Third-line Treatment Research Articles

Significant response to margetuximab in Chinese HER2-positive metastatic breast cancer patient who progressed after second-line targeted therapy.

Activation of the antibody-dependent cellular cytotoxicity is one of the key mechanisms of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody treatment. Margetuximab is a fragment C (Fc)-modified chimeric anti-HER2 immunoglobulin G1 monoclonal antibody that shares epitope specificity with trastuzumab. In this case, we reported that margetuximab plus chemotherapy was effective as later-line therapy in a postmenopausal Chinese woman with metastatic diseases, who was diagnosed with estrogen receptor -, progesterone receptor (PR)-, HER2+ invasive ductal carcinoma. This patient used paclitaxel-albumin plus trastuzumab and pertuzumab as the first-line therapy with progression-free survival (PFS) of 14 months, and pyrotinib in combined with vinorelbine as the second-line therapy with a PFS of 17 months. Then she received margetuximab plus capecitabine as the third-line treatment, the metastatic lesions in the liver were obviously shrunk, indicating clinical partial response and the PFS was 7 months. This case revealed that margetuximab plus chemotherapy may be an appropriate option for the patients who progressed after treating with anti-HER2 monoclonal antibodies and pyrotinib.

Empirical rescue treatment of Helicobacter pylori infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on H. pylori management (Hp-EuReg)

ObjectiveTo evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe.DesignInternational, prospective, non-interventional registry of the clinical practice of European...

Efficacy and Safety of TACE Combined with Regorafenib versus TACE in the Third-Line Treatment of Colorectal Liver Metastases.

The liver is the most common site of metastasis in colorectal cancer. In patients with unresectable colorectal liver metastases, the 5-year survival rate is less than 5%. Many patients with colorectal liver metastases require effective subsequent therapy after the failure of standard first-line/second-line therapy. The purpose of this study is to investigate the efficacy and safety of TACE combined with Regorafenib versus TACE in the third-line treatment of patients with colorectal liver metastases. The clinical data of 132 patients with colorectal liver metastases were collected. There were two groups: TACE + Regorafenib group (N = 63); TACE group (N = 69). TACE uses CalliSpheres® drug-loaded microspheres (loaded with irinotecan). Regorafenib is administered at a dose of 120 mg once daily. If the patient is severely intolerable, the regorafenib dose is adjusted to 80 mg once daily. Primary study endpoints were (1) to evaluate the tumor response, ORR, and DCR and (2) to evaluate OS and PFS in the two groups. Secondary study endpoints were (1) to compare the performance status, CEA, CA19-9 after treatment between the two groups and (2) to compare the incidence of adverse events between the two groups. There were significant differences in tumor response, ORR, DCR, OS, and PFS after treatment between the two groups. TACE combined with the Regorafenib group versus the TACE group: ORR (57.1% vs 33.3%), DCR (82.5% vs 68.1%), mOS (18.2 months vs 11.3 months), and mPFS (8.9 months vs 5.3 months). The performance status after treatment was better in the TACE + Regorafenib group than in the TACE group (P < 0.05). The CEA and CA19-9 negative rates after treatment were higher in the TACE + Regorafenib group than in the TACE group (P < 0.05). For the third-line treatment of colorectal liver metastases, the combination of TACE + Regorafenib had better tumor response, OS, and PFS than TACE TACE + Regorafenib combination could be considered as salvage therapy for colorectal liver metastases who failed the first- and second-line standard therapy.

Individualized medical treatment options in Cushing disease.

Cushing disease (CD) is caused by a pituitary tumor which oversecretes adrenocorticotropic hormone (ACTH). It is a serious endocrine disease associated with increased mortality and impaired quality of life. The management of CD remains challenging. Although transsphenoidal surgery is the treatment of choice in most cases, in approximately half of CD patients, second or third-line treatment options are needed. Currently, new medical therapies are available which target adrenal steroidogenesis, pituitary somatostatin and dopamine receptors, and glucocorticoid receptors. Selection of which medication to use should be individualized and is determined by many factors including severity of the disease, possible side effects, patients preferences and local availability. The aim of this article is to describe currently available medical therapy to help clinicians individualize the treatment options in the context of recently updated Pituitary Society recommendations.

Interventional treatment of haemorrhoids in anticoagulated patients

Anticoagulants are currently widely used for cardiological reasons, stroke prevention and in other vascular diseases. Colorectal surgeons face patients suffering from haemorrhoids who are put on anticoagulant therapy in their everyday practice. Anticoagulation strategy for patients undergoing interventional treatment of haemorrhoids has not been discussed in detail in the literature so far. Standard management of grade 1-3 haemorrhoids includes rubber band ligation (RBL), sclerotherapy (SCL) and infrared coagulation (IRC) after unsuccessful conservative treatment. The rates of postprocedural bleeding range from 0.9-2.8% after rubber band ligation, 0-2.7% after sclerotherapy and 5% after infrared coagulation. Surgical procedures including dearterialization, haemorrhoidectomy and stapled haemorrhoidopexy are indicated in more advanced degrees as the third line of treatment and are complicated by postoperative bleeding in 1.4-5.9% and 2-7.9% patients, respectively. Haemorrhoidectomy is the best option in grade 4 haemorrhoids and is associated with 6.2-8.4% risk of bleeding. However, closed haemorrhoidectomy, Ligasure technique and/or anal tamponade can reduce this risk. Surgical guidelines recommend continuing acetylsalicylic acid in low bleeding risk procedures, including haemorrhoidal surgery. However, postoperative bleeding after rubber band ligation was more common in the aspirin group. On the other hand, haemorrhage incidence after sclerotherapy did not differ significantly between the group on anticoagulation compared with the group without anticoagulation. Haemorrhoidectomy should be postponed for 6 months in patients receiving dual antiplatelet therapy. According to the guidelines, vitamin K antagonists should be discontinued 5 days before haemorrhoidal surgery. Minimal bleeding risk procedures do not require discontinuation of anticoagulation,but this option seems to be hazardous for patients undertaking rubber band ligation. Sclerotherapy, on the other hand, could not require warfarin discontinuation if the international normalized ratio (INR) is within therapeutic range. Novel oral anticoagulants (NOACs) should be discontinued 1 day before low bleeding risk operations, including haemorrhoidectomy and resumed 1 day after the procedure. In conclusion, all anticoagulants should be ceased prior to operation except for aspirin. There are not clear recommendations on the perioperative protocols for continuation or discontinuation of blood thinners in patients undergoing minimally invasive procedures.

Clinical Outcomes, Treatment and Testing Patterns in Patients with Advanced Non-Small Lung Cell Cancer with Epidermal Growth Factor Receptor Mutations: Results of the Romanian Cohort From a Multi-national Retrospective Chart Review (REFLECT)

"Background: REFLECT was a retrospective, non-interventional study conducted in eight countries, including eleven sites from Romania, on patients with advanced stage non-small cell carcinoma (NSCLC). Aim: To characterize clinical outcomes, treatments and the proportion of T790M EGFR mutation testing in patients with advanced non-small cell lung cancer (NSCLC) receiving first- or second-generation (1G/2G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs ) as first-line (1L) treatment in the Romanian cohort of an international study. Methods: Comprehensive data were retrieved from the medical records of ninety patients with EGFR-mutated advanced NSCLC treated with 1G/2G EGFR TKIs between January 2015 and June 2018. All analyses are descriptive. Results: The median age at lung cancer diagnosis in the Romanian cohort was 67.5 years, with 68% females. The distribution of EGFR TKIs was 50% erlotinib, 31% afatinib, and 19% gefitinib. First line treatment was stopped in 76 (84%) patients due to progression (79%), toxicities (3%), the patient’s decision (1%) or surgery (1%). The median progression- free survival on 1L treatment was 12.0 months (95% CI 10.3-15.6), and the median overall survival from the start of first line therapy was 26.4 months (95% CI 22.4-34.2). EGFR T790M mutation testing was performed on 69% of patients at the time of progression on 1L therapy, with 57% of patients testing positive. Second-line (2L) therapy was started in 63% of patients discontinuing 1L therapy. Third-line treatment was started in 50% of patients discontinuing 2L treatment. Conclusion: Survival results mirrored those of randomized trials. The suboptimal T790M testing rate (69%) underlines the importance of reflex testing procedures, while attrition rates on 1L (26%) emphasize the need for an upfront selection of the most effective treatments."

Perianal Psoriasis as the First Manifestation of the Disease

Abstract Introduction Inverse psoriasis affects the skin of flexural areas, such as the groin, axillae, umbilicus, intergluteal fold, and external genitalia. Clinical Case We herein report the case of a man who presented with anal pruritus and, upon physical examination, a perianal dermatosis was found, which was characterized by erythematous plaques, with fine scaling. The case was initially managed with zinc oxide, and when no improvement was observed, we decided to take an incisional biopsy, which indicated histological changes suggestive of psoriasiform dermatitis. Discussion Inverse psoriasis affects 3% to 7% of patients with psoriasis, and it manifests with erythematous plaques without the classic scaling appearance. The skin in these areas is susceptible to maceration, irritation, and ulceration, which alter the classic clinical picture. It may present with typical lesions or, less frequently, in isolation in the anogenital region. In the anogenital presentation only, the diagnosis should be made by biopsy, looking for the classic histopathological features of psoriasis. As for the first-line treatment, low- or medium-potency topical steroids are used for short periods of time; the second-line treatment is with emollients and tar-based products; and the third-line treatment uses an immunomodulator. Conclusion This presentation is infrequent, and it requires a high index of suspicion for the diagnosis, always supported by biopsies, in search of the classic histopathological features of psoriasis.

Healthcare Resource Utilization and Associated Costs of German Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Health Claims Data Analysis.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma with increasing prevalence. Although the disease burden associated with DLBCL is high, only limited data on healthcare resource utilization (HCRU) and associated costs of German patients with DLBCL is available. Using a large claims database of the German statutory health insurance with 6.7 million enrollees, we identified patients who were newly diagnosed with DLBCL between 2011 and 2018 (index date). Treatment lines were identified based on a predefined set of medication. HCRU and related costs were collected for the entire post index period and per treatment line. A total of 2495 incident DLBCL patients were eligible for the analysis. The average follow-up time after index was 41.7months. During follow-up, 1991 patients started a first-line treatment, 868 a second-line treatment, and 354 a third-line treatment. Overall, patients spent on average (SD) 5.24 (6.17) days per month in hospital after index. While on anti-cancer treatment, this number increased to nine (10.9) in first-line, 8.7 (13.7) in second-line, and 9.4 (15.8) in third-line treatments. Overall costs per patient per month (PPPM) increased from €421 (875.70) before to €3695 (4652) after index. While on a treatment line, PPPM costs were €17,170 (10,246) in first-line, €13,362 (12,685) in second-line, and €12,112 (16,173) in third-line treatments. Time-unadjusted absolute costs sum up to €59,868 (43,331), €35,870 (37,387), and €28,832 (40,540) during first-line, second-line, and third-line treatments, respectively. The main cost drivers were hospitalizations (71% of total costs) and drug acquisition costs (18% of total costs). The financial burden of DLBCL in Germany is high, mainly due to hospitalization and drug costs. Therefore, there is a high medical need for new cost-effective therapeutic options that can lower the disease burden and remain financially viable to support the growing number of patients with this aggressive disease.

Pathological complete remission in ALK-positive lung cancer patient after multiple lines of conversion therapy.

Traditional therapeutic approaches for the treatment of advanced non-small-cell lung cancer (NSCLC) are based on chemotherapy. However, the discovery and understanding of oncogenic driver alterations has led to the development of targeted therapies that have substantially improved patient outcomes. Still, to date, there have been no reports of patients with advanced anaplastic lymphoma kinase (ALK)-positive lung cancer achieving clinical complete response (cCR) in the systemic lesion and pathological complete remission (pCR) in primary lung lesion after multiple lines of conversion therapy. In this case, a 55-year-old man was diagnosed with ALK-positive, stage IV lung adenocarcinoma using immunohistochemistry and next generation sequencing (NGS) tests. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, were used respectively as first-line, second-line, and third-line therapy. The patient received treatment with crizotinib and achieved partial response (PR), but 5 months later the efficacy was evaluated as progressive disease (PD). Ceritinib was used as the second-line treatment, but the disease progressed 6 months later. Alectinib was used as the third-line treatment, but the efficacy was evaluated as PD. From April 2019 to November 2019, the patient received 4 cycles of induction chemotherapy with pemetrexed/carboplatin/bevacizumab and then switched to pemetrexed/bevacizumab as the fourth-line treatment, and received the fifth line treatment, cetuximab/paclitaxel liposome/nedaplatin, for 1 cycle, but the disease still progressed. Then the patient received the sixth line of treatment, camrelizumab/lorlatinib, for 9 antitumor cycles, resulting in PR. The patient underwent surgery followed by maintenance treatment with lorlatinib and achieved cCR. To our knowledge, this is the first documented case of cCR in a patient with ALK-positive advanced lung adenocarcinoma treated with multiple lines of therapy followed by surgical treatment. This case reveals the possible survival benefit of immunotherapy after multiple line treatment in ALK-positive advanced lung adenocarcinoma, indicating that it is possible find new therapeutic targets based on NGS molecular detection and provide precise therapeutic strategies for clinical practice when drug resistance or progression occurs in cancer therapy.

National Trends in Third-Line Treatment for Overactive Bladder Among Commercially Insured Women, 2010-2019

ObjectiveTo investigate whether the 2010 introduction of percutaneous tibial nerve stimulation and the 2013 introduction of intradetrusor onabotulinumtoxinA were associated with an increase in overall utilization of third-line treatments. MethodsUsing medical claims data from IBM Marketscan database 2010-2019, diagnosis codes were used to identify adult women with overactive bladder. Procedure codes were used to identify third-line treatments. The annual proportion of patients receiving third-line treatments was calculated, as well as the proportion of each treatment received. These were modeled as a function of treatment year using linear regression; a regression coefficient significantly different from 0 was considered evidence of a significant change in utilization over time. ResultsWe identified 3,067,515 unique individuals with a diagnosis of overactive bladder, including 14,652 who initiated third-line treatments. The annual percentage of women with overactive bladder who initiated third-line treatment was 0.18% and did not change significantly over 10 years (P = .82). However, the proportion receiving sacral neuromodulation decreased significantly (P <.001), with a compensatory increase in intradetrusor onabotulinumtoxinA. Within 6 years of its introduction, onabotulinumtoxinA accounted for almost half of third-line treatments initiated. ConclusionOverall, third-line therapies for non-neurogenic overactive bladder are utilized infrequently among privately insured women. Over the past decade, the introduction of new treatment options has led to a shift in the type of treatment initiated, rather than to an increase in the overall utilization of third-line therapies.

A multi-center effectiveness comparison study of fruquintinib with constructed external control cohort of other targeted kinase inhibitors using real-world data in third-line treatment of metastatic colorectal cancer.

The objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs. The arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan-Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively. Overall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95%CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042). With the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as third-line mCRC treatment.

Abstract #1324976: Effect of Tamoxifen on The Management of Dopamine Agonist–Resistant Prolactinomas: A Systematic Review

Management of dopamine agonist (DA)–resistant prolactinomas that are not responding to second- and third-line treatments is challenging and necessitates alternative medical therapy. The presence of estrogen receptors on pituitary tumors accompanied by the variable behavior of pituitary tumors in the presence of estrogen prompted the study of the role of antiestrogen in the treatment of DA-resistant prolactinomas. The purpose of this paper is to provide a systematic review of the role of tamoxifen in the treatment of prolactin-secreting adenomas resistant to dopamine agonists.

A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients

Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-DOTATATE) has become an established second- or third-line treatment option for patients with somatostatin receptor (SSTR)-positive advanced well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Clinical evidence of the efficacy of PRRT in tumor control has been proven and lower risks of disease progression or death are seen combined with an improved quality of life. When appropriate patient selection is performed, PRRT is accompanied by limited risks for renal and hematological toxicities. Treatment of NET patients with PRRT requires dedicated clinical expertise due to the biological characteristics of PRRT and specific characteristics of NET patients. This review provides an overview for clinicians dealing with NET on the history, molecular characteristics, efficacy, toxicity and relevant clinical specifics of PRRT.

Long-term Durable Response after Treatment with 177Lu-PSMA Therapy in Combination with Enzalutamide

A75 years-old male with metastatic castration-resistant prostate cancer (mCRPC) who had progressed under enzalutamide was treated with 4 cycles of 177Lulutetium-prostate specific membrane antigen (PSMA), as the third line of treatment for mCRPC, without discontinuing enzalutamide. The patient showed near complete response and maintained on enzalutamide for four years after PSMA-targeted radioligand therapy (PRLT) without a need for further rechallenge PRLT. Also, the patient had a long term diabetes mellitus but no nephrotoxicity regarding PRLT was observed. Long-term durable responses after PRLT without recurrence is rare and biomarkers for such phenomenon warrants further studies.

Early-onset juvenile dermatomyositis: A tertiary referral center experience and review of the literature

Background/ObjectivesThe aim of our study is twofold: To evaluate the presentation, diagnosis, clinical course, and management of juvenile dermatomyositis (JDM) in children under three years of age, and to compare with older-onset patients. MethodsNine patients with early-onset, and 63 patients with older-onset JDM followed between December 2010 and April 2022 are included. We also reviewed the literature on early-onset JDM from the inceptions of the PubMed/MEDLINE and Scopus databases up to April 1st, 2022. ResultsEarly-onset JDM patients were characterized by longer median diagnostic delay (p = 0.005), calcinosis (p = 0.006), anti-NXP2 antibody (p = 0.049). Diagnostic pathway included muscle biopsy (77.7% versus 50.8%). Muscle biopsy findings were more severe in the early-onset group (p<0.001). Although there was no difference in the partial and complete remission rates, the relapse rate was significantly higher in the early-onset group (p = 0.001), reflected to requirement of intravenous immunoglobulin (p = 0.001), cyclophosphamide (p = 0.011), and biological agents (p = 0.016). Literature search revealed 32 articles reporting 75 patients. The median diagnostic delay was 5 (1–30) months. Calcinosis was present in 29.5%. Twenty-three of the 44 patients (52.3%) had a muscle biopsy. Forty-one patients (64.1%) received second and third-line treatments. Complete remission was achieved in almost half of these patients (48.9%), but relapse was observed in 75%. The mortality rate was 10.2%. ConclusionDiagnosis can be challenging and delayed in early-onset JDM patients. Compared to older-onset JDM patients, this group had higher relapse rate, more severe muscle biopsy findings, and received intensive immunosuppressive treatment.

Identifying predictive biomarkers of apatinib in third-line treatment of advanced colorectal cancer through comprehensive genomic profiling.

Apatinib is a selective inhibitor of vascular endothelial growth factor receptor-2. Despite encouraging anticancer activity in different cancer types, some patients may not benefit from apatinib treatment. Herein, we characterized genomic profiles in colorectal cancer (CRC) patients to explore predictive biomarkers of apatinib at molecular level. We retrospectively recruited 19 CRC patients receiving apatinib as third-line treatment. Tissue samples before apatinib treatment were collected and subjected to genomic profiling using a targeted sequencing panel covering 520 cancer-related genes. After apatinib treatment, the patients achieved an objective response rate of 21% (4/19) and disease control rate of 57.9% (11/19). The median progression-free survival (PFS) and overall survival were 5 and 8.7 months, respectively. Genetic alterations were frequently identified in TP53 (95%), APC (53%), KRAS (53%) and PIK3CA (26%). Higher tumor mutation burden levels were significantly observed in patients harboring alterations in ERBB and RAS signaling pathways. Patients harboring FLT1 amplifications ( n = 3) showed significantly worse PFS than wild-type patients. Our study described molecular profiles in CRC patients receiving apatinib treatment and identified FLT1 amplification as a potential predictive biomarker for poor efficacy of apatinib. Further studies are warranted to validate the use of FLT1 amplification during apatinib treatment.

Daily practices in chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma: METESTOMAC French prospective cohort.

Around 50% of gastric cancers are diagnosed at an advanced stage. Several chemotherapy regimens are now internationally validated. Few data are available on the routine daily management of advanced gastric or gastroesophageal junction cancers. We aimed to describe chemotherapy practices, tolerance, and efficacy overall survival (OS) and Progression free survival (PFS) in a prospective French cohort. Patients starting palliative chemotherapy were prospectively enrolled in 49 French centres. The primary objective was to report and describe patients' characteristics and treatment strategies. Secondary objectives were OS, PFS, objective response rate, adverse events rate, performance status deterioration during the chemotherapy. A total of 182 patients were included; 179 were analysed. Most patients received platinium-based chemotherapy as the first treatment and FOLFIRI as second; 62.0% of patients received a second line, and 32.4% a third line. More than two thirds of Her2-positive patients were first treated with trastuzumab. The FOLFIRI regimen was the most frequently used second-line therapy. Median OS was 13.3months, similar whatever the chemotherapy or combinations used in the first line. One- and 2-year OS increased with the number of chemotherapy lines received, from respectively 24.7% and 5.7% (1 line), to 46.9% and 12.4% (2 lines) and 88.1% and 29.9% (3 or more lines) (p < 0.0001). Our study showed that treatment strategies in France are based on a succession of doublets, making it possible to offer a second and third line of treatment more often. This treatment strategy must be taken into account for future trials with immunotherapy combinations.

The full management from first-line to third-line treatments in patients with Her-2-negative advanced gastric cancer.

The aim of this study was to retrospectively evaluate the efficacy of full management from first-line to third-line treatments in patients with human epidermal growth factor receptor 2 (Her-2)-negative advanced gastric cancer (GC). The efficacy and survival time of a total of 126 patients who received the first-line treatment with oxaliplatin plus fluoropyrimidine (S-1 or capecitabine or fluorouracil), the second-line treatment with nab-paclitaxel, and the third-line treatment of immune checkpoint inhibitors between September 2019 and December 2021 were analyzed. A total of 42, 36, and 48 patients received CapeOX, FOLFOX, and SOX as a first-line treatment, respectively. All patients received nab-paclitaxel alone as a second-line treatment. In addition, 31, 56, and 39 patients received nivolumab, sintilimab, and tislelizumab as a third-line treatment, respectively. The median PFS1, median PFS2, and median PFS3 was 6.9 months [95% confidence interval (CI), 6.8-7.4], 5.5 months (95% CI, 5.3-5.7), and 3.5 months (95% CI, 3.4-3.7). The median PFS3 was 3.8 months (95% CI, 3.3-4.2) and 3.5 months (95% CI, 3.3-3.7) among the Epstein-Barr virus (EBV)-positive and EBV-negative, respectively (P = 0.09). In addition, the median PFS3 was 4.2 months (95% CI,3.6-4.7) and 3.5 months (95% CI, 3.3-3.6) in the patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥5 and CPS <5, respectively (P = 0.02). The median OS was 17.4 months (95% CI, 17.2-18.1). The multivariate analysis showed that the two parameters were associated with a significantly longer OS: number of metastatic sites <3 and PD-L1 CPS ≥5. The patients who received three lines of treatment had a long survival time, and the efficacy of immunotherapy was not affected by the EBV subtypes in advanced GC. The toxicity was managed, and the concept of full management needs to be confirmed in the future.

Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma in a Real-Life Population in France: The Remix Study

Background Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Efficacy and safety have been demonstrated in the phase 3 Tourmaline-MM1 clinical trial (1), which has recently reported the longest median overall survival (mOS) in phase III studies of Rd-based triplets (53.6 months, mo) (2). The REMIX study has been conducted since IXA became available in France in 2017. It is the largest cohort of RRMM pts receiving IXA-Rd combination in real life. The final analysis was performed with a median follow-up of 28.7 mo. Methods REMIX is a non-interventional, prospective study conducted in 59 sites (public and private) in pts with RRMM in France. To be eligible pts had to receive IXA-Rd in second line or later and IXA had to be initiated concomitantly to Rd (pts who started lenalidomide (lena) more than 6 weeks before IXA were excluded). After inclusion, pts were assessed every 3 mo during 24 mo and then every 6 mo as per standard practice. Analysis comprised OS, progression-free survival (PFS), overall response rate (ORR), very good partial response (VGPR) and tolerance. The analysis was conducted for the overall population and in subgroups of interest: age and lines of treatment (L2, L3 or L4+). Results A total of 376 eligible pts were included. Median age was 71 years (y) with 18.4% of patients aged ≥80y. At IXA-Rd initiation, 48.8% of pts were frail and 21.8% had renal clearance ≤50 ml/min. Comorbidities were reported in 62.8% of pts, including diabetes (8.8%), renal disease (8.8%) or solid tumour (6.4%). At inclusion, the cytogenetic risk was standard, high or unknown in 44.4%, 12% and 43.6% of pts, respectively. MM was diagnosed at a median of 4y before IXA-Rd initiation. 44.5% of pts had previous autologous stem cell transplantation (ASCT). IXA-Rd was initiated in L2, L3 or advanced lines (L4+) in 60.4%, 18.1% and 21.5% of pts, respectively. Regarding previous treatment received, 66.0% of pts had received IMID (including 39.2% lena and 11.7% pomalidomide), 93.1% had received PI (including 91.7% bortezomib and 7.5% carfilzomib) and 13.9% had received daratumumab. Most pts were previously exposed to lena in L3 (73.5% of L3, n=50/68, for a median duration of 16 mo) and L4+ (91.3% of L4+, n=73/81, for 17 mo) compared to L2 (10.6% of L2, n=24/227, for 18 mo). Out of all pts, 26, (7.9%) were considered lena-refractory during previous therapy. The median washout (WO) period between lena discontinuation and IXA-Rd start was 22.8 mo (SD: ±23.9). IXA was used for a median of 12.4 mo (13 cycles) at a 4-mg dose for 90.4% of pts. The median PFS (mPFS) was 19.1 mo (95% CI: 14.9-21.5) for the overall cohort, with a mPFS of 21.5 mo (95% CI: 19.2-24.8) for L2 (n=213), 21.9 mo (95% CI: 16.2-28.7) for L3 (n=65) and 5.8 mo (95% CI: 4.8-9.4) for L4+ (n=80). In the subgroups of pts aged <80y (n=293) and ≥80y (n=65), mPFS were 19.1 mo (95% CI: 15.9-21.9), and 17.4 mo (95% CI: 10.8-23.0), respectively. The mOS was not reached for the overall cohort; 36mo and 48mo OS rates were respectively 58.3% (95% CI: 52.6%-63.9%) and 52.4% (95% CI: 44.2%-60.5%). The 36mo OS rates were 63.4% (95% CI: 56.1-70.8%), 68.9% (95% CI: 57.1-80.7%) and 35.3% (95% CI: 23.9-46.7%) in L2, L3 and L4+ pts respectively. Among the 331 pts with available response according to investigators, the ORR was 73.1% (79.8% in L2, 70% in L3 and 54.4% in L4+ patients) and the VGPR rate was 45% (52.7% in L2, 41.7% in L3 and 25% in L4+ pts). IXA discontinuation was reported in 74.1% of pts (n=278). Discontinuation was related to AE in 21% of cases (n=79). Serious adverse events (SAE) were reported in 54.3% (n=204), including 57 (15.2%) pts with SAE considered related to IXA. Most frequent (>10%) AEs were diarrhoea (52%), thrombocytopenia (45.9%), asthenia (29.7%), neutropenia (23.6%) and anaemia (22.3%). Conclusion The REMIX study reported a mPFS in real-world conditions of 19.1 mo consistent with MM1 (20.6 mo), while half of patients were considered frail and 39.2% had previously received lenalidomide. The effectiveness in third line of treatment is similar to that in second line but was lower in L4+ as expected (5.7 mo). mOS is not reached at 48mo which aligns with MM1 final analysis. Reported AEs are consistent with the known safety profile of Ixazomib. Funding Takeda Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Sequencing and Survival in Follicular Lymphoma: A National Population-Based Study

Introduction Follicular lymphoma (FL) is characterised by a vast clinical and molecular heterogeneity. Whereas early progression of disease (POD) within 24 months has been identified as an important prognostic factor in different cohorts, potential associations with number of treatment lines, treatment sequencing and survival have not been thoroughly described in real world data. To further identify patient groups with a high need for novel therapeutic strategies in clinical routine and for inclusion in clinical trials we aimed to describe treatment patterns and survival in a national population-based setting. Methods We identified all patients diagnosed with FL in the nationwide Swedish Lymphoma register (coverage >95%) during the period 2007 to 2014, with follow-up through 2020. Information on progression, relapse, transformation and treatments was collected through review of medical records. A total of 2,079 patients were identified. Patients who did not provide informed consent (n=40), were diagnosed with transformed FL (n=144) or grade 3B (n=72), or where medical record data was missing (n=51) were excluded. The main analysis included patients receiving any first-line systemic treatment. Patients who were initially managed with radiotherapy (RT) only or a watch and wait (WaW)-approach were included in the main analysis if/when they received their first systemic treatment. Consolidation treatment including RT, maintenance with anti-CD20 antibody therapy or autologous stem cell transplantation (ASCT) was noted but did not count as separate treatment lines. Overall survival (OS) was illustrated graphically with the Kaplan-Meier method. Results In the final cohort of patients with FL (N=1,772), median age at diagnosis was 65 (18-98) years, and median follow-up time was 6.7 (0.003-13.9) years. Overall, 412 patients (23%) were managed with WaW only during the entire follow-up. Among patients with stage I or limited stage II disease treated curatively with RT at diagnosis (n=304), 60% (n=181) never needed additional therapy. In total, 1,174 patients (66%) received any first systemic treatment. The most common first-line treatment was R-CHOP (425/1,174, 36%), followed by R-single (361, 31%) and BR (184, 16%). The use of R-CHOP as first-line treatment decreased between calendar periods, whereas the use of BR and R-single in first line increased. Among patients starting any first line, 460 (39%) received systemic second-line treatment. Here, BR was most commonly administered (143/460, 31%) followed by R-CHOP (136/460, 30%) and R-single (60/460, 13%). A third-line treatment was administered to 204 patients (17%). Again, BR was most commonly chosen (67, 31%), followed by R-CHOP (41, 19%) and platinum-based chemotherapy (28, 13%). Only 81 (7%) patients required fourth-line treatment, and the maximum number of treatment lines administered were seven. The number of patients treated with the varying regimens in first and subsequent treatment lines are presented as a Sankey plot in Figure 1. Time to next treatment decreased with increasing number of treatment lines, as did OS. Time to next treatment was 2 years on average from the first to second treatment lines, 1.4 years to third line and 1 year to fourth line. The 5-year OS from first-line treatment was 75%, and the corresponding figures following second, third and fourth lines of therapy were 53%, 36% and 24%, respectively (Figure 2). During the whole study period, 173 (15%) patients received systemic treatment due to transformation, 258 (22%) received R-maintenance and 79 (7%) patients underwent ASCT. Conclusion In this national population-based cohort of FL, one in four patients never needed active oncological treatment. Among patients starting any first-line systemic therapy, 39% required a second line, and 18% a third line over a median follow-up of about 7 years. Further, time to next treatment decreased with increasing number of treatment lines and number of treatment lines was associated with dramatically worse survival. We conclude that, in addition to patients with FL experiencing POD24, patients who require multiple treatment lines (≥3) constitute a group with a large clinical unmet need, and methods to identify these patients at an early stage are warranted. The present results provide valuable real-world reference data for the design and interpretation of clinical trials of new treatments in FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal