Favorable Progression-free Survival Research Articles

Utility of assessing early tumor shrinkage as an efficacy predictor in patients with non-surgically indicated or recurrent esophageal cancer treated with nivolumab plus ipilimumab.

Nivolumab plus ipilimumab combination therapy has been administered as a first-line treatment in Japan since 2022 for patients with unresectable progressive or recurrent esophageal cancer. The efficacy and safety of this immune checkpoint inhibitor (ICI) doublet therapy is now being evaluated, and it is necessary to identify populations that benefit from this treatment at an early phase after initiation. For patients not showing early benefit, changing as soon as possible to other therapeutic strategies could improve their survival outcomes. Therefore, we attempted to identify decision-making factors such as early tumor shrinkage (ETS) based on treatment experience with ICI doublet therapy. The study included 19 patients who received nivolumab plus ipilimumab for non-surgically indicated or recurrent esophageal cancer between July 2022 and November 2023. Tumors were assessed approximately every 2 months after treatment initiation. The effects of ETS, depth of response (DpR), and clinicopathologic features, including immune-related adverse events (irAEs), on progression-free and overall survival were evaluated using Kaplan-Meyer plots and Cox proportional hazard models. The mean duration of ICI doublet administration was 5.89 months (range, 1-16 months). At first evaluation, patients who exhibited no tumor progression >20% indicated possible response to ICI doublet therapy, and patients whose tumors shrank even minimally exhibited favorable progression-free survival. Higher DpR at any cut-off line exhibited better progression-free survival than those with lower DpR. Fifteen patients experienced irAEs, with 13 of these patients experiencing irAEs within 3 months of treatment initiation. irAEs were associated with the efficacy of ICI doublet therapy, but efficacy could not be predicted based on early irAE experience. ETS-high, DpR-high, and irAEs might be associated with favorable responses to nivolumab plus ipilimumab. As a predictor of efficacy at an early phase, ETS >0% could be a deciding factor for continuing ICI doublet therapy.

Evolving consolidation patterns and outcomes for a large cohort of patients with primary CNS lymphoma

AbstractConsolidation strategies for primary central nervous system lymphoma (PCNSL) after induction chemoimmunotherapy include whole-brain radiotherapy (WBRT; ≤24 Gy reduced-dose [RD], >24 Gy standard-dose) and cytarabine, nonmyeloablative chemotherapy (NMC), or autologous hematopoietic cell transplantation (AHCT); however, comparative outcomes are lacking. PCNSL outcomes from 1983 to 2020 were stratified by decade and Memorial Sloan Kettering Cancer Center recursive partitioning analysis (RPA) class. Clinicodemographic associations with consolidation were analyzed by multinomial logistic regression. Progression-free survival (PFS) and overall survival (OS) were analyzed by proportional hazards from consolidation. Of 559 patients, 385 (69%) were consolidated. Median follow-up and OS were 7.4 and 5.7 years, respectively. WBRT use declined (61% in 1990s vs 12% in 2010s), whereas AHCT (4% in 1990s vs 32% in 2010s) and NMC (27% in 1990s vs 52% in 2010s) rose. Compared with RPA 1 (age of <50 years), RPA 2 (age of ≥50 years, Karnofsky performance status [KPS] ≥70) was more likely to receive NMC. Those with partial response to induction were less likely to receive AHCT (odds ratio, 0.36; P = .02). Among 351 with complete response to consolidation, only receipt of rituximab, methotrexate, procarbazine, and vincristine induction was associated with improved PFS (hazard ratio, 0.5; P = .006). Among RPA 1, median PFS and OS were not reached for AHCT or RD-WBRT, vs 2.5 and 13.0 years, respectively, after NMC. Among RPA class 3 (KPS <70), median PFS and OS after RD-WBRT were 4.6 and 10 years, respectively, vs 1.7 and 4.4 years after NMC. No significant adjusted survival differences were seen across consolidation strategies. NMC is increasingly used in lieu of RD-WBRT despite a trend toward less favorable PFS. RD-WBRT can be considered in patients ineligible for AHCT.

Prognostic Role of Pre-Treatment Body Composition Parameters in Patients Undergoing First-Line Immunotherapy for Metastatic Renal Cell Carcinoma.

We investigated the relationship between body mass index (BMI), radiological body composition, and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) underwent first-line immune checkpoint inhibitor (ICI)-based therapy. Analyzing data from 102 patients treated between November 2019 and March 2023, pre-treatment computed tomography (CT) scans assessed fat and muscle areas. BMI and body composition indices were examined, including skeletal muscle index, subcutaneous fat index (SFI), visceral fat index, and total fat index. Kaplan-Meier curves and Log rank tests compared progression-free survival (PFS) and overall survival (OS), while multivariable Cox proportional regression analysis was performed to identify the variables significantly associated with survival outcomes. 54 patients (52.9%) experienced disease progression, and 26 (25.5%) died during a median follow-up of 17.4 months. High SFI was significantly associated with improved OS (p = 0.018) but not PFS (p = 0.090). Multivariable analysis confirmed the positive impact of high SFI on OS (adjusted HR: 0.37, p = 0.029) and suggested a trend towards improved PFS (adjusted HR: 0.61, p = 0.088). Notably, in the ipilimumab + nivolumab subgroup, high SFI significantly correlated with both PFS and OS (p = 0.047 and p = 0.012, respectively). High SFI predicts favorable OS in patients with mRCC receiving first-line ICI-based therapy, especially patients treated with ipilimumab + nivolumab displayed a significant association between high SFI and favorable PFS and OS.

Liver involvement with Langerhans cell histiocytosis in adults.

Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

Paclitaxel, Ifosfamide, and Cisplatin as Initial Salvage Chemotherapy for Germ Cell Tumors: Long-Term Follow-Up and Outcomes for Favorable- and Unfavorable-Risk Disease.

Paclitaxel, ifosfamide, and cisplatin (TIP) is an established salvage regimen for germ cell tumors (GCT) on the basis of a phase II trial, but efficacy on a large patient cohort including patients with unfavorable risk features and long-term outcomes has not been reported. Herein, we report updated treatment efficacy and long-term follow-up with TIP. Patients with GCT who received TIP after cisplatin-based chemotherapy were eligible. Favorable response (complete response or partial response with negative tumor markers), overall survival (OS) and progression-free survival (PFS) rates, relapse, and toxicity were determined. Disease was reclassified according to the International Prognostic Factor Study Group (IPFSG) score. Of the 104 patients, 87 had favorable risk factors and 17 had at least one unfavorable factor by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Ten patients were treated for a second gonadal primary GCT. With a median follow-up of 8.9 years, the 5-year PFS and OS rates were 66% (95% CI, 55 to 74) and 69% (95% CI, 59 to 77), respectively. Among 87 patients with favorable-risk disease, 69 (79%) achieved a favorable response with 5-year PFS and OS rates of 67% (95% CI, 56 to 76) and 72% (95% CI, 61 to 80), respectively. Among 17 patients with MSKCC unfavorable-risk disease, 13 (76%) achieved a favorable response with 5-year PFS and OS rates of 59% (95% CI, 33 to 78) and 56% (95% CI, 28 to 76), respectively. After IPFSG reclassification, 5-year PFS and OS rates for patients with ≤intermediate-risk disease were 75% (95% CI, 50 to 89) and 73% (95% CI, 55 to 85), respectively. TIP is an effective second-line regimen for patients with GCT. Similar outcomes were observed in patients with favorable- and unfavorable-risk disease. The randomized TIGER trial (ClinicalTrials.gov identifier: NCT02375204) comparing TIP with high-dose chemotherapy will determine the optimal second-line treatment approach.

Immune-Related Adverse Events Can Predict Progression-Free and Overall Survival In Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors

BackgroundDifferent combination therapies using anti - PD-1 / PD-L1 or CTLA-4 immune checkpoint inhibition (ICI) are widely used in patients with metastatic renal cell carcinoma (mRCC). In the absents of established biomarkers, immune-related adverse events (irAEs) have been discussed as potential predictors of response. MethodsIn this retrospective cohort study, data of 134 patients with mRCC undergoing ICI treatment (Nivolumab, Ipilimumab and Nivolumab, Pembrolizumab and Axitinib or Avelumab and Axitinib) between 2015 and 2021 were analyzed. To examine the utility of irAEs as predictors of overall survival (OS) and progression-free survival (PFS), separate Kaplan–Meier analyses and Cox proportional regression analyses were applied. Landmark analysis was conducted after 12 weeks to reduce immortal time bias. ResultirAEs were observed in 85 patients (63.4%). Cutaneous (n = 52, 38.8%), endocrine (n = 33, 24.6%) and hepatic (n = 19, 14.2%) irAEs were most commonly observed. In Kaplan–Meier analysis, patients experiencing irAEs showed favorable median PFS (15 months, 95% CI, 9.91-20.09) compared to the non-irAE subgroup (5 months, 95% CI, 3.56-6.44, P < .001). The median OS was 25 months (95% CI, 16.79-33.21) in the non-irAE subgroup, while it was not reached in the irAE subgroup (P = .002). In multivariable analysis, the presence of any irAE was associated with favorable PFS (HR 0.46 [95% CI, 0.26-0.82] P = .008) and OS (HR: 0.28 [95% CI, 0.12-0.63] P = .002), respectively. Landmark analysis after 12 weeks showed mixed results depending on the classification of the irAE subgroup at the landmark time. ConclusionThe presence of irAEs under ICI therapy in patients with mRCC is associated with better PFS and OS. Thus, manageable irAEs should not be cause for premature discontinuation of ICI therapy, as they seem to indicate favorable outcomes.Considering the time-dependent nature of irAEs is crucial estimating their value as predictive markers.

Activated CD4+ T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.

Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4+CD25+CD127+ T cells (hereafter referred to as "activated CD4+ T cells" ) among the total CD4+ T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4+ T cells among the total CD4+ T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.

Real‑world evidence of advanced non‑small cell lung carcinoma treated with an immune checkpoint inhibitor plus chemotherapy.

Immunotherapy is an effective treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). Although clinical trials on immunotherapy have provided promising results, real-world research in clinical practice is needed to assess the effectiveness and safety of immunotherapy. The present study aimed to characterize real-world outcomes in patients with advanced NSCLC treated with immune checkpoint inhibitor (ICI)-based regimens. The medical records of patients with advanced NSCLC, who were treated with programmed cell death protein-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitors, were reviewed for data collection. The primary objectives were to evaluate progression-free survival (PFS) and overall survival (OS). Therefore, multiple Cox regression models were used to investigate the predictive factors for survival outcomes. Furthermore, survival curves for PFS and OS were created using Kaplan-Meier estimates and compared using the log-rank test. The present study included a total of 133 patients with advanced NSCLC who received therapy with ICIs between January 1, 2019 and December 31, 2022. The final follow-up date was August 24, 2023. The median PFS and OS times were 9.8 and 27.2 months, respectively. Univariate Cox regression analysis demonstrated that sex, clinical stage, PD-L1 status, previous systemic therapy, and brain and liver metastases were associated with PFS, while Eastern Cooperative Oncology Group (ECOG) status, clinical stage, PD-L1 status and brain metastasis were associated with OS. Furthermore, multivariate Cox regression analysis demonstrated that a PD-L1 tumor proportion score (TPS) of ≥50% was an indicator of favorable PFS and OS. An ECOG performance status score of ≥1 was also associated with poor OS but not with PFS. Furthermore, brain metastasis was an indicator for poor PFS and OS, while liver metastasis was only associated with a poor PFS. Finally, the results of the present study demonstrated that PD-L1 status was an independent predictor for PFS and OS in patients with advanced NSCLC, especially adenocarcinoma, who were treated with ICIs plus chemotherapy. The results also suggested that patients with a PD-L1 TPS of ≥50% could benefit when the aforementioned regimens were administrated as a first-line or later-line therapy.

Stereotactic body radiation therapy is beneficial for a subgroup of patients with urothelial cancer and solitary metastatic disease: a single institution real-world experience

BackgroundStandard treatment options for patients with metastatic urothelial cancer (mUC) include systemic platinum-based chemotherapy, immunotherapy, antibody-drug-conjugates, and targeted therapy. Oligometastatic disease (OMD) may be an intermediate state between localized and generalized cancer. The best treatment strategy for OMD and oligoprogressive (OPD) disease is poorly studied in mUC but local stereotactic body radiation therapy (SBRT) could be an option to avoid or delay systemic treatment. The aim of this study was to assess the efficacy and feasibility of SBRT given in a real-world patient population.MethodsAll patients with mUC treated with SBRT at Karolinska University Hospital, Stockholm, Sweden between 2009 and 2022 were included in this study. Baseline clinical characteristics, treatment data, SBRT dosimetry data and treatment outcome were collected retrospectively. The study endpoints were local control rate (LCR), progression-free-survival (PFS), overall survival (OS) and feasibility of SBRT.ResultsIn total 39 patients were treated with SBRT. The median follow-up was 25.6 months. The LCR was 82%. PFS and OS were 4.1 and 26.2 months, respectively. Treatment was well tolerated; all patients but one (treatment related pain) completed the planned SBRT. Number of metastases irradiated with SBRT was significantly associated with outcome; patients with only one irradiated lesion had more favourable PFS compared to individuals with 2 or more metastases (HR 4.12, 95% CI: 1.81–9.38, p = 0.001). A subgroup of patients (15%) achieved a sustained long-term survival benefit and never required systemic treatments after SBRT.ConclusionsSBRT was well tolerated and associated with high LCR. A subpopulation of patients with single metastatic lesion achieved long-term OS and never required subsequent systemic treatment after SBRT. Prospective randomized studies are warranted to discover treatment predictive biomarkers and to investigate the role of SBRT in oligometastatic UC.

Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial.

LBA8505 Background: Amivantamab (ami) plus lazertinib (laz) demonstrated antitumor activity in EGFR-mutated advanced NSCLC. Subcutaneous (SC) ami administration takes ≤7 mins and has low infusion-related reaction (IRR) rates. PALOMA-3 (NCT05388669) evaluated SC ami+laz vs IV ami+laz for pharmacokinetics (PK), efficacy, and safety among pts with EGFR Ex19del or L858R-mutated advanced NSCLC and disease progression on osimertinib and platinum-based chemotherapy. Methods: SC ami at 1600 mg (2240 mg, ≥80 kg) was manually injected weekly for the first 4 weeks, then every 2 weeks; IV ami was given at the approved dose of 1050 mg (1400 mg, ≥80 kg). Laz was orally dosed at 240 mg daily. Co-primary PK noninferiority endpoints were trough concentration (Ctrough on Cycle [C] 2 Day [D] 1 or C4D1) and C2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR; noninferior) and progression-free survival (PFS). OS was a predefined exploratory endpoint. Prophylactic anticoagulation was recommended for the first 4 months (mo) of treatment. Results: In total, 418 patients (pts) were randomized (SC, n = 206; IV, n = 212); 416 received ≥1 dose. Overall, median age was 61 years, 67% were female, 61% Asian, and median 2 prior lines. At a median follow-up of 7.0 mo, PALOMA-3 met both co-primary endpoints. Geometric mean ratios (GMRs) comparing SC ami+laz vs IV for Ctrough were 1.15 (90% CI, 1.04–1.26) for C2D1 and 1.43 (90% CI, 1.27–1.61) for C4D1. GMR for C2 AUCD1-D15 was 1.03 (90% CI, 0.98–1.09). ORR was 30.1% (95% CI, 24–37) in the SC arm and 32.5% (95% CI, 26–39) for IV (relative risk, 0.92; P= 0.001), meeting the noninferiority criteria. Median duration of response (DoR) was longer for SC ami+laz vs IV (median, 11.2 vs 8.3 mo among confirmed responders). A favorable PFS trend was observed for SC ami+laz over IV (median, 6.1 vs 4.3 mo; HR, 0.84; P= 0.20). OS was notably longer for SC ami+laz vs IV (HR, 0.62; 95% CI, 0.42–0.92; nominal P= 0.017). At 12 mo, 65% were alive in the SC arm vs 51% for IV. IRRs were ~5-fold lower in the SC arm: 13% vs 66% for IV, primarily grade 1-2 (0.5% vs 4% grade ≥3, respectively). Overall, 81% received prophylactic anticoagulants, with VTE reported by 9% in the SC arm vs 14% for IV. Across both arms, VTE incidence was 10% for pts who received prophylactic anticoagulants vs 21% for pts who did not. Severe bleeding risk was low among all pts receiving anticoagulants (1% grade ≥3). Conclusions: SC ami demonstrated noninferior PK and ORR compared to IV. Unexpectedly, DoR, PFS, and OS were longer in the SC arm vs IV, suggesting that the route of administration or formulation may affect outcomes. The safety profile was improved for SC ami, with lower IRR and VTE rates. Prophylactic anticoagulation can be safely implemented and reduces VTE risk. Clinical trial information: NCT05388669 .

Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03.

1023 Background: DESTINY-Breast (DB)-01, -02, and -03 evaluated T-DXd in pts with HER2+ mBC who received ≥1 prior line of therapy. These studies showed confirmed objective response rates by independent central review (ICR; blinded for DB-02 and -03) of 62%, 70%, and 79% and complete response (CR) rates of 7%, 14%, and 21%, respectively, with T-DXd. We report a pooled analysis according to pts’ best confirmed response in DB-01, -02, or -03. Methods: Endpoints included best confirmed response per (blinded) ICR ([B]ICR) based on RECIST v1.1, duration of response (DoR), progression-free survival (PFS) by (B)ICR, overall survival (OS), and safety. Results: The median (range) duration of T-DXd treatment for pts with a CR, partial response (PR), or stable disease (SD)/progressive disease (PD) was 27.4 (4.5-45.1) mo, 14.0 (2.1-39.3) mo, or 6.2 (0.7-40.1) mo, respectively. Of 834 evaluable pts assigned to T-DXd in DB-01, -02, or -03, 125 (15.0%) had a CR, 477 (57.2%) had a PR, and 232 (27.8%) had SD/PD. Pts with CR had a median of 2 prior regimens (range, 1-11) in the metastatic setting, whereas pts with PR or SD/PD had a median of 3 prior regimens. As shown in the Table, pts with CR had more favorable PFS and OS outcomes vs pts with PR or SD/PD. The proportion of pts with drug-related, serious treatment-emergent adverse events (TEAEs) was numerically lower in pts with CR (8.0%) than those with PR (12.4%) or SD/PD (15.5%). Pts with CR also had numerically lower rates of drug-related TEAEs associated with T-DXd discontinuation (14.4% vs 17.8% or 16.8%) and adjudicated drug-related interstitial lung disease (ILD)/pneumonitis (8.8% [0 fatal] vs 15.1% [2 fatal] or 11.6% [5 fatal]) and longer median time to first ILD onset (461 days vs 211 or 125 days) vs pts with PR or SD/PD. Conclusions: Pts treated with T-DXd benefited from durable responses resulting in prolonged PFS and OS, especially those with a CR. Despite longer treatment duration in responders, safety remained generally manageable and did not result in a higher percentage of pts with TEAEs over time. These results further support the use of T-DXd across broad pt groups with HER2+ mBC. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]

A phase 2 trial of the CDK4 inhibitor dalpiciclib in well-differentiated or dedifferentiated liposarcoma.

11547 Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in &gt; 90% of well-differentiated liposarcomas (WDLS) and dedifferentiated liposarcomas (DDLS). Previous studies have already demonstrated the clinical benefit of CDK4 inhibitors in the treatment of WDLS and DDLS. Dalpiciclib is a more potent and novel CDK4 inhibitor. We designed a multi-center phase 2 study to evaluate the safety and efficacy of dalpiciclib in patients with advanced WDLS/DDLS. Methods: Eligible patients were adults aged 18 years and older, with a confirmed diagnosis of advanced WDLS/DDLS, measurable lesions according to RECIST 1.1, any (or no) priory therapy, and a history of progression by RECIST 1.1 in the 6 months prior to enrollment. All patients were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma (RB) protein expression by immunohistochemistry. All patients were treated with dalpiciclib 150 mg orally once per day for 21 consecutive days within a 28-day treatment cycle. The primary endpoint was progression free survival (PFS) at 12 weeks. Secondary end points included objective response rate and adverse events. Results: From August 2022 to October 2023, a total of 32 patients were enrolled, and 30 were evaluable for the primary end point. Median (range) age was 59 (40-76) years; 22 patients (69%) were male. At 12 weeks, PFS was 61.3% (95% CI, 44-78.5%). The median PFS was 17.4 weeks (95% CI, 10.65-24.15 weeks). Only one patient had a partial response to the treatment. Grade 3 to 4 events included neutropenia (37.5%), anemia (6.25%), thrombocytopenia (6.25%), and nausea (3.13%). Conclusions: Treatment with the CDK4 inhibitor dalpiciclib was associated with a favorable PFS rate in patients with advanced CDK4-amplified and RB-expressing WDLS/DDLS. Clinical trial information: ChiCTR2200062868.

Correlation of distinct circulating cytokine/chemokine profiles with clinical benefits of Pexa-Vec (thymidine kinase-deactivated vaccinia virus plus GM-CSF) and cemiplimab (REGN2810; anti-PD-1) in metastatic or unresectable renal cell carcinoma (mRCC).

e14539 Background: This study explores the transformation of 'cold' tumour microenvironments into 'hot' ones in mRCC, focusing on the potential of Oncolytic Viruses (OVs) for personalized immunotherapy. Recognizing the variability in patient responses, the research underscores the necessity for reliable biomarkers. The objective is to examine the correlation between plasma cytokine/chemokine levels and the efficacy of Pexa-Vec and cemiplimab, proposing that these biomarkers could predict treatment outcomes and contribute to more personalized cancer treatment protocols. Methods: In this study, mRCC patients from the REN026 trial were categorized into three treatment groups: Pexa-Vec (Intratumoral and intravenous) and cemiplimab combination therapy (N=65), intravenous Pexa-Vec and cemiplimab combination therapy (N=54), and cemiplimab monotherapy (N=14). Blood samples were collected at baseline, during treatment, and at end of treatment (EOT) for analysis. Subsequently, the plasma samples underwent analysis using the Human Cytokine 96-Plex Discovery Assay through the Luminex 200 system. The statistical approach included the Mann–Whitney U-test or Wilcoxon signed-rank test, along with a Cox proportional hazards model. The False Discovery Rate (FDR) method was employed to control type I error. Results: During the follow-up period from June 2018 to February 2023, key outcomes were observed as follows (Table): In the Pexa-Vec and cemiplimab cohort, a lower baseline of MCP-3 or an increased rate of change in post-treatment levels of IFNβ, Eotaxin, IL-1α, and sFasL were associated with improved Progression-Free Survival (PFS). Specifically, a low baseline of MCP-3 or an increased level of Eotaxin and sFasL post-treatment correlated with enhanced Overall Survival (OS). In the intravenous Pexa-Vec and cemiplimab group, a rise in post-treatment levels of IFNβ, Eotaxin, IL-17F, and sFasL were indicative of better PFS, with elevated Eotaxin also suggesting improved OS. Within the cemiplimab monotherapy group, an increase in post-treatment IP-10 was linked to favourable PFS. Conclusions: Our findings suggest the potential utility of plasma cytokine and chemokine profiles in clinical benefits of mRCC patient to the combination of Pexa-Vec and cemiplimab, thereby aiding in future personalized treatment approaches.

Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): Updated results from a single-center, real-world study.

e13118 Background: We evaluated the Tx patterns, efficacy and safety of eribulin for heavily pretreated ABC in real-world practice. Previous results were reported at the 2023 ASCO (e13118), updated results for longer follow-up and additional enrollment are presented here. Methods: Patients (pts) with ABC who had progression on anthracycline taxane Tx and received eribulin (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) between April 2020 and October 2023 were enrolled. Response was evaluated using RECIST v1.1. Pts were considered as taxanes sensitive if taxanes treatment duration of last line use exceeds 6 months, otherwise were considered as taxanes resistant. Results: 89 pts were enrolled. Median (range) age was 54 (30–79) years; 80.9% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, and 40.4% pts had a median of 3 prior lines of chemotherapy. 67.4% of pts had Ki67 &gt;30% and 46.0% had HR+/HER2− disease. 88.7% of pts had visceral metastasis. Eribulin was monotherapy in 30.3% of pts, and combined with bevacizumab, capecitabine, bevacizumab + capecitabine, and anti-HER2 agents in 28.1%, 9.0%, 3.4%, and 25.8%, respectively. The objective response rate was 22.5%; disease control rate was 84.3%. Median progression-free survival (PFS) overall was 6.0 (95% CI, [3.5–8.5]) months (mo). Univariate analysis indicated pts with HER2+ disease had longer PFS than pts with HR+/HER2− or triple-negative BC (median, 13.5, 4.5, and 3.7 mo, respectively; P = 0.011; Table). Pts with Ki67 expression ≤30% had longer PFS than pts with Ki67 &gt;30% (median, 8.0 vs. 4.0 mo; P = 0.02). Pts with grade I-II had longer PFS than pts with grade III (median, 10.5 vs. 4.0 mo; P = 0.003). Pts sensitive to Taxane had longer PFS than pts resistant to Taxane (median, 8.0 vs. 4.0 mo; P = 0.007). Among the 18 pts with a partial response, median PFS was 11.4 mo. The most common adverse events were leukopenia (44.9%), neutropenia (37.1%) and anemia (36.0%). Neurotoxicity was rare (6.7%). Conclusions: In this single-center study of pts with heavily pre-treated ABC in China, eribulin Tx resulted in favorable PFS irrespective of molecular subtype, with a manageable safety profile. In pts with a large tumor burden and a good PS, eribulin-based combinations may further improve outcomes. [Table: see text]

Impact of time-of-day infusion of camrelizumab combined with chemotherapy on efficacy in advanced malignant tumors.

e14634 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy has emerged as a standard first-line treatment strategy for advanced cancers. Camrelizumab and Tislelizumab, representative ICIs, have approval by the Chinese NMPA for first-line treatment of advanced cancers such as lung cancer and esophageal cancer. Previous studies have indicated that the timing of drug administration can influence the efficacy of ICIs. However, studies on the ICIs plus chemotherapy are lacking. Therefore, we conducted a retrospective study to explore the effect of the timing of infusion on patients with advanced cancer undergoing treatment with ICIs combined chemotherapy. Methods: We retrospectively enrolled a total of 253 patients diagnosed with advanced cancers between 2017 and 2023 in Guangdong Second Provincial General Hospital. Among these patients, 109 received camrelizumab (Cam cohort) plus chemotherapy and 65 received tislelizumab (Tis cohort) plus chemotherapy. Patients were grouped into morning (AM) and afternoon (PM) categories based on the timing of their ICIs administration (&lt; 1 times versus ≥ 1 times after 16:00). The Response Evaluation Criteria in Solid Tumors Criteria V.1.1 was used to evaluate the response to treatment. The primary endpoint was progression-free survival (PFS). Results: The results consistently showed that the PM group had a longer PFS than the AM group in the overall patients (p &lt; 0.01). In the Cam cohort, the PM group (n = 48) exhibited a longer PFS compared to the AM group (n = 61) (16.8 months vs. -, p = 0.02). However, no significant difference in PFS was observed among patients in the Tis cohort (AM vs. PM, n = 34 vs. n = 31, 16.1 months vs. -, p = 0.51). Subgroup analyses indicated that the PM group had a more favorable PFS treatment effect in most subgroups. The incidence of any Treatment Emerged Adverse Event (TEAE) (Cam cohort, AM vs. PM, 98.52% vs. 92.68%; Tis cohort, AM vs. PM, 97.05% vs. 100.00%) and grade 3 TEAEs (Cam cohort, AM vs. PM, 5.80% vs.7.30%; Tis cohort, AM vs.PM - vs. 12.90%) was similar in the Cam cohort and Tis cohort. The most common adverse events are anemia (Cam cohort vs. Tis cohort, 70.58% vs. 79.41%), thrombocytopenia (Cam cohort vs. Tis cohort, 54.41% vs. 58.82%) and lymphopenia (Cam cohort vs. Tis cohort, 44.11% vs. 44.11%). Conclusions: The findings of this study highlight a significant variation in daily rhythms among advanced cancer patients undergoing treatment with ICIs plus chemotherapy. Interestingly, a trend was observed in patients treated with camrelizumab, where those receiving treatment in the afternoon demonstrated a longer PFS. However, this trend was not observed in patients treated with tislelizumab. These results suggest that time-of-day infusion could potentially serve as a personalized strategy for patients treated with combination ICIs therapy.

Active surveillance and emerging medical treatment options for desmoid: when and for whom?

This article discusses the evolving approaches to desmoid tumors management, shedding light on recent developments. Active surveillance has become the primary approach for managing primary peripheral desmoid tumors. This strategy was initially based on evidence from retrospective studies. Roughly 50% of cases managed with active surveillance show spontaneous stabilization or regression. Recent prospective trials conducted in Italy, The Netherlands, and France (2022-2023) confirm the efficacy of active surveillance, revealing 3-year progression-free survival rates ranging from 53.4 to 58%. For the patients under active surveillance, decisions regarding treatment are based on significant tumor growth or progressive symptoms. Moreover, three contemporary randomized trials investigated medical treatments for progressive or recurrent desmoid tumors. Sorafenib, pazopanib, and nirogacestat demonstrated clinical activity, as evidenced by favorable progression-free survival and objective response rates. Active surveillance has solidified its position as the primary management approach for desmoid tumors, validated by three robust prospective studies. Three recent randomized trials explored medical treatment for progressive or recurrent desmoid tumors, revealing promising clinical activities.

Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial

sCoinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18–60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75–46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7–87.9 vs. 67.8% 95% CI 60.0–76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6–78.8 vs. 57.6%, 95% CI 49.6–67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0–12.2 vs. 30.3%, 95% CI 30.1–30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3–4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.

Abstract PO3-16-10: Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial

Abstract Background: Ribociclib (RIB), a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET) yielded significant improvement in progression-free survival (PFS) and overall survival (OS) across three phase III MONALEESA trials including patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC) in first-line (1L) and second-line (2L) setting. In the previous interim analyses of REACH AUT trial, 1L RIB + ET showed tolerable safety and favorable PFS results in a real-world setting. Results from the preplanned fourth interim analysis are reported here. Methods: REACH AUT is a noninterventional study conducted in Austria reporting data on the real-world clinical experience of RIB + ET (aromatase inhibitor [AI] or fulvestrant [FUL]) in premenopausal, perimenopausal, or postmenopausal pts with HR+, HER2– MBC. Pts with no prior ET for advanced disease and maximum up to 1 prior line of chemotherapy (CT) in the advanced setting were included. Results: At data cutoff (March 27, 2023) with a median duration of follow-up of 23.8 months, out of 281 analyzed pts (12.5% of premenopausal/perimenopausal and 85.1% of postmenopausal, 2.5% of unknown status) 31.7% of pts were receiving ongoing treatment. The most common reasons for treatment discontinuations (68.3%) were disease progression (39.1%) and adverse events (AEs, 22.1%). The median age was 63 years (&amp;lt; 65 years, n=156, 55.5%; ≥65 years, n=125, 44.5%) and ECOG PS ≥2: 1.8%. In 106 pts (37.7%), de novo metastatic disease was reported. Visceral metastases (lung, liver) were present in 116 pts (41.3%) and bone-only metastases in 80 pts (28.5%). Prior adjuvant therapy was received by 139 pts (49.5%): AI ± GnRH: n=80 (26.7% without and 1.8% with GnRH); tamoxifen ± GnRH: n=74 (21.7% without and 4.6% with GnRH); CT: n=56 (19.9%); antibody therapy n=3 (1.1%). In the metastatic setting, 1L RIB was prescribed in combination with an AI in 223 pts (79.4%; letrozole: n=139 [49.5%]; anastrozole: n=48 [17.1%]; exemestane: n=47 [16.7%]) and with FUL in 52 pts (18.5%). Prior CT for MBC was received by 5 pts (1.8%). The median PFS was 29.7 months in the overall population; 28.3 months in pts with bone only and 26.9 months in pts with visceral metastatic disease. In pts evaluable for response, the objective response rate and clinical benefit rate were 31.3% and 60.9%, respectively. The OS rates were 91.9%, 81.7%, and 63.7% at 12 months, 24 months, and 36 months, respectively. The trial is ongoing with ~40% of subjects end of documentation and ~27% of deaths. In total, 69.4% of pts had RIB dose interruptions and 48.8% of pts had a RIB dose reduction. The majority of all reported AEs were grade 1 (50.1%) or grade 2 (31.2%); the median time to first AE was 0.5 months. The most common AE was neutropenia (all grades: n=143, 50.9%; grade 1: n=39, 13.9%; grade 2: n=68, 24.2%; grade 3: n=98, 34.9%; grade 4: n=5, 1.8%). QTc prolongation of any grade was observed in 32 pts (11.4%; grade 1: n=24, 8.5%; grade 2: n=11, 3.9%; grade 3: n=1, 0.4%). Hepatobiliary toxicity of any grade was observed in 42 pts (14.9%; grade 1: n=12, 4.3%; grade 2: n=18, 6.4%; grade 3: n=22, 7.8%; grade 4: n=3, 1.1%). Overall, currently 101 pts (35.9%) received a follow-up therapy after progression on RIB + ET. The most common first subsequent therapies were targeted therapies + ET (40.0%), followed by cytotoxic chemotherapy (22.0%) and endocrine monotherapy (19.0%). Conclusion: 1L RIB + ET continues to show favorable efficacy and a tolerable safety profile in the routine clinical practice. The results are consistent with the data from MONALEESA trials. The OS is showing a positive trend but is still immature during this study follow-up. Efficacy Outcomes With RIB + ET in Patients With HR+, HER2– MBC (Overall Population, Nf281) XX XX Citation Format: Christian F. Singer, Daniel Egle, Richard Greil, Edgar Petru, Leopold Oehler, Marija Balic, Laurenz Schöffmann, Georg Pfeiler, Maximilian Marhold, Christine Brunner, Karin Haider, Arik Galid, Ursula Pluschnig, Ferdinand Haslbauer, Michael Hubalek, Andreas Redl, Julia Flatschacher, Shanow Uthman, Bernhard Mraz, Rupert Bartsch. Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-10.

Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 plus Imatinib for Advanced Treatment-refractory Gastrointestinal Stromal Tumors.

In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD-1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). Advanced GIST patients whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3+3 dose escalation scheme was applied. PDR001 400 mg intravenously every 4 weeks plus imatinib (300 mg and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate (DCR) at 12 weeks. Exploratory biomarker analysis was performed based on PD-L1 immunohistochemistry, next-generation sequencing, and multiplexed immunohistochemistry. No dose-limiting toxicity was observed in the phase Ib part (n=10), and dose level 2 was selected as the recommended phase II dose. In the phase II part (n=29), there was no objective response and the DCR at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n=36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3-4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T cell density was associated with a favorable PFS, but to a limited degree. Tumor mutation burden and PD-L1 were not associated with better PFS. In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

Abstract CT243: Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL)

Abstract Background: R/R FL is an incurable disease and outcomes worsen with successive relapses. A high unmet need remains for therapies that improve tumor control and extend survival after relapse. Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy, generally manageable safety, and maintenance of pt-reported overall quality of life scores from baseline in an interim analysis of the ELM-2 study (NCT03888105) in heavily pretreated pts with R/R FL (Villasboas et al. ASH 2023). Here, for the first time, we present the primary analysis of R/R FL in ELM-2. Methods: IV odronextamab was administered in 21-day cycles (C) until disease progression/unacceptable toxicity. Steroid prophylaxis and step-up dosing (0.7/4/20 mg) were used in C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg on Days (D) 1, 8, and 15 of C2-4. Maintenance dosing continued at 160 mg Q2W, or Q4W if complete response (CR) was durable for 9 months (mo). Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Primary analysis was performed when 128 pts had ≥52 weeks’ follow-up. Results: At data cutoff (Oct 20, 2023), 128 pts with FL Grade (Gr) 1-3a were evaluable for efficacy and safety: median age 61 yrs (range 22-84); FLIPI risk score 3-5 57.8%; POD24 49.2%; median 3 prior lines of therapy (2-13); 71.9% refractory to last treatment (Tx); 74.2% refractory to an anti-CD20 antibody. The median no. of Tx cycles was 19.4 (0.1-95.9); 95.3% and 85.2% of pts completed C1 and C4, respectively.Median efficacy follow-up was 20.1 mo; ORR was 80.5% and CR rate was 73.4% confirmed by ICR. Responses were durable (median DOR 22.6 mo; median DOCR 25.1 mo). Median PFS was 20.7 mo and 24-mo PFS was 46.1%. Median OS was not reached and 24-mo OS was 70.1%.The odronextamab safety profile was generally manageable and consistent with previous reports. Tx-emergent adverse events (AEs) occurred in all pts (Gr ≥3 85.9%); 15.6% had AEs leading to Tx discontinuation. With 0.7/4/20 mg step up (n=60), CRS events were mostly low grade (Gr 1 45.0%; Gr 2 10.0%; Gr 3 in 1 pt), occurred mostly in C1, and resolved in a median of 2 days; ICANS was reported in 1 pt (Gr 2). Infection rates were consistent with heavily pretreated, immunosuppressed pts (Leonard et al. JCO 2019; Hayne et al. BBMT 2020), occurring in 79.7% (102/128) of pts (Gr 4/5 14.0%; COVID-19 36.7% [Gr 5 6.3%]).Conclusion: Odronextamab demonstrated deep and durable responses in heavily pretreated pts with R/R FL; 91% of responders achieved CR, correlating with favorable PFS and OS at 24 mo. Odronextamab had a generally manageable safety profile and a low incidence of Gr 3 CRS/ICANS. Odronextamab could offer an important off-the-shelf Tx option for pts with heavily pretreated R/R FL. Citation Format: Geoffrey Chong, Michal Taszner, Silvana Novelli, Seok-Goo Cho, Jose C. Villasboas, Ana Jiménez Ubieto, Benoît Tessoulin, Michelle Poon, David Tucker, Jan Walewski, Yuqin Song, Emmanuel Bachy, Stephanie Guidez, Aranzazu Alonso, Deepa Jagadeesh, Stefano Luminari, Laura Magnano Mayer, Elżbieta Iskierka-Jażdżewska, Monica Tani, Jingxian Cai, Amulya Uppala, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Tae Min Kim. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT243.