Maintenance Therapy Research Articles

Efficacy and safety of fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

166 Background: Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290). Methods: Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m 2 , orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance. Conclusions: Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC. Clinical trial information: NCT05659290 .

Safety and preliminary efficacy of ivaltinostat, an HDAC inhibitor, plus capecitabine in patients with pretreated metastatic pancreatic adenocarcinoma (mPDAC): Results of a phase Ib study.

742 Background: Front-line chemotherapy for patients (pts) with mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses cell proliferation, and promotes apoptosis. Preclinical data demonstrated synergy with 5-FU/capecitabine (cape) in mouse models. We report here results of the Phase Ib portion of a Ib/2 trial evaluating the safety and recommended phase 2 dose (RP2D) of this combination to use in a randomized study of ival + cape vs cape as maintenance therapy. Methods: Key eligibility criteria for phase 1b included unresectable or metastatic PDAC; ≥18 years old; ≥1 prior therapy; ECOG PS 0-1; and no known germline BRCA1/2 mutation. Three cohorts were enrolled, receiving ivaltinostat at 60, 125, or 250mg/m 2 iv (weekly on days 1 and 8) in combination with cape (1000mg/m 2 po BID on days 1-14) of a 21-day cycle. 1o objectives: safety, tolerability and RP2D; 2o objectives: pharmacokinetics (PK) of ival + cape. Results: A total of 28 patients were enrolled at the 60 (n=6), 125 (n=10) and 250 (n=12) mg/m 2 ival dose levels. Median prior lines of therapy: 2 (range 1-7). Median age: 67 years (range 50-83). Only one DLT (G4 thrombocytopenia) was observed at 250mg/m 2 dose level. Treatment-emergent AE profile was similar across dose levels, with common TEAEs including fatigue (n=15, 53.6%), nausea (n=14, 50.0%), palmar-plantar erythrodysesthesia syndrome (n=12, 42.9%), diarrhea (n=10, 35.7%), and constipation (n=9, 32.1%). G3 AEs included neutropenia (n=6, 21.4%), anemia (n=4, 14.3%), abdominal pain (n=3, 10.7%) and diarrhea (n=3, 10.7%). G4 AEs included 1 (3.6%) event of neutropenia and 1 (3.6%) of thrombocytopenia. No SAEs related to study drugs occurred in any of the 3 dose cohorts. PK analyses indicated dose proportional increases in exposure with increasing doses of ival. Histone H3K27 acetylation for ival showed the similar trend in optical density evaluation. Across all dose levels and prior treatments, median OS and PFS were 9.6 and 3.3 months, respectively. Conclusions: The combination of ival and cape was generally well tolerated in this heavily pretreated patient population. Ival 250 mg/m 2 is the dose selected for the ongoing randomized study of ival + cape vs cape in the maintenance setting for mPDAC pts post-FOLFIRINOX, which is expected to finish accrual in 2025. Clinical trial information: NCT05249101 .

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Bevacizumab plus mFOLFOX6/FOLFIRI sequential bevacizumab plus capecitabine maintenance in RAS-mutated advanced colorectal cancer: A real-world study of first-line/second-line conversion therapy.

77 B ackground: Currently, the standard first-line/second-line treatment for advanced colorectal cancer with RAS mutations is chemotherapy combined with bevacizumab. Patients with colorectal cancer confirmed maintenance therapy can effectively improve progression-free survival, improve patient quality of life. Therefore, this study aims to evaluate the efficacy and safety of bevacizumab combined with mFOLFOX6/FOLFIRI sequential bevacizumab combined with capecitabine as first-line/second-line conversion therapy for RAS-mutated advanced colorectal cancer. M ethods: This is an open-label, single-center study in previously untreated patients with RAS mutant mCRC. Eligible patients received first-line chemotherapy of bevacizumab (5mg/m 2 ) combined with mFOLFOX6/FOLFIRI for 12 cycles randomly, during which the efficacy was assessed every 4 cycles, then followed by bevacizumab(7.5mg/m 2 ) in combination with capecitabine maintenance therapy which assessed every 2 cycles until disease progression, and then switched to the second-line therapy FOLFIRI/mFOLFOX6 combined with bevacizumab which was assessed every 4 cycles until disease progression or intolerable toxicity. Imaging studies were performed to assess treatment efficacy according to RECIST1.1 criteria, and the primary endpoint was progression-free survival (PFS), including first-line PFS and second-line PFS after progression, and the secondary endpoints included disease response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. R esults: This study recruited 78 subjects from January 2021 to May 2024. As of September 10, 2024, a total of 70 subjects were analyzable for the first-line treatment, of which 6 subjects met the surgical criteria after treatment and achieved NED status; 45 patients reached the first-line PFS endpoint, with a median PFS (mPFS) of 249 days (95% CI: 204.4-293.6), an ORR of 38.6%, and a DCR of 95.7% . Twenty patients entered the first-line maintenance therapy, with a mPFS of 358 days (95% CI: 53.8-662.2). For the second-line treatment, a total of 43 subjects were analyzable, of which 35 patients reached the second-line PFS endpoint, with a second-line mPFS of 171 days (95% CI: 89.8-252.1). 41 subjects underwent at least one efficacy evaluation, with ORR of 14.6% and DCR of 75.6%. The most common grade 3 treatment-related adverse events were neutropenia, leukopenia, anemia, hypertension, diarrhea, and thrombocytopenia. There were no treatment-related deaths. No new adverse events occurred during the entire combination treatment period. C onclusions: This real world study has demonstrated good tolerability and encouraging clinical efficacy, especially with potential implications for treatment planning and management strategies for advanced colorectal cancer with RAS mutations. Clinical trial information: ChiCTR2100042553 .

Preliminary results of benmelstobart plus anlotinib combined with SOX in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with low PD-L1 expression: A single-arm, multicenter phase II clinical trial.

444 Background: First-line chemotherapy for advanced HER2-negative gastric/gastroesophageal (G/GEJ) adenocarcinoma has limited efficacy. PD-1 inhibitors plus chemotherapy show promise but need improvement, especially for patients (pts) with low PD-L1 expression. Anlotinib, a multi-targeted TKI for tumor angiogenesis/proliferation, is approved in China. This study aims to evaluate the efficacy and safety of benmelstobart a PD-L1 blockade) in combination with anlotinib and SOX (S-1 plus oxaliplatin) as a first-line regimen for advanced G/GEJ adenocarcinoma in patients with low PD-L1 expression, Preliminary findings will be reported promptly. Methods: Pts with HER2-negative, unresectable, locally advanced, or metastatic G/GEJ adenocarcinomas and a PD-L1 Combined Positive Score (CPS) < 5, who had not received prior systemic therapy were included. They received benmelstobart (1200mg, iv, d1, q3w) combined with anlotinib (10mg, po, d1~14, q3w), oxaliplatin (130mg/m 2 , d1, iv, q3w) and S-1 (40mg, po, bid, d1~14, q3w) for 6 cycles as initial therapy. Maintenance therapy with benmelstobart (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) followed for non-progressive diseaseuntil PD or unacceptable toxicity occurred. Tumor responses were evaluated by RECIST 1.1 criteria. The target sample size was 37, with ORR as the primary endpoint, and safety, DCR, DoR, PFS, and 1-year OS rate as secondary endpoints. Results: From Jun 2023 to Sep 2024, 28 pts were enrolled and 27 were available for efficacy and safety evaluation. The patients’ characteristics were as follows; median age (range): 59 (38-77) years, Male/Female: 19 (70%)/8 (30%), ECOG PS 0/1: 2 (7%)/25 (93%), Surgical history yes/no: 6 (22%)/21 (78%), CPS: ＜1/ ≥1: 4 (15%)/23 (85%), respectively. In the response assessment, 19 PR (70.4%), 6 SD (22.2%), and 2 NE (7.4%) were observed, yielding an ORR of 70.4% (95% CI: 49.8-86.2) and DCR of 92.6% (95% CI: 75.7-99.1). As of September 17, 2024, 6 of 27 patients discontinued (3 due to PD, 3 voluntary), leaving 21 ongoing. The longest DoT was 15.08 months, and the median PFS was not reached. Common TEAEs ≥10% included thrombocytopenia (37%), anemia (33%), leukopenia (22%), HFS (19%), fatigue (15%), liver function abnormalities (15%), and appetite loss (11%). Grade ≥3 TEAEs were thrombocytopenia (4%) and anemia (4%). Conclusions: Preliminary findings indicate that the combination of benmelstobart and anlotinib with the SOX regimen as a first-line treatment for advanced G/GEJ adenocarcinoma with low PD-L1 expression demonstrates promising therapeutic efficacy and tolerable adverse events. Further validation of these results in a larger, consecutive patient population is warranted. Clinical trial information: ChiCTR2400085396.

Rhythmanalysis of care: Daily practices among informal caregivers of children with cancer.

An increasing number of people face the challenge of providing long-term, unpaid, informal care to children with cancer. The repetitive and staged processes of treatment create inherently rhythmic care practices, imposing a strict schedule on caregivers' daily routines. To explore the rhythmic nature of pediatric cancer informal care, we discuss the rhythms of daily life during intensive chemotherapy and maintenance therapy, and negotiated strategies of caring practice. We draw upon Lefebvre's rhythmanalysis and activity diary, and conduct semi-structured interviews with informal caregivers. We demonstrate the scale, stage, and dynamic nature of the daily life rhythm of caregivers of children with cancer, which is characterized by linear "alienation," arrhythmia, and "metastable" harmony. Structured therapeutic rhythms do not have overwhelming power; rhythms are intervened through insertion, negotiated adjustment, recharging, and alliances to maintain eurhythmia in caregivers of children with cancer. This study provides specific insights into the care of children with cancer in the context of the relationship between time, space, energy, and rhythm, which may help provide support to caregivers and reduce their burden of care.

XPO1 inhibition as a clinically viable strategy to enhance durability of response to KRAS G12D inhibitor in pancreatic ductal adenocarcinoma.

736 Background: The OFF State (GDP bound) KRASG 12D inhibitor MRTX1133 is currently being evaluated in pancreatic ductal adenocarcinoma (PDAC) patients. Nevertheless, as with other OFF state KRAS G12C inhibitors sotorasib and adagrasib, the KRAS G12D inhibitor may yield only a modest increase in disease-free survival due to emergence of drug resistance. This underscores the need to identify strategies that can enhance the efficacy of KRAS inhibitors in PDAC. Nuclear protein transport plays an important role in several pro-tumorigenic pathways and has been shown to be a therapeutic vulnerability in KRAS mutant cancers. XPO1 is the major nuclear exporter and plays a pivotal role in shuttling various critical tumor suppressors, genome surveillance proteins, and transcription factors out of the nucleus and is frequently overexpressed in various cancers, including PDAC. In this study, we employed a KRAS G12D inhibitor resistant model and evaluated its sensitivity to nuclear exporter protein inhibitor. Methods: We examined the cytotoxic and molecular effects of KRAS G12D inhibitor MRTX1133 in combination with nuclear transport inhibitor eltanexor in KRAS G12D inhibitor resistant models. The preclinical antitumor efficacy of the combination was evaluated in KRAS G12D mutant PDAC cell derived xenograft (CDX) subcutaneous and orthotopic models. Results: Eltanexor treatment reversed MRTX1133 resistance in vitro yielding suppressed proliferation of KRAS G12D mutant 2D and 3D cultures of PDAC cell lines and patient derived primary tumors cells. High throughput P-kinome analysis showed suppression of a larger repertoire of MAPK substrates in combination treatment compared to single agent group. Eltanexor and MRTX1133 combination led to reduction in protein expression of KRAS downstream effectors and cell cycle markers. Furthermore, a combined administration of eltanexor and MRTX1133 at sub-optimal doses resulted in remarkable tumor growth inhibition in multiple subcutaneous and orthotopic KRAS G12D mutant mice models. Moreover, eltanexor as a maintenance therapy also prevented tumor relapse indicating durability of response in PDAC. Conclusions: This is the first study demonstrating that nuclear transport inhibitors can overcome KRAS G12D inhibitor MRTX1133 resistance in PDAC cells. This study provides a rationale for combining MRTX1133 with eltanexor for the treatment of PDAC patients with KRAS G12D mutant tumors.

Fruquintinib plus camrelizumab combined with paclitaxel liposome and nedaplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, phase II clinical trial.

445 Background: Camrelizumab in combination with chemotherapy has become a standard of care for the first-line treatment of advanced ESCC. Previous studies have indicated synergistic effect of fruquintinib in combination with chemotherapy or immunotherapy. Hence, we conducted a phase II trial to evaluate the efficacy and safety of fruquintinib plus camrelizumab, paclitaxel liposome, and nedaplatin as a first-line therapy for advanced ESCC. Methods: This is a single-arm, phase II study consisting of a dose-finding and a dose-expansion phase. A total of 33~36 patients aged 18~80 years with previously untreated advanced ESCC and an ECOG PS of 0-2 were planned to be enrolled. The dose-finding phase followed a 3+3 approach in order to determine the recommended phase II dose (RP2D) of fruquintinib for dose expansion. Patients received fruquintinib (3 mg, 4 mg, and 5 mg once daily on days 1-14, starting at 4 mg) orally, plus intravenous camrelizumab 200 mg d1, paclitaxel liposome 135 mg/m 2 d1, and nedaplatin 70 mg/m 2 d1, 21 days as one cycle. A maximum of 6 cycles was conducted, followed by maintenance therapy with fruquintinib in combination with camrelizumab. The primary endpoint was objective response rate (ORR, RECIST 1.1). Secondary endpoints included RP2D, disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). Results: As of August 24, 2024, 11 patients (9 males) were enrolled with a median age of 66 years (range 50-76). All patients had distant metastases, and the median number of sites of metastasis was 2 (range 1-5). In the dose-finding phase, 3 patients were treated with 4 mg of fruquintinib, and 6 patients were treated with 5 mg of fruquintinib. No dose-limiting toxicities (DLTs) were observed. Thus, the RP2D of fruquintinib was established as 5 mg once daily on days 1-14, 21 days as one cycle. Of the 7 evaluable patients, 6 achieved partial response, and 1 had stable disease. The ORR was 85.7% (95% CI 42.1%-99.6%), and the DCR was 100.0% (95% CI: 59.0%-100.0%). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were anemia (7/11), hypercholesterolemia (6/11), hypoalbuminemia (5/11), oral mucositis (5/11), hematuria (4/11), hypertension (4/11), fatigue (4/11), constipation (3/11), and neutropenia (3/11). Grade 3 TRAEs were identified in 2 patients, including oral mucositis (2/11), and anemia (1/11). No treatment-related serious adverse events (SAEs) or deaths occurred. Conclusions: The combination of fruquintinib, camrelizumab, paclitaxel liposome, and nedaplatin demonstrated significant efficacy and manageable toxicity profiles as a first-line treatment for advanced ESCC, suggesting a potential new treatment strategy. Clinical trial information: NCT06010212 .

Preliminary safety and efficacy of upfront FOLFOXIRI and bevacizumab with cadonilimab in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer: A multicenter phase II study (SYLT-026).

198 Background: The AtezoTRIBE phase II trial reported that adding Atezolizumab to upfront FOLFOXIRI plus Bevacizumab significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, the improvement in OS was modest within the pMMR/MSS subgroup (HR, 0.80 [80% CI, 0.63–1.02]; P = 0.117) [1]. Cadonilimab, a humanized bispecific antibody targeting both PD-1 and CTLA-4, may offer enhanced therapeutic benefits. Therefore, this study aims to investigate whether the addition of Cadonilimab to upfront FOLFOXIRI plus Bevacizumab improves efficacy while maintaining safety in patients with pMMR/MSS mCRC. Methods: This multicenter, single-arm phase II study enrolled treatment-naive patients with pMMR/MSS mCRC, aged 18–75, who had at least one measurable lesion according to RECIST 1.1, an ECOG performance status (PS) of 0–2, and adequate organ function. Patients with dMMR/MSI-H tumors or prior immunotherapy were excluded. Eligible participants received FOLFOXIRI (irinotecan 165 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2400 mg/m² as a 48-hour infusion), along with Bevacizumab (5 mg/kg), and Cadonilimab (6 mg/kg). Treatment was administered for up to twelve 14-day cycles, followed by maintenance therapy with fluoropyrimidine and Bevacizumab plus Cadonilimab for up to 52 weeks, or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were equally enrolled, with 10 having liver metastases and 10 without. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of August 30, 2024, 20 patients were enrolled, with a median age of 65.5 years (range: 33–74). Of these, 40% had an ECOG PS of 1 or 2, 55% had three or more metastatic organs, and 7 patients (35%) had RAS or BRAF mutations. The median follow-up was 5.0 months. Fifteen patients underwent at least two imaging assessments, revealing a confirmed ORR of 100% (15/15) and a disease control rate (DCR) of 100%. The median progression-free survival (PFS) and OS data were not yet mature. All 20 patients experienced treatment-emergent adverse events, most of which were grade 1 or 2. One patient (5%) discontinued treatment due to immune-mediated colitis. The most common grade 3/4 adverse events included neutropenia (55%), leukopenia (15%), infusion reactions (5%), dermatitis (5%), colitis (5%), anemia (5%), elevated ALT (5%), and diarrhea (5%). No new safety signals were identified. Conclusions: In conclusion, Cadonilimab in combination with FOLFOXIRI and Bevacizumab demonstrated promising efficacy and a manageable safety profile as a first-line treatment for patients with pMMR/MSS mCRC. Further investigation in larger trials is warranted. 1. Antoniotti, et al, J Clin Oncol, 2024. Clinical trial information: NCT05839470 .

Real-world outcomes of PARP inhibitor maintenance in advanced ovarian cancer: a focus on disease patterns and treatment modalities at recurrence.

The utilization of poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) as a first-line maintenance therapy for advanced ovarian cancer has increased significantly, with ∼80% of patients potentially eligible. This expansion has led to a rise in the population experiencing platinum-sensitive recurrence, yet data on first recurrence during PARPi are limited. This real-world study from a high-volume referral center aims to elucidate recurrence rates, disease distribution, and treatment modalities at the time of progression in PARPi-treated patients. We analyzed our prospectively maintained database to identify patients receiving first-line PARPi maintenance from January 2019 to December 2022 at our institution. A total of 373 cases were identified, 51.5% of which had a BRCA mutation. With a median follow-up of 38 months, 44.8% of patients experienced recurrence, with 90.3% having a platinum-free interval exceeding 6 months. Recurrences were oligometastatic in 44.9% of cases, with BRCA mutations strongly predicting this pattern (hazard ratio 3.014, confidence interval 1.486-6.113, P= 0.002). The median progression-free survival was 39 months, significantly longer for BRCA-mutated and homologous recombination deficiency-positive patients. Over one-third of platinum-sensitive recurrent patients were candidates for local treatments, and PARPi administration was prolonged in 53.7%. Despite the notable survival improvement, a significant proportion of the population will experience a platinum-sensitive recurrence on PARPi, for which local treatments are often a viable option. Our study highlights the need for further research to determine whether the ablation of oligometastatic sites has a significant impact on post-recurrence survival and to identify if there are patient categories that would benefit from personalized follow-up due to their susceptibility to oligometastatic recurrences and local treatments.

Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated (HRD) metastatic pancreatic cancer.

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

The value and indications for surgery in pancreatic cancer with synchronous liver metastases.

714 Background: Over half of pancreatic cancer patients present with advanced disease and distant metastases, primarily in the liver, at initial diagnosis. Although systemic combination therapies have improved outcomes, the role of surgery remains contentious. This study seeks to pinpoint prognostic factors for patients with synchronous liver metastatic pancreatic cancer (sPDACLM) who receive effective treatments, and to identify patients likely to benefit from surgery. Methods: This is a retrospective cohort study. Included patients received first-line chemotherapy (AG/mFOLFIRINOX), with efficacy assessed every 4-6 cycles through imaging and biochemical evaluations. Imaging assessments were conducted according to RECIST 1.1 criteria, while biochemical evaluation focused on the reduction of CA19-9 (calculating cutoff values). Patients with good responses were considered for curative surgery, while those with minor responses decided between surgical treatment or continued maintenance therapy after being fully informed. Results: From May 2017 to February 2024, a total of 48 patients with sPDACLM who met the inclusion criteria were recruited for this study. The prognosis of patients with resectable or borderline resectable primary tumors was significantly superior to unresectable cases (18 months vs 11 months, p = 0.0011). Multivariate analysis revealed independent favorable prognostic factors: surgery (HR 0.22; p = 0.026), partial response (PR) per RECIST 1.1 criteria (HR 0.09, p = 0.040), and tumor marker reduction >85% (HR 27.99; p = 0.005). Achieving conversion effectiveness, as defined by imaging and biochemical criteria, was associated with a significantly improved prognosis compared to cases where conversion was ineffective (28 months vs. 12 months, p = 0.0086). Notably, effective surgery patients had a median survival of 49 months and a 5-year survival rate of 33%. Conversely, for patients who did not respond to systemic therapy, surgery did not confer any significant impact on overall survival; however, the corresponding survival curve indicated a trend towards shorter survival compared to those who did not undergo surgery. Conclusions: Patients with sPDACLM fulfill both imaging and biochemical criteria, exhibit improved prognoses; additionally, surgery has been shown to significantly prolong their median overall survival times. Research indicates that accurate screening for cases suitable for conversion surgery can significantly improve the survival rates of sPDACLM. Overall survival time and survival rates in patients with synchronous liver metastatic pancreatic cancer undergoing conversion therapy. OS 1-year survival rate 2-year survival rate 3-year survival rate 5-year survival rate Effective group Surgery 49 months 100% 88% 66% 33% Non-surgery 18 months 80% 20% - - Non-effective group Surgery 11 months 33% - - - Non-surgery 12 months 36% - - - OS, overall survival time.

A phase II study of anlotinib as first-line maintenance therapy for advanced ovarian cancer.

Anlotinib, a tyrosine kinase inhibitor, has shown encouraging antitumor activity in platinum-resistant/refractory ovarian cancer. The efficacy of anlotinib as maintenance therapy in advanced ovarian cancer remains unclear. Therefore, we designed this study to evaluate the efficacy and safety of anlotinib maintenance therapy following first-line treatment with paclitaxel and platinum-based chemotherapy in advanced ovarian cancer. In this single-arm, phase II clinical trial, patients with newly diagnosed advanced ovarian cancer were received anlotinib monotherapy as maintenance therapy once after a response to platinum-based chemotherapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival. From April 2020 to June 2021, 24 patients were enrolled in this study. The median follow-up was 40.17 months (interquartile range, 32.40-47.93 months). Of 21 patients with efficacy value, the median progression-free survival and median overall survival were 15.8 months (95% confidence interval, 6.8-24.8 months) and 43.8 months (95% confidence interval, 25.45-62.15 months). The quality-adjusted progression-free survival was 14.4 months and there were no observed treatment-related deaths or serious treatment-emergent adverse events, demonstrating the safety of anlotinib in maintenance therapy. Anlotinib shows significant potential as a first-line maintenance therapy for advanced ovarian cancer, extending survival and providing a reliable treatment option.

Multiple Myeloma: Improved Outcomes Resulting from a Rapidly Expanding Number of Therapeutic Options.

Multiple myeloma (MM) is a bone-marrow-based cancer of plasma cells. Over the last 2 decades, marked treatment advances have led to improvements in the overall survival (OS) of patients with this disease. Key developments include the use of chemotherapy, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. MM remains incurable, with outcomes influenced by many factors, including age, sex, genetics, and treatment response. This review summarizes recent studies regarding monitoring and treatment of MM, emphasizing the efficacy of new therapies, the impact of maintenance treatments, and approaches for managing relapsed or refractory MM. The role of specific drug classes used to treat MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and newer treatments such as chimeric antigen receptor T-cell therapies and bispecific antibodies are discussed. Combination therapies have significantly improved outcomes. Maintenance therapies, particularly with lenalidomide, have been effective in extending OS but lead to an increased risk of secondary cancers. Venetoclax, selinexor, and ruxolitinib have shown potential as new therapeutic options for patients with relapsed or refractory MM. Immune-based treatments, such as chimeric antigen receptor T-cell therapy and bispecific antibodies, mark a major advancement for heavily pretreated patients, although challenges remain related to cost, availability, and side effects. The treatment landscape for patients with MM has seen significant progress, with current therapies providing a longer OS and better quality of life. Future research should focus on optimizing these strategies, personalizing therapies, and exploring new therapeutic targets.

The Effectiveness of Budesonide Once Daily as Maintenance Treatment of Eosinophilic Esophagitis.

Swallowed topical corticosteroids (STC) are an effective first-line therapy for patients with eosinophilic esophagitis (EoE), both for induction and maintenance of remission. All interventional trials with STC used twice-daily dosing regimens. However, in other inflammatory gastrointestinal disorders, corticosteroids are given once daily (OD) with equal outcomes and improved compliance. To evaluate the effectiveness of topical budesonide maintenance treatment in a once-daily dosing schedule. Retrospective analysis of confirmed patients with EoE, treated with topical budesonide as maintenance therapy OD, with adequate follow-up available. Patients currently treated with budesonide were contacted to fill out online questionnaires regarding symptoms and health-related quality of life (HRQOL). The primary end point was histologic remission, defined as peak eosinophil count (PEC) <15 eosinophils per high power field (HPF) after >12 weeks of budesonide OD. We included 29 patients on STC OD (1mg, N=28; 0.5mg, N=1), either budesonide orodispersible tablet (BOT, Jorveza, Dr. Falk Pharma; N=12) or budesonide viscous solution (BVS; N=17). After a median follow-up of 767 days on OD dosing (range: 103 to 2396), 86% of patients were in histologic remission. Four patients had histologic disease activity, of which one was treated with BOT. Two patients experienced a slight increase in PEC after dose reduction of BVS to OD (to PEC of 25 and 35/HPF, respectively). However, after switching the formulation to BOT OD they achieved histologic remission. In this retrospective study, we demonstrated favorable results in the majority of patients treated with budesonide 1mg OD as maintenance treatment for eosinophilic esophagitis.

Maintenance-phase serum anti-TNF levels are not associated with mucosal healing in pediatric Crohn's disease.

Mucosal healing (MH) is a key therapeutic target in Crohn's disease (CD) and is associated with improved outcomes. While adult studies indicate a positive correlation between serum anti-tumor necrosis factor (TNF) levels and MH, data in pediatric patients is limited. We aimed to define the association of serum anti-TNF levels with MH in pediatric patients with CD during maintenance therapy. Retrospective data (2014-2023) was collected from pediatric CD patients treated with infliximab or adalimumab who performed an ileocolonoscopy at least 26 weeks after initiating therapy. Serum anti-TNF levels around endoscopic time were compared with endoscopic findings. MH was defined as complete absence of inflammatory or ulcerative lesions across all segments of the gastrointestinal tract. Univariable and multivariable logistic regression analysis was conducted to identify factors associated with MH. Data were obtained from 107 patients (41 infliximab and 66 adalimumab), with a median age at diagnosis of 12.6 (9.9-14.0) years. Median time until ileocolonoscopy following anti-TNF initiation was 89.0 (56.3-152.3) weeks. MH was identified in 31 (29.0%) patients. Anti-TNF serum levels were comparable in the MH and non-MH groups (9.5 [4.9-13.9] vs. 9.3 [6.4-15.7] µg/mL; p = 0.73), without differences in patients treated with infliximab or adalimumab. In multivariable analysis, diagnosis weight Z-score (odds ratio [OR] = 2.860, 95% confidence interval [CI] = 1.005-8.138; p = 0.049), along with C-reactive protein (OR = 0.037, 95% CI = 0.002-0.687; p = 0.027) and fecal calprotectin (OR = 0.995, 95% CI = 0.990-1.000; p = 0.037) at time of ileocolonoscopy were significantly associated with MH. In our cohort, anti-TNF levels during maintenance were not associated with MH in pediatric CD.

Anti-tumor Necrosis Factor Drug Concentration Is Not Associated with Disease Outcomes in Pouchitis: A Retrospective, International Study.

Therapeutic drug monitoring is important for optimizing anti-tumor necrosis factor-α (TNF-α) therapy in inflammatory bowel disease. However, the exposure-response relationship has never been assessed in pouchitis. To explore associations between anti-TNF-α drug concentration and pouchitis disease activity in patients with a background of ulcerative colitis. A retrospective, multicenter, cross-sectional study was conducted in adult patients with pouchitis requiring anti-TNF-α treatment. Rates of clinical and endoscopic remission were calculated, and drug concentrations during maintenance therapy were compared between remission and non-remission cohorts. Sixty-three patients were included: median age, 48years (IQR 36-59) and median time since pouchitis diagnosis, 7years (IQR 2-13). Patients received infliximab, n = 27 (43%), adalimumab, n = 29 (46%), or both n = 7(11%). Thirty-two (51%) patients received concomitant immunomodulation. Median infliximab trough concentrations (mg/ml) were similar between patients in clinical remission (n = 21) vs non-remission (n = 11), 5.3 vs. 4.4, p = 0.73. For adalimumab, median drug concentrations did not significantly differ between remission/non-remission groups based on clinical (n = 18/18), 11.4 vs 7.6, p = 0.32, or endoscopic assessment, (n = 7/29), 9.0 vs. 7.8, p = 0.78. Four patients had positive anti-drug antibodies with undetectable drug concentration. In a cohort of patients with pouchitis, higher anti-TNF-α drug concentrations were not associated with more clinical or endoscopic remission.

Frontline treatment of follicular lymphoma: What will it take to change current practice?

Follicular lymphoma is the most common subtype of indolent lymphoma. Despite multiple trials over the past decade showing improved progression-free survival with new first-line therapeutic strategies -such as anti-CD20 maintenance therapy and new glycoengineered anti-CD20 antibodies- no standardized approach has been widely adopted in routine clinical practice. Several factors may explain this, including the increased incidence of infectious adverse events associated with these therapies, particularly during the COVID-19 pandemic, and the lack of overall survival benefit despite long-term follow-up. A general consensus has emerged acknowledging the high prognostic variability of follicular lymphoma, which complicates the adoption of a one-size-fits-all first-line treatment strategy. A plethora of prognostic scores (FLIPI, FLIPI2, PRIMA-PI, m7-FLIPI, FLEX, 23-gene score, etc) has been proposed but none can reliably identify the ~20% of patients that will die within 10 years of first-line immunochemotherpay and for whom a critical medical need remains despite recent therapeutic improvements. Consequently, current prognostic models mainly serve as tools to cross-compare and stratify clinical trials. In this review, we highlight current and future strategies aimed at reshaping frontline treatment paradigms to improve outcomes, including tailored approaches based on risk- or response-adapted designs, development of new predictive -rather than prognostic- tools, approaches to reduce adverse events to enhance health-related quality of life, and the potential use of T-cell-engaging therapies to improve survival in the highest risk patients.

Efficacy and safety of a modified DVD regimen followed by lenalidomide for the treatment of Newly Diagnosed Multiple Myeloma.

The common drugs used for the treatment of Newly Diagnosed Multiple Myeloma (NDMM) include bortezomib and lenalidomide, but the adverse effects of lenalidomide cannot be ignored, especially when it is used in the initial therapy. This retrospective study evaluated the efficacy and safety of a modified DVD regimen (pegylated liposomal doxorubicin, bortezomib, and dexamethasone) followed by lenalidomide in the treatment of NDMM. A total of 40 NDMM patients were treated with a reduced dose of pegylated liposomal doxorubicin (20 mg/m2) on day 1, subcutaneous bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11, and dexamethasone (20 mg) on days 1, 2, 3, 4, 8, 9, 11, and 12 (20 days for each course). When patients failed to achieve partial or better response after 2 courses of treatment, a regimen containing lenalidomide was administered. After the induction therapy, 15 eligible patients received Peripheral Blood Stem Cells (PBSC) mobilization and transplantation followed by maintenance therapy with lenalidomide. The response rate (≥ very good partial response) was 55% and 80% after 2 and 4 courses, respectively. The 18-month Progression Free Survival (PFS) and Overall Survival (OS) were 78.6% and 83.4%, respectively. Grade 3 or 4 hematologic toxicity occurred in less than 10% of patients. In addition, all 15 transplant-eligible patients successfully mobilized PBSC (median CD34+cells = 4.59 × 106/kg) and underwent autologous PSBC transplantation. This study suggests that the modified DVD regimen followed by lenalidomide is an effective and well-tolerated regimen, and has little influence on the PBSC collection and transplantation for patients with NDMM.

Clinical experience with the third-generation antipsychotic brexpiprazole in the treatment of schizophrenia spectrum disorders in a psychiatric inpatient settings

Objective: to summarize the clinical experience of the antipsychotic brexpiprazole in the treatment of schizophrenia spectrum disorders in a psychiatric hospital.Materials and Methods. A group of 26 patients (16 women; 61.5%) aged 19 to 64 years (mean age 35.73±9.33) with leading delusional, hallucinatorydelusional, manic-delusional, depressive-delusional or depressive-paranoid symptomatology constituted the study material. Patients were followed up for 6 weeks after brexpiprazole administration. The severity of psychotic symptomatology was assessed by selected items of the Positive and Negative Syndrome Rating Scale (PANSS). The General Clinical Impression Scale (CGI) was used for objective assessment of the patients' condition: the severity of condition subscale (CGI-S) and the mental status dynamics subscale (CGI–I). Patients' satisfaction with therapy was assessed in the dynamics of treatment and after the end of the follow-up period.Results. Brexpiprazole was administered both on admission to hospital (65.4%) and after prior antipsychotic therapy (34.6%). The range of maximum doses was 2 to 4 mg per day. Side reactions were registered in 3 cases (11.5%), and only in one case it required withdrawal of the drug. Statistically significant improvement of mental state by the 7th day of therapy was registered for the majority of PANSS items (Delirium, Suspiciousness, Agitation, Anxiety, Tension, Aggressiveness). A statistically significant decrease in the severity of mental state according to CGI was observed from the second week of therapy. A distinct dynamics of change of attitude to therapy towards positive attitude to therapy was established (p=0,029).Conclusions: clinical experience of brexpiprazole use in psychiatric inpatient settings demonstrated good results both in terms of therapy efficacy and safety, which allows us to evaluate the drug as promising for use in the treatment of psychotic exacerbations and maintenance therapy of patients with schizophrenia and schizophrenia spectrum disorders.