Absence Of Progression Research Articles

Dichloroacetate and chloroquine in combination with arsenite suppress ROS-induced oral squamous cell carcinoma (OSCC) development and improve BALB/c mice survival.

Oral squamous cell carcinoma (OSCC) is a disabling tumor with poor response to chemotherapy. Here, we sought to explore a new chemotherapeutic approach based on a combined induction of cytotoxic ROS and targeting of autophagy and aerobic glycolysis as central contributors to OSCC carcinogenesis and chemoresistance. To this end, tongue OSCC was generated in BALB/c mice using 4NQO. Treatment of mouse-derived OSSC explants with NaAsO2 resulted in a strong inhibition of MTT activity and Bcl-2 and Ki-67 expression. The addition of chloroquine (CQ) and dichloroacetate (DCA) to arsenite, resulted in additive inhibitory effects on Bcl-2 and Ki-67 expression. Whereas NaAsO2 alone inhibited aerobic glycolysis (LDHA), it also alleviated autophagy (LC3B) and ROS levels (MDA). DCA improved NaAsO2-dependent inhibition of aerobic glycolysis. CQ addition to arsenite, suppressed autophagy without affecting the Warburg effect. NaAsO2 combination with CQ and DCA improved the oxidative status balance by boosting anti-oxidative CAT and SOD and controlling pro-oxidant MDA activity. The administration of the combo to 4NQO-mice resulted in a significant survival advantage over the control group (90% vs. 35% survival at week 32, p< 0.02; HR (log-rank) = 0.166, CI 95% 0.03-0.73). This effect was accompanied by a significant increase in mice's mean body weight (p< 0.009). Contrarily to the control, administration of the combo resulted in the absence of progression towards severe dysplasia and OSCC and an overrepresentation of low/mild dysplasia events (100%). Interestingly, signs of hepatocellular and renal toxicity following combo administration were limited in comparison to control. Taken together, these results suggest that NaAsO2 combined with CQ and DCA may constitute an interesting alternative to eliminating chemo-resistant OSSC tumors by inhibiting aerobic glycolysis and autophagy and controlling ROS generation. In vivo, the drugs may provide a survival advantage by inhibiting tumor development.

40 Gray in 5 Fractions for Salvage Reirradiation of Spine Lesions Previously Treated With Stereotactic Body Radiotherapy.

A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed. We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk. Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%. In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario.

A phase I study of the combination of atezolizumab, tiragolumab, and stereotactic body radiation therapy in patients with metastatic multiorgan cancer

BackgroundImmunotherapy targeting the PD-1/PD-L1 pathway is a standard of care in a number of metastatic malignancies, but less than a fifth of patients are expected to respond to ICIs (Immune Checkpoint Inhibitors). In a clinical trial, combining the anti-TIGIT (T cell immunoreceptor with Ig and ITIM domains) Mab (monoclonal antibody) tiragolumab with atezolizumab improved outcomes in non-small cell lung cancer. In preclinical models, SBRT (Stereotactic Body Radiation Therapy) could increase expression levels of the inhibitory co-receptors TIGIT and PD-L1. We aim to assess the combination of tiragolumab with atezolizumab and SBRT in metastatic, previously treated by ICIs, non-small cell lung cancer, head and neck cancer, bladder cancer, and renal cell cancer.MethodsThis phase I study (ClinicalTrials.gov NCT05259319) will assess the efficacy and safety of the combination of atezolizumab with tiragolumab and stereotactic body radiation therapy in patients with histologically proven metastatic non-small cell lung cancer, renal cell cancer, bladder cancer, and head and neck cancer previously treated. First part: 2 different schedules of SBRT in association with a fixed dose of atezolizumab and tiragolumab will be investigated only with metastatic non-small cell lung cancer patients (cohort 1). The expansion cohorts phase will be a multicentric, open-label study at the recommended scheme of administration and enroll additional patients with metastatic bladder cancer, renal cell cancer, and head and neck cancer (cohort 2, 3 and 4). Patients will be treated until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient refusal in the absence of progression or intolerance. The primary endpoint of the first phase is the safety of the combination in a sequential or concomitant scheme and to determine the expansion cohorts phase recommended scheme of administration. The primary endpoint of phase II is to evaluate the efficacy of tiragolumab + atezolizumab + SBRT in terms of 6-month PFS (Progression-Free Survival). Ancillary analyses will be performed with peripheral and intratumoral immune biomarker assessments.Trial registrationThis study is registered on ClinicalTrials.gov: NCT05259319, since February 28th, 2022.

Association Between Duration of Immunotherapy and Overall Survival in Advanced Non–Small Cell Lung Cancer

For patients with advanced non-small cell lung cancer (NSCLC) treated with frontline immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown. To assess practice patterns surrounding ICI treatment discontinuation at 2 years and to evaluate the association of duration of therapy with overall survival in patients who received fixed-duration ICI therapy for 2 years vs those who continued therapy beyond 2 years. This retrospective, population-based cohort study included adult patients in a clinical database diagnosed with advanced NSCLC from 2016 to 2020, who received frontline immunotherapy-based treatment. The data cutoff was August 31, 2022; data analysis was conducted from October 2022 to January 2023. Treatment discontinuation at 2 years (between 700 and 760 days, fixed duration) vs continued treatment beyond 2 years (greater than 760 days, indefinite duration). Overall survival from 760 days was analyzed using Kaplan-Meier methods. Multivariable Cox regression that adjusted for patient-specific and cancer-specific factors was used to compare survival beyond 760 days between the fixed-duration group and the indefinite-duration group. Of 1091 patients in the analytic cohort who were still on ICI treatment at 2 years after exclusion criteria for death and progression were applied, 113 patients (median [IQR] age, 69 [62-75] years; 62 [54.9%] female; 86 [76.1%] White) were in the fixed-duration group, and 593 patients (median [IQR] age, 69 [62-76] years; 282 [47.6%] female; 414 [69.8%] White) were in the indefinite-duration group. Patients in the fixed-duration group were more likely to have a history of smoking (99% vs 93%; P = .01) and be treated at an academic center (22% vs 11%; P = .001). Two-year overall survival from 760 days was 79% (95% CI, 66%-87%) in the fixed-duration group and 81% (95% CI, 77%-85%) in the indefinite-duration group. There was no statistically significant difference in overall survival between patients in the fixed-duration and indefinite-duration groups, either on univariate (hazard ratio [HR] 1.26; 95% CI, 0.77-2.08; P = .36) or multivariable (HR 1.33; 95% CI, 0.78-2.25; P = .29) Cox regression. Approximately 1 in 5 patients discontinued immunotherapy at 2 years in the absence of progression. In a retrospective clinical cohort of patients with advanced NSCLC who were treated with immunotherapy and were progression-free at 2 years, approximately only 1 in 5 discontinued treatment. The lack of statistically significant overall survival advantage for the indefinite-duration cohort on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years.

Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer (BTC): BilT-02.

4113 Background: Gemcitabine, cisplatin and durvalumab followed by maintenance durvalumab is standard of care first-line (1L) therapy for patients (pts) with advanced BTC. In this trial, we investigated the combination of a PARP inhibitor with anti-PD1 antibody in absence of progression after at least 4 months of standard 1L platinum-based chemotherapy. Methods: Pts with advanced BTC, ECOG PS 0-1 and absence of progression on 1L platinum-based therapy were enrolled on a phase 2 trial to receive rucaparib 600 mg PO BID in combination with nivolumab 240 mg IV Q2 weeks every 28 days for up to 2 years. The primary endpoint was 4-month progression-free survival (PFS) rate from the date of first study treatment with an alternative hypothesis of 85%. Secondary endpoints included median PFS and overall survival (OS) from first study treatment (PFS1, OS1) as well as from start date of first-line chemotherapy (PFS2, OS2), best overall response, and safety. Results: 31 pts were enrolled of which 14 (45%) were women, 25 (80.6%) Caucasian and 24 (77.64%) with ECOG 1. Primary disease site was intrahepatic, extrahepatic hilar and distal, and gallbladder cancer in 21 (67.7%), 4 (12.9%), 1 (3.2%) and 4 (12.9%), respectively. 1L platinum-based treatment included gemcitabine/cisplatin based in 26 (83.9%), FOLFOX in 3 (9.7%) and carboplatin/paclitaxel in 1 (3.2%) pts. Mean (range) cycles of rucaparib and nivolumab were 6.75 (1-24) and 5.9 (1-24). The median follow-up time is 28.7 months using reverse censoring methodology. PFS rate at 4 months was 54.8% (95% CI, 36-70.3), comparable to the 63% null estimate based on ABC-02 trial. Median PFS1 and OS1 are estimated to be 4.6 months (95% CI, 3.7-6.2) and 15.9 months (95% CI, 9.8-24.1). Median PFS2 and OS2 calculated from date of 1L chemotherapy are estimated as 9.9 months (95% CI, 8.3-11.3) and 21.4 months (95% CI, 14.8-26.7). Two (6.4%) pts had partial response (with IDH R132G and KRAS G12D) as best response with stable disease in an additional 22 (71%) pts. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 15 (48.4%) pts, including 1 patient who died on therapy due to possibly-related immune-related myocarditis. The most common grade 2 or greater TRAEs included fatigue (9, 29.0%), anemia (7, 22.6%), neutropenia (6, 19.3%), elevated AST (5, 16.1%) and elevated ALT (4, 12.9%). Reasons for treatment discontinuation included death (2), progression (27), adverse event (1) while 1 patient completed 2 years of study treatment. Conclusions: The primary endpoint of PFS rate at 4 months was not met but the preliminary measures of PFS1 and OS1 are much longer than expected, and hypothesis generating for rational combination of PARP inhibitor with maintenance immunotherapy in this rare cancer. Exploratory endpoint of association of genomic analysis with efficacy is ongoing and will be discussed. Clinical trial information: NCT03639935 .

Prophylactic cerebral irradiation or active brain magnetic resonance imaging surveillance in small-cell lung cancer patients (EORTC-1901: PRIMALung).

TPS8614 Background: PRIMALung is an EORTC-sponsored study. Primary objective is to show that overall survival with brain MRI surveillance alone is non-inferior to brain MRI surveillance combined with PCI in patients with SCLC. PCI is currently SOC in most institutions, but can be associated with neurocognitive toxicity and impact quality of life. 600 patients will be recruited from 50 EORTC centres in 10 countries. This study is currently recruiting and will play an important role in clarifying whether MRI surveillance is a viable strategy in SCLC. Furthermore, it will answer important questions about the role of PCI in the era of immunotherapy, particularly in ES-SCLC. Methods: Key eligibility: ECOG performance status ≤ 2 patients with SCLC (Limited or Extensive-Stage, stage I-IV) who did not progress after (≤ 16 weeks from day 1 of last cycle of chemotherapy to randomisation) completed standard therapy. Absence of progression, brain metastases or leptomeningeal disease after completing therapy. Trial Interventions: Patients will be randomised 1:1 to receive brain MRI surveillance with or without PCI (25Gy in 10 fractions). Primary objective - to show that overall survival with brain MRI surveillance alone is non-inferior to brain MRI surveillance combined with PCI. Secondary objectives - cognitive failure-free survival, quality of life and acute/late toxicities according to CTCAE v5.0. The trial was open to recruitment on 27/10/2022. Three countries open to date (Belgium, Switzerland, UK). Further sites in France, Poland and Austria will be open to recruitment Q1 2023. The first patient has been randomized on the 4th of January 2023. Further information: https://clinicaltrials.gov/ct2/show/NCT04790253 contact: 1901@EORTC.org. Clinical trial information: NCT04790253 .

Trabectedin failure-free survival (TFFS) after resuming trabectedin (T) in advanced myxoid liposarcoma (MLPS) patients.

11573 Background: To explore the time to trabectedin failure-free survival after resumption of T in advanced MLPS patients who were stable or responding to T at the time of discontinuation. Methods: We retrospectively collected the cases of all patients with advanced MLPS treated with T at our institution from September 2002, highlighting those who were free from progression (according to RECIST) after 6 cycles of T. Trabectedin failure-free survival (TFFS) was defined as time from the first cycle of T to progression (PD) or death, whichever occurred first. Survival analyses were performed using the Kaplan-Meier method. Results: Since September 2002, 75 patients with recurrent myxoid liposarcoma received T at our institution. A total of 56 patients were free from progression (according to RECIST) after 6 cycles of T and were included in this analysis. Among them, 25/56 (45%) interrupted their treatment in absence of progression, while 31/56 (55%) patients received T until progression of disease. In the former group, 11/25 had surgery of their residual disease, 3/25 received radiotherapy, 5/25 interrupted T for toxicity and 6/25 patients shared the decision to stop with the clinician. Among patients who received surgery, 2/11 had monofocal disease (longest diameter &lt; or = 5cm), 4/11 had monofocal disease (longest diameter between 10-18 cm) and 5/11 had plurifocal disease. The interruption of T in these 25 patients occurred after a median of 12 cycles (interquartile range = 9-14). Median TFFS was 43.4 months (95%CI 38.7-NA). In the concurrent group of patients who received T continuously, the median TFFS was 14.2 months (95% CI: 10.8-21.9). Conclusions: While the longer TFFS of patients undergoing discontinuation cannot be compared with the shorter of those who did not interrupt, the former group being biased favorably (feasibility and exploitation of surgery, other likely determinants of physician’s decision to stop), we speculate that there may be a subgroup of selected patients with advanced myxoid liposarcoma primarily responding to T, who could benefit from a “stop and go” policy, thus prolonging the overall time interval within which T remains active. Prospective studies in selected subgroups of MLPS patients on optimization of treatment strategy with T are worthwhile.

TROPHY-U-01 Cohort 4 (C4): Sacituzumab govitecan (SG) in combination with cisplatin (cis) as first-line (1L) therapy, followed by maintenance avelumab plus (+) SG or zimberelimab (zim) + SG in patients (pts) with treatment (Tx)-naïve metastatic urothelial cancer (mUC).

TPS4611 Background: SG is a Trop-2–directed antibody-drug conjugate. In the TROPHY-U-01 study, SG monotherapy showed a 27% objective response rate (ORR) and 10.9 months median overall survival (OS) with an overall manageable safety profile in pts with mUC who received platinum (PT)-containing chemotherapy and a checkpoint inhibitor (CPI), resulting in accelerated FDA approval in this population. PT-based chemotherapy followed by avelumab maintenance is standard 1L therapy in pts with Tx-naïve mUC. Zim (anti–PD-1) is a CPI under clinical investigation for antitumor activity. C4 of TROPHY-U-01 will evaluate safety, tolerability, and clinical activity of SG+cis followed by maintenance avelumab+SG or zim+SG in cis-eligible pts with Tx-naïve mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 study. C4 will evaluate 1L SG in combination with cis in pts with cis-eligible mUC or unresectable locally advanced disease. Eligibility requirements include ECOG PS 0-1; no prior anticancer monoclonal antibody within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic and hepatic function. Pts will be treated with cis at 70 mg/m2 on D1 of 21-D cycles (if creatinine clearance [CrCl] ≥60 mL/min) or at an optional split dose of 35 mg/m2 on D1 and D8 of 21-D cycles (if CrCl 50-59 mL/min), followed by SG (5, 7.5, or 10 mg/kg, based on 10-pt safety lead-in of a 3+3 design) on D1 and D8 of 21-D cycles. Granulocyte colony-stimulating factor support is not allowed in the safety lead-in but was permitted during escalation and expansion. SG+cis will continue for up to 6 cycles, followed by maintenance (4 to 8 wk after last induction dose of SG+cis and when RP2D is determined) in the absence of progression. Dose escalation maintenance consists of avelumab 800 mg q2w, then SG 10 mg/kg on D1 and D8 of 21-D cycles. Dose expansion maintenance consists of zim 360 mg (D1 of a 21-D cycle) and SG 10 mg/kg (D1 and D8 of 21-D cycles) and will begin once safety lead-in of 6-8 pts receiving zim+SG of a 21-D cycle in Cohort 5 is deemed safe and completed. Pts will continue Tx until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per RECIST v1.1 by central review. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per central review and investigator assessment. OS and safety will also be evaluated. All statistical analyses will be performed using a two-sided hypothesis test approach at the overall 5% level of significance. Time to event endpoints will be assessed via the Kaplan-Meier method. Enrollment is ongoing; up to 57 pts expected across ~120 sites in North America and Europe. Clinical trial information: NCT03547973 .

Serial lung ultrasound in monitoring viral pneumonia: the lesson learned from COVID-19.

Lung ultrasound (LUS) has proven to be useful in the evaluation of lung involvement in COVID-19. However, its effectiveness for predicting the risk of severe disease is still up for debate. The aim of the study was to establish the prognostic accuracy of serial LUS examinations in the prediction of clinical deterioration in hospitalised patients with COVID-19. Prospective single-centre cohort study of patients hospitalised for COVID-19. The study protocol consisted of a LUS examination within 24 h from admission and a follow-up examination on day 3 of hospitalisation. Lung involvement was evaluated by a 14-area LUS score. The primary end-point was the ability of LUS to predict clinical deterioration defined as need for intensive respiratory support with high-flow oxygen or invasive mechanical ventilation. 200 patients were included and 35 (17.5%) of them reached the primary end-point and were transferred to the intensive care unit (ICU). The LUS score at admission had been significantly higher in the ICU group than in the non-ICU group (22 (interquartile range (IQR) 20-26) versus 12 (IQR 8-15)). A LUS score at admission ≥17 was shown to be the best cut-off point to discriminate patients at risk of deterioration (area under the curve (AUC) 0.95). The absence of progression in LUS score on day 3 significantly increased the prediction accuracy by ruling out deterioration with a negative predictive value of 99.29%. Serial LUS is a reliable tool in predicting the risk of respiratory deterioration in patients hospitalised due to COVID-19 pneumonia. LUS could be further implemented in the future for risk stratification of viral pneumonia.

Safety and efficacy of salvage conventional re-irradiation following stereotactic radiosurgery for spine metastases.

There has been limited work assessing the use of re-irradiation (re-RT) for local failure following stereotactic spinal radiosurgery (SSRS). We reviewed our institutional experience of conventionally-fractionated external beam radiation (cEBRT) for salvage therapy following SSRS local failure. We performed a retrospective review of 54 patients that underwent salvage conventional re-RT at previously SSRS-treated sites. Local control following re-RT was defined as the absence of progression at the treated site as determined by magnetic resonance imaging. Competing risk analysis for local failure was performed using a Fine-Gray model. The median follow-up time was 25 months and median overall survival (OS) was 16 months (95% confidence interval [CI], 10.8-24.9 months) following cEBRT re-RT. Multivariable Cox proportional-hazards analysis revealed Karnofsky performance score prior to re-RT (hazard ratio [HR] = 0.95; 95% CI, 0.93-0.98; p = 0.003) and time to local failure (HR = 0.97; 95% CI, 0.94-1.00; p = 0.04) were associated with longer OS, while male sex (HR = 3.92; 95% CI, 1.64-9.33; p = 0.002) was associated with shorter OS. Local control at 12 months was 81% (95% CI, 69.3-94.0). Competing risk multivariable regression revealed radioresistant tumors (subhazard ratio [subHR] = 0.36; 95% CI, 0.15-0.90; p = 0.028) and epidural disease (subHR = 0.31; 95% CI, 0.12-0.78; p =0.013) were associated with increased risk of local failure. At 12 months, 91% of patients maintained ambulatory function. Our data suggest that cEBRT following SSRS local failure can be used safely and effectively. Further investigation is needed into optimal patient selection for cEBRT in the retreatment setting.

Abstract P1-11-19: A real-world evidence study of treatment patterns in patients with HER2-positive metastatic breast cancer who have received at least 2-lines of therapy

Abstract Background. Standard-of-care treatment for HER2-positive metastatic breast cancer (HER2+ mBC) patients has traditionally included targeted therapies such as trastuzumab and/or pertuzumab in first line (1L) and ado-trastuzumab emtansine (T-DM1) in the second line (2L). In 2021, fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu®) was approved following DESTINY-Breast 03 trial results, demonstrating a significant reduction in the risk of progression compared to T-DM1 in 2L. Contemporary data on treatment patterns and clinical outcomes for HER2+ mBC patients after their 1L therapy in a real-world setting is limited and would help understand whether all eligible patients receive optimal and timely targeted therapies. This study aimed to report 2L treatment patterns and outcomes among HER2+ mBC patients in the United States (US). Methods. Adult HER2+ mBC patients with ≥2 lines of therapy were identified from the Syapse Learning Health Network (LHN) database; a longitudinal US oncology database integrating data from community health systems, labs and other external sources. Included patients initiated 2L treatment for metastatic disease between January 2014-February 2021 (index date), allowing for 12-months of follow-up. Descriptive statistics for patient characteristics, treatment patterns including prior metastatic treatments, time to treatment discontinuation (TTD), and reasons for 2L discontinuation were reported. Results. Of the 15,241 breast cancer patients in the LHN with abstracted data, 312 HER2+ mBC patients received ≥2L treatment. The patients were mostly White (69%) or African American (21%), median age of 59 years (interquartile range [IQR], 50-66) at start of 2L. The African American population was typically diagnosed young (median age 50 [IQR, 44-61] vs. 54 [IQR, 46-62] years) with stage IV disease at initial diagnosis (69% vs 62%) versus Whites. Majority of the 312 patients had stage IV disease at initial diagnosis (62%); most common sites of metastasis at mBC diagnosis were bone (52%), distant lymph node(s) (38%), liver (36%) and brain (10%). The median length of follow-up was 22 months (IQR, 13-37), 54% had initiated their 2L therapy since 2018. Majority of the 312 patients had received a trastuzumab-based (T-based) regimen in 1L (78%). Among the 312 patients, 37% had received only 2 lines of therapy in the metastatic setting, 28% received 3 and 35% received ≥4 lines of therapy. In 2L, 89% of the 312 patients received a HER2-targeted treatment (monotherapy or combination); the most frequent 2L regimens included T-DM1 monotherapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Subsequently, 197 of the 312 patients (63%) received 3L therapy. Among these 197 patients, T-DM1 monotherapy (19%), T-DXd monotherapy (10%) and capecitabine/lapatinib (8%) were the most frequently reported 3L regimens. Around 88% (n=274) of the 312 patients discontinued their 2L therapy. Median TTD of 2L from index date was 7.2 months (95% CI, 6.5-8.9); median TTD was 10.6 months (95% CI, 7.4-14.0) among a sub-group of patients who received a T-based regimen in their 2L (N=116). Approximately 47% of patients discontinued their 2L regimen due to progression/worsening of cancer, 17% discontinued from intolerance/toxicity in the absence of progression. Conclusions. This study suggests the treatment trajectory of US HER2+ mBC patients is variable in the real world clinical practice. Approximately two-thirds of the 2L patients had to receive a subsequent therapy and disease progression was the most common reason for 2L treatment discontinuation, reflecting a remaining need to improve outcomes for patients in 2L HER2+ disease. Citation Format: Della Varghese, Giovanna I. Cruz, Colden Johanson, Liz Toland, Miguel Miranda, Eleanor C. Faherty, David Harland, Henry G. Kaplan. A real-world evidence study of treatment patterns in patients with HER2-positive metastatic breast cancer who have received at least 2-lines of therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-19.

TROPHY-U-01 cohort 6: Sacituzumab govitecan (SG), SG plus zimberelimab (ZIM), SG plus ZIM plus domvanalimab (DOM), or carboplatin (CARBO) + gemcitabine (GEM) in cisplatin-ineligible patients (pts) with treatment-naive metastatic urothelial cancer (mUC).

TPS592 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 via a proprietary hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). The results led to accelerated FDA approval of SG for this population. ZIM (anti-PD-1) and DOM (anti-TIGIT) are CPIs under clinical investigation for anti-tumor activity. Cohort 6 of TROPHY-U-01 trial (C6) will assess SG monotherapy vs SG plus CPI combinations (SG + ZIM; SG + ZIM + DOM) vs CARBO/GEM followed by avelumab maintenance in treatment naive cis-ineligible pts with locally advanced or mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. C6 includes pts with cis-ineligible unresectable locally advanced or mUC who are ≥18 y; have an ECOG performance status 0-1; have available tissue for biomarker testing; have no prior mUC therapy, except (neo)adjuvant chemotherapy with recurrence &gt;12 mo from completion; are CPI-naive or &gt;12 mo from completion; have adequate hematologic and hepatic function; and have creatinine clearance ≥30 mL/min. A safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk. A second safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk + DOM 1200 mg q3wk. After the safety lead-in, pts will be randomized 1:2:2:2 to: Arm 1: SG 10 mg/kg on D1 and D8 of a 21-D cycle; Arm 2: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk; Arm 3: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk and DOM 1200 mg q3wk; and Arm 4: CARBO (AUC 4.5-5) on D1 of each 21-D cycle + GEM 1000 mg/m2 on D1 and D8 of each 21-D cycle for the first 4-6 cycles followed by switch maintenance avelumab 800 mg q2wk in the absence of progression. All pts will continue treatment until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per central review based on RECIST 1.1. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate by central review and investigator review, as well as ORR by investigator review, and OS, and safety and tolerability (Arms 1-3). C6 aims to enroll an estimated 226 pts. With 60 subjects each in Arms 2-4, a comparison of Arm 2 or 3 vs Arm 4 will have ~88% power at one-sided α of 0.05 to demonstrate an improvement in ORR, with a null hypothesis of ORR 40% for Arms 2-3 and an alternative hypothesis of ORR at 65% for Arms 2-4. Clinical trial information: NCT03547973 .

40 Gray in 5 Fractions for Salvage Re-Irradiation of Spine Lesions Previously Treated with Stereotactic Body Radiotherapy

<h3>Purpose/Objective(s)</h3> This is a retrospective single-center analysis of the safety and efficacy of re-irradiation to 40 Gray (Gy) in 5 fractions in patients previously treated with stereotactic body radiotherapy (SBRT) to the spine. <h3>Materials/Methods</h3> We identified 62 consecutive patients with various solid malignancies treated between January 2016 and December 2021 to 40 Gy in 5 fractions regardless of dose and fractionation at the first course of SBRT. Patients were followed clinically and with routine imaging. Acute (≤3 months) and late (>3 months) toxicities were assessed according to CTCAE v5.0. Local control was defined as absence of progression within the treated target volume. Time to progression was calculated from date of completion of SBRT to the date of an imaging study indicating progression. The probability of local progression before death was estimated using a cumulative incidence curve, and death without local progression was considered a competing risk. <h3>Results</h3> Most patients had oligometastatic disease (53.2%) and treated to the thoracic spine (51.6%). The most common fractionation regimen in the first course of SBRT was 27 Gy in 3 fractions, and the median time to re-irradiation was 13.1 months (range, 2.4-86.9 months). Twenty-four patients (38.7%) had surgery before re-irradiation. At time of simulation, 49 patients (79%) had epidural disease, including 19, 13, 12 and 5 patients with epidural spinal cord compression (ESCC) scale 1a, 1b, 1c and 2, respectively. Accordingly, myelogram simulations were performed in 82.2% of patients. Both the vertebral body and posterior elements were treated in 93.5% of patients. All early toxicities were low grade, apart from one case of grade 3 fatigue, one case of grade 3 diarrhea and one case of grade 3 pneumonitis. Five patients experienced a pain flare (8.1%). Two thirds of patients who reported pain at baseline, achieved improvement (33%) or complete resolution of pain (33%). About 40% of patients had at least a partial response in magnetic resonance imaging (MRI). At a median follow up time of 11.9 months (range, 1.8- 39.6 months), six patients (9.7%) suffered local progression. The median time to progression was 4.1 months (range, 1.93-13.8 months). The estimated incidence rate of local progression before death at 6-months and 12-months was 7%. Five patients (8.1%) developed radiation-related neuropathy (grade 1, 2 and 3 in two, one and two cases, respectively). No patient suffered grade 4 or higher late toxicity. The vertebral compression fracture rate was 16%. Three patients (4.8%) eventually underwent kyphoplasty and two patients underwent surgery (3.2%) for vertebral fractures. <h3>Conclusion</h3> Re-irradiation with 40 Gy in 5 fractions seems safe and effective for the salvage of lesions progressing after a previous course of SBRT in a cohort of patients with extensive disease involvement. Prospective randomized trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Persistent lymph nodes after curative chemoradiotherapy for head and neck cancer: imaging predictors of response for decision-making.

To identify response predictors in patients with head and neck squamous cell carcinoma (N + HNSCC) and persistent lymph nodes after curative chemoradiotherapy treatment (CCRT). Consecutive patients with N + HNSCC treated with CCRT and persistent lymph nodes at first follow-up between 2015 and 2021 were identified and analyzed. Complete response was defined as the absence of lymph node metastatic involvement in patients with salvage lymphadenectomy or the absence of progression after 1 year of successive follow-ups. Tumour type and location, staging, and human papillomavirus (HPV) status were considered for analysis. The number and size of lymph nodes, type, shape, enhancement and margins on diagnostic and follow-up CT were also analyzed. The cohort included 46 patients with 134 pathological lymph nodes. Logistic regression models showed the following variables to be significant: performance of salvage lymphadenectomy (OR 0.094, [CI 95% 0.004-0.61], p = 0.037); the type of lymphadenopathy on diagnostic CE-CT (solid vs. cystic) (N1: OR = 4.11, [CI 95% 1.11-17.93], p = 0.042 and N3: OR 6.42, [CI 95% 1.2-42.56], p = 0.036); the change of shape (round to oval) on the follow-up CE-CT (OR 9.76, [CI 95% 1.79-8.57], p = 0.016) and the time in days between CCRT and the first follow-up CE-CT (OR 1.06, [CI 95% 1.004-1.13], p = 0.048). In our experience, the presence of solid lymph nodes on pre-treatment CT and the change in shape from round to oval on post-treatment CT are predictors of response to treatment in patients with N + HNSCC persistent lymph nodes after CCRT. Increasing the temporal interval between treatment and follow-up CT should be considered to avoid unnecessary nodal dissections.

P7.01: Selecting Candidates for Multi-Visceral Transplantation in Neuroendocrine Tumors (NET) of the Gastrointestinal Tract: A Review of Two Cases

Introduction: Neuroendocrine tumors (NETs) are rare neoplasms arising neurologic or endocrine tissues. These tumors can be seen in nearly any organ system, though they mostly would be present in the gastrointestinal and respiratory systems. In this study, we report two cases of multi-visceral transplantations (MVT) in NET and discuss our indications for MVT among NET patients. Methods and Results: Case 1: A 44-year-old lady referred with a complaint of acute abdominal pain and small bowel obstruction symptoms in June 2018. In laparotomy, an obstructive jejunal mass, a huge retroperitoneal lesion involving the mesentery and liver, was found. A partial resection of the jejunal mass and palliative anastomosis of the bowel was performed. Histopathologic examinations revealed a well-differentiated NET [G1 (ki67:1%)]. The patient underwent MVT. She developed an entero-cutaneous fistula ten days after the surgery which was managed. After which the patient was relatively well till February 2021, when she was admitted with severe watery diarrhea. Severe mucosal ulcerations were seen in endoscopy, and rejection was confirmed through pathologic assessments. The patient died despite our efforts. Case 2: A 46-year-old man who had been suffering from vague abdominal pain and dyspepsia was referred to our clinic in February 2021. He gave a history of 5 kilograms weight loss in the preceding six months. Computed tomography (CT) showed a large lobulated heterogeneously enhancing mass about 150*90 mm in the pancreas with extension to the liver hilum and involvement of spleen and stomach, and signs of partial port vein thrombosis. The pathologist reported a well-differentiated NET (G2, ki67<15%, mitosis 1-2/10 HPF). Exploratory laparotomy, performed in May 2021, showed locally advanced pancreatic NET with celiac encasement and involvement of stomach and colon and portal vein thrombosis with varicose veins and portal hypertension, but no evidence of hepatic metastases. MVT was performed in June 2021. The grafts, including stomach, duodenum, liver, pancreas, and small bowel, were implanted. One month later, the patient complained of diarrhea, 3rd-grade acute T-cell rejection, in a small bowl biopsy was reported. However, the liver biopsy was insignificant. Favorably the patient responded well to the treatment, and after six months, closure of ostomy was performed. The patient is alive and well to this day. Conclusion: We propose the following criteria for MVTx in NETs: Well-differentiated NETs; absence of progression in the last six months; extensive porto-mesenteric thrombosis; intestinal failure with liver metastases; Both superior mesenteric artery and celiac trunk involvement; absence of extra-abdominal involvement that is confirmed by Ga-68 dotatate scan. We should note that this was a case report and larger series are required to support our conclusion.

Delayed reconstruction of the bladder and rectum after evisceration of the pelvic organs in patients with relapse of malignant neoplasms and radiation injuries (2 clinical observations)

The study presents two clinical observations of delayed reconstructive surgeries: 1) in a patient with recto-bladder fistula formed after a course of external beam therapy due to recurrent prostate cancer; 2) in a patient with progressing cervical carcinosarcoma, tumor invasion in the bladder wall, and metastases in the rectoperineal lymph nodes. Absence of standards of care, algorithms of diagnostic and surgical manipulations for this patient category creates a need for personalized approach to the stated problems. An interdisciplinary meeting allows to realize a plan of surgical help for these patients to address oncological process and complications of its treatment. At the reconstructive stage, we used techniques of formation of a new continent heterotopic reservoir from the ileocecal segment and coloanal anastomosis. The presented clinical observations are interesting due to delayed stage of reconstructive interventions which in the absence of progression of the main disease allows to perform correcting operations to improve patients’ quality of life.

Durvalumab (D) plus tremelimumab (T) immunotherapy in patients (Pts) with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy (CTx): Interim results of the IMMUNOBIL GERCOR D18-1 PRODIGE-57 study.

4108 Background: D (anti-PDL1) plus T (anti-CTLA-4) combination immunotherapy showed encouraging results in hepato-biliary cancers. Its efficacy in non-Asian Pts with pretreated BTC is unknown. Methods: IMMUNOBIL GERCOR-D18-1 PRODIGE-57 was initially a 2-arm, open-label, randomized non-comparative phase II study. Pts with recurrent/advanced pathologically proven BTC (intrahepatic cholangiocarcinoma [iCCA]/extrahepatic CCA [eCCA]/gallbladder cancer [GC]), ECOG PS 0-1, pre-treated with platinum-based CTx were randomized (1:1) to D (1500 mg Q4W) plus T (75 mg Q4W x 4 cycles [T75]) (Arm A) or D plus T in combination with weekly paclitaxel (Arm B). Arm B was closed prematurely for toxicity after inclusion of 10 Pts. The study continued with Arm A only. It was further amended to modify the T schedule (300 mg at cycle 1 [T300], amended Arm A) due to higher efficacy reported in other tumors as compared to T75 mg x 4. The new primary endpoint was the overall survival (OS) rate at 6 months (M6) in amended Arm A (D + T300) with a Fleming two-stage design (H0: 50%, H1: 65%, one-sided alpha: 5%, power: 90%). A total of 100 evaluable Pts were required (efficacy threshold: 59%). We present here the efficacy data of Arm A (D + T75). Results: From 12/2018 to 12/2020, 106 Pts were included in Arm A; 103 were evaluable for OS at M6. Median age was 66 years, 47% were male, 46% had ECOG PS 0, 69%/18%/13% had iCCA/eCCA/GC, 76% had metastatic disease, and 28% had prior tumor resection. First-line CTx was GEMCIS/GEMOX/5-FU-based/other in 63%/22%/4%/11%. The M6-OS rate was 59.2%. With a median follow-up of 12 months (95% Cl 11.4-14.9), the median OS was 8.0 months (95% Cl 5.7-11.7) and median PFS was 2.5 months (95% Cl 2.0-3.2). Complete response (CR) was observed in 2 (1.9%) Pts, partial response (PR) in 8 (7.8%), and stable disease (SD) in 32 (31.1%), resulting in an objective response rate of 9.7% and a disease control rate of 40.8%. Absence of progression (PD, iRECIST) after 2 cycles (M6-OS rate: 84% vs 41%, median OS: 17.9 months vs 4.4 months) and CR/PR as a best overall response (M6-OS rate: 100% vs 84% and 39% for SD and PD, respectively) were associated with markedly prolonged OS. 65 (63.1%) Pts had ≥1 grade 3-4 (G3-4) adverse event (AE) and 22 (21.4%) had ≥1 G3-4 treatment-related AE (TRAE). The most commonly reported G3-4 AEs were fatigue (12.6%), abdominal pain (5.8%), and aspartate aminotransferase increase (5.8%) and G3-4 TRAEs were fatigue (4.9%) and diarrhea (2.9%). One death was possibly related to treatment. Conclusions: Although no statistical conclusions can be drawn from this exploratory analysis of Arm A, D+T75 reached the pre-defined threshold for efficacy, with no unexpected toxicity. Results from amended Arm A (D+T300, N = 106 additional Pts), quality of life, and ancillary studies are pending. Clinical trial information: NCT03704480.

Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update.

To update evidence-based guideline recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 545 articles. Outcomes of interest included efficacy and safety. Of the 545 publications identified and reviewed, 14 were identified to form the evidentiary basis for the guideline recommendations. HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab deruxtecan for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations. There is a lack of head-to-head trials; therefore, there is insufficient evidence to recommend one regimen over another. The patient and the clinician should discuss differences in treatment schedule, route, toxicities, etc during the decision-making process. Options include regimens with tucatinib, trastuzumab emtansine, trastuzumab deruxtecan (if either not previously administered), neratinib, lapatinib, chemotherapy, margetuximab, hormonal therapy, and abemaciclib plus trastuzumab plus fulvestrant, and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4-6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive or progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.Additional information is available at www.asco.org/breast-cancer-guidelines.

Comparing Outcomes of Oligometastases Treated with Hypofractionated Image-Guided Radiotherapy (HIGRT) with a Simultaneous Integrated Boost (SIB) Technique versus Metastasis Alone: A Multi-Institutional Analysis.

Simple SummaryHypofractionated image-guided radiotherapy (HIGRT) is a common method in which high doses of radiation are delivered to treat oligometastatic disease. We have previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. Both SIB and MA irradiation of oligometastases achieved high rates of tumor metastases control and similar pain control. Further investigation of this technique with prospective trials is warranted.Purpose: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. Methods: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan–Meier method and compared between the two techniques using the log-rank test. Results: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4–71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55–74%; p = 0.24)), disease-free survival (60% (95% CI: 40–75%; p = 0.40)), or overall survival (88% (95% CI: 73–95%; p = 0.26)), between the MA and SIB cohorts. Conclusion: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Comparative analysis of the results of surgical correction of idiopathic thoracic scoliosis in patients with active bone growth

Objective. To conduct a comparative analysis of surgical treatment results for idiopathic thoracic scoliosis in patients during active bone growth and to identify the most effective methods of scoliosis correction for the considered age group.Material and Methods. The results of surgical treatment of 343 patients aged 10–14 years with continued active growth and progressive idiopathic thoracic scoliosis were analyzed. The patients were operated on in 1998–2018 using five surgical techniques: hybrid fixation with and without anterior stage, transpedicular fixation, and laminar fixation with and without anterior stage.Results. Statistically significant deformity progression was observed in patients operated on using laminar (Group IV) and hybrid (Group I) fixation. An additional anterior stage (discectomy and interbody fusion) in combination with laminar fixation (Group V) does not prevent deformity progression after surgery. In patients who underwent hybrid fixation in combination with the anterior stage (Group II) or total transpedicular fixation (Group III), no statistically significant progression of scoliotic deformity was observed in the postoperative period. Patients operated on with total transpedicular fixation (Group III) show improvement in all domains of the SRS-24 questionnaire: no increase in pain throughout the entire follow-up period, higher assessment of appearance after surgery and satisfaction with the treatment result. In groups II and III, there was no negative dynamics of topographic parameters in the long-term period after treatment; the initial correction of the deformity was maintained throughout the entire postoperative follow-up.Conclusion. Total transpedicular fixation provides the best correction of scoliosis in the absence of progression in the long-term postoperative follow-up in children during the period of active bone growth (age 10–14 years). According to the survey data, patients operated on with total transpedicular fixation demonstrate improvement in the following domains: the absence of pain syndrome throughout the entire postoperative follow-up period, the highest assessment of appearance after surgery and satisfaction with the result of surgical treatment. Hybrid fixation in combination with the anterior stage and total transpedicular fixation ensure the absence of negative dynamics of topographic parameters in the long term after surgery with maintenance of the initial surgical correction of spinal deformity.