) for whom surgery is not feasible. Durability of response after discontinuation of pexidartinib and the safety and efficacy of restarting pexidartinib have not been previously recorded. This phase 4 study was designed to mimic the real-world experience with pexidartinib to evaluate the effects of discontinuation of and retreatment with pexidartinib in patients with TGCT who previously benefited from the drug.MethodsThis was a global, multicenter, phase 4 study that enrolled patients with TGCT who were experiencing clinical benefit from pexidartinib in one of four prior phase 1 or phase 3 studies investigating pexidartinib in the disease. Patients could choose to continue pexidartinib at the same dose (the treatment-continuation cohort) or discontinue treatment with the option to restart pexidartinib (the treatment-free/retreatment cohort). Tumor progression determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, patient-reported outcomes (the Patient-Reported Outcomes Measurement Information System-Physical Function [PROMIS-PF] questionnaire and the EuroQol 5-dimension, 5-level [EQ-5D-5L] visual analog scale), and safety were assessed every 3 months. The primary end point was the proportion of patients in the treatment-free/retreatment cohort who remained treatment-free at month 12 and 24; this did not depend on disease progression.ResultsThirty-two patients were enrolled: 21 chose to enter the treatment-continuation cohort, and 11 entered the treatment-free/retreatment cohort. During the treatment-free period, six of 11 (54.5%) patients in the treatment-free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1, whereas no patient in the treatment-continuation cohort had disease progression. Over the 24-month study, three of 11 (27.3%) patients in the treatment-free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symptomatic progression, or both (n = 1 each). The probability of remaining treatment-free in the treatment-free/retreatment cohort was 73% (95% confidence interval, 37%-90%). In the treatment-free/retreatment cohort, the median progression-free survival of the treatment-free period was 22.8 months (95% confidence interval, 1.6 months to not estimable). By 6 months of retreatment, all retreated patients achieved new disease stabilization with no new safety concerns; two patients had clinically significant improvements in PROMIS-PF and EQ-5D-5L visual analog scale scores. The mean PROMIS-PF and EQ-5D-5L scores remained stable throughout the study. There was no hepatotoxicity and no new safety signal in either cohort.ConclusionsIn this small phase 4 study designed to evaluate outcomes in patients who stopped and restarted pexidartinib, 54.5% of patients who discontinued pexidartinib showed PD, with a median progression-free survival of 22.8 months. Each of the three patients who restarted pexidartinib stopped progressing, and some reported a new gain in physical function. No PD was detected in patients who remained on treatment, and the safety profile did not indicate long-term hepatotoxicity or any new safety concerns.Plain Language Summary Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended. This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed. Thirty-two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years. Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened. Restarting pexidartinib was safe and effective in these patients.

PURPOSE:SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort. EXPERIMENTAL DESIGN:Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites. RESULTS:19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited. CONCLUSIONS:Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients. TRIAL REGISTRATION NUMBER:NCT02834013.

Abstract Purpose: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART) trial presents initial results of ipilimumab/nivolumab in vulvar cancers. Patients and Methods: DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR; confirmed complete response and partial response (PR)] per RECISTv1.1, whereas progression-free survival (PFS), overall survival, clinical benefit rate (CBR; ORR plus stable disease ≥6 months), and toxicity were secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years; 0–6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. The ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); the PFS was 34.1, 16.7. 15.5, 7.2, and 7.0 months for these five patients, respectively. The median PFS and overall survival were 2.2 and 7.6 months, respectively. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3 to 4 adverse events occurred in 25% of patients (n = 4). There was one grade 1 to 2 adverse event (6.7%) that led to discontinuation and one (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in 3 of 16 patients, all of whom had durable responses lasting over 1 year. Notably, two additional patients experienced durable stable disease and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.

BACKGROUND:Malignant perivascular epithelioid cell tumors (PEComas) are ultra-rare, aggressive mesenchymal neoplasms associated with poor outcomes. Standard-of-care systemic therapy includes mammalian target of rapamycin (mTOR) inhibition and chemotherapy. Immune checkpoint inhibition has not been previously studied in patients with advanced PEComas in a prospective clinical trial. METHODS:This is an open-label phase 2 trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) in rare tumors; here we report the cohort of patients with advanced malignant PEComa recruited from >1,000 sites across the USA. Primary end point was objective response rate, with progression-free survival, overall survival, and toxicity as secondary end points. RESULTS:17 patients were enrolled (N=16 evaluable). Median age was 59.5 years (range, 22-77 years) and the majority were female (81%). Best responses included partial response (18.8%), stable disease for <6 months (25.0%), and progressive disease (56.3%). Median OS was 7.5 months (95% CI 3.4 to 34.6) and median PFS was 1.9 months (95% CI 1.8 to 11.8). PFS in responding patients was 11.8, 18.9, and 34.6 months. Available genomic sequencing showed TSC, ATRX, and TP53 mutations; no TFE3 fusions were identified (N=7). Nearly all patients experienced a treatment-related adverse event (AE) of any grade, while 37.5% experienced a grade 3-4 AE. Most common AEs were fatigue (43.8%), pruritus (37.5%), rash (25.0%), and aspartate aminotransferase increase (25.0%). There were no grade 5 AEs. CONCLUSIONS:The combination of ipilimumab and nivolumab demonstrated responses in 18.8% of patients with advanced malignant PEComas. Dual immunotherapy may be an alternative treatment option for certain patients, including those who are unable to tolerate or do not desire prolonged treatment with chemotherapy or mTOR inhibition or have failed to respond to other therapies. Ipilimumab and nivolumab warrants further investigation in this and other rare soft tissue sarcomas.

BACKGROUND:Pexidartinib is approved in the US, Taiwan, and Korea for adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery based on the phase III ENLIVEN study (NCT02371369). We report the final long-term efficacy and safety results from ENLIVEN. METHODS:Adults with symptomatic TGCT not eligible for surgery were enrolled and randomized to pexidartinib or placebo (part 1). The blinded phase (part 1) ended at week 25; patients received pexidartinib (800 mg/day) until progression, toxicity, or study completion (part 2). This analysis includes patients who received pexidartinib at any time during ENLIVEN. Centrally reviewed overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and tumor volume score (TVS), time to response, duration of response (DOR), patient-reported outcomes (PROs), and long-term safety were assessed. RESULTS:Overall, 91 patients received pexidartinib. With a median follow-up of 31.2 (range: 2-66) months, ORR was 60.4% and 68.1% by RECIST and TVS, respectively. Median DOR by RECIST was not reached (range: 0.03-63.4 months). Most responses were within the first 6 months of treatment; most responders were on 800 mg vs 600/400 mg dose levels, respectively. Throughout parts 1 and 2, 3 (3%) patients had progressive disease per RECIST without dose reduction/interruption. PROs improved or were maintained. The most common grade 3/4 treatment-emergent adverse events were aspartate aminotransferase (AST) increase (9%), alanine aminotransferase (ALT) increase (10%), and hypertension (8%). Twenty-eight (31%) patients had AST or ALT ≥3 times the upper limit of normal (ULN); 17 (19%) patients had AST or ALT ≥5 times the ULN. No new safety signals were observed after long-term pexidartinib treatment. CONCLUSIONS:Final long-term ENLIVEN results demonstrated that pexidartinib sustained clinical benefit, with increased ORR by RECIST and TVS compared to the end of the blinded phase at week 25. No new safety signals were reported.

SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) administered ipilimumab and nivolumab to patients with primary vaginal cancers. DART is a prospective, open-label, multicenter, multi-cohort phase II clinical trial of ipilimumab (1 mg/kg intravenously) every six weeks plus nivolumab (240 mg intravenously) every two weeks. The trial was carried out by the Early Therapeutics and Rare Cancers Committee (NCI/SWOG) and opened at >1000 sites. Cohort 33 included patients with vagina cancers only. The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] (RECISTv1.1), progression-free survival (PFS), and overall survival (OS); clinical benefit rate [CBR: ORR plus stable disease (SD)>6 months] and toxicity were secondary endpoints. Seven evaluable patients (median age, 60 years; performance status 0-1; no prior exposure to immunotherapy) were analyzed (adenocarcinoma, N=3; squamous cell carcinoma (SCC) (N=2); small cell carcinoma and undifferentiated histology (N=1 each). The ORR was 29%: one, CR (undifferentiated) (lasting 14.8 months); one, PR (SCC) (lasting 45.2 months). The CBR was 43% (3/7 patients) (included one adenocarcinoma with 8 months SD). The 6-month PFS rate was 43%; median OS, 11.7 months. Five patients (71.4%) experienced an adverse event (AE); four, a grade 3-4 AE including one patient (14.3%) with elevated liver function tests leading to drug discontinuation. The most common AEs (any grade, at least possibly related to treatment) were cough (42.9%), fever (42.9%) and diarrhea (42.9%). Ipilimumab plus nivolumab in vaginal cancers resulted in an ORR of 29% and CBR of 43% including one CR, one PR and one patient with 8 months of stable disease; the longest response lasted 45.2 months. Further prospective studies exploring the role of both monotherapy and dual immunotherapy in vaginal cancers are warranted. Young K. Chae, Josie Czeskleba, Sandip P. Patel, Alex Menter, William Robinson, Nathaniel L. Jones, Murtuza Rampurwala, Aung Naing, Joseph M. Beck, Carolyn Moloney, Liam IL-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Sara Threlkel, Megan Othus, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: Vaginal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT092.

PURPOSE:Doxorubicin is the first-line treatment for metastatic soft-tissue sarcomas. Ribociclib, a cyclin-dependent kinase 4/6 intargets the retinoblastoma pathway to induce cell-cycle arrest at the G1-S cell-cycle checkpoint. We hypothesized that administering ribociclib prior to doxorubicin to synchronize cell-cycle progression among tumor cells may enhance the efficacy of doxorubicin. PATIENTS AND METHODS:Doxorubicin-naïve patients with metastatic soft-tissue sarcoma were enrolled in this phase Ib study. Every 21 days, subjects received ribociclib daily for 7 days followed by 3 days of no treatment before administration of doxorubicin. The primary objective was to establish the recommended phase II dose of the sequenced drug combination. Secondary objectives included progression-free survival and objective response rate. Exploratory correlative studies assessed pharmacokinetic and pharmacodynamic measures. RESULTS:Of 38 screened patients, 16 were enrolled and 15 were evaluable for dose determination. The most common reason for exclusion was lack of normal retinoblastoma protein expression. At dose level 0 (ribociclib 400 mg and doxorubicin 75 mg/m2), four of seven patients experienced febrile neutropenia as a dose-limiting toxicity. Of the eight patients treated at dose level -1 (ribociclib 400 mg and doxorubicin 60 mg/m2), one had a dose-limiting toxicity of grade 4 anemia. Three patients achieved partial response (objective response rate, 20.0%). Ribociclib pharmacokinetic levels were lower than predicted. Levels of phosphorylated retinoblastoma protein in on-treatment tumor biopsy tissue were variable and did not correlate with ribociclib plasma levels. CONCLUSIONS:The recommended phase II dose is ribociclib 400 mg followed by doxorubicin 60 mg/m2, which demonstrated an acceptable toxicity profile.

We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19–50%), and the 12-month OS, 75% (95% CI, 57–100%). Median PFS was 9.3 months (95% CI, 3.3–NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013 ).

BACKGROUND AND OBJECTIVE:EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology. METHODS:Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms. KEY FINDINGS AND LIMITATIONS:Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC.

Abstract Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in rare solid cancers is yet to be established. This study presents the first results of ipilimumab and nivolumab in the sarcomatoid carcinoma of lung cohort (#11) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Fourteen evaluable patients (median age, 64 years) with sarcomatoid carcinoma lung tumors were analyzed. ORR was 28.6% (4/14) with 1 CR and 3 PRs. The patient with CR has a duration of response (DoR) and OS of 32.4+ months. Three patients with PR showed 100% regression with resolution of one of two non-measurable non-target lesions (DoR 36.8 months), 92% regression (DoR 6.6 months), and 52% regression (DoR 23.0+ months), respectively. Clinical benefit rate (CBR; no progression > 6months) was 50.0% (7/14). The median PFS was 6.1 months, median OS was 10.9 months. The most common adverse events were fatigue and dyspnea (46.2%, n=6 each), and pruritus and hypothyroidism (30.8%, n=4 each). Grade 3-4 adverse events occurred in 30.8% of patients (n=4). There were no adverse events that led to discontinuation. There was one grade 5 adverse event due to respiratory failure. Conclusion: Ipilimumab plus nivolumab in sarcomatoid carcinoma of lung resulted in an ORR of 28.6% and CBR (SD>6 months/PR/CR) of 50.0%, with PFS of 36.9, 32.4+, 23.0+, 17.0, 13.3, 6.6, and 6.6 months. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies are warranted. Citation Format: Young Kwang Chae, Megan Othus, Sandip Patel, Peeran Sandhu, Larry R. Corum, Jeremy P. Cetnar, Shayan Rayani, Anna Moseley, Liam Il-Young Chung, Hye Sung Kim, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: sarcomatoid carcinoma of lung (cohort 11) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT262.