First-line Therapy For Patients Research Articles

Abstract 4118762: Large-scale multinational trends in the use of cardioprotective antihyperglycemic agents as first-line therapy in patients with type 2 diabetes and cardiovascular disease: a LEGEND-T2DM study

Background: US guidelines for type 2 diabetes (T2DM) recommend metformin as first-line anti-hyperglycemic therapy (AHT), but prioritizing the use of AHTs that reduce cardiovascular disease (CVD) risk – GLP1-RAs and SGLT2is – is increasingly suggested for people with CVD. We examine the multinational use patterns of GLP1-RAs, SGLT2is, DPP4is, and sulfonylureas (SUs) as first-line therapies for patients with CVD. Methods: In 10 US and 6 non-US databases between 2016 and 2021 mapped to a common data model [A], we measured yearly initiation of GLP1-RAs, SGLT2is, DPP4is, and SUs as first-line AHTs in patients with T2DM with and without CVD [B]. We also compared the initiation of the drug classes as second-line after metformin. We calculated the annual rate of change in proportional initiation of each drug class as first-line AHT and assessed differences in trends as group x time interactions in linear mixed models. Results: Across all data sources, 3.3 million patients with T2DM used GLP1-RAs, SGLT2is, DPP4is, or SUs as first-line AHTs, and 3.9m initiated these drug classes as second-line AHT after metformin. Within the first-line cohort, 1.4m (41%) had established CVD compared with 1.2m (31%) in the second-line cohort. For GLP1-RAs and SGLT2is, the annual rate of their relative use as first-line agents increased among patients with T2DM with CVD (GLP1RAs: ranging 1.3-5.4% in US [C] and 0.3-0.8% in non-US [D], SGLT2is: 2.1-12.9% in US [E] and 8.1-10.6% in non-US databases [F]). There was a larger relative increase in the use of SGLT2i and a smaller increase in GLP1RA use in CVD vs non-CVD cohorts (P interaction <.001). While there was a larger increase in GLP1RAs uptake in the US cohorts, SGLT2i use increased more in non-US cohorts ([C-F], P interaction <.001 for all, except .01 for SGLT2i). Of note, across cohorts, the uptake of GLP1RA and SGLT2i as first-line was higher than second-line use among those with CVD (P interaction <.001). In contrast, DPP4i and SU use as first-line was lower than GLP1RA and SGLT2is and decreased over time (P<.001). Conclusions: In a large-scale multinational, federated cohort of patients with T2DM, the use of cardioprotective agents increased as first-line AHT, with variation in SGLT2i and GLP1RAs uptake across study cohorts.

Using Soluble CD38 to Overcome Daratumumab Interference in Pretransfusion Compatibility Testing

Background: CD38 is a protein highly expressed on myeloma (MM) cells that has been shown to be an effective target antigen for monoclonal antibody therapies, so treatment with anti-CD38 monoclonal antibodies is a first line therapy for patients with MM. Although CD38 is weaker expressed on erythocytes anti-CD38 binds to CD38 on reagent RBCs and cause panreactivity in vitro and subsequent false positive reactions in indirect antiglobulin tests (IAT), antibody detection (screening) tests, antibody identification panels, and anti-human globulin (AHG) crossmatches. These findings suggest that the soluble CD38 method could improve transfusion safety for patients receiving anti-CD38 therapy, particularly in urgent clinical settings This study aims to evaluate the effectiveness of a new soluble CD38-based method in mitigating Daratumumab interference during pretransfusion compatibility testing." Methods: We evaluated the Grifols sCD38 method in 20 patients and compared it with the DTT method Results: In our experience the sCD38 method reduced testing time from 150 to 50 minutes and demonstrated 100% efficacy, compared to 90% with DTT. The sCD38 effectively mitigated the interference caused by anti-CD38 antibodies in 10 (100% efficacy) of patient samples tested while DTT was successful in only 9/10 (90% efficacy); no interference was observed in patients presenting anti erythrocyte antibodies. Moreover, there was no negative influence on DTT sensitive blood group systems such as KEL upon sCD38 treatment. Conclusions: In our Laboratory, in the year 2023, we processed 129 patients treated with anti-CD38. Therefore the reduction from 150 to 50 minutes in the time needed to perform tests for mitigation of anti-CD38 interference appears to be relevant with a recovery of approximately 210 technical-hours per year. Another highly appreciated operational aspect was the possibility of treating the patient's plasma and perform tests using automatic instruments (Erytra Grifols) available in our laboratory. In the evaluation of this new method, we did not observe failures in the mitigation of anti-CD38 interference. Furthermore, the results obtained in the samples that presented allo or auto antibodies were not affected by the treatment with sCD38. In our experience Grifols sCD38 assay is straightforward and quick to perform ant it is superior to DTT treatment in the mitigation of anti-CD38 antibody interference in MM patients treated with Daratumumab.

Comparative Effectiveness of Ozanimod and Vedolizumab as First-Line Advanced Therapies in Ulcerative Colitis: A Propensity-Matched Cohort Analysis.

There is limited real-world evidence comparing the effectiveness of ozanimod to vedolizumab as first-line advanced therapies in patients with ulcerative colitis (UC). We conducted a retrospective cohort study using TriNetX, a multi-institutional US database in adults with UC who were initiated on ozanimod compared to vedolizumab between January 1, 2021 and 22 June, 2024. The primary outcome was to compare the risk of a composite outcome of corticosteroid use, colectomy, or change to another advanced therapy between the 2 cohorts within 12 months. 1:1 propensity score matching (PSM) was performed for demographics, comorbid conditions, disease extent, laboratory parameters, and previous corticosteroid use. The risk was expressed as an adjusted odds ratio (aOR) with 95% CIs. We identified 222 patients in the ozanimod cohort (mean age 41.2 ± 15.7, 46.3% male sex, 68% White, and 22.5% ulcerative proctitis), and 4145 patients in the vedolizumab cohort (mean age 47.4 ± 18.3, 45.2% male sex, 69.7% White, and 17.2% ulcerative proctitis). After PSM, there was no significant difference in the risk of the composite outcome (aOR 0.92, 95% CI, 0.63-1.36) and corticosteroid use (aOR 0.80, 95% CI, 0.53-1.18) between the 2 cohorts within 12 months. There was a higher risk of change in therapy in the ozanimod cohort (aOR 1.95, 95% CI, 1.09-3.49) compared to the vedolizumab cohort. Colectomy rates were low in both cohorts (<0.04%). Our real-world study showed that ozanimod use is associated with similar corticosteroid use but higher odds of a change in therapy compared to vedolizumab when used as first-line therapy in patients with UC. Further prospective studies are needed to understand long-term outcomes.

Impact on survival benefits of asymptomatic primary tumor resection after bevacizumab plus FOLFIRI as first-line therapy for patients with metastatic colorectal cancer with synchronous unresectable metastasis

BackgroundMetastatic colorectal cancer (mCRC) poses a clinical challenge and requires a combination of systemic therapy and conversion surgery. Although first-line chemotherapy and targeted therapy are considered the standard treatments for mCRC, the role of primary tumor resection (PTR) in asymptomatic synchronous mCRC with unresectable metastatic lesion after initial therapy remains relatively underexplored.MaterialsA retrospective review was conducted from January 2015 to January 2021, involving 74 patients with synchronous mCRC who received bevacizumab plus FOFIRI as first-line systemic therapy. All 74 patients had unresectable metastatic lesions confirmed through multidisciplinary team discussion. Patient characteristics, PTR data, and radiotherapy (RT) and overall survival (OS) outcomes were analyzed. The patients were categorized into a “PTR” group and a “No PTR” group and then further stratified into “4A,” “4B,” and “4C” subgroups based on the initial mCRC stage. Additionally, four subgroups—namely “PTR( +)/RT( +),” “PTR( +)/RT( −),” “PTR( −)/RT( +),” and “PTR( −)/RT( −)”—were formed to assess the combined effects of PTR and RT.ResultsThe median OS for all the patients was 23.8 months (20.5–27.1 months). The “PTR” group exhibited a significantly higher median OS of 25.9 months (21.3–30.5 months) compared with 21.4 months (15.8–27.1 months) in the “No PTR” group (p = 0.048). Subgroup analyses revealed a trend of improved survival with PTR in patients with stage IVA and IVB; however, the results were not statistically significant (p = 0.116 and 0.493, respectively). A subgroup analysis of PTR and RT combinations revealed no significant difference in median OS rates.ConclusionFor asymptomatic mCRC with synchronous unresectable distant metastasis, PTR following first-line therapy with bevacizumab plus FOLFIRI may provide a potential survival benefit, particularly in stage IVA/IVB patients compared with stage IVC patients. Additionally, RT for primary tumor did not provide an additional OS benefit in mCRC with unresectable metastasis. A prospective randomized trial with a larger sample size is essential to further elucidate the role of PTR in this context.

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

OA02.04 A Phase III Study of Rilertinib Versus Gefitinib as First-Line Therapy for Patients with Locally Advanced or Metastatic EGFR-Mutated NSCLC

OA02.04 A Phase III Study of Rilertinib Versus Gefitinib as First-Line Therapy for Patients with Locally Advanced or Metastatic EGFR-Mutated NSCLC

FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas.

In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.

Alterations of Nutrient Elements in Hepatocellular Carcinoma Patients Treated with Atezolizumab-Bevacizumab

Currently, the combination of atezolizumab and bevacizumab (Atez/Bev) is recommended as the first-line therapy for patients with advanced hepatocellular carcinoma (HCC). However, there is a lack of research on the levels of nutrient elements in advanced HCC patients receiving Atez/Bev treatment. In this study, data from 35 patients with advanced HCC and 37 healthy individuals of similar age and sex were included. The levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly increased in patients with HCC. These levels returned to the reference range after three rounds of Atez/Bev treatment. Additionally, the levels of blood urea nitrogen and creatinine (Cr) increased after Atez/Bev treatment. In HCC patients, the levels of calcium (Ca), iron (Fe), and copper (Cu) were significantly higher, while the levels of sodium (Na), magnesium (Mg), and zinc (Zn) were significantly lower compared to healthy individuals. These changes were reversed after Atez/Bev treatment. In conclusion, our findings indicate that treatment with Atez/Bev influences the levels of Ca, Fe, Cu, Na, Mg, and Zn in patients with HCC. The alterations in these elements caused by Atez/Bev treatment require mechanistic research in the future.

Pembrolizumab for the First-Line Treatment of Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma: Results from the Single-Arm, Open-Label, Phase III KEYNOTE-913 Study.

The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC). The aim was to report results from the primary analysis of KEYNOTE-913. Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200mg intravenously every 3weeks for up to 35 treatments (~2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7-59.4). The ORR was 49% (95% confidence interval [CI] 35-63), with 12 complete responses and 15 partial responses. The median DOR was 39.8 months (range 4.8-52.5+), and the 24-month DOR rate was 69%. The median PFS was 9.3 months (95% CI 3-26), and the 24-month PFS rate was 39%. The median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. Any-grade treatment-related adverse events (AEs) occurred in 38 patients (69%); 13 patients (24%) experienced grade 3-5 AEs. The most common treatment-related AEs were fatigue (n = 12 [22%]), pruritus (n = 12 [22%]), and lipase increase (n = 10 [18%]). One patient died of treatment-related Guillain-Barré syndrome. Pembrolizumab provided durable antitumor activity and promising survival and had a manageable safety profile in patients with recurrent locally advanced or metastatic MCC, supporting its use in this population. Clinicaltrials.gov, NCT03783078.

The role of intravenous immunoglobulin in autoimmune diseases with dermatological implications.

Intravenous immunoglobulin (IVIG) therapy has emerged as a promising treatment option for various dermatological autoimmune diseases due to its immunomodulatory potential and low incidence of severe side effects. Despite its widespread use, the mechanism of action of IVIG in treating autoimmune diseases remains a topic of debate. IVIG is derived from the plasma fractionation of a large pool of donors, primarily consisting of the IgG isotype. Its main mechanisms of action involve neutralizing circulating autoantibodies via the F(ab')2 portion, inhibiting complement-mediated tissue destruction, and reducing the half-life of circulating autoantibodies through the Fc portion. This paper explores the growing utilization of IVIG as an off-label therapy in dermatological autoimmune or immune-mediated diseases, including autoimmune bullous disease (AIBS), dermatomyositis (DM), lupus erythematosus (LE), systemic sclerosis, scleromyxedema, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), pyoderma gangrenosum (PG), and necrobiotic xanthogranuloma (NXG). In this context, the sole large prospective, randomized trial was the 2022 ProDERM study, which demonstrate efficacy of IVIG in improving cutaneous manifestations among 95 DM patients compared to the placebo group. Moreover, although considered off-label, the use of IVIG is regarded as the first-line therapy for patients with scleromyxedema. As a first line of therapy, IVIg is only approved for Kawasaki Disease (KD) in the setting of vasculitis. The treatment in all other indications is mostly considered as adjuvant therapy only after failure of immunosuppressive therapy or in the presence of contraindications.

Randomized Phase II Trial of Amrubicin Plus Irinotecan Versus Cisplatin Plus Irinotecan in Chemo-naïve Patients With Extensive-Disease Small-Cell Lung Cancer: Results of the Japan Multinational Trial Organization (JMTO) LC 08-01

BackgroundWe conducted a randomize phase II study to evaluate the efficacy and safety of topoisomerase II inhibitor amrubicin plus topoisomerase I inhibitor irinotecan (AI) compared with cisplatin plus irinotecan (PI) as first-line therapy in patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and MethodsChemo-naïve patients with pathologically proven ED-SCLC (including limited disease (LD) SCLC with malignant effusion) were enrolled. Patients were randomized 1:1 to receive either AI (amrubicin 90mg/m2 on day 1 and irinotecan 50mg/m2 on days 1 and 8 of a 21-day cycle) or PI (cisplatin 60mg/m2 on day 1 and irinotecan 60mg/m2 on days 1, 8 and 15 of a 28-day cycle). The primary endpoint was overall survival proportion at 1 year. ResultsA total of 100 patients were randomly assigned to AI (n = 50) or to PI (n = 50). The 1-year overall survival proportions were 68.0% (95% confidence interval (CI): 56.2-82.2%) for AI and 59.2% (46.9-74.7%) for PI (1-sided P = .18). Median survival time was 14.8 months for AI and 13.5 months for PI with a hazard ratio (HR) of 0.618 (0.398-0.961, stratified log-rank test P = .031). Median progression-free survival time was 4.8 months for AI and 5.4 months for PI (stratified log-rank test, P = .54). Objective response rate was 70.0% (55.4-82.1%) for AI and 55.1% (40.2-69.3%) for PI (Fisher exact test, P = .15). There was no significant difference in hematological toxicity, whereas rates of vomiting, loss of appetite, diarrhea, and elevated serum creatinine are more frequent in PI. Interstitial lung disease (Grade 2 or 3) developed in 5 patients in AI and in 1 patient in PI. There was no treatment-related death. ConclusionAlthough the study did not meet its primary endpoint, AI showed promising efficacy and good tolerability in chemo-naïve patients with ED-SCLC.

P3.12D.01 A Phase Ib Study of Osimertinib and Tegavivint as First-Line Therapy in Patients with Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

P3.12D.01 A Phase Ib Study of Osimertinib and Tegavivint as First-Line Therapy in Patients with Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

Economic evaluation of camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma in the United States and China.

Camrelizumab combined with rivoceranib has been proven effective for treating unresectable hepatocellular carcinoma (uHCC). However, their higher prices than sorafenib could impose a substantial economic burden on patients. This study aimed to evaluate the relative cost-effectiveness of the combination of camrelizumab and rivoceranib versus sorafenib as first-line therapy for patients with uHCC from the perspective of the US and Chinese payers. Using data from the CARES-310 trial, a partitioned survival model (PSM) was developed, considering the perspectives of the US and Chinese payers. The model employed a 15-year time horizon and a biweekly cycle. Direct medical costs and utility data were collected from previous studies and open-access databases. Primary outcomes included quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Price simulations, sensitivity analyses, and subgroup analyses were conducted. The ICER for the US and China was $122,388.62/QALY and $30,410.56/QALY, respectively, falling below the willingness-to-pay (WTP) thresholds of $150,000/QALY for the US and $35,898.87/QALY for China. Price simulations indicated the cost-effectiveness of camrelizumab plus rivoceranib when the price of camrelizumab (200mg) remained below $6275.19 in the US and $558.09 in China. The primary determinant of cost-effectiveness in both regions was the cost of camrelizumab. The combination of camrelizumab and rivoceranib is a cost-effective first-line therapy for uHCC in both the US and China. Lowering their prices could significantly influence their cost-effectiveness and accessibility to patients. These findings will guide clinicians in treating uHCC and help decision-makers formulate value-based drug pricing strategies.

OA11.05 Results of a Phase III Trial of Prolgolimab with Chemotherapy as First-Line Therapy for Patients with Advanced Non-Squamous NSCLC: DOMAJOR

OA11.05 Results of a Phase III Trial of Prolgolimab with Chemotherapy as First-Line Therapy for Patients with Advanced Non-Squamous NSCLC: DOMAJOR

Real-World Survival Outcomes of First-Line Therapies in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis from Two Centres in Saudi Arabia.

Background: Metastatic renal cell carcinoma (mRCC) represents a challenging condition characterised by poor prognosis and limited response to chemoradiotherapy. In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. Methods: This study included 84 patients diagnosed with clear cell mRCC between January 2016 and December 2023. Patients were grouped based on treatment regimens. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and Cox proportional hazards regression. Results: The median first-line PFS was 9.7 months (95% CI: 5.3-14.1) for the overall cohort, with no significant difference between the single-agent tyrosine kinase inhibitor (TKI) group (9.4 months; 95% CI: 6.4-12.4), combination ICI group (9.0 months; 95% CI: 0.0-24.9), and single-agent ICI group (21.2 months; 95% CI: 2.6-39.8; p = 0.591). The median OS for the overall cohort was 42.0 months (95% CI: 14.9-69.2), with the single-agent TKI group having a median OS of 33.3 months (95% CI: 0.0-71.7), the combination ICI group, 42.0 months (95% CI: 0.06-84.0), and the single-agent ICI group, 23.0 months (95% CI: 19.2-26.7; p = 0.73). In comparison, the ICI-based combination therapy group exhibited a higher ORR of 41.0% (95% CI: 26.3-57.8%), while the single-agent ICI group had an ORR of 20.0% (95% CI: 3.5-55.8%). Cox regression identified liver metastasis as a significant independent predictor of PFS (HR = 1.8, p = 0.043), while a lower Karnofsky Performance Status was a significant independent predictor of OS (HR = 3.5, p < 0.001). Conclusions: In real-world practice from Saudi Arabia, first-line, single-agent ICI therapy offers promising anti-tumour activity and non-inferior survival outcomes compared to standard ICI-based combinations and single-agent TKIs.

Risk Stratification and Management of Intermediate- and High-Risk Pulmonary Embolism.

Acute pulmonary embolism (PE) is a leading cause of mortality. Not only is PE associated with short-term mortality, but up to ~20% of patients might suffer from long-term consequences such as post-PE syndrome and chronic thromboembolic pulmonary hypertension. Current risk stratification tools poorly predict those who are at risk for short-term deterioration and those who develop long-term consequences. Traditionally, systemic thrombolysis has been considered the first-line therapy for patients with high-risk PE without contraindications; however, it comes with the risk of major bleeding (notably intracranial hemorrhage). The use of catheter-directed interventions (embolectomy or thrombolysis) has been increasing owing to their low bleeding risk; however, randomized trial data supporting their efficacy in improving clinical outcomes are limited. In this review, we highlight the evidence supporting the available advanced therapies for high- and intermediate-risk PE and summarize the ongoing trials which are evaluating these therapies.

A Phase I Open-Label Study of Cediranib Plus Etoposide and Cisplatin as First-Line Therapy for Patients With Extensive-Stage Small-Cell Lung Cancer or Metastatic Neuroendocrine Non–Small-Cell Lung Cancer

IntroductionSmall cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC). MethodsPatients received up to six 21-day cycles of etoposide (100 mg/m2, days 1-3) and cisplatin (80 mg/m2, day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose. ResultsTwenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage. ConclusionsCediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity.

387P A prospective phase II study on efficacy and safety of AK105, anlotinib combined with nab-paclitaxel (nab-P) as a first-line therapy in patients (pts) with advanced triple-negative breast cancer (TNBC)

387P A prospective phase II study on efficacy and safety of AK105, anlotinib combined with nab-paclitaxel (nab-P) as a first-line therapy in patients (pts) with advanced triple-negative breast cancer (TNBC)

Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer.

Anti-oestrogen-based therapies, often combined with a CDK4/6 inhibitor, are the current standard-of-care first-line therapy for patients with advanced-stage hormone receptor-positive (HR+) breast cancer. Resistance to anti-oestrogen agents inevitably occurs, mediated by oestrogen receptor (ER)-dependent or ER-independent mechanisms that drive tumour progression. Emerging endocrine therapies include, but are not limited to, next-generation oral ER degraders and proteolysis targeting chimeras, which might be particularly effective in patients with ESR1-mutant breast cancer. Furthermore, cancers harbouring driver alterations in oncogenic signalling pathways, including AKT and PI3K, might be susceptible to novel combination strategies involving targeted inhibitors. Next-generation CDK2/4 inhibitors are an area of active clinical investigation, and efforts are ongoing to evaluate the role of sequential CDK inhibition. Approved and emerging antibody-drug conjugates exploiting novel target antigens have also demonstrated promising clinical activity. These novel agents, as well as further identification and characterization of predictive biomarkers, will hopefully continue to improve clinical outcomes, reduce the incidence of toxicities, and limit the extent of overtreatment in this population. In this Review, we describe the evolving treatment paradigm for patients with metastatic HR+ breast cancer in light of the growing armamentarium of drugs and biomarkers that will helpto shape the future therapeutic landscape. These strategies are expected to involve tumour molecular profiling to enable the delivery of precision medicine.

Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway).

Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms. BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62-73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11). In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.