Improvement In Progression-free Survival Research Articles

Efficacy and safety of cabozantinib for advanced gastrointestinal (GI) neuroendocrine tumors (NET) after progression on prior therapy: Subgroup analysis of the phase 3 CABINET trial (Alliance A021602).

666 Background: In the phase 3 CABINET trial (NCT03375320), cabozantinib (CABO) significantly prolonged median progression-free survival (PFS) compared to placebo (PB) in patients with advanced, previously treated, progressive extrapancreatic NET (epNET) [HR 0.38 (95% CI, 0.25-0.59, P<0.0001)] and pancreatic NET (pNET) [HR 0.23 (95% CI, 0.12-0.42, P<0.0001)] (Chan et al., NEJM, 2024). In this analysis, we focus on outcomes of patients with epNET arising in the GI tract. Methods: Patients with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. The epNET cohort included patients with tumors arising in the GI tract (not including pancreas), lung, unknown primary, and other rare primary sites. In this subgroup analysis of the epNET cohort, patients with GI NET were included. Eligibility included progression by RECIST within 12 months (mo) prior to registration, ≥ 1 prior systemic therapy. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints: objective response rate, overall survival, safety. Results: 116 of the 203 patients in the epNET cohort had GI NET (CABO, n=70; PB, n=46). Median age was 66 yrs; females: 46%; G1/G2/G3/unknown grade: 35%/57%/6%/2%. ECOG performance status: 0/1-2: 43%/57%. White race: 86%. The most common primary tumor locations were ileum/cecum (54%), small intestine with location not specified (20%); non-cecum colon or rectum (11%), stomach (4%); duodenum (3%); jejunum and nonspecified midgut site (3% each). Prior systemic therapies included somatostatin analogs (SSA) (100%), everolimus (59%); Lu-177 dotatate (77%); temozolomide +/- capecitabine (16%). In patients with GI NET, CABO was associated with improved PFS by BICR compared to PB (stratified HR, 0.50; 95% CI: 0.28-0.88, 1-sided stratified log-rank P=0.007). Median PFS with cabozantinib was 8.5 mo (95% CI, 6.0-16.7) compared to 5.6 mo (95% CI, 3.9-11.0) with PB. CABO demonstrated potential benefit in patients with midgut GI NET and across clinical factors including grade, functional status related to hormone secretion, concurrent SSA use, and prior therapy with Lu-177 dotatate or everolimus. The most frequent grade 3/4 adverse events attributed to therapy with CABO included hypertension (19%), diarrhea (13%), fatigue (10%). Conclusions: CABO is associated with improvement in PFS compared to PB in patients with advanced GI NET. Potential benefit was observed across clinical factors including grade, functional status, concurrent SSA, and prior treatment. The safety profile for CABO in patients with GI NET is consistent with that previously reported. Support: U10CA180821, U10CA180882; U10CA180820 (ECOG-ACRIN), U10CA180868 (NRG Oncology), U10CA180888 (SWOG); Exelixis; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03375320 .

Intra-tumoral CD40 antibody with irreversible electroporation (IRE) in locally advanced pancreas cancer.

TPS787 Background: Irreversible electroporation (IRE) is a form of non-thermal tumor ablation that is currently in clinical use for selected patients with locally advanced pancreatic cancer (LAPC). Preclinical and clinical studies have suggested that IRE generates an in situ vaccination effect by releasing tumor neoantigens in the setting of inflammation. Our published data from syngeneic, orthotopic mouse models demonstrate that combination of IRE with local CD40 agonism induces systemic anti-tumor immune effects, including neoantigen-specific T-cell responses and inhibition of liver metastases (1). Mitazalimab, a second-generation CD40 agonistic IgG1 mAb, has demonstrated promising clinical antitumor activity when delivered systemically in combination with modified FOLFIRINOX in metastatic pancreatic cancer (2). Methods: This clinical trial (NCT06205849) is a phase I dose-escalation study of an agonistic CD40 antibody (mitazalimab) injected intratumorally at the time of surgical IRE in patients with LAPC who have not demonstrated distant disease progression after a minimum of 4 months of optimal standard of care (SOC) chemotherapy (modified FOLFIRINOX). The doses investigated are 25, 75 (starting dose), and 200 µg/kg, in an interval 3+3 design, with a maximum of 18 subjects. The primary endpoints are the rates of dose limiting toxicities (DLTs) and treatment-emergent adverse events (AEs). The secondary endpoints are progression-free survival (PFS) and overall survival (OS). At a liberal alpha of 25%, appropriate for this proof-of-concept early phase study, we have 80% power to detect an improvement in PFS from 12 months (based on prior studies of IRE alone) to 18 months, with an expected 16 evaluable subjects and an anticipated 11 observed events, using a one-sided log-rank test. Candidate neoantigens will be identified by profiling nucleic acids derived from tumor biopsies obtained intraoperatively prior to IRE using our Identification-Prioritization-Validation (IPV) bioinformatic pipeline (3). Blood samples will be collected pre-operatively and 12-weeks post-operatively to evaluate for evidence of neoantigen-specific T-cell reactivity and other neoantigen-independent analyses of immune response. We have enrolled two patients since the study opened in September 2024. 1. J. Shankara Narayanan et al., JITC 2023. 2. J. Van Laethem et al., Lancet Oncol 2024. 3. A. Miller et al., Sci Transl Med. 2024. Clinical trial information: NCT06205849 .

First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW.

LBA143 Background: The CheckMate 8HW study met its dual primary endpoint with NIVO + IPI demonstrating superior progression-free survival (PFS) by blinded independent central review (BICR) vs chemotherapy (chemo) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC in the first-line (1L) setting (HR 0.21; 95% CI 0.14–0.32; P < 0.0001). We report first results from the other dual primary endpoint of PFS for NIVO + IPI vs NIVO across all lines of therapy in pts with centrally confirmed MSI-H/dMMR mCRC. Methods: Immunotherapy-naive pts with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0 or 1 prior line of therapy were randomized 2:2:1 to (i) NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), (ii) NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), or (iii) chemo ± targeted therapies. Pts who had received ≥ 2 prior lines of therapy were randomized 1:1 to the NIVO + IPI or NIVO arms. Treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). Results: Across all lines of therapy,707 pts were randomized to NIVO + IPI (n = 354) or NIVO (n = 353); 55% and 52% received study treatment in the 1L setting, respectively. Of all randomized pts, 296 in the NIVO + IPI arm and 286 in the NIVO arm had centrally confirmed MSI-H/dMMR status. With 47.0 months (mo) of median follow-up (range, 16.7–60.5), NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS by BICR vs NIVO (HR 0.62; 95% CI 0.48–0.81; P = 0.0003) and higher 12-, 24-, and 36-mo PFS rates vs NIVO (Table). Objective response rate (ORR) by BICR was significantly higher with NIVO + IPI vs NIVO (71% vs 58%; P = 0.0011; Table); best overall response of progressive disease was reported in 10% and 19% of pts, respectively. No new safety concerns were identified (Table). Conclusions: In the first randomized study to compare dual- vs single-agent immunotherapy in MSI-H/dMMR mCRC, NIVO + IPI demonstrated superior PFS vs NIVO across all lines of therapy, with a manageable safety profile. These results establish NIVO + IPI as the potential new standard-of-care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Efficacy by BICR (all lines; centrally confirmed MSI-H/dMMR by IHC and/or PCR test) NIVO + IPI(n = 296) NIVO(n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI); P value 0.62 (0.48–0.81); 0.0003 PFS rate (12/24/36-mo), % 76/71/68 63/56/51 ORR, n (%); 95% CI, % 209 (71); 65–76 165 (58); 52–64 P value 0.0011 Safety (all lines; all treated), n (%) NIVO + IPI (n = 352) NIVO (n = 351) Any-grade/grade 3–4 TRAEs 285 (81)/78 (22) 249 (71)/50 (14) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (14)/33 (9) 21 (6)/14 (4) Treatment-related deaths 2 (< 1) 1 (< 1) IHC, immunohistochemistry; NE, not estimable; NR, not reached; PCR, polymerase chain reaction; TRAE, treatment-related adverse event.

Safety, efficacy, and outcomes of 90-yttrium radioembolization in combination with immune checkpoint inhibitors as a definitive first-line treatment approach in non-surgical hepatocellular carcinoma.

617 Background: Immune checkpoint inhibitors (ICI) have emerged as first line therapy for advanced-stage hepatocellular carcinoma (HCC). However, response rates remain modest (<20%). Combination treatments offer potential to improve initial response rates while extending duration of response. While early studies of 90 Yttrium transarterial radioembolization ( 90 Y)-ICI showed fewer adverse events (AE) and improved objective responses (OR) (30-40%), there were no improvements in time to progression (TTP) and overall survival (OS). This study evaluates safety, efficacy, and outcomes of first line 90 Y-ICI while evaluating the role of ICI regimen and treatment sequencing. Methods: A retrospective, multi-center study was conducted in BCLC A-C stage HCC patients (ECOG 0-1) receiving first line 90 Y-ICI with atezolizumab/bevacizumab (A+B) or tremelimumab/durvalumab (STRIDE). Treatment response was recorded at 90 Y follow-up. TTP, progression-free survival (PFS), and OS were primary endpoints, with AE and safety as secondary outcomes. Results: The study included 40 patients receiving 90 Y-ICI from 2021–2024, with a median follow-up of 12 months. The cohort was predominantly Child-Pugh A (96%) with HCV-related cirrhosis (76%), BCLC-C stage (51%), and a median target HCC size of 7.7 cm (IQR, 6-11 cm). Grade 3-4 AEs occurred in 15 patients (37%), leading to steroid use (12, 29%), treatment delays (13, 31%), or discontinuation (4, 10%). The first cycle target OR rate was 82% (32/39), with a 51% (20/39) complete response (CR) rate. The first cycle overall OR was 59% (23/39), with a 41% (16/39) CR rate. No significant differences were found in adverse events, delays, or discontinuations based on sequencing or regimen. Sequencing had no significant effect on target or overall OR with no downstream effect on TTP (P = 0.968) or PFS (P = 0.906). Similarly, there was no effect of ICI regimen on OR, TTP (P = 0.813) or PFS (P = 0.904), although the data trended toward higher response rates with the STRIDE regimen. Log-rank analysis revealed target CR was associated with improved TTP (P = 0.004) and PFS (P = 0.009), but not OS (P = 0.237). Achieving an overall CR was associated with further improvements in TTP (P < 0.001) and PFS (P < 0.001). The cohort 2-year OS was 55% with median OS not yet reached. Conclusions: First line 90 Y-ICI therapy in BCLC A-C stage HCC is an effective treatment strategy with AEs in the expected range of systemic therapy and low rates of treatment discontinuation. Sequencing and ICI regimen did not significantly impact AEs or treatment outcomes. However, patients achieving CR showed significantly improved TTP and PFS. Although follow-up is limited, these findings suggest achieving CR is key to optimal long-term outcomes. We anticipate long-term follow-up will demonstrate an OS benefit linked to first line CR rate.

Congress of Neurological Surgeons systematic review and evidence-based guidelines for the role of surgery in the management of patients with diffuse low grade glioma: update.

Target populationAdults with imaging suggestive of a WHO grade II diffuse gliomas (oligodendrogliomas or astrocytomas)QuestionIn adults with imaging suggestive of a WHO grade II diffuse gliomas (oligodendrogliomas or astrocytomas), does surgical resection improve overall survival compared to observation or biopsy?Updated Recommendation from the Prior Version of These Guidelines:Level III: In adults with imaging suggestive of a WHO grade II diffuse gliomas (oligodendrogliomas or astrocytomas), surgical resection is suggested over observation or biopsy to improve overall survival.Question Q2In adults with imaging suggestive of a WHO grade II diffuse gliomas (oligodendrogliomas or astrocytomas), does maximal surgical resection improve progression free survival (PFS) and overall survival (OS) compared to subtotal resection/biopsy?Unchanged Recommendations from the Prior Version of These GuidelinesLevel II It is recommended that GTR or STR be accomplished instead of biopsy alone when safe and feasible so as to decrease the frequency of tumor progression recognizing that the rate of progression after GTR is fairly high.Level III Greater extent of resection can improve OS in WHO grade II diffuse gliomas patients. New RecommendationsLevel III: It is suggested that extent of resection be maximized as is safely possible for IDH mutant and IDHwt WHO grade II diffuse gliomas. to improve PFS and OS. Level III: There is insufficient evidence that greater extent of resection of 1p19q codeleted oligodendrogliomas (WHO grade II diffuse gliomas) improves OS Question Q3In adults with imaging suggestive of a WHO grade II diffuse gliomas (oligodendrogliomas or astrocytomas), does the addition of intraoperative MRI and/or intraoperative ultrasound during surgery improve extent of resection?Unchanged Recommendation from the Prior Version of These GuidelinesLevel III: The use of intraoperative MRI is suggested to increase the extent of resection for adults with WHO grade II diffuse glioma.New RecommendationLevel III: The use of intraoperative ultrasound is suggested to increase the extent of resection compared to conventional surgery for adults with WHO grade II diffuse glioma.Question 4In adults with imaging suggestive of a WHO grade II diffuse glioma (oligodendrogliomas or astrocytomas) with seizures, does maximal surgical resection improve seizure control compared to observation or subtotal resection/biopsy?Updated Recommendation from the Prior Version of These GuidelinesLevel III: In adults with imaging consistent with a WHO Grade II diffuse glioma who present with seizure activity, surgical resection of greater than 90% of the lesion, when it can be accomplished safely, is suggested over observation or lesser extent of resection/biopsy to improve seizure control.New Questions and RecommendationsQuestion 5In adults with imaging suggestive of a WHO grade II diffuse glioma (oligodendrogliomas or astrocytomas), does use of intraoperative fluorescent guided surgery improve extent of resection?RecommendationLevel III: Intraoperative fluorescent guided surgery with 5-ALA is not suggested to improve the extent of resection for WHO grade II gliomas.Question 6In adults with imaging suggestive of a WHO grade II diffuse glioma (oligodendrogliomas or astrocytomas) in eloquent brain cortex, does awake craniotomy or other methods of intraoperative mapping increase extent of resection compared to conventional surgery without these techniques?RecommendationLevel III: It is suggested that awake craniotomy and other methods of intraoperative mapping can be used to increase the extent of resection for adults with WHO grade II diffuse glioma.Question 7In adults with imaging suggestive of a WHO grade II diffuse glioma (oligodendrogliomas or astrocytomas) in eloquent brain cortex, does use of advanced preoperative imaging modalities in the form of fMRI and/or DTI decrease surgical morbidity?RecommendationLevel III: The use of functional MRI and DTI related modalities are suggested to decrease surgical morbidity in adults with WHO grade II diffuse glioma.

Efficacy and safety of PD-1 inhibitor plus chemotherapy in advanced nasopharyngeal carcinoma: A meta-analysis.

The combination of programmed cell death protein 1 (PD-1) inhibitors and chemotherapy has shown promising results in the treatment of various malignancies. This meta-analysis aims to evaluate the effectiveness and safety of combing PD-1 inhibitor with chemotherapy in patients with advanced NPC. A thorough search of the literature was carried out using comprehensive methods. The assessed outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). This meta-analysis included seven studies with a total of 1204 patients. The use of a combination therapy involving PD-1 inhibitor and chemotherapy demonstrated significant improvements in OS (HR=0.60, 95%CI: 0.45, 0.80; P<0.001), PFS (HR=0.51, 95%CI: 0.42, 0.61; P<0.001), ORR (RR=1.23, 95%CI: 1.07, 1.40; P=0.003) and DCR (RR=1.13, 95%CI: 1.03, 1.23; P=0.003) compared to other treatments in patients with advanced NPC. Subgroup analyses based on PD-1 inhibitor type, chemotherapy regimen and study design indicated that these factors influenced OS but not PFS. Prognostic factor analysis consistently demonstrated a PFS benefit associated with the combination treatment across various patient subgroups. The incidences of AEs, grade 3 or higher AEs were comparable between the two groups. However, the combination group was significantly more likely to discontinue treatment because of AEs. This meta-analysis provides evidence supporting the effectiveness and safety of PD-1 inhibitor plus chemotherapy in advanced NPC. The combination therapy showed superior outcomes in terms of OS, PFS, ORR, and DCR.

An Updated Systematic Review and Network Meta-Analysis of First-Line Triplet vs. Doublet Therapies for Metastatic Hormone-Sensitive Prostate Cancer.

Purpose: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies. Methods: We conducted a systematic search for RCTs on systemic therapies for mHSPC using MEDLINE, Embase, and the Web of Science Core Collection in September 2024. An NMA utilizing random-effects models was performed to compare progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence (PROSPERO: CRD42024591458). Results: A total of 12 RCTs (n = 11,954) were included in our NMAs. Triplet therapies were associated with significant improvements in PFS compared to ARPI-based doublet therapies (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59-0.93; p = 0.01), but the difference did not reach the conventional levels of statistical significance for OS (HR: 0.82; 95% CI: 0.67-1.01; p = 0.059). In a subset analysis, compared to ARPI-based doublet therapies, triplet therapies showed a significant improvement in PFS in patients with high-volume disease (HR: 0.64; 95% CI: 0.47-0.88; p < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; p = 0.7). No significant difference in grade ≥ 3 AEs was observed between triplet therapies and ARPI-based doublet therapies. The main limitations include patient heterogeneity and limited follow-up in some studies. Conclusions: Triplet therapies can improve the oncologic outcomes of patients with mHSPC compared to ARPI-based doublet therapies, without significantly increasing severe AEs. These findings warrant further confirmation in a head-to-head trial powered for overall survival.

The Efficacy and Safety of Anlotinib in the Treatment of Thyroid Cancer: A Systematic Review.

Background and Objectives: Anlotinib, a novel multi-kinase inhibitor targeting angiogenesis and tumor proliferation pathways, has shown promising efficacy in various cancers. Its role in treating thyroid cancer, particularly radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), is of significant clinical interest. This systematic review aims to evaluate the efficacy and safety of Anlotinib in patients with thyroid cancer, analyzing outcomes such as progression-free survival (PFS), overall survival (OS), response rates, and adverse events. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases up to October 2023. The review included randomized controlled trials and prospective studies assessing Anlotinib in thyroid cancer patients. Data extraction and quality assessment were performed independently by two reviewers following PRISMA guidelines. Results: Six studies involving a total of 277 patients were included. In patients with RAIR-DTC, Anlotinib demonstrated significant improvement in median PFS and objective response rates. In advanced or metastatic MTC, Anlotinib significantly prolonged median PFS compared to placebo, with high objective response rates. Subgroup analyses showed that older patients and those with bone metastases benefited significantly from Anlotinib treatment. In patients with ATC, Anlotinib-based chemotherapy yielded a 60% objective response rate. Anlotinib was also effective as neoadjuvant therapy in locally advanced thyroid cancer, achieving an objective response rate of 76.9%. Common adverse events included hypertension, proteinuria, and palmar-plantar erythrodysesthesia syndrome, which were generally manageable. Conclusions: Anlotinib appears to be an effective and well-tolerated treatment option for patients with various types of thyroid cancer, providing significant improvements in PFS and objective response rates. Further large-scale randomized studies are warranted to confirm these findings and to explore long-term outcomes.

Thermal ablation included in multimodality treatment predicts enhanced survival in advanced non-small cell lung cancer: a propensity score-matched outcome study

Background Advanced non-small cell lung cancer (NSCLC) presents significant treatment challenges, with limited effective therapies for late-stage patients. This study aimed to evaluate the impact of adding thermal ablation (TA) in treatment regimens for advanced NSCLC to improve survival outcomes. Methods A retrospective cohort study was conducted at a medical center in Taiwan, analyzing data from 1,083 patients diagnosed with stage IIIB or IV NSCLC between 2008 and 2020. Survival outcomes were compared between patients treated with TA and those who received conventional therapies. Statistical analyses, including propensity score matching and Cox regression models, were used to account for potential confounders. Results The TA group demonstrated a significantly longer median overall survival (OS) of 37 months compared to 15 months in the non-TA group (p < 0.001), with five-year OS rates of 32.4% and 9.8%, respectively. Median progression-free survival (PFS) was 36 months in the TA group versus 14 months in the non-TA group, with five-year PFS rates of 24.1% versus 6.3% (p < 0.001). Subgroup analyses showed enhanced survival in patients undergoing targeted therapy and chemotherapy when TA was included. Survival outcomes with TA were comparable to lobectomy, offering a less invasive option for selected patients. Conclusions Thermal ablation is associated with significant improvements in OS and PFS in patients with advanced NSCLC, providing a viable treatment option for those not eligible for surgery. The results support the integration of TA into standard care protocols, with further prospective studies needed to confirm these findings and optimize treatment strategies.

Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models.

In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA (NR3C1) and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

Лечение пациентов с рецидивами и рефрактерным течением первичной медиастинальной (тимической) В-крупноклеточной лимфомы: собственные данные и обзор литературы

AIM. To determine the optimal strategy of chemotherapy for patients with relapsed/refractory (r/r) primary mediastinal (thymic) large B-cell lymphoma (PMBCL). MATERIALS &amp; METHODS. The study is based on the clinical data from 26 patients with r/r PMBCL treated at the NN Blokhin National Medical Cancer Research Center from 2010 to 2024. The patients were 20–48 years of age (median 33 years); there were 21 (81 %) women. All patients had a bulky mediastinal tumor mass (&gt; 10 cm in maximum dimension). RESULTS. All calculations were performed in the combined group (n = 26) which included patients with both primary refractory PMBCL (n = 21) and tumor relapses (n = 5). Refractoriness was confirmed by PMBCL progressing within less than 6 months from the completion of the first therapy program. Relapses developed during 2 years after the first-line therapy. The treatment of r/r PMBCL included the R-DHAP, R-ICE, R-BeGeV, and R-B protocols. In 24 out of 26 patients, the second- or subsequent-line salvage therapy programs included immune checkpoint inhibitor (CPI; nivolumab or pembrolizumab) and immunoconjugate (brentuximab vedotin, BV) boosts. CPIs were received by 11 (42 %) patients, and CPI + BV were administered to 13 (50 %) patients. With the follow-up median of 28 months in the total group of r/r PMBCL patients (n = 26), the 3-year progression-free survival (PFS) was 41.7 % (median 14 months), whereas the 3-year overall survival (OS) was 73.7 % (median not reached). Radiotherapy (RT) was administered to 11 (42 %) patients. The RT recipients showed the 3-year PFS of 72.7 % and OS of 100 % as compared to non-recipients with 20.3 % and 56.3 %, respectively. Autologous hematopoietic stem cell transplantation (auto-HSCT) was performed in 12 (46 %) patients. Auto-HSCT recipients showed the 3-year OS of 100 % as compared to non-recipients with 51 %. CONCLUSION. This study demonstrated that new drugs, in particular CPI ± BV, added to the second- and subsequent-line salvage therapy protocols in r/r PMBCL can be used to overcome the primary tumor refractoriness and neutralize this extremely unfavorable factor. High-dose chemotherapy (conditioning) with subsequent auto-HSCT is clearly associated with the best long-term survival rates. By the time of drafting this paper, 12 followed-up auto-HSCT recipients remained tumor-free. In cases of RT infeasibility at the initial stage, it was mediastinal radiation in the therapy for r/r PMBCL which showed its crucial prognostically favorable value and led to considerable improvement of PFS and OS rates. In general, the capacity of chemotherapy for patients with r/r PMBCL includes CPI ± BV-boosted salvage therapy protocols as well as added auto-HSCT and RT.

Novel anti-HER2 ADCs vs dual anti-HER2 antibody for HER2-positive metastatic breast cancer failed to tyrosine kinase inhibitor.

Both novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) and pertuzumab and trastuzumab (HP) combined with chemotherapy(C) regimens are the choice of treatment for HER2 positive metastatic breast cancer (MBC) after tyrosine kinase inhibitors (TKIs). Our team's previous research has shown significant therapeutic effects of novel anti-HER2 ADCs in patients with TKIs treatment failure. Unfortunately, there is currently no data available to compare novel anti-HER2 ADCs with HP combined with chemotherapy regimens. This study was conducted to compare the efficacy and safety of novel anti-HER2 ADCs with that of the HP combined with chemotherapy regimen in patients for whom TKI treatment failed. HER2-positive MBC who used novel anti-HER2 ADCs and HP combined with a chemotherapy regimen from January 2019 to August 2023 were included, and all patients received TKIs. The primary study endpoint was progression-free survival (PFS), while the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety. A total of 150 patients, of which 83 are in the novel anti-HER2 ADCs group and 67 are in the HP combined with chemotherapy. Among these novel anti-HER2 ADCs, 36 patients received treatment with trastuzumab deruxtecan (T-Dxd), and 47 patients received treatment with other new types of ADCs. The median PFS of the novel anti-HER2 ADCs group and HP combined with the chemotherapy group were 7.0 months and 8.9 months, respectively, with ORR of 51.8% and 26.9%, and CBR of 69.9% and 65.7%, respectively. In subgroup, patients receiving T-Dxd showed improvement in PFS compared to the HP combined with chemotherapy group. The most common grade 3-4 adverse events in the novel anti-HER2 ADCs group and the HP combined with chemotherapy group were neutropenia and gastrointestinal symptoms. In HER2-positive MBC for whom TKI treatment has failed, novel anti-HER2 ADCs and the HP combined with chemotherapy regimen both showed moderate efficacy and tolerable toxicity. Novel anti-HER2 ADCs are the preferred treatment recommendation for TKI failure patients. Meanwhile, based on the results of this study, the HP combined with chemotherapy regimen may also be an option, especially for patients with low accessibility.

Comparative efficacy and safety of PD‐1 versus PD‐L1 inhibitors in breast cancer treatment: A systematic review and meta analysis

AbstractThe comparative efficacy and safety of programmed death‐ligand 1 (PD‐L1) inhibitors versus programmed death protein 1 (PD‐1) inhibitors in breast cancer treatment remain inconclusive, as no head‐to‐head randomized controlled trials (RCTs) conducted. This study aims to evaluate the efficacy and safety of PD‐1/PD‐L1 inhibitors as monotherapy or in combination with chemotherapy for breast cancer. A systematic review and meta‐analysis were performed using major databases and oncology conference proceedings. The primary outcomes were overall survival (OS) for advanced breast cancer and pathological complete response (PCR) rate for early breast cancer. Secondary outcomes included progression‐free survival (PFS) for advanced breast cancer and incidence of adverse events (AEs). Seventeen studies met the inclusion criteria, consisting of seven RCTs on early‐stage and 10 on advanced breast cancer. For advanced breast cancer, PD‐1/PD‐L1 inhibitors modestly improved OS compared to chemotherapy, with no significant differences between PD‐1 and PD‐L1 inhibitors. PD‐L1 inhibitors showed greater improvement in PFS compared to PD‐1 inhibitors. The likelihood of AEs of any grade was higher with PD‐L1 inhibitor treatment than with PD‐1 inhibitor treatment. In early breast cancer, combining PD‐1/PD‐L1 inhibitors with chemotherapy inducing higher PCR rates than chemotherapy alone, with PD‐1 inhibitors achieving better outcomes than PD‐L1 inhibitors. PD‐1 inhibitors were linked to slightly higher rates of grade &gt;2 AEs compared to PD‐L1 inhibitors. The findings indicate that PD‐1 inhibitors may offer advantages for advanced breast cancer due to similar OS and a lower rate of AEs. For early breast cancer, PD‐1 inhibitors are recommended given their superior PCR rates.

Stereotactic body radiotherapy as metastasis-directed therapy in oligometastatic prostate cancer: a systematic review and meta-analysis of randomized controlled trials

BackgroundThe use of stereotactic body radiotherapy (SBRT) to definitively treat oligometastases in prostate cancer has drawn large clinical and research interests within radiation oncology. However, the evidence is considered in its early stages and there is currently no systematic review of randomized controlled trials (RCTs) in this field. We aimed to evaluate the efficacy and safety of SBRT as metastasis-directed therapy (MDT) in oligometastatic prostate cancer (OMPC) compared to no MDT reported in RCTs.MethodsMEDLINE, Embase, CINAHL Complete, and Cochrane Library were searched on October 28, 2023. Eligible studies were RCTs comparing SBRT as MDT with no MDT in extracranial OMPC, without restrictions on follow-up time, publication status, language, or year. Participant subsets fulfilling the eligibility criteria were included. Critical outcomes were overall survival and grade ≥ 3 toxicity, and additional important outcomes were progression-free survival (PFS), local control, grade 5 toxicity, health-related quality of life, and systemic therapy-free survival. Meta-analyses were planned. Risk of bias was assessed using the Cochrane risk-of-bias tool version 2, and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation.ResultsIn total, 1825 unique study reports were identified and seven phase II RCTs with 559 eligible participants were included. Four trials included multiple types of primary cancer. Outcome definitions were heterogeneous except for overall survival and toxicity. For overall survival, only one study reported events in both arms. Meta-analysis of the grade ≥ 3 toxicity results from two trials showed no difference (pooled risk ratio 0.78, 95% confidence interval 0.37–1.65, p = 0.52). Four trials reported significantly longer PFS, with a pooled hazard ratio of 0.31 (95% confidence interval 0.21–0.45, p < 0.00001). Risk of bias was of some concerns or high. Quality of evidence was low or moderate.ConclusionsPhase II trials have shown promising improvements in PFS for several OMPC states without excess toxicity. Overall survival comparisons are immature. In future confirmatory phase III trials, adequately large sample sizes, blinding of outcome assessors, and/or increased adherence to assigned intervention could improve the quality of evidence.PROSPERO registration number: CRD42021230131.

An Indirect Treatment Comparison of Lenvatinib for the First-Line Treatment of Patients with Unresectable Hepatocellular Carcinoma.

This study compared the relative efficacy of first-line lenvatinib, a standard-of-care treatment for unresectable hepatocellular carcinoma (uHCC), vs licensed/license in-progress comparators. Using inverse probability of treatment weighting (IPTW) and network meta-analysis (NMA), updated evidence for lenvatinib monotherapy from LEAP-002, in addition to evidence from REFLECT, was included in the analyses. Randomized controlled trials (RCTs) were identified via systematic review. REFLECT and LEAP-002 investigated lenvatinib in uHCC, with patient-level data available for each; however, only REFLECT included a comparator arm of interest (sorafenib). The lenvatinib arm from LEAP-002 was adjusted to match aggregate data for confounding factors from REFLECT using IPTW. Weighted Cox regressions, including matching variables as covariates, were used to derive hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). These HR estimates were included in Bayesian NMAs to compare lenvatinib with comparators; survival was significantly improved if the 95% credible interval for the HR did not include 1.0. Scenario analyses explored alternative choices for IPTW estimators. Eight RCTs (including REFLECT) and the single-arm adjusted lenvatinib data from LEAP-002 were included in the NMA base case. Lenvatinib demonstrated significant improvement in OS compared with sorafenib 400 mg twice daily (BID) and significant improvement in PFS compared with sorafenib 400 mg BID, tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks (Q4W), and durvalumab 1500 mg Q4W. These results suggest that patients with uHCC treated with lenvatinib have similar or significantly improved OS and PFS compared with licensed/license in-progress therapies.

SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers.

SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 intravenously once per day on days 1 and 8 of a 21-day cycle). Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.

Sarcoma: Last Year's Practice Changing Papers.

In 2023 and 2024, a wide variety of new studies have been published in the field of soft tissue sarcomas, representing the enormous heterogeneity of sarcoma histotypes, anatomical location, treatment variability, and biological behavior. This article summarizes the, in our view, seven most important publications in the field that will have an impact on the surgical practice and future treatment strategies of our patients. In the last year, we gained more insight in the genetic background of patients with sarcoma from a large Australian study, which will have an impact on future counseling and screening of our patients. Also, the role of radiotherapy in retroperitoneal liposarcoma became clearer in the combined STRASS-STREXIT study. Radiotherapy for extremity sarcomas can now also be done in a 3-week, hypofractioned manner, which is a major improvement for our patients. Furthermore, more evidence has been presented regarding the improved outcome of patients with retroperitoneal sarcoma when treated in high volume centers. Landmark studies with systemic treatment include the positive trial with nirogacestat in desmoid tumors, which have finally shifted the paradigm of desmoid treatment from surgery to systemic treatment. Also, the results of 2 phase 3 randomized controlled trials recently showed 1) that the combination of doxorubicin with trabectedin significantly improved progression free survival for patients with leiomyosarcoma when compared with doxorubicin alone and 2) that the combination of neoadjuvant pembrolizumab and radiotherapy followed by 1-yr adjuvant pembrolizumab significantly improved disease free survival for patients with primary localized undifferentiated pleomorphic sarcoma/myxofibrosarcoma or dedifferentiated/pleomorphic liposarcoma of the extremities or girdles. Key papers from the last year informs us that management of soft tissues sarcoma is constantly improving, since more data became available to guide us in defining the best treatment strategies.

US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations.

The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test. Approval was based on CAPItello-291, a randomized, double-blind, multicenter trial of 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients with PIK3CA/AKT1/PTEN tumor alterations. Patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily for 4 days per week with fulvestrant versus placebo with fulvestrant. Random assignment was stratified by presence of liver metastases, previous treatment with CDK4/6i, cyclin-dependent kinase four and six (CDK4/6) inhibitors, and geographical region. A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51 to 0.71]); this result was driven by 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37 to 0.68]). An exploratory analysis of investigator-assessed PFS in the 313 (44%) patients in the biomarker-negative population showed uncertain benefit (HR, 0.78 [95% CI, 0.60 to 1.01]). With capivasertib, more patients had Grade ≥3 toxicities. Key concerns included hyperglycemia (18% all-grade, 2.8% Grade ≥3), cutaneous toxicity (58% all-grade, 17% Grade ≥3), and diarrhea (72% all-grade, 9% Grade ≥3). Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.

Real-World Survival Outcomes in Non-Small Cell Lung Cancer: The Impact of Genomic Testing and Targeted Therapies in a Latin American Middle-Income Country.

Targeted therapies are indicated for patients with non-small cell lung cancer (NSCLC) and driver tumor mutations. However, real-world studies on the survival benefits of these agents are limited. This study aimed to evaluate the effect of targeted therapies matched to a genomic alteration on the survival of patients with NSCLC. This retrospective study included 446 patients with advanced NSCLC who underwent next-generation sequencing between 2016 and 2023 at the Instituto Nacional de Cancerología in Mexico. The primary outcomes were progression-free survival (PFS) and overall survival (OS). For the entire cohort, the PFS and OS were 10.71 months (95% CI, 9.35 to 12.06) and 47.77 months (95% CI, 29.67 to 65.86). PFS was significantly longer in patients with actionable mutations treated with targeted therapies (19.41 months [95% CI, 14.27 to 24.55]; P < .001) than in patients without actionable mutations (6.4 months [95% CI, 4.4 to 8.4]) or not treated with targeted therapies (6.6 months [95% CI, 5.3 to 7.89]). Similarly, OS was significantly longer in patients with actionable mutations treated with targeted therapies (89.69 months [95% CI, 45.54 to 133.84]; P < .001) than in patients without actionable mutations (17.11 months [95% CI, 8.65 to 25.57]) or not treated with targeted therapies (22.3 months [95% CI, 12.48 to 32.1]). Survival gains were driven by significant improvements in PFS and OS in patients with EGFR and ALK mutations. This real-world data analysis demonstrated that targeted therapies improve the survival of patients with NSCLC with actionable mutations, which supports a recommendation for widening access to broad-based genomic testing and targeted therapies.

Efficacy and Safety Evaluation of Immune Checkpoint Inhibitors in Combination With Chemotherapy for Extensive Small Cell Lung Cancer: Real-World Evidence.

Extensive small cell lung cancer (ES-SCLC) are currently managed using first-line chemotherapy options, including atezolizumab (Atezo) plus etoposide and carboplatin (CE) or durvalumab (Durva) plus etoposide with either cisplatin (PE) or carboplatin (CE). However, a definitive distinction in therapeutic effects between Atezo and Durva in these regimens remains unestablished. We analyzed data from 100 patients diagnosed with ES-SCLC who received immune checkpoint inhibitors (ICIs) as first-line chemotherapy. Among them, 70 were administered Atezo + CE, 12 received Durva + PE, and 18 received Durva + CE. We assessed the efficacy of the two ICIs across various factors. The progression-free survival (PFS) and overall survival (OS) did not significantly differ between Atezo + CE and Durva + CE/PE as first-line chemotherapy treatments for SCLC. We observed no significant differences in age, sex, performance status (PS), liver metastasis, bone metastasis, or platinum-based agent usage between the treatment cohorts. However, a marked improvement in PFS and OS was observed in the solitary patient with brain metastasis treated with Atezo + CE. The primary distinction between these treatments was observed in the management of patients with brain metastasis. The literature lacks comparative studies on the effects of first-line ICI treatment on the central nervous system, rendering our findings significant in clinical practice. Despite the retrospective nature of this study and the potential for various biases, we recommend the preferential use of Atezo + CE in patients with brain metastasis to potentially enhance prognosis.