Intra-Arterial Catheter Guided Steroid Administration For The Treatment Of Steroid-Refractory Intestinal GvHD

Background Acute gastrointestinal GvHD (GI-aGvHD) refractory to first line treatment with systemic corticosteroids is resulting in death in the majority of patients. Intra-arterial local dose intensification in the gut has been reported in pediatric but not in adult patients. We prospectively assessed the feasibility and efficacy of regional intra-arterial steroid treatment in adult patients with severe (>= grade III) GI-aGvHD not responding to first line treatment. Patients and Methods Patients with more than +++ GI-aGvHD not responding to intravenous methylprednisolone at a dose of 2 mg/kg/day within 14 days were eligible for inclusion. Catheter guided intra-arterial steroid administration (IASA) was performed by accessing the right or left common femoral artery; a 4 Fr angiography catheter was used to locate and select the superior and inferior mesenteric artery and, in patients with upper gastrointestinal symptoms into the celiac trunk (9 patients) and the left gastric artery (2 patients). The mean total dose of methylprednisolone administered over 1 minute was 180 mg (120-240 mg). In 7 patients with persistent or recurring symptoms, IASA was repeated within 14 days. Response assessment was at 28 days after IASA. CR was defined as complete resolution of GI symptoms; partial response was defined as reduction of GI score from +++ to ++. Non-response was defined as the same grade of aGvHD, progression of symptoms or death within 28 days after IASA. Results Between January 2010 and June 2012, 12 consecutive patients with steroid-refractory GI-aGvHD received IASA as second line treatment. The patient's baseline characteristics are summarized in Table 1. The mean patient's age was 53 years (range 30 - 69), 9 were male and 3 female. All patients received peripheral blood stem cells as stem cell source. All 12 patients had grade III GI-aGvHD. At time of initial IASA, 4 patients had skin (grade + - +++) and 2 patients had liver (grade +) involvement. In all patients the overall grade of aGvHD was III. The median time from HSCT to onset of GI-aGvHD was 20 days (range 6 - 278). The median time from onset of GI-aGvHD to initial IASA was 19 days (range 9 - 41). 7 patients not responding to the first IASA received a second IASA (median period of time between IASA was 13 days, range 6 - 14). 83% of patients had gastrointestinal response including four patients (33%) with complete response at 28 days after IASA (Table 2). 6/12 patients were alive at a median time of 531 days (389 – 1362) after IASA. During IASA no technical complications occurred. There was one duodenal ulcer in one patient two days after second IASA that resolved after treatment. Conclusion Regional treatment of severe GVHD with IASA treatment seems to be a safe and effective second line treatment for steroid-refractory GI-aGvHD in adult patients. Our results compare favorably with reported results of steroid-refractory GI-aGvHD. Disclosures: No relevant conflicts of interest to declare.

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Outcomes of patients (pts) with advanced gastro-intestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib (IM) as first-line treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.11532 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 11532-11532

Author(s):

Alice Boileve ◽

Armelle Dufresne ◽

Ali N. Chamseddine ◽

Sarah Naomie Dumont ◽

Medhi Brahmi ◽

...

Keyword(s):

Median Time ◽

Phase Ii ◽

Kinase Inhibitors ◽

Molecular Profile ◽

Time To Failure ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Mutational Status ◽

First Line Treatment

11532 Background: IM is the standard first-line therapy in advanced GIST, with a median progression-free survival (PFS) of 30 months. Recent multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result in increased PFS (by the addition of a new line of treatment), or in early emergence of resistance to approved MKIs. Methods: A retrospective chart review was performed in GIST pts who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by IM as second line. Data on demographics, molecular profile, PFS, and overall survival (OS) were collected in two French referral centers. Results: Of 47 pts, (57% females), 22 (47%) had a KIT exon 11 mutation, one a KIT exon 9 mutation (2%), one a PDGFR D842V mutation (2%). Five patients were wild-type for KIT and PDGFR. The mutational status was unknown in 18 pts (38 %). From 2005 to 2011, 21 pts (45%) received masitinib, 18 (38%) received dasatinib and 8 pts (17%) received nilotinib. Median PFS on first-line treatment was 18.9 months [95%IC: 9.0-26.0]. Median time-to-failure (TTF) with IM was 19.7 months [95%IC: 14.8-53.4]. Median time to second relapse was 50.2 months [95%IC: 31.2-92.2]. Thirty-five patients (74.5%) were dead at the end of follow-up. The median OS from time of initial diagnosis was 5.9 years [95%IC: 4.5-8.2]. Conclusions: GIST pts who received MKIs other than IM as first-line treatment and IM as second-line had a time to second relapse longer than that observed historically with IM in first line. This suggests that using MKIs other than IM in first line does not decrease IM efficacy in second line. Further comparative studies are needed to confirm these findings, but this is encouraging to further develop studies with other MKIs in the first line setting.

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First-Line Treatment with a Cyclin-Dependent Kinase 4/6 Inhibitor Plus an Aromatase Inhibitor for Metastatic Breast Cancer in Alberta

Current Oncology ◽

10.3390/curroncol28030209 ◽

2021 ◽

Vol 28 (3) ◽

pp. 2270-2280

Author(s):

Carla P. Amaro ◽

Atul Batra ◽

Sasha Lupichuk

Keyword(s):

Aromatase Inhibitor ◽

Median Time ◽

Metastatic Breast ◽

Progression Free Survival ◽

Line Treatment ◽

Second Line ◽

Cyclin Dependent Kinase ◽

Time To Progression ◽

First Line ◽

First Line Treatment

In this analysis, we describe population-based outcomes for first-line treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) combined with an aromatase inhibitor (AI). All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 were included. Patient demographics, tumour and treatment characteristics were collected and described. Survival distributions were estimated using the Kaplan–Meier method. Multivariate analysis (MVA) was constructed to examine associations between potentially prognostic clinical variables and progression-free survival (PFS). In total, 316 patients were included. The median age was 61 years. After a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7–NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45–3.88; p = 0.001) and CDK4/6i dose reduction (HR, 1.51; 95% CI, 1.06–2.16; p = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed, 89% received second-line treatment. Median time to progression on second-line chemotherapy was 9.0 (5.8–17.6) months, and median time to progression on second-line hormonal therapy +/− targeted agent was 4.0 (3.4–8.6) months (p = 0.012). CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favourable PFS and early OS outcomes.

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Steroid-Refractory Acute Gvhd in Children: Retrospective Analysis of the AIEOP HSCT Registry

Blood ◽

10.1182/blood-2018-99-114862 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4578-4578

Author(s):

Marco Zecca ◽

Daria Pagliara ◽

Franca Fagioli ◽

Attilio Rovelli ◽

Edoardo Lanino ◽

...

Keyword(s):

Board Of Directors ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

Grade Ii ◽

Grade Iii ◽

Steroid Refractory

Abstract Introduction. Severe acute graft-versus-host disease (GVHD) remains the most relevant complication after allogeneic HSCT. Although its incidence in the pediatric population is lower than in adults, children with severe acute GVHD and who do not respond to first-line treatment with systemic steroids still have a poor prognosis. The exact incidence of steroid-refractory acute GVHD in children is still not precisely defined, as well as the risk of non-relapse mortality (NRM) due to steroid-refractory acute GVHD. Aim of our study was to analyze the frequency of acute GVHD unresponsive to first-line steroid treatment in children and adolescents given allogenic HSCT, to describe the second line treatment employed, and the outcome of patient with this complication. Patients and methods. This retrospective study included patients younger than 18 years at the time of transplantation and given a first allogeneic HSCT between 2010 and 2015 in one of the HSCT Centers of the Italian Association for Pediatric Hematology / Oncology (AIEOP). Overall, 1608 patients (59% M and 41% F) were analyzed. Median age at HSCT was 8 years (range 0.2 - 18) 1084 (67%) were affected by malignant diseases and 524 (33%) by non-malignant disorders. The donor was an HLA-matched family donor (MFD) in 28% of cases, an unrelated donor (UD) in 52% and an HLA-haploidentical family donor in 20%. In MFD transplants Cyclosporine (CSA) was used as GVHD prophylaxis in 30% of cases and the combination of CSA + short-term methotrexate (MTX) in 48%. 75% of UD transplant recipients received CSA + MTX + anti-thymocyte globulin (ATG) as GVHD prophylaxis, and 25% other drug combinations. Ex vivo T-cell depletion of the graft was employed in most patients given a HLA-haploidentical HSCT (79% of transplants), and high-dose post-transplant cyclophosphamide in 11% of cases. Results. The cumulative incidence (CI) of grade II-IV acute GVHD was 31%, while that of grade III-IV acute GVHD was 10%. The overall incidence of chronic GVHD was 13% and that of extensive chronic GVHD was 6%. The CI of NRM was 14% for grade 0 acute GVHD patients, 9% for grade I, 11% for grade II, 26% for grade III and 68% for grade IV (P < 0.001). Of the 491 patients with grade II-IV acute GVHD, 250 (51%) required a second-line treatment after first-line steroid therapy (30% of grade II, of 75% grade III and 83% of grade IV patients). Acute GVHD requiring second-line treatment was more frequent in UD transplant recipients (21% of patients) than in matched sibling or haploidentical donor recipients (7% and 13% respectively, P < 0.01), while age at HSCT and diagnosis (malignant vs. non-malignant disease) were not associated with this complication. Second-line treatment was extracorporeal photochemotherapy in 60% of patients, mofetil mycophenolate (MMF) in 46%, mesenchymal stromal cells (MSC) in 12%, monoclonal antibodies (MoAbs) in 5% and other treatments in 28%; 32% of patients received more than one second line treatment. Overall NRM was 13% for patients with grade 0-I acute GVHD, 15% for grade II-IV responding to steroids, and 25% for grade II-IV patients requiring second-line therapy (P < 0.001). The addition of a second-line treatment partially decreased NRM only in patients with grade IV acute GVHD, but the difference was not statistically significant (66% vs. 78%; P = 0.313). In multivariable analysis, grade III (HR = 1.84; P = 0.044) and grade IV acute GVHD (HR = 7.07; P < 0.001), and the use of an UD (HR = 1.63; P = 0.007) were associated with an increased NRM, while the use of a second-line treatment did not decrease this risk (HR = 0.80; P = 0.368). Conclusions. Despite being less frequent than in adults, severe steroid-refractory acute GVHD is still associated with a very high NRM also in pediatric patients. Second or third-line treatments adopted so far have not been effective in improving control of the complication and in decreasing NRM. The prospective evaluation of acute GVHD biomarkers (such as ST2 and REG3α) could help in identifying patients at higher risk of NRM. Prospective studies are warranted to define new treatment modalities that could decrease the mortality rate associated with the most severe form of disease. Disclosures Zecca: Chimerix: Honoraria. Locatelli:bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

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Sequential Treatments in Chronic Phase Chronic Myeloid Leukemia (CML) Patients without Optimal Response after Frontline Nilotinib or Dasatinib: An Italian CML Campus Study

Blood ◽

10.1182/blood-2020-141077 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-46

Author(s):

Gabriele Gugliotta ◽

Mario Annunziata ◽

Isabella Capodanno ◽

Davide Rapezzi ◽

Immacolata Attolico ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Chronic Phase ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

Optimal Response ◽

First Line Treatment

INTRODUCTION: Frontline therapy with second generation (2G) tyrosine-kinase inhibitors (TKIs) in chronic phase (CP) chronic myeloid leukemia (CML) patients demonstrated higher efficacy as compared to imatinib, with less patients experiencing treatment failure and progression to advanced disease. However, limited information are currently available on the management and outcome of those CML pts not achieving an optimal response to first-line treatment with a 2G-TKI. AIM: To describe the clinical outcome of CP CML patients without an optimal response to a frontline 2G-TKI that switched to alternative TKIs. METHODS: We performed a retrospective analysis in 22 Centers cooperating within the Italian CML Campus Project. Main inclusion criteria were: 1) diagnosis of CP-CML after 2010; 2) first-line treatment with a 2G-TKI; 3) switch to second-line treatment in case of non-optimal response (either following ELN recommendations or as for clinical practice); 4) CML in CP at the time of switching to second-line treatment. The main exclusion criteria were a switch to second-line treatment for intolerance or for low adherence to therapy. RESULTS: The main findings of this analysis are summarized in the table. Seventy-one pts meeting the inclusion/exclusion criteria were identified; the median age of pts at CML diagnosis was 46 (21-80) years. Sokal risk score was low, intermediate, and high in 24 (34%), 30 (42%), and 17 (24%) pts, respectively. First-line treatment was performed with nilotinib in 47 (66%) pts and dasatinib in 24 (34%) pts. According to the ELN 2020 recommendations, 51 (72%) pts fulfilled the criteria for "failure" and 20 (28%) pts those for "warning". BCR-ABL mutations were identified in 12 of 65 (18%) evaluable pts (T315I in 1 pt). Additional chromosomal abnormalities in Ph+ cells were identified in 6 of 54 (11%) evaluable pts. Second-line treatment was started after a median time of 16 (4-72) months, with ponatinib (40 pts, 56%), dasatinib (21 pts, 30%), nilotinib (7 pts, 10%), or bosutinib (3 pts, 4%). Median follow-up from start of second-line treatment was 25 (2-90) months. Best response to second-line treatment was MR2 in 18 (25%) pts and MR3 in 37 (51%) pts. Nineteen (27%) pts (13 for resistance and 6 for intolerance) switched to third-line treatment (ponatinib, 11 pts; nilotinib, 3 pts; dasatinib, 4 pts; imatinib, 1 pt), after a median time of 8 (1-72) months. Mutations were identified in 2 of 17 evaluable pts, and both patients harbored a T315I mutation. MR3 was reached by 9 (47%) of these pts. Lastly, 7 (10%) pts switched (6 for resistance and 1 for intolerance) to fourth-line treatment (asciminib, 4pts; dasatinib, 2 pts, nilotinib, 1 pt). Overall, 44 (62%) patients reached with sequential TKI treatments a MR3 (31/51 pts among "failures"; 13/20 among "warnings"). Allogeneic stem-cell transplantation (SCT) was performed in 7 (9.5%) pts (6 among "failures"), after a median time of 20 (15-60) months from CML diagnosis. Progression to advanced phase occurred in 2 (3%) pts; both pts previously met the ELN2020 "failure" criteria. Estimated 4-y PFS was 92.5%. Death occurred in 3 (4%) pts (1 after progression to blast phase, 2 for cardiovascular adverse events). Estimated 4-y OS was 93.7% CONCLUSION Our findings show that CP-CML patients not achieving an optimal response to frontline 2G-TKI therapy, despite a complex management, still have a favorable prognosis and survival due to the availability of both multiple TKI options and SCT. Figure Disclosures Gugliotta: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Di Raimondo:Amgen, Takeda, Novartis: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GILEAD, Incyte: Research Funding; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Rosti:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Saglio:Pfizer: Research Funding; Ariad: Research Funding; Roche: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Breccia:Abbvie: Consultancy; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

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Outcomes of patients with metastatic gastrointestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib as first-line treatment

ESMO Open ◽

10.1136/esmoopen-2020-001082 ◽

2020 ◽

Vol 5 (6) ◽

pp. e001082

Author(s):

Alice Boilève ◽

Armelle Dufresne ◽

Ali Chamseddine ◽

Elise Nassif ◽

Sarah Dumont ◽

...

Keyword(s):

Median Time ◽

Phase Ii ◽

Kinase Inhibitors ◽

Retrospective Chart Review ◽

Progression Free Survival ◽

Subsequent Treatment ◽

Line Treatment ◽

Second Line ◽

First Line ◽

First Line Treatment

BackgroundImatinib is the standard first-line therapy in metastatic gastrointestinal stromal tumours (GIST). Investigational multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result either in increased survival or in early emergence of resistance to approved MKIs.MethodsTo assess whether using MKIs other than imatinib in first line decreases imatinib efficacy in second line for patients with GIST, a retrospective chart review was performed from 2005 to 2011 in two French tertiary centres of patients with GIST who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by imatinib as second line.ResultsOf 46 patients, (55% women, median age 55 years (range 24–81)), 22 (47%) had a KIT exon 11 mutation, 1 a KIT exon 9 mutation (2%), 1 a PDGFRA D842V mutation (2%). Out of 46 patients, 21 (46%) received masitinib, 17 (37%) received dasatinib and 8 (17%) received nilotinib as first-line treatment with a median progression-free survival of 18.0 months (95% CI: 8.5 to 25.5). Median time to imatinib failure was 19.7 months (95% CI: 13.5 to 29.0). Median time to second relapse was 48.7 months (95% CI: 31.2 to 72.0). Median overall survival from time of initial metastasis diagnosis was 5.7 years (95% CI: 4.5 to 7.4).ConclusionsPatients with GIST who received investigational MKIs as first-line treatment and imatinib as second line had a time to second relapse longer than that observed historically with imatinib in first line, suggesting that using MKIs other than imatinib in first line does not decrease the efficacy of subsequent treatment lines.

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Immediate hypersensitivity reaction followed by successful oral desensitization to ursodiol

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-021-00578-7 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Erika Yue Lee ◽

Christine Song

Keyword(s):

Hypersensitivity Reaction ◽

Primary Biliary Cholangitis ◽

Line Treatment ◽

Second Line ◽

Immediate Hypersensitivity ◽

First Line ◽

Case Presentation ◽

Desensitization Protocol ◽

First Line Treatment ◽

Oral Desensitization

Abstract Background Immediate hypersensitivity reaction to ursodiol is rare and there is no previously published protocol on ursodiol desensitization. Case presentation A 59-year-old woman with primary biliary cholangitis (PBC) developed an immediate hypersensitivity reaction to ursodiol—the first-line treatment for PBC. When she switched to a second-line treatment, her PBC continued to progress. As such, she completed a novel 12-step desensitization protocol to oral ursodiol. She experienced recurrent pruritus after each dose following desensitization, which subsided after a month of being on daily ursodiol. Conclusion Immediate hypersensitivity reaction to ursodiol is uncommon. Our case demonstrated that this novel desensitization protocol to ursodiol could be safely implemented when alternative options are not available or have proven inferior in efficacy.

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Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

Clinical & Translational Oncology ◽

10.1007/s12094-021-02568-y ◽

2021 ◽

Author(s):

B. González Astorga ◽

F. Salvà Ballabrera ◽

E. Aranda Aguilar ◽

E. Élez Fernández ◽

P. García-Alfonso ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Option ◽

Scientific Evidence ◽

Treatment Options ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Effective Therapeutic Option ◽

Line Setting ◽

First Line Treatment

AbstractColorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

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Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

International Journal of Molecular Sciences ◽

10.3390/ijms22147717 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7717

Author(s):

Guido Giordano ◽

Pietro Parcesepe ◽

Giuseppina Bruno ◽

Annamaria Piscazzi ◽

Vincenzo Lizzi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Line Treatment ◽

Second Line ◽

Wild Type ◽

First Line ◽

Braf Mutations ◽

Mutational Status ◽

First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

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Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

Pharmaceuticals ◽

10.3390/ph14020151 ◽

2021 ◽

Vol 14 (2) ◽

pp. 151

Author(s):

Anica Högner ◽

Peter Thuss-Patience

Keyword(s):

Cell Death ◽

Gastric Carcinoma ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Disease Free Survival ◽

Line Treatment ◽

Second Line ◽

First Line ◽

The Usa ◽

First Line Treatment

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

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First-line treatment with a cyclin-dependent kinase 4/6 inhibitor combined with an aromatase inhibitor for hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: Population-based outcomes for patients treated in Alberta, Canada.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13020 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13020-e13020

Author(s):

Carla Pires Amaro ◽

Atul Batra ◽

Sasha M. Lupichuk

Keyword(s):

Hormonal Therapy ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Population Based ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Hormone Receptor Positive ◽

Targeted Agent ◽

First Line Treatment

e13020 Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in combination with an aromatase inhibitor (AI) has emerged as the standard first line treatment in patients with hormone receptor positive, human epidermal growth factor receptor-2 (HER-2) negative metastatic breast cancer (MBC). In this analysis, we describe population-based outcomes for first-line treatment with a CDK4/6i combined with an AI. Methods: All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 in a large Canadian province were included. Descriptive statistics were used to summarize patient demographics, tumor and treatment characteristics. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) using a Cox proportional hazards model was constructed to examine associations between potentially prognostic clinical variables and progression free survival (PFS). Results: A total of 316 patients were included. Median age was 61 years (interquartile range, 53-70 years), 82% were postmenopausal women, 39% had de novo MBC, and 48% had non-visceral disease. Palbociclib was prescribed in 94% of patients and the remaining patients received ribociclib. The CDK4/6i was dose-reduced upfront or during treatment in 47%. While 70% of the patients discontinued treatment due to progression, 30% stopped due to toxicity/patient preference/physician recommendation. With a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; P = 0.001) and dose reduction of the CDK4/6i (HR, 1.51; 95% CI, 1.06-2.16; P = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed (n = 131), 89% received second-line treatment (chemotherapy in 46%, single agent hormonal therapy in 35%, hormonal therapy plus a targeted agent in 15%, and other in 4%). Median time to progression on second line chemotherapy was 9.0 (5.8-17.6) months and second line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (P = 0.012). Conclusions: The real-world outcomes of first-line use of CDK4/6i and AI are encouraging. PR negative tumors and dose reduction appear to be negative prognostic markers. CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favorable PFS and early OS outcomes.

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