Line Treatment For Patients Research Articles

1460P GALLANT-1: GB1211 galectin-3 (Gal-3) inhibitor plus atezolizumab (atz) for first line treatment in patients (pts) with advanced/metastatic non-small cell lung cancer (NSCLC)

1460P GALLANT-1: GB1211 galectin-3 (Gal-3) inhibitor plus atezolizumab (atz) for first line treatment in patients (pts) with advanced/metastatic non-small cell lung cancer (NSCLC)

Pulmonary sarcoidosis: A comprehensive review: Past to present

Sarcoidosis is a sterile non-necrotizing granulomatous disease without known causes that can involve multiple organs with a predilection for the lung and thoracic lymph nodes. Worldwide it is estimated to affect 2–160/100,000 people and has a mortality rate over 5 years of approximately 7%. For sarcoidosis patients, the cause of death is due to sarcoid in 60% of the cases, of which up to 80% are from advanced cardiopulmonary failure (pulmonary hypertension and respiratory microbial infections) in all races except in Japan were greater than 70% of the sarcoidosis deaths are due to cardiac sarcoidosis.Scadding stages for pulmonary sarcoidosis associates with clinical outcomes. Stages I and II have radiographic remission in approximately 30%–80% of cases. Stage III only has a 10%–40% chance of resolution, while stage IV has no change of resolution. Up to 40% of pulmonary sarcoidosis patients progress to stage IV disease with lung parenchyma fibroplasia, bronchiectasis with hilar retraction and fibrocystic disease. These patients are at highest risk for the development of precapillary pulmonary hypertension, which may occur in up to 70% of these patients. Sarcoid patients with pre-capillary pulmonary hypertension can respond to targeted pulmonary arterial hypertension medications. Stage IV fibrocytic sarcoidosis with significant pulmonary physiologic impairment, >20% fibrosis on HRCT or pre-capillary pulmonary hypertension have the highest risk of mortality, which can be >40% at 5-years.First line treatment for patients who are symptomatic (cough and dyspnea) with parenchymal infiltrates and abnormal pulmonary function testing (PFT) is oral glucocorticoids, such as prednisone with a typical starting dose of 20–40 mg daily for 2 weeks to 2 months. Prednisone can be tapered over 6–18 months if symptoms, spirometry, PFTs, and radiographs improve. Prolonged prednisone may be required to stabilize disease. Patients requiring prolonged prednisone ≥10 mg/day or those with adverse effects due to glucocorticoids may be prescribed second and third line treatements. Second and third line treatments include immunosuppressive agents (e.g., methotrexate and azathioprine) and anti-tumor necrosis factor (TNF) medication; respectively. Effective treatments for advanced fibrocystic pulmonary disease are being explored. Despite different treatments, relapse rates range from 13% to 75% depending on the stage of sarcoid, number of organs involved, socioeconomic status, and geography. ConclusionThe mortality rate for sarcoidosis over a 5 year follow up is approximately 7%. Unfortunately, 10%–40% of patients with sarcoidosis develop progressive pulmonary disease, and >60% of deaths resulting from sarcoidosis are due to advance cardiopulmonary disease. Oral glucocorticoids are the first line treatment, while methotrexate and azathioprine are considered second and anti-TNF agents are third line treatments that are used solely or as glucocorticoid sparing agents for symptomatic extrapulmonary or pulmonary sarcoidosis with infiltrates on chest radiographs and abnormal PFT. Relapse rates have ranged from 13% to 75% depending on the population studied.

Synergistic effect of LCI with ESWT on treating patients with mild to moderate CTS: a randomized controlled trial

BackgroundApplying radial extracorporeal shock wave therapy (R-ESWT) with LCI(local corticosteroid injection) in carpal tunnel syndrome (CTS) management is gaining momentum. The objective is to actualize the topic of this study.MethodsIn this prospective randomized controlled trial, forty patients with mild to moderate CTS are divided into two sham- R-ESWT and R-ESWT groups subject to LCI(local corticosteroid injection). The first group received four sessions of sham-ESWT weekly, which involved sound but no energy; the second group received R-ESWT at equal intervals and were assessed for pain score (VAS score) and symptoms (GSS) baseline, 1st month, 3rd month, and 6th month.ResultsA considerable improvement is observed in both groups for pain at (P < 0.05) and symptoms at (P < 0.05) in the 3rd month. The second group revealed more significant symptom improvement at (P < 0.05) in the 6th month.ConclusionThe R-ESWT + LCI combined therapy course is the first line of treatment in patients with mild to moderate symptoms and leads to control and reduction of symptoms and the need for surgery, thus a primary concern in CTS treatment with an orthopedist.

Mechanisms of synergistic suppression of ALK-positive lung cancer cell growth by the combination of ALK and SHP2 inhibitors

Lung cancer is a major cause of cancer-related deaths. Alectinib is the first line of treatment for patients with ALK-positive lung cancer, but the survival rate beyond 2–3 years is low. Co-targeting secondary oncogenic drivers such as SHP2 is a potential strategy for improving drug efficacy. This is because SHP2 is expressed ubiquitously, but ALK expression is largely restricted to cancer cells. Thus, the combination of ALK and SHP2 inhibitors may provide a way to restrict synergistic cytotoxicity to cancer cells only, by reducing the dose of SHP2 inhibitors required for anticancer action and minimising SHP2-dependent systemic toxicity. The objective of this study was to investigate whether the combination of a SHP2 inhibitor (SHP099) with alectinib would synergistically suppress the growth of ALK-positive lung cancer cells. Our results demonstrated that the drug combination significantly and synergistically decreased cell viability at relatively low concentrations in ALK-positive H3122 and H2228 cells, due to G1 cell cycle arrest and increased apoptosis because of suppressed downstream RAS/MAPK signalling. The drug combination also induced the expression of mediators of the intrinsic apoptotic pathway, Bim and cleaved caspase-3, and modulated the expression of cell cycle mediators cyclin D1, cyclin B1, and phosphorylated CDK1.

Patent foramen ovale closure with the Occlutech Figulla flex II device: A long-term (up to 10-years) follow-up

BackgroundPercutaneous closure represents the first line of treatment in patients with cryptogenic stroke and documented patent foramen ovale (PFO). Scarce data report the long-term outcomes of patients undergoing PFO closure with the Figulla Flex II device (Occlutech, Germany). MethodsConsecutive patients undergoing PFO closure with a Figulla Flex II device at a single, high-volume Institution were included. Baseline clinical and procedural features were collected and patients were followed up for up to 10 years. The device's long-term safety was assessed, as well as mortality, recurrent cerebrovascular events, new-onset atrial fibrillation (AF) and residual shunt. ResultsOverall, 442 patients were included. The main indication for PFO closure was cryptogenic stroke/transitory ischemic attack (65.5%), followed by migraine (21.7%), silent lesions at MRI (10.8%), and decompression disease (2.0%). Atrial septal aneurysm was present in 20.8% of cases, Eustachian valve in 9.0%, Chiari network in 19.9%. The most frequently implanted device was the 23/25 mm (49.5% of cases). One procedural failure due to device embolization; in-hospital complications occurred in 15 cases (3.4%; 4 minor access site complications, 11 transient supraventricular tachycardias (SVT)/AF). After a follow-up of 9.2 years, 2 patients suffered recurrent TIA (with no residual R-L shunt detected). A moderate or severe residual shunt was observed in 3 patients after discharge. ConclusionsFigulla Flex II devices for PFO closure are associated with high procedural success and low incidence of adverse events even at long-term follow-up.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in advanced soft tissue sarcoma: A single-arm, phase 2 trial.

11553 Background: Anthracycline plus ifosfamide is the standard first line treatment regime for advanced soft tissue sarcoma (STS). Anlotinib, a multikinase angiogenesis inhibitor, has evolved as a standard second line treatment option in Chinese advanced STS patients. This study was performed to evaluate the efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in the first line treatment of patients with advanced STS. Methods: This prospective, open-label, single-arm, phase 2 trial was conducted in Shandong Cancer Hospital and Institute (ChiCTR2100054711). The key inclusion criteria included: (a) age was 18-70 years; (b) ECOG performance state of 0-1; (c) histologically confirmed high-grade STS; (d) unresectable or metastatic STS; (e) previously untreated, and sensitive to chemotherapy; (f) having measurable lesions according to RECIST 1.1. All patients received up to 6 cycles of anlotinib (12 mg QD on day1-14, 21 days per cycle) combined with anthracycline (epirubicin 40mg/m2/d on day 1-2, 21 days per cycle; or liposomal doxorubicin 30mg/m2/d on day 1, 21 days per cycle) and ifosfamide (2g/m2/d on day 1-3, 21 days per cycle) followed by anlotinib maintenance until disease progression, unacceptable toxicity or death. Pegylated recombinant human granulocyte colony-stimulating factor was administered following chemotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse effect (AE). Results: From December 2021 to December 2022, 31 patients (median [range] age, 53 [18-69] years; 20 [64.5%] male) were enrolled. 29 were evaluable for objective response, and the ORR and DCR were 31.03% (95%CI, 17.28-49.23%) and 82.76% (95%CI, 65.45-92.4%), respectively. With a median follow-up duration of 6.3 months (range, 0.8–14.0), the median PFS for all 31 patients was 6.9 months (95% CI, 2.62-11.17). The median OS was not reached. Treatment-related AEs of any grade occurred in all patients. The most common AEs included nausea/vomiting (88.46%), anemia (23.08%), leukopenia (19.23%), venous thrombosis (15.38%), hand-foot syndrome (11.54%) and elevated alanine aminotransferase or aspartate aminotransferase (11.54%). The most frequent ≥ grade 3 AEs were leukopenia (11.54%) and thrombocytopenia (7.69%). 2 serious AEs (1 left heart failure and 1 intestinal obstruction) were recorded. No treatment-related death occurred. Conclusions: This study suggested that anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance demonstrated encouraging efficacy with a manageable safety profile in the first line treatment of patients with advanced STS. Clinical trial information: ChiCTR2100054711 .

Ultra-sensitive, tumor-informed ctDNA profiling in patients with gastroesophageal cancer and treated with pembrolizumab and longitudinal ctDNA kinetics.

4040 Background: Metastatic esophagogastric cancer (mEGC) is a lethal disease with poor long-term survival. Recent studies have established anti-PD-1 therapy in combination with chemotherapy as the standard of care for first-line therapy for mEGC. KeyLargo (NCT03342937) was a single arm phase II study of pembrolizumab in combination with oxaliplatin and capecitabine in the first line treatment of patients (pts) with HER2 negative mEGC. While high response rates were noted, not all pts received benefit, emphasizing the need for better biomarkers. Paired tumor biopsies and plasma were collected for optimal biomarker testing. In this retrospective study, we employed a novel, tumor-informed ctDNA approach as a tool for longitudinal disease monitoring and dynamic tumor evolution. Methods: Thirty-six pts were enrolled between January 2018 and January 2020. Of 34 evaluable pts, 25 pts achieved a response (ORR = 74%), including 6 pts with a complete response (CR) and 19 pts with a partial response (PR). Our initial analysis includes baseline tumor samples collected from 16 pts with over 59 corresponding on-treatment (OT; up to cycle 35) plasma samples. NeXT Personal, a tumor-informed ctDNA assay, generated personalized liquid biopsy panels derived from somatic variants (SV) from tumor whole genome sequencing. Each personalized assay includes up to 1,800 SVs for sensitive minimal residual disease (MRD) detection and a constant set of 2,100 clinically actionable variants (CAV). Results: Of the 36 pts who enrolled on KeyLargo, 32 pts had baseline tumor and longitudinal plasma samples collected and stored for testing. In this initial cohort of 16 pts, MRD events dynamically varied from 5.3 to 302,000 parts per million (PPM). 16/16 (100%) pts were MRD-positive at baseline, with a limit of detection between 1.5 and 4.6 PPM. OT samples were collected every 3 cycles (9 weeks). The ratio of PPM (rPPM) between baseline and the first available OT sample (typically Cycle 4 to 7) correlated with progression free survival (PFS; p = 0.0004, logrank). rPPM was significantly reduced in pts having a best overall response of PR/CR (98% mean rPPM) versus progressive disease (25% mean rPPM, p &lt; 0.037, U-test). Two pts demonstrated CR, each with 11/11 (100%) MRD-negative plasma samples over approximately two years. CAVs were identified in longitudinal samples with TP53 repeatedly detected in 5 patients and a PIK3CA mutation emerging in the final 3 (of 9) timepoints from one patient. Conclusions: ctDNA was present in all pts at baseline; OT PPM reductions correlated with PFS and best overall response. CAV profiling suggested a de novo PIK3CA variant arising during therapy in one patient. These findings suggest that tumor-informed plasma-based ctDNA profiling in mEGC may detect known CAVs arising during therapy, and with subsequent investigations, may inform therapeutic decisions.

Pre-treatment plasma-informed circulating tumor DNA detection as an early identification of therapeutic benefit for patients with untreated advanced lung squamous cell carcinoma.

9041 Background: Circulating tumor DNA (ctDNA) detection as a promising prognostic factor to assess treatment response has been widely studied with customized tumor-informed strategies, the application of which was limited by the inaccessibility for tumor biopsies in a substantial proportion of patients. To overcome this challenge, we presented a proof-of-concept study for the development of a novel personalized pre-treatment plasma-informed next generation sequencing (NGS) panel and investigated its prognostic value for first line treatment in patients with advanced lung squamous cell carcinoma (LUSC). Methods: Paired plasma and white blood cell (WBC) samples were collected from 227 of stage IIIB-IV LUSC patients who were treated with first line either chemotherapy or chemotherapy plus PD-1 blockade at pre- and post-treatment. Somatic mutations in pre-treatment plasma were identified with a 769-gene based NGS panel (Genecast, Wuxi, China) followed with germline or clonal hematopoietic variants filtering by referring to the WBC samples. Positive variants detected in the pre-treatment plasma served as a basis for personalized variants tracking in post-treatment plasma. ctDNA kinetics was measured by plasmaDelta (Δgenevaf=((post-treatment genevaf – pre-treatment genevaf) / pre-treatment genevaf; genevaf was defined by variant allele frequency for each individual gene). Progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint were assessed. Results: ctDNA positivity was observed in 80% (182/227) of pre-treatment samples and subsequently 54% (99/182) of post-treatment samples. ctDNA positivity at post-treatment was shown to be a significant predictor for both PFS and OS in the whole group as well in the sub-treatment groups (Table). After adjusting for clinicopathologic variables, ctDNA positivity remained significantly associated with both worse PFS and OS (PFS: HR = 2.3, P &lt;0.001 and OS: HR= 2.56, P &lt;0.001). ctDNA kinetics further identified a worse treatment response group. Patients with high plasmaDelta had remarkably worse outcomes than patients with low plasmaDelta (PFS: HR =4.8; 95%CI=2.8-8.3; P &lt; 0.001 and OS: HR=2.8; 95%CI=1.7-4.6; P &lt;0.001). Conclusions: These results demonstrated the feasibility of pre-treatment plasma-informed ctDNA detection and kinetics for monitoring treatment response in LUSC patients whose tumor biopsies were unavailable. [Table: see text]

Results of phase I-II bridging study for Nous-209, a neoantigen cancer immunotherapy, in combination with pembrolizumab as first line treatment in patients with advanced dMMR/MSI-h colorectal cancer.

e14665 Background: Microsatellite instability (MSI) is a molecular hallmark in which systemic deficiency of DNA mismatch-repair (dMMR) generates tumor-specific frameshift peptides (FSPs). Nous-209 is an off-the-shelf cancer vaccine targeting 209 FSPs selected from dMMR/MSI-H tumors (Leoni, G. et al., 2020). Treatment options for unresectable dMMR/MSI-H tumors have improved, but further efforts to increase long-term progression-free survival are needed. NOUS-209-01 Phase I demonstrated that Nous-209 and pembrolizumab is safe, well tolerated, and provides clinical benefit in advanced gastric and CRC dMMR/MSI-H tumors (Fakih et al., 2022). Moreover, Nous-209 induces durable specific anti-tumoral immune response, capable of successfully infiltrating the tumor (D’Alise et al., 2022). Here, we present data from NOUS-209-01 study Phase I-II expansion cohort at the recommended phase 2 dose (RP2D) of Nous-209 and pembrolizumab in adults with dMMR/MSI-H locally advanced unresectable or metastatic colorectal cancer (mCRC) eligible for 1st line immune checkpoint inhibition. Methods: NOUS-209-01 ( NCT04041310 ) Phase I-II bridge expansion cohort receives one GAd20-209-FSP prime intramuscularly at the 1st infusion of pembrolizumab, followed by 3 MVA-209-FSP boosts with the 2nd, 3rd and 4th pembrolizumab cycles. Patients can continue treatment with pembrolizumab for 18 months. Response assessment is evaluated every 9 (+/-1) weeks by CT imaging, according to RECIST v1.1 criteria. ctDNA assessments are at baseline, 11, 28, 49, 79 weeks and at objective progression on study. Results: Phase I-II bridge enrolled 8 patients with dMMR/MSI-H treatment-naïve mCRC. One patient had clinical progression before 1st scan and was excluded as non-evaluable and 7 were evaluable for tumor response. 5/7 (71%, CI: 95% 29.0, 96.3) patients achieved objective response: 1 (14%) complete response (CR) and 4 (57%) partial responses (PR). 2 patients (29%) had disease progression (PD) at the 1st scan. ctDNA assessments were available for 6 out of 7 patients (4 PR; 2 PD); ctDNA levels reduced &gt;50% at week 11 in the 4 PR patients, in contrast to a 28% increase in 1 PD. Interestingly 1 PD patient had ctDNA &gt; 50% reduction. The median follow-up at data cut-off was 7.5 months (range: 3.3-8.4), median progression free survival and median duration of response have not been reached. 6/7 (85.7%) patients had treatment emergent adverse events (TEAE), all mild or moderate grade; no TEAEs were serious or led to treatment discontinuation. Conclusions: The combination of Nous-209 and pembrolizumab is safe, well tolerated and shows encouraging clinical efficacy in patients with treatment-naive dMMR/MSI-H mCRC eligible for anti-PD-1 therapy. The study is ongoing and expanding to Phase II randomization with a new accelerated Nous-209 vaccination schedule. Clinical trial information: NCT04041310 .

A phase 2, two-stage study of avelumab and axitinib in patients with mismatch repair–proficient (MMR-P) recurrent or persistent endometrial cancer (EC).

TPS5628 Background: Despite significant strides in understanding the molecular pathogenesis of EC, there remain few effective therapies for recurrent disease. Deeper insight into the roles of disordered tumor vasculature and HIF1α- and VEGF-mediated immunosuppressive effects on myeloid-derived suppressor cells, T-cells, and PD-L1 expression contributed to the development of new targeted regimens. By inhibiting VEGF receptor (VEGFR) and PD-L1 signaling, immunologically “cold” tumors may become inflamed. The combination of the anti-PD-L1 antibody avelumab with axitinib, an inhibitor of VEGFR 1-3 and PDGFR with more potent IC50 inhibitory activity than lenvatinib, has also shown synergistic activity and is FDA approved as first line treatment for patients with renal cell cancer. We therefore hypothesized that this combination would be well tolerated and efficacious in recurrent MMR-P EC. Objectives:This is a non-randomized two-stage phase 2 study in patients with MMR-P EC evaluating the activity of combined avelumab and axitinib, as assessed by the co-primary endpoints of (1) frequency of patients surviving progression-free for at least 6 months (PFS6), and (2) the objective response rate (ORR) as measured by RECIST 1.1. Methods: Patients must have MMR-P EC and have received at least one chemotherapeutic regimen, with no upper limit on the number of prior lines received. Prior use of immune checkpoint inhibitors (ICI) is excluded. Eligible patients received avelumab 800 mg IV every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. In the first stage of the study, 16 patients were enrolled; if there were ≥2 objective responses or ≥2 PFS6 responses, accrual continued to the second stage with enrollment of an additional 19 patients. The combination of avelumab/axitinib would be considered worthy of further study if overall there were ≥4 objective responses or ≥8 PFS6 responses. Results: As of the data-cutoff in September 2022, a total of 28 patients had received study treatment; one patient withdrew from the study due to toxicity, prior to her first radiographic assessment. The median number of prior lines was 1 (range 1-4). Median follow-up was 12.7 months. Of the 28 patients receiving study treatment, eleven patients (39.3%, 95% CI 21.5%-59.4%) achieved a PR [11/28; 8 confirmed PR (28.6%) and 3 unconfirmed PR (10.7%)]. An additional 39.3% (11/28) had stable disease as best response. Median PFS was 7.3 months (95% CI 3.9-9.0). PFS6 was 59.3% (95% CI 35.7%-76.7%) and at 6 months, 10 patients were still alive and progression-free. Updated efficacy data and safety data will be reported at the time of the meeting. Conclusions: With 8 confirmed PRs and 10 PFS6 responses, the co-primary endpoints were met and the combination of avelumab/axitinib is considered worthy of further study in this population of MMR-P EC. Clinical trial information: NCT02912572 .

Clinical development of the bispecific PSMAxCD3 antibody CC-1.

2534 Background: While being highly efficient in hematological malignancies, bispecific antibodies (bsAbs), alike CAR T cells, are yet not successful in solid tumors. Moreover, all available T cell-mobilizing strategies cause side effects that endanger patients and, in case of bsAbs, limit applicable doses and thus efficacy. We report on the clinical development of CC-1, a PSMAxCD3 bsAb, in an IgG-based format that induces fully target cell-restricted T cell activity (Zekri et al, EMBO Mol Med, 2020). Targeting PSMA, which is expressed on malignant cells and on the neovasculature, improves accessibility of the tumor site for immune effector cells as critical prerequisite for success in solid tumors. Notably, CC-1 binds a unique PSMA epitope which is expressed on malignant cells both of prostate carcinoma (PC) and 50% of patients with squamous cell carcinoma (SCC) of the lung. Methods: A FIH trial evaluating CC-1 with pre-emptive Tocilizumab included patients with metastatic castration resistant prostate carcinoma (mCRPC) (NCT04104607) and consisted of two parts. Dose escalation (n=10-66) using a novel intra-individual dose escalation design to rapidly reach the target dose of 826µg to determine safety, tolerability and maximum tolerated dose (MTD) (Labrenz et al, Pharm Stat, 2022). The dose expansion cohort exposed patients to CC-1 at MTD and explored efficacy to define RP2D (n=14). Our second phase I trial enrolls patients with SCC of the lung (NCT04496674) to receive CC-1 in combination with checkpoint inhibition. Based on the meanwhile available very favorable safety and preliminary efficacy data, a third phase I trial was initiated where CC-1 is evaluated as first line treatment in patients with hormone sensitive biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly lower side effects and long-lasting efficacy are expected. Results: Recruitment in the dose escalation part of the trial in mCRPC has been completed and the target dose was reached and MTD defined without DLT upon treatment of the 9th and 14th patient, respectively. 24 patients completed treatment, with the most frequently observed toxicity being cytokine release syndrome (CRS, max. 2°) (88%). Besides grade 1 to 2 hypertension (46%) and xerostomia (8%), no further CC-1 related toxicities were observed. A rapid and profound decline of elevated PSA levels was observed in all but one patient, with up to 60% reduction compared to baseline. So far 5 patients received multiple treatment cycles at MTD-level. One patient with SCC of the lung has been treated and CC-1 was escalated up to 153µg without occurrence of CRS. In the phase I trial in BCR of PC, the first three patients were enrolled in February 2023. Conclusions: CC-1 is a promising compound with a favourable toxicity profile and promising clinical activity. Details on study designs and updated data from the 3 clinical trials will be presented at the meeting. Clinical trial information: NCT04104607 , NCT04496674 , NCT05646550 .

ProSperA: Phase I study to evaluate safety, tolerability and preliminary efficacy of a bispecific PSMAxCD3 antibody in men with biochemical recurrence of prostate cancer.

TPS5114 Background: Bispecific antibodies (bsAbs), alike CAR T cells, are not yet successful in solid tumors. Recently we developed a PSMAxCD3 bsAb termed CC-1 in an IgG-based format mediating fully target cell-restricted T cell activation and potent antitumor activity (Zekri et al, EMBO Mol Med, 2020). In prostate cancer (PC), PSMA is not only expressed on the malignant cells themselves, but also on tumor vessels. Targeting the latter improves accessibility of the tumor site for immune effector cells, a critical prerequisite for success. CC-1 is under evaluation in a First in Human trial enrolling patients with castration resistant prostate carcinoma (NCT04104607) and, in combination with checkpoint inhibition, in a phase I trial enrolling patients with squamous cell carcinoma of the lung (NCT04104607). On the basis of the meanwhile available very favorable safety and preliminary efficacy data, CC-1 is now being evaluated as first line treatment in patients with biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly further reduced side effects and sustained efficacy are expected. Methods: This is an ongoing open label, single center phase I clinical trial evaluating CC-1 without androgen deprivation therapy as first line treatment in men with BCR of PC. Key eligibility criteria include low risk of disease progression (PSA-Doubling time &gt; 1 year after prostatectomy or interval to BCR &gt; 18 months after radiation; ISUP grade &lt; 4; PSA ≥ 0.2 ng/ml and &lt; 5 ng/ml) and no androgen deprivation therapy except in a neoadjuvant/adjuvant setting. The clinical trial consists of (i) a dose escalation part (24-42 patients) using a 3+3 design to determine overall safety, tolerability as well as maximum tolerated dose (MTD) and (ii) a dose expansion part, in which 14 patients are treated at the MTD. CC-1 is applied twice-weekly over 21 days as three-hour infusion in up to six 28-day cycles. In the first cycle, step dosing (day 1: 10µg, day 2: 28µg, day 3 and thereafter: target dose) is performed, and 7 patient cohorts receiving dose levels from 78µg to 600µg are evaluated. Premedication includes acetaminophen, dimetindene and cortisone to minimize the risk of infusion reactions and cytokine release syndrome (CRS). The primary objectives are definition of MTD and recommended phase II dose. Assessment of safety is based on the frequency of adverse events according to CTCAE v5.0. Dose limiting toxicities are defined as ≥ 3° adverse drug reactions (e.g. CRS) with predefined exceptions (e.g. temporary laboratory abnormalities). Efficacy is determined by serial PSA-measurements (PSA-response: ≥50% decrease compared to baseline). Furthermore, percentage of patients with no clinical relapse, no salvage and no subsequent antineoplastic therapy will be assessed. Clinical trial information: NCT05646550 .

Influence of levothyroxine concomitant treatment on treatment responses and outcomes in patients with metastatic colorectal adenocarcinoma.

e15593 Background: Hypothyroidism is the most common thyroid disorder and levothyroxine is the mainstay treatment. Levothyroxine is mainly used to restore the euthyroid clinical and biochemical status in the gland. Recent literature has correlated chronic hormonal treatment with adverse effects on bone and heart function, as well as correlated with an increased risk of tumor onset. Data available in the literature are controversial, therefore the aim of our study was to evaluate the correlation between chronic levothyroxine intake and outcomes and response to first line treatments in patients affected by metastatic colorectal cancer. Methods: We retrospectively collected the data from 139 patients with metastatic colorectal adenocarcinoma, belonging to the Medical Oncology Department of the University Hospital of Cagliari from 2016 to 2019. All patients enrolled in the study had received metastatic first-line treatment with doublet or triplet chemotherapy associated with anti-VEGF or anti-EGR monoclonal antibody. Patients with ECOG PS ≤1 with no more than two relevant comorbidities were included in the study. The primary objective of the study was median overall survival (mOS) and secondary objectives were: median progression free progression (PFS), median overall survival (mOS) differences between RAS wild type and mutant tumour. BRAF mutant tumors were excluded from the evaluation. Results: Median age was 65 years (±10), 51% were male and 49% were female. 63% patients had an ECOG-PS 0, while 37% had an ECOG-PS 1. 67% developed from the left colon; 33% from the right colon and the transverse colon. All patients had synchronous metastases. 18% patients took levothyroxine and 82% patients did not take it. Among the patients receiving levothyroxine therapy, 64% had a RAS wild type and 36% a RAS mutated. Levothyroxine treated patients showed a significantly lower median OS than not treated patients (15 months versus not reached, p = 0,0001). Levothyroxine treated patients also showed a significantly lower median PFS than non treated patients (6 versus 8 months, p = 0,035). Within levothyroxine treated pts, no statistically significant differences were found in mOS and mPFS between RAS wt and RAS mut (mOS 15 versus 14 months, respectively, p = 0.9; mPFS 8 versus 7 months, respectively, p = 0,7). Conclusions: The results show a possible correlation between levothyroxine therapy and outcomes in mCRC. This would deserve further study to understand further biological-molecular aspects, to date partially explained by preclinical studies, in order to clarify some of the possible underlying mechanisms.

Safety and efficacy of immune checkpoint inhibitor (ICI) naïve cohort from study of PDS0101 and pembrolizumab in HPV16-positive head and neck squamous cell carcinoma (HNSCC).

6012 Background: Up to 70% of oropharyngeal cancers in the US are reported to be HPV-mediated with most caused by HPV16 infection. First line treatment for patients with unresectable, recurrent or metastatic (R/M) disease is pembrolizumab with or without chemotherapy, but most patients eventually experience disease progression. PDS0101 is a novel, investigational HPV16-targeted immunotherapy that stimulates a potent, targeted T cell attack against HPV16-positive cancers. Methods: VERSATILE-002 (NCT04260126) is an open-label, non-randomized, Simon 2-stage study evaluating the combination of PDS0101 and pembrolizumab in subjects with HPV16-positive R/M HNSCC in 2 cohorts: ICI-naïve and ICI-refractory. All subjects receive pembrolizumab IV Q3W with PDS0101 SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (max 5 doses). The primary endpoint of the study is confirmed Best Overall Response per RECIST 1.1. Herein we update the safety, PFS, and OS data for the ICI-naïve subjects. Results: Forty-eight subjects who received at least one cycle of combination therapy (safety population) had a median age of 62.5 (range 45 – 83), were 93.8% male, 93.8% White, and 62.5% ECOG 0. Among this population, the median overall treatment duration in months was 3.5 (range 0.0 – 19.5). The median number of PDS0101 doses was 4 (range 1 – 5); 56.3% received 4 doses and 22.9% received 5 doses. The median number of pembrolizumab doses was 5 (range 1 – 29); 27.1% received ≥10 doses. Efficacy was evaluated in 34 subjects (47.1% with CPS ≥20) who had assessment of tumor response following treatment (efficacy population). Tumor reduction (maximum percent change from baseline) was seen in 23 (67.6%) subjects. Nine subjects (26.5%) had confirmed response including 1 CR and 8 PR, 15 subjects had SD (44.1%), and 9 subjects had PD (26.5%). One subject was not evaluable (2.9%). The median PFS was 10.4 months (95% CI 4.2, 15.3). Among the safety population, median overall survival was non-estimable due to the ongoing survival status of study subjects. The estimated 12-month OS rate was 87.1%. Thirty-three (68.5%) subjects had mild or moderate (Grade 1 or 2) PDS0101-related TEAE (TRAE); the most common were fatigue and injection site reactions (ISRs). Only 3 subjects (6.3%) had Grade 3 TRAEs: fatigue, ISR, blood alkaline phosphatase increased, and hyperglycemia. No subjects had Grade 4 or 5 TRAE. No subject came off study due to toxicity. Conclusions: PDS0101 with pembrolizumab is well tolerated in this ICI naïve R/M HPV-associated HNSCC population. Median PFS was 10.4 months which compares favorably to published median PFS of 2-3 months for approved ICIs when used as monotherapy in patients with similar PD-L1 levels. The estimated 12-month OS of 87.1% is promising compared to published results of about 36-50%. These results justify a confirmatory randomized, controlled study. Clinical trial information: NCT04260126 .

Catheter ablation as first line treatment in patients with ischemic cardiomyopathy, tolerated ventricular tachycardia and left ventricular ejection fraction over 35%: long term outcomes

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients with ischemic cardiomyopathy (ICM) and monomorphic, sustained ventricular tachycardia (VT) are considered to be at risk for arrhythmia-related sudden cardiac death (SCD). Prior studies have suggested that patients with well-tolerated VTs and preserved or moderately reduced left ventricular ejection fraction (LVEF) and successful VT ablation may not benefit from cardioverter defibrillator implantation (ICD Current guidelines indicate that in selected patients catheter ablation should be considered instead of ICD, but supporting evidence is limited. Aim This study aims to analyze arrhythmia outcomes of ICM patients referred for VT ablation without prior ICD implantation according to LVEF, hemodynamical stability during VT and ablation outcome. Methods ICM patients without prior ICD implantation undergoing VT ablation in a tertiary center between 2009 and 2022 were included. Patients who presented with a first episode of tolerated VT and w a LVEF≥35% were offered catheter ablation (CA) as first-line therapy. Patients were categorized according to (1) LVEF, (2) clinical presentation (hemodynamically tolerated/non-tolerated VT) and (3) acute ablation outcome. According to the institutional protocol, ICD was offered to all patients after ablation, but was subject to shared decision making, explaining the available evidence supporting ICDs for the different categories. Results Eighty-six ICM patients without ICD underwent ablation for VT. Mean age was 69±9 years and 72 (84%) were men, mean LVEF was 41±9% and 34 patients (28%) were using anti-arrhythmic drugs (AAD). The median VT cycle length (VTCL) at presentation was 323ms [300 – 375] and VT was tolerated in 58 (67%) patients (median tolerated VTCL 325ms [300 – 371]). In 66 (77%) patients, the LVEF was ≥35% of which 51 had well-tolerated VT. Of these 51 patients, 37 (73%) were rendered non-inducible after ablation and in 14 patients non-clinical VTs remained inducible (median remaining VTCL 238ms [203-288]). In 5/37 non-inducible and in 11/14 inducible patients, an ICD was implanted. Of the 35 patients who had LVEF&amp;lt;35% and/or non-tolerated VTs, 7 refused ICD implantation. (Figure 1) During a median follow-up of 35 [22 – 53] months, 10 patients (12%) had VT-recurrence and one patient with an ICD had SCD. Mortality was 22%. In the 37 patients with LVEF≥35%, tolerated VT and non-inducibility post procedure, no SCD or VT-recurrence was observed. Also, in this group no patient was using AAD for VT at last follow-up. In the 14 remaining patients with LVEF≥35% and tolerated VT who were still inducible after ablation, no SCD occurred but VT recurred in 29% (median VTCL 303ms [200-374]) with AAD-use for VT in 29%. Conclusion This study supports that ICM patients without prior ICD and LVEF≥35% who present with hemodynamically well-tolerated VT and are non-inducible after ablation have an excellent prognosis. Successful CA without ICD implantation seems to be safe in these selected patients.

Exercise Therapy for Knee and Hip Osteoarthritis: Is There An Ideal Prescription?

Exercise therapy is the first line treatment for patients with knee and hip osteoarthritis (OA) but is consistently underutilized. In this review, we aim to provide health care professionals with an overview of the latest evidence in the areas of exercise therapy for OA, which can serve as a guide for incorporating the ideal exercise therapy prescription in the overall management plan for their patients with OA. Evidence continues to be produced supporting the use of exercise therapy for all patients with knee or hip OA. Ample evidence exists suggesting exercise therapy is a safe form of treatment, for both joint structures and the patient overall. Several systematic reviews show that exercise therapy is likely to improve patient outcomes, regardless of disease severity or comorbidities. However, no single type of exercise therapy is superior to others. Health care practitioners and patients should be encouraged to incorporate exercise therapy into treatment plans and can be assured of the safety profile and likelihood of improvement in important patient outcomes. Since no single exercise therapy program shows vastly superior benefit, patient preference and contextual factors should be central to the shared decision-making process when selecting and individualising appropriate exercise therapy prescriptions.

Effects of Palliative Chemotherapy in Unresectable or Metastatic Colorectal Cancer Patients With Poor Performance Status

IntroductionColorectal cancer is the second most common cancer in both genders and often presents as a metastatic, unresectable, or recurrent disease in early follow-up. It is uncertain the benefit of oxaliplatin-based palliative chemotherapy (CT) in the first line of treatment in patients with compromised performance status (PS), Eastern Cooperative Oncology Group (ECOG) 3 and 4. These patients are systematically excluded from clinical trials but may be treated in clinical practice. MethodsWe conducted a prospective observational cohort whose primary outcome was improving at least 2 points in the worst symptom in the Edmonton Symptom Assessment System Scale (ESAS-r), without grade 3 to 4 toxicity, comparing baseline and fourth week of treatment. Secondary endpoints included quality of life using the European Quality of Life-5 dimensions questionnaire, toxicity, response rate, clinical improvement of ECOG PS, and overall survival (OS). ResultsWe included 28 patients, and 12 (42.8%) achieved the primary endpoint. Median overall survival was 86 days, 46% of patients did not respond to the fourth-week reevaluation due to clinical deterioration, and 17.8% presented toxicity grade ≥3, with 5 patients dying from toxicity. In addition, ECOG PS 4 or cholestasis had poorer overall survival. Finally, 25% and 53.6% of patients received these treatments in the last 14 and 30 days of life, respectively. ConclusionIn the present study, palliative multiagent chemotherapy in poor performance status patients with non-molecularly selected colorectal cancer tended to impact tumor symptoms control; however, there is no benefit in OS and a considerable risk of toxicity and treatment-related death.

Activity of TNT: a phase 2 study using talimogene laherparepvec, nivolumab and trabectedin for previously treated patients with advanced sarcomas (NCT# 03886311).

Intratumoral injection of talimogene laherparepvec evokes a cytotoxic immune response. Therefore, the combination of talimogene laherparepvec with trabectedin and nivolumab may have synergistic effects in advanced sarcomas. This phase 2 trial was conducted from May 30, 2019 to January 31, 2022. Endpoints: Primary: Progression free survival rate at month 12. Secondary: Best overall response, progression free survival rate at 6 and 9 months, overall survival rate at 6, 9, and 12 months, incidence of conversion of an unresectable tumor to a resectable tumor, and incidence of adverse events. Eligible patients had to be ≥ 18 years of age, have advanced histologically proven sarcoma, at least 1 previous chemotherapy regimen, and at least one accessible tumor for intratumoral injection. Treatment: Trabectedin intravenously (1.2 mg/m2 q3 weeks), nivolumab intravenously (3 mg/kg q2 weeks), and intratumoral talimogene laherparepvec (1x108 plaque forming units/ml q2 weeks). Median time of follow-up: 15.2 months. Efficacy analysis: Thirty-nine patients who had completed at least one treatment cycle and had a follow-up computerized tomography were evaluable for efficacy analysis. Median number of prior therapies: 4 (range 1-11). Progression free survival rate at month 12, 36.7%. Confirmed Best Overall Response by Response Evaluation Criteria in Solid Tumors v1.1 = 3 partial responses, 30 stable disease, 6 progressive disease. Best Overall Response Rate, 7.7%, Disease Control Rate, 84.6%; median progression free survival, 7.8 (95% Confidence Intervals: 4.1-13.1) months; 6-, 9-, 12-month progression free survival rates, 54.5%/45.9%/36.7%; median overall survival 19.3 (95% Confidence Intervals: 12.8 -.) months; 6-, 9- and 12-month overall survival rate, 86.9%/73.3%/73.3%. One patient had a complete surgical resection. Fifty percent of patients had a ≥ grade 3 treatment related adverse events which included anemia (6%), thrombocytopenia (6%), neutropenia (4%), increased alanine transaminase (4%), decreased left ventricular ejection fraction (4%), dehydration (4%), hyponatremia (4%). Taken together these data suggest that the TNT regimen is effective and safe for advanced previously treated sarcomas, and is worth being further studied in a randomized phase 3 trial as first- or second- line treatment for patients with advanced sarcomas.

AB102. SOH23ABS_250. A profile of patients with shoulder pain attending the musculoskeletal triage clinic in Connolly Hospital

Background: Clinical specialist physiotherapists (CSP) have been assessing patients in musculoskeletal (MSK) triage clinics nationally since 2010. There is a close correlation between physiotherapists and surgeons in making the correct diagnosis. Physiotherapy involving a structured exercise program is the first line treatment for patients with rotator cuff related shoulder pain (RCRSP) and is recommended prior to orthopaedic consultant referral. The benefit of an early magnetic resonance imaging (MRI) in these patients is questionable and may cause patients undue concern about normal age-related changes in their shoulder.