Second-line Treatment In Patients Research Articles

Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.

Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. In this phase 2, nonrandomized,prospective study, eligible patients received camrelizumab (200mg, d1, Q3W), apatinib (250mg, qd, d1-d21, Q3W), and capecitabine (1000mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in thefirst-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in thefirst-line setting. NCT04720131.

Real-world efficacy of low dose osimertinib as second-line treatment in patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer.

Response rates of epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) to lower doses of osimertinib [20 mg once daily (OD) and 40 mg OD] are similar to those of the recommended dose of 80 mg OD, but there is a lack of real-world evidence on the effect of the lower doses of osimertinib on survival outcomes. We conducted this study to assess the efficacy and safety of lower osimertinib doses for patients with EGFR-mutated advanced NSCLC whose disease had progressed on earlier generation EGFR tyrosine kinase inhibitors (TKIs) in a real-world clinical practice. This multicenter, retrospective study included patients with EGFR-mutated advanced NSCLC treated with low doses of osimertinib after failing first- or second-generation EGFR TKIs due to acquired T790M mutation. Data on demographics, staging, treatment history, best overall response rate (ORR) based on RECIST 1.1, and adverse events (AEs) were collected from the patients' case notes. Descriptive data were described in percentages and medians. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Of the 22 patients studied [males =8 and females =14; Eastern Cooperative Oncology Group (ECOG) 1 or 2 =7 and ECOG 3 or 4 =15], 45.5% were on 40 mg OD, 31.8% were on 80 mg every other day (EOD), and 22.7% on 40 mg EOD. First-line EGFR TKIs used included afatinib, erlotinib, and gefitinib. The ORR with lower doses of second-line osimertinib was 77.3%. Overall, the median PFS was 10.0 months [95% confidence interval (CI): 8.6-11.4] and median OS was 13.0 months (95% CI: 9.4-16.6). In patients with ECOG 1 or 2, the median PFS was 18.0 months (95% CI: 5.8-30.2) and the median OS was not reached at the time of analysis. In patients with poor ECOG performance status of 3 and 4, good survival outcomes were also seen with a median PFS of 7.0 months (95% CI: 4.7-9.3) and median OS of 10.0 months (95% CI: 7.5-12.5). All AEs except one case of paronychia were Grade 1. There were no Grade 3 or 4 AEs. Treatment with low dose osimertinib demonstrated good efficacy and tolerability in EGFR-mutated advanced NSCLC patients who failed first-line treatment with first- or second-generation EGFR TKIs due to T790M mutation.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study

BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%.MethodsECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsTarget enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35–48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67–29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent.ConclusionsEpacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted.Trial registrationClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Management of Diabetes Mellitus in Acromegaly and Cushing's Disease with Focus on Pasireotide Therapy: A Narrative Review.

Patients suffering from acromegaly and Cushing's Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts' consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.

The Evolving Role of Bispecific Antibodies in Diffuse Large B-Cell Lymphoma.

The advent of targeted therapies such as monoclonal antibodies, adoptive T-cell therapies, and antibody-drug conjugates (ADCs) dramatically changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL) over the last two decades. Rituximab was the first one approved. Chimeric antigen receptor T-cells are currently approved as second-line treatment in patients with DLBCL refractory to first-line chemo-immunotherapy. Polatuzumab, a CD79b-targeting ADC, is approved as first-line treatment in high-risk patients in combination with chemo-immunotherapy. Bispecific antibodies (BsAbs) are a novel category of drugs that are also changing the treatment paradigm of patients with DLBCL. They are engineered to bind to two different targets at the same time. To date, two BsAbs (glofitamab and epcoritamab) are approved as monotherapy in third-line treatment in DLBCL. Combination strategies with chemotherapy, immunotherapy, and ADCs are currently under investigation with encouraging results in first-line or subsequent lines of treatment. In the following review, we focus on the structure of BsAbs, the mechanism of action, clinical efficacy, and the mechanisms of resistance to BsAbs.

Tislelizumab with anlotinib and chemotherapy for second-line treatment of pancreatic ductal adenocarcinoma: A pilot study early result.

e16316 Background: Advanced pancreatic ductal adenocarcinoma is a malignant tumor with poor prognosis. At present, chemotherapy is still the standard treatment, however the efficacy is unsatisfied. The lack of second-line treatment options for pancreatic cancer results in progression-free survival often lasting less than 3 months. For pancreatic cancer is an immune desert type of tumor, immunotherapy has not brought breakthrough therapeutic regimen compared to the remarkable data in other tumors.There is still insufficient therapeutic evidence treated with PD1 antibody in pancreatic cancer. Anlotinib is a tyrosine kinase inhibitor (TKI) with anti-tumor effects. It has been shown the combination of PD1 and multi-target tyrosine kinase inhibitors can increase immunotherapy efficacy. The purpose of this study is to evaluate the efficacy and tolerability of Tislelizumab combined with Anlotinib, as well as chemotherapy (the choice of the investigator) in second-line treatment of patients with pancreatic ductal adenocarcinoma. Methods: In this single arm, phase II, prospective exploratory study, it was planned to recruit 30 adult patients with treated pancreatic ductal adenocarcinoma who have never received any PD (L) 1 and TKI. Eligible patients received Tislelizumab (iv, 200mg, Q3W), Anlotinib (PO, 10mg, QD), and chemotherapy (determined by the researchers) till disease progression or death. The primary endpoint was median progression-free survival (mPFS), the secondary endpoints were objective response rate (ORR), median overall survival(mOS), disease control rate (DCR), and treatment safety profile. Results: 14 eligible patients were recruited till Jan 2024, 12 patients with PFS records were included. Median follow-up time was 208 days (104 days-504 days). mPFS was 106 days, OS is not reached, BOR (best of response) was stable disease. The 3-months DCR rate was 58.3%, 6-months DCR rate was 25%. One patient was observed to have a 20% tumor shrinkage after two cycles of treatment and is still being followed up. The most common treatment-related adverse events(TRAEs) was neutropenia with level ≤grade 3, observed in 8/14 patients. The immune-related adverse event of concern was hypothyroidism(grade 1/2), which occurred in two patients. Two patients experienced grade 4 obstructive jaundice caused by the progression of the disease. Conclusions: The second-line combination regimen of Tislelizumab with Anlotinib based on chemotherapy demonstrated survival improvement trend and no new safety signals identified in pancreatic cancer. These data suggest Tislelizumab + Anlotinib+Chemo may be a promising novel treatment option for patients with pancreatic cancer. Clinical trial information: NCT05681390 .

FDA analysis of immune checkpoint inhibitors in combination with vascular endothelial growth factor tyrosine kinase inhibitors in the second-line treatment of patients with advanced non-small cell lung cancer.

8595 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit. [Table: see text]

Efficacy and safety of regorafenib and/or immune checkpoint inhibitors as a second-line therapy for advanced hepatocellular carcinoma: A real-world study from a single center.

e16165 Background: This study aimed to assess the efficacy and safety of regorafenib and/or immune checkpoint inhibitors (ICIs) as a second-line treatment in patients with pretreated hepatocellular carcinoma (HCC). Methods: Patients diagnosed with advanced HCC who had received regorafenib treatment in our hospital from January 2020 to November 2023 were reviewed. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and toxicity were the secondary end points. Results: Forty-five patients were included with a median age of 61 (31-83) years. Thirty-two patients (71.1%) were in Barcelona Clinic Liver Cancer (BCLC) stage C. Twenty-three patients (51.1%) had extrahepatic metastasis. ICIs were applied to 30 patients (66.7%) at the use of regorafenib. Local treatments were applied to 17 patients (37.8%). The median OS was 14.5 (11.3, 26.4) months in all patients. Regorafenib plus ICIs had a longer survival than regorafenib alone (20.5 [11.6, NA] vs 11.3 [3.0, 13.9] months, P = 0.019). Local treatment had no obvious effect. The median PFS was 6.8 (4.5, 11.7) months in all patients. The median PFS was 9.7 (4.6, 14.5) months in regorafenib plus ICIs that was longer than regorafenib alone with 3.0 (2.0, 8.0) months. Local treatment only showed a trend of prolongation (11.8 [2.5, 22.6] vs 4.7 [3.5, 9.7] months, P = 0.059). The 1-year OS and PFS were 43.2% and 20.0%, respectively. ORR and DCR was 29.0% and 71.0% according to mRECIST criteria, respectively. The most common any-grade treatment-related adverse events (TRAEs) were rash/itching (41.3%), hand-foot syndrome (19.6%), and anorexia (13.0%). Grade≥3 TRAEs occurred in 8.9% (4/45) of the patients and hypertension (4.4%) had the highest proportion. Conclusions: Regorafenib plus ICIs therapy is an effective promising regimen regardless of first-line treatments in advanced HCC. Combined with local treatment only showed a trend of PFS, further prospective research is needed.

A multi-center retrospective study on the efficacy and safety of regorafenib plus immune checkpoint inhibitors with or without TACE as a second-line treatment for advanced hepatocellular carcinoma.

e16147 Background: At present, there are no definitive optimal treatment options for patients with hepatocellular carcinoma (HCC) following first-line treatment failure. To maximize the survival benefit of patients, we compared the efficacy and safety of regorafenib plus immune checkpoint inhibitors (ICIs) with transarterial chemoem bolization (R+ICIs+TACE) versus regorafenib plus ICIs (R+ICIs) as a second-line treatment for patients with advanced HCC. Methods: This retrospective study included patients with advanced HCC from our multicenter who received R+ICIs+TACE or R+ICIs as a later-line therapy from June 2020 to August 2022.Objective response rate (ORR), disease control rate (DCR), median progression-free survival (m-PFS), and safety were evaluated according to the modified Response Evaluation Criteria in Solid Tumors(m-RECIST). Factors affecting PFS and OS were analyzed using a Cox proportional-hazards regression model. Results: A total of 78 patients were included in the study (regardless of first-line treatment), including 48 who received R+ICIs+TACE and 30 who received R+ICIs. The R+ICIs+TACE group had a significantly higher ORR (31.6% vs. 9.8%, P = 0.021), higher DCR (73.8%vs. 45.7%, P = 0.008), longer PFS (median 8.5 vs.3.6 months, P < 0.0001) and and a longer OS (14.6 vs 8.5 months, P = 0.024) than those who received R+ICIs group. Child-Pugh class A6 and B7, R+ICIs and extrahepatic metastasis were found as independent prognostic factors for poor PFS. R+ICIs, a-fetoprotein > 400 ng/mL and Child-Pugh class were noted as independent prognostic factors for poor OS.There was no notable difference in the total incidence of treatment-related adverse effects (TRAEs) (76.8% vs. 71.3%, P = 0.41) and the incidence of grade 3/4 serious adverse effects (6.2% vs. 16.1%, P = 0.21) between the two group. Conclusions: Regorafenib plus ICIs with TACE showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients.

First relapse in patients with multiple myeloma: Outcomes and predictors.

7558 Background: Survival in patients with multiple myeloma (MM) continues to improve with the newer therapies, but there is no clear evidence of a cure and patients continue to relapse. However, most patients have the most extended period without progression with their first-line therapy, and subsequent therapies often provide a shorter duration of response due to the use of drugs with overlapping mechanisms of action and, more importantly, a shorter first remission, pointing toward more aggressive disease biology. With newer immunotherapies being used at 1st relapse, this may change. We designed this study to explore the natural history of MM after the 1st relapse and define the predictors of outcome after the initial relapse. Methods: We identified all patients in the Mayo Clinic database diagnosed between Jan 2004-June 2019 who had had initial disease progression. The study cohort included 2005 patients. We explored the overall survival (OS) from the time of documented disease progression or the start of second-line treatment in patients who had not met IMWG criteria before second-line therapy. Front-line therapy was grouped into those with either an IMiD or PI, both IMiD and PI, daratumumab with IMiD and PI, and none of these agents. The IMiD and PI were always used with dexamethasone with or without an alkylator. Results: The median age was 63 (range 24-95) years and 60% were male. The median estimated follow-up from diagnosis for all patients was 86 mos. (95% CI; 82, 88) and the median time to progression from the start of therapy was 25 mos. (95% CI; 24, 26). The median OS from the first progression was 45 mos. (95% CI; 42, 50), 36 mos. for those diagnosed before 2009, and 52-53 mos. for those diagnosed later. On univariate analysis, age <70 at 1st relapse, RISS I, novel agents in initial therapy, CR in the first line, diagnosis after 2009, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse (Table). On multivariate analysis, age <70, RISS I, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse. Conclusions: The study provides an estimate of the outcomes and significant predictors of outcomes after 1st relapse in patients with MM. These factors should be taken into consideration when designing clinical trials in this patient population. In particular, these factors identify a high-risk group of patients not always identified by baseline characteristics and should be the focus of future trials. [Table: see text]

Long-term pasireotide-LAR treatment in the personalized therapy of patients with complex acromegaly: a collection of clinical experiences.

Pasireotide-LAR is recommended as a second-line treatment for patients with acromegaly. Although the effects of pasireotide-LAR have been well characterized in clinical studies, real-practice evidence is scant, especially in the long term and within the individualization of therapy in patients with comorbidities. To provide additional insight on the individualized approach to acromegaly management, six clinical cases of complex acromegaly treated with pasireotide-LAR for more than 5 years were reported. Pasireotide-LAR allowed the normalization of insulin-like growth factor 1 (IGF1) values in all patients and reduced tumour residue volume where present. A good safety profile and long-term tolerability were also reported.

Abstract RF02-03: Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is approved in over 40 countries for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (a score of 1+ on immunohistochemistry [IHC] analysis or an IHC score of 2+ and negative results on in-situ hybridization) breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. DESTINY-Breast08 (DB-08) was designed to establish the safety, tolerability, and preliminary activity of T-DXd in combination with widely used standard of care therapies in HER2-low hormone receptor (HR)+ metastatic breast cancer (mBC). Results reported here are from the dose-expansion stage of the Phase 1b, multicenter, open-label, parallel-assignment DB-08 study arms investigating T-DXd–endocrine therapy (ET) combinations [NCT04556773]. Methods: Eligible patients had centrally confirmed HER2-low advanced/mBC with measurable disease per RECIST 1.1 and were documented as HR+. Among patients with mBC, ≤1 prior line of ET ± a targeted therapy was allowed, and prior chemotherapy in the mBC setting was exclusionary. Patients received T-DXd 5.4 mg/kg intravenously (IV) every three weeks (Q3W) + anastrozole 1 mg orally daily (T-DXd + ANA) or T-DXd 5.4 mg/kg IV Q3W + fulvestrant 500 mg intramuscularly Q4W, with a 500 mg loading dose on Cycle 1 Day 15 (T-DXd + FUL). Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival, duration of response (all evaluated by investigator per RECIST 1.1), and overall survival (OS). Data cutoff (DCO) was ~24 weeks after the last patient in each arm had received study treatment. Results: As of February 20, 2023, 21 patients in the T-DXd + ANA arm and 20 patients in the T-DXd + FUL arm had received study treatment. Median age was 55 and 66 years, 67% and 75% of patients received a prior line of ET ± a targeted therapy for mBC, 33% and 25% had no prior line of treatment for mBC, and median follow up in censored patients was 12.1 months (range 4.0, 17.3) and 8.5 months (range 1.3, 15.1) in the T-DXd + ANA and T-DXd + FUL arms, respectively. Adverse events (AEs) occurred in 95.2% (20/21) of patients in the T-DXd + ANA arm and 100% (20/20) of patients in the T-DXd + FUL arm, with AEs ≥Grade 3 occurring in 47.6% (10/21) and 55.0% (11/20) of patients in each arm, respectively. The most common any-grade AEs, occurring in ≥30% of patients in either arm, are reported in the Table. Three (15%) adjudicated drug-related interstitial lung disease/pneumonitis events were reported in the T-DXd + FUL arm (all Grade 2; at DCO, one case had resolved, one was resolving, and one was not resolved); none were reported in the T-DXd + ANA arm. AEs were manageable by drug interruption and dose reduction. Confirmed ORR was 71.4% (15/21; 95% confidence interval [CI] 47.8, 88.7) in the T-DXd + ANA arm, and 40.0% (8/20; 95% CI 19.1, 64.0) in the T-DXd + FUL arm (Table). OS data were not mature at this DCO. Conclusions: Safety profiles for T-DXd-ET combinations were generally comparable to T-DXd monotherapy and manageable with dose modification and routine clinical practice. T-DXd in combination with anastrozole or fulvestrant was active in first- or second-line treatment of patients with HER2-low HR+ mBC. Citation Format: Komal Jhaveri, Fabrice André, Erika Hamilton, Peter Schmid, Carey Anders, Laura Testa, Inna Ganshina, Yen-Shen Lu, Seock-Ah Im, Robyn Young, Magdalena Wrona, Caron Lloyd, Yiwen Zhang, Sherene Loi. Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) [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 RF02-03.

Efficacy of upadacitinib in the achievement of clinical and endoscopic remission in hospitalized patients with ulcerative colitis.

Janus kinase (JAK) inhibitors have been developed and are clinically available for management of active UC patients although most studies have been conducted for the outpatients and few studies have demonstrated its efficacy in endoscopic and histological remission of hospitalized patients with UC. The aim of the present study was to investigate the efficacy of upadacitinib, which is a novel selective JAK1 inhibitor, in the treatment of ulcerative colitis. We present the cases of three hospitalized patients with ulcerative colitis who achieved clinical remission after significant and rapid improvement with upadacitinib. While upadacitinib was used as the second-line treatment for patients with insufficient treatment effects for corticosteroids or ustekinumab, a patient received it just after admission because they were steroid dependent and previously used advanced therapy before hospitalization. All patients demonstrated rapid clinical responses within 7days and the partial Mayo scores were 0 at week 8. All patients achieved confirmed endoscopic and histological remissions. We conclude that upadacitinib is a potential treatment option for hospitalized patients with an inadequate response to other biologics and JAK inhibitors.

Varlitinib and Paclitaxel for EGFR/HER2 Co-Expressing Advanced Gastric Cancer: a Multicenter Phase Ib/II Study (K-MASTER-13).

Varlitinib is a pan-human epidermal growth (HER) inhibitor targeting epidermal growth factor receptor (EGFR), HER2, and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (IHC) (≥1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median PFS and overall survival (OS) were 3.3 months and 7.9 months, respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), AST/ALT elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer

BackgroundCombining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting...

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

Real-World Effectiveness and Safety of Ramucirumab as a Second-Line Treatment for Patients with Unresectable Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma in Japan and South Korea: A Systematic Literature Review.

Gastric cancer has the highest incidence and mortality in Eastern Asia. The efficacy and safety of ramucirumab (RAM) monotherapy or in combination with paclitaxel (PTX) for patients with unresectable advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEA) have been established in clinical trials. To assess the effectiveness and safety of RAM or RAM-based therapy as a second-line treatment in real-world clinical practice in Eastern Asia and to pave the way for future research, a systematic literature review (SLR) was conducted. Studies published between January 2014 and December 2021 were identified in PubMed, Embase, Cochrane Library, CNKI, Wanfang, and CBM databases. This SLR included 23 studies from Japan and South Korea, of which 22 were retrospective and 11 were full-text articles. Most studies investigated RAM + PTX (range of median overall survival [mOS] 7.4-12.2months; median progression-free survival [mPFS] 3.35-7.0months). Data were limited for RAM, RAM + albumin-bound paclitaxel, and RAM + taxane. RAM + PTX was associated with longer survival (mOS 9.3-12.2months vs. 5.2-9.7months; mPFS 4.1-5.1months vs. 3.0-4.1months) than PTX. Patients with prior anti-programmed cell death1 (anti-PD-1) exposure experienced longer mPFS (4.8 vs. 3.4months) from RAM + taxane than those without prior anti-PD-1 exposure. Few patients (3.3-6.3%) discontinued RAM or RAM-based therapy because of adverse events (AEs). Hematological toxicities were most frequently occurring AEs and no new safety signals were identified compared to clinical trials. RAM + PTX as a second-line treatment is effective and associated with an acceptable toxicity profile in patients with advanced or metastatic G/GEA in real-world settings of Japan and South Korea. More studies are recommended to further evaluate effectiveness and safety of RAM or RAM-based therapy, especially after anti-PD-1 therapy, in a wider Eastern Asian population. INPLASY registration number INPLASY2022120023.

Comparison of Cabozantinib and Axitinib as Second-line Therapy After Nivolumab Plus Ipilimumab in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Comparative Analysis of Retrospective Real-world Data

BackgroundTo date, no studies have compared the treatment outcomes of second-line therapies in patients with metastatic clear cell renal cell carcinoma (ccRCC). This study retrospectively evaluated the efficacy of cabozantinib and axitinib as second-line treatments in patients with metastatic ccRCC who previously received immune-oncology combination therapy. Patients and MethodsPatients with metastatic ccRCC treated with cabozantinib and axitinib as second-line therapy after nivolumab-ipilimumab treatment were identified among 243 patients with RCC treated between August 1, 2018 and January 31, 2022 at 34 institutions belonging to the Japanese Urological Oncology Group. Patients were assessed for treatment outcomes, including progression-free survival (PFS), overall survival, objective response rate (ORR), and incidence rate of treatment-related adverse events (AEs). ResultsForty-eight patients treated with cabozantinib and 60 treated with axitinib as second-line therapy after nivolumab-ipilimumab treatment for metastatic ccRCC were identified. The median PFS (95% confidence interval) was 11.0 months (9.0–16.0) with cabozantinib and 9.5 months (6.0–13.0) with axitinib. The ORRs were 37.5% (cabozantinib) and 38.3% (axitinib). The rates of any-grade AEs and grade ≥3 AEs were 79.2% (cabozantinib) versus 63.3% (axitinib; P = .091) and 35.4% (cabozantinib) versus 23.3% (axitinib; P = .202), respectively. In the poor-risk group, PFS was longer in the cabozantinib group than in the axitinib group (P = .033). ConclusionThe efficacy and safety of cabozantinib and axitinib were comparable. In the poor-risk group, cabozantinib was more effective than axitinib. These findings provide valuable insights into the selection of second-line treatment options after nivolumab-ipilimumab treatment in patients with metastatic ccRCC.

Evaluating photodynamic therapy versus brolucizumab as a second-line treatment for polypoidal choroidal vasculopathy.

To compare the one-year outcomes between intravitreal brolucizumab (IVBr) monotherapy and photodynamic therapy (PDT) as a second-line treatment in patients with polypoidal choroidal vasculopathy (PCV) who did not respond to first-line therapy. This case-control study included eyes with PCV that do not respond to aflibercept or ranibizumab. The patients were retrospectively registered. We compared outcomes, including best-corrected visual acuity (BCVA), anatomical results, and the need for additional treatments, between IVBr and a combination therapy using PDT as second-line treatments for refractory PCV, after adjusting for potential confounders. We analyzed E-values to evaluate the robustness of the results against unmeasured confounders. Twenty-two eyes received IVBr, and twenty-four underwent PDT. No apparent differences were observed in BCVA and central macular thickness (CMT) changes from baseline between the groups (IVBr vs. PDT: BCVA, 0.01 ± 0.47 logMAR vs. 0.04 ± 0.18 logMAR, P-value = 0.756; CMT: -36.3 ± 99.4μm vs. -114.7 ± 181.4μm, P-value = 0.146). Only in the PDT group, five eyes (20.8%) did not require additional treatment after the second-line treatment, the adjusted odds ratio indicating no further treatment needed was 11.98 (95% confidence interval: 1.42-2070.07, P-value = 0.019). The E-value for the adjusted odds ratio was 23.44. Both second-line treatments for PCV exhibited similar visual and anatomical outcomes. Only in the PDT-treated eyes were there some patients who did not require further treatment after second-line therapy.

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer

BackgroundBintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell...