Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.

9502 Background: Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen. Methods: We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response (RECIST 1.1) was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses. Results: A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( < 10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (≥50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1 -year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts (p = 0.016). There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment. Conclusions: Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

Retrospective Evaluation of Rituximab, Methotrexate, Procabazine, Vincristine and Etoposide Followed By Consolidation with Rituximab, Aracytine and Ifosfamide for Elderly Patients with Newly Diagnosed Primary CNS Lymphoma

Introduction Primary cerebral lymphoma (PCNSL) is an uncommon subtype of diffused large B-cell lymphoma (DLBCL) with a particular poor outcome as compared to systemic DLBCL, especially in elderly. For patients older than 60 years, standard treatment consists of high-dose methotrexate (HD-MTX) chemotherapy without consolidation brain radiotherapy to reduce the risk of leukoencephalopathy. Rituximab in combination with HD-MTX, procarbazine, vincristine followed by HD-cytarabine consolidation is one of standard of treatments for PCNSL patients with a 2-year PFS rate of 47% for patients aged of 60 or older in prospective trial (Morris JCO 2013). Etoposide and Ifosfamide are two drugs that can diffuse across blood-brain barrier and commonly used for relapsed/refractory PCNSL. To improve efficacy of R-MPVA protocol, we developed a new regimen which consisted in adding etoposide and ifosfamide for patients with a newly diagnosed PCNSL aged between 60 and 75 years old. Patients & Methods The protocol consisted of 3 cycles every 28 days of rituximab (375mg/m2, J1 and J15), MTX (3.5 g/m2, J1 and J15), vincristine (1.4 mg/m2, J1 and J15), vepeside (100mg/m2, J2) and procarbazine (100mg/m2, J1-7). Consolidation therapy consisted of 2 cycles every 21 days rituximab (375mg/m2, J1) in combination with cytarabine (3g/m2, J1-2) with ifosfamide (1.5 g/m2, J1-3). Response evaluations were planned after the 3 cycles of induction (R-MPV-VP16) and after consolidation (R-AraC-Ifo). We retrospectively reviewed treatment modalities, toxicities, response and outcome with this protocol and compared results with a matched group of patients with the same range age (60 - 75 years) treated with R-MPVA. Results Between 2013 and 2018, 28 PCNSL patients were treated with this protocol. The median age was 67.5 years old (range, 61-74). Poor performance status (PS 3-4) was presented in 9 patients (32%). As compared to 31 patients treated between 2007 and 2018 with R-MPVA, patients treated with intensive protocol were younger (66 vs. 69 years, P=0.01) and had less frequently a poor PS 3-4 (32% vs. 61%, P=0.04). In intent-to-treat analysis, 27 patients received 3 cycles of R-MPV-VP16 but one received only 2. Among them, five patients achieved PR and then received 1 to 2 additional cycles of R-MPV-VP16. Following this induction, 25 patients underwent 2 cycles R-AraC-ifo consolidation, 3 of them did not received ifosfamide for the second cycle because of hematological toxicity and poor PS. One patient in complete response (CR) after whole treatment received high-dose therapy followed by autologous stem cell transplantation. After R-MPV-VP16, 10 patients (36%) achieved CR and 14 partial responses (50%) (PR) as compared to 12 CR (39%) and 12 PR (39%) for patients treated with R-MPVA. After consolidation phase, 23 patients (82%) achieved CR after R-AraC-Ifo as compared to 21 CR (68%) after R-AraC in the historical arm. Differences were not statistically significant. R-MPV-VP16 regimen was associated with favorable toxicity profile with 13 (46%) grade 4 hematological toxicity, 8 (28%) grade 3 and one grade 4 (3%) renal toxicity, 3 (10%) grade 3 and one grade 4 (3%) hepatic toxicity, 6 (21%) grade 3 and 4 grade 4 (14%) and infectious toxicity. With a median follow-up of 46.5 months, patients treated with R-MPV-VP16 followed by R-AraC-ifo had a median event-free survival (EFS) of 33.2 months (95%CI, 17.6 - not reached [NR]) with a 2-year EFS rate of 52%; the median overall survival (OS) was not reached (95%CI, 58.6-NR) with a 2-year OS rate of 70%. With a median follow-up of 94.2 months, patients treated with R-MPVA had a median EFS of 18.3 months with a 2-year EFS rate of 39% (P=0.14, Fig 1); the median OS was 65.9 months with 2-year OS rate of 64% (P=0.33, Fig 1). Conclusions In this retrospective analysis of two HD-MTX and HD-AraC based regimens for PCNSL patients aged between 60 and 75 years performed in real-life setting, R-MPVA was more frequently proposed for older patients with a poorer PS. Combination of vepeside to R-MPV and ifosfamide to R-AraC was feasible with a favorable toxicity profile. Despite not statistically different, we observed a trend for an improvement of response rate at the end of treatment (82% vs. 68% of CR) and reduced rate of relapses (2-year EFS rates: 52% vs. 39%) with the intensified protocol. These first results deserve a confirmative larger prospective study of R-MPV-VP16 followed by R-AraC-ifosfamide for elderly PCNSL patients. Disclosures Ferrant: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Amgen: Research Funding; Roche, Gilead: Consultancy.

Carboplatin versus cisplatin for the treatment of extensive-stage small cell lung cancer (SCLC): A National VA Database analysis.

9061 Background: Current standard of care first line treatment for extensive stage SCLC includes combination of platinum-etoposide doublet with an immune checkpoint inhibitor. Carboplatin is preferred over cisplatin in the extensive stage disease because of its favorable toxicity profile. Data comparing the efficacy of carboplatin with cisplatin in the metastatic setting are limited. Methods: Data from the National VA Cancer Cube database were compiled. Only pathologically confirmed cases of extensive stage SCLC that received platinum-based multiagent chemotherapy were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Results: Overall, 2600 SCLC cases were studied: 1968 received carboplatin-based therapy (Carbo-SCLC) while 632 received cisplatin-based therapy (Cis-SCLC). Median OS of Carbo-SCLC and Cis-SCLC was 0.71 years (95% CI 0.68-0.75) versus 0.70 years (95% CI 0.64-0.76), respectively (HR = 0.99; 95% CI 0.90-1.10; p = 0.90). Median OS of patients with ECOG-PS of 0, 1, 2 and 3 was similar for Carbo-SCLC and Cis-SCLC. HR of death for Carbo-SCLC compared to Cis-SCLC stratified by performance status were: ECOG-PS 0: 1.04 (95% CI 0.78-1.38; p = 0.80); ECOG-PS 1: 0.87 (95% CI 0.71-1.06; p = 0.17); ECOG-PS 2: 0.92 (95% CI 0.69-1.24; p = 0.6); ECOG- PS 3: 1.13 (95% CI 0.66-1.92; p = 0.66). Multivariable regression analysis accounting for age and ECOG-PS shows a HR of 0.92 (95% CI 0.80-1.05; p = 0.24). Conclusions: Cisplatin-based chemotherapy was not associated with a survival advantage over carboplatin-based chemotherapy in extensive-stage SCLC., including in patients with robust performance status and young patients. The findings from this large dataset along with the favorable toxicity profile of carboplatin support its use as the platinum agent of choice in extensive stage SCLC.

Ixabepilone: new perspectives for its use in breast cancer

Despite significant advances in recent years, the drug therapy for breast cancer (BC) is still based on chemotherapy. The introduction of new effective cytostatic agents with a favorable toxicity profile is likely to remain an urgent objective for modern pharmacology in oncology. Ixabepilone, first in a new class of antineoplastic agents, the epothilones, has demonstrated high efficacy in the treatment of breast cancer both in its early stages and in patients, who have received 2 or more lines of chemotherapy. The article discusses the results of major studies, as well as the last meta-analysis of Ixabepilone studies in locally advanced and metastatic breast cancer. It presents the results of two large randomized studies of Ixabepilone in adjuvant regimens in patients with early breast cancer with an unfavourable prognosis.

2-Deoxyglucose

Metabolic regulation of excitability is increasingly appreciated as a strategy to control seizures and reduce pathogenesis. Inhibiting or bypassing glycolysis may be one way in which the ketogenic diet suppresses seizures. 2-deoxy-D-glucose (2DG) is a glucose analog that partially inhibits glycolysis and has antiseizure effects in several acute and chronic seizure models. The mechanisms underlying the acute and chronic effects of 2DG are being investigated. Preliminary studies provide evidence that the acute anticonvulsant actions of 2DG involve activity-dependent presynaptic suppression of excitatory synaptic transmission during network synchronization. The chronic effects of 2DG entail reduction of the expression of brain-derived neurotrophic factor and its receptor, tyrosine kinase B. Preclinical toxicology studies demonstrate that 2DG has a favorable toxicity profile at doses effective for seizure protection. Currently available preclinical studies support 2DG as a novel first-in-class metabolic treatment for epilepsy with an antiglycolytic mechanism distinct from all other anticonvulsants.

A successful case of multiple stereotactic radiosurgeries for ipsilateral recurrent trigeminal neuralgia

Trigeminal neuralgia is a common pain syndrome primarily managed medically, although many patients require surgical or radiotherapeutic intervention. Stereotactic radiosurgery has become a preferred method of treatment given its high efficacy rates and relatively favorable toxicity profile. However, many patients have refractory pain even after repeat courses of stereotactic radiosurgery. Historically, 2 courses have been the limit in such patients. The authors present a case of multiply recurrent trigeminal neuralgia treated with a third course of radiosurgery in which the patient had successful pain control and no additional toxicity. Meticulous attention to the therapeutic technique allows the continued application of stereotactic radiosurgery in patients.

Anaphylactic Reaction to Pemetrexed: A Case Report

Pemetrexed is approved to treat non-small cell lung cancer and has an overall favorable toxicity profile. We describe a 58-year-old man who developped an anaphylactic shock within few minutes from the beginning of pemetrexed perfusion. Pemetrexed was discontinued and the patient’s symptoms gradually resolved with administration of symptomatic treatment. Serum tryptase level remained normal and intra dermal skin tests were negative eventhough a nonspecific papule was noted. This case suggests that caution should be exercised when prescribing pemetrexed and clinicians must be warranted for the possibility of serious adverse events associated with pemetrexed use. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.