Increase In Overall Response Rate Research Articles

Single centre retrospective analysis of extracorporeal photopheresis (ECP) therapy in patients heavily pre-treated for chronic graft-versus-host disease (cGvHD) with steroid failure

BackgroundExtracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. MethodsWe evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. ResultsWith a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. ConclusionECP is an effective treatment option for heavily pre-treated cGvHD patients.

Correlations between overall response rate, progression-free survival and overall survival with kinase inhibitors in radioiodine-refractory differentiated thyroid cancers: A systematic review and meta-analysis.

e18087 Background: Differentiated thyroid cancer (DTC) has a good prognosis; however, about 30% of patients will experience a recurrence after treatment and become refractory to radioiodine therapy. Some studies, including randomized controlled trials (RCTs), have shown the efficacy of kinase inhibitors in these patients, but whether overall response rate (ORR) can predict progression-free survival (PFS) and/or overall survival (OS) has not been well established in the literature. We examined the correlations between ORR and PFS/OS with kinase inhibitors in radioiodine (RAI)-refractory DTC. Methods: PubMed, SCOPUS, Embase, and ClinicalTrials.gov were queried for studies that used kinase inhibitors in RAI-refractory DTC. Eligibility included a clinical diagnosis of RAI-refractory DTC, the use of kinase inhibitors, and articles published in English. ORR, PFS, and OS data were manually retrieved from the studies, and correlative analyses using Spearman's rank correlation coefficient ( rs) were conducted to determine their relationships. Results: Two hundred ninety articles were identified from the literature search; after removing duplicates and screening for relevance and eligibility, 24 studies (6 RCTs and 18 observational), consisting of 1,791 participants, were included for analysis. The kinase inhibitors used were: sorafenib, lenvatinib, donafenib, apatinib, sunitinib, cabozantinib, and vemurafenib. There was no significant correlation between ORR and PFS or OS, and between PFS and OS. However, a sub-analysis of the 6 RCTs (n = 410) alone showed a significantly strong positive correlation between ORR and PFS ( rs = 0.92, p = 0.003) with a 20% increase in ORR corresponding to a prolonged PFS by about five months. No significant correlation was found between any two endpoints in the observational studies. Conclusions: Overall response rate is a predictor of PFS and can be used as a surrogate endpoint for the latter (PFS) in RCTs with kinase inhibitors in RAI-refractory DTC, especially when the time to reach PFS data may be protracted, costly, and delayed treatment. The lack of correlations between ORR and PFS or OS in the observational studies may be due to different populations with varying responses, less controlled settings, time to reach OS data, and probably smaller sample sizes.

A phase 2 trial of chemotherapy, pembrolizumab, and propranolol in patients with advanced esophageal/gastroesophageal junction adenocarcinoma (EGAC).

TPS4171 Background: Chronic stress suppresses the immune system and promotes cancer cell growth. In animal studies, we reported that this is mediated by the beta-adrenergic (BA) pathway. We further showed that concurrently blocking the BA pathway with β-blockers (BB) can improve immune checkpoint inhibitor (ICI) efficacy. Our retrospective data analysis revealed that esophageal cancer (EC) patients taking BB for other non-cancer reasons while receiving chemoradiation had significantly better survival and distant control than those not taking BB. We hypothesized that blocking the effects of adrenergic stress with a commonly used BB, propranolol, will improve response to therapies in EC patients. Methods: This is an open-label, non-randomized, phase 2 study of propranolol combined with pembrolizumab and standard chemotherapy in frontline unresectable/metastatic EGAC. Eligible patients must be treatment-naïve, have adequate organ function, have an ECOG performance status of 0 –1, and be able to swallow and retain oral medication. Patients with Her-2 positive cancer, active autoimmune disease, active HIV, Hepatitis B or C, or a history of non-infectious pneumonitis/interstitial lung disease that requires treatment, are ineligible. Patients who are on BB for various indications are also ineligible. Eligible patients will receive mFOLFOX6 every two weeks in combination with pembrolizumab 400 mg intravenously every six weeks and propranolol 30 mg orally twice daily. The mFOLFOX6 dosing regimen will consist of dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by bolus 5-FU 400 mg/m2 and a 48-hour infusion of 5-FU 2400 mg/m2. The study will include an initial safety lead-in cohort of six patients. The primary endpoint is the overall response rate (ORR) determined by RECIST 1.1. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS), and ORR as determined by iRECIST. Correlative studies will assess baseline levels or changes in the levels of biomarkers, like, peripheral T-cell subsets/myeloid-derived suppressor cells (MDSC)/cytokines/ and perceived stress scale PSS/chronotropic effects of exercise with efficacy (ORR, PFS, OS). Assuming a historic ORR of 50% with standard treatment, 37 evaluable pts are needed to show a 20% increase in ORR with our proposed treatment with 80% power at a one-sided significance level of α = 0.1. In stage 1, n1= 23 evaluable pts will be enrolled. If there are 13 or more ORRs, an additional n2= 14 pts will be enrolled in stage 2. If 24 or more ORRs are observed in the total n = 37 evaluable pts, the proposed treatment regimen will be considered promising for further study. The study is currently open to enrollment. Clinical trial information: NCT05651594 .

Phase 1 Results of the First-in-Class CXCR1/2 Inhibitor SX-682 in Patients with Hypomethylating Agent Failure Myelodysplastic Syndromes

Background: SX-682 is an oral dual allosteric inhibitor of the CXCR1 and CXCR2 (CXCR1/2) chemokine receptors, a signaling pathway involved in the recruitment of immunosuppressive MDSCs and autocrine growth of disease-initiating leukemic stem cells (LSCs) in AML and myelodysplastic syndromes (MDS). CXCR2 overexpression is predictive of transfusion dependence in MDS. CXCR2 inhibition reduces proliferation of leukemic cell lines and primary MDS/AML patient (pt) samples in vitro and impairs leukemic growth in an in vivo AML animal model. CXCR2 is also involved in normal neutrophil egress from the bone marrow and thus absolute neutrophil count (ANC) serves as a pharmacodynamic (PD) marker for CXCR1/2 inhibition by SX-682. In pts with normal bone marrow, 25-400 mg SX-682 twice-daily (BID) dose-dependently reduces ANC, with maximum ANC reduction (-66% of baseline) obtained at >150 mg BID, consistent with maximum CXCR1/2 inhibition above this dose. ANC rapidly (24 hrs) normalizes with dose-holding. This NHLBI funded trial (HL142389, NCT04245397) explored the safety and efficacy of SX-682 monotherapy in pts with hypomethylating agent (HMA) failure MDS. Methods: This Phase 1 dose-escalation with expansion study treated five cohorts of HMA failure MDS pts with escalating 25-400 mg BID doses of SX-682 in six continuous 28-day cycles with responding pts continuing treatment. Steady-state pharmacokinetics (PK) were obtained. Response assessment was at the end of cycles 1, 3 and 6 and every third cycle thereafter using IWG criteria (Cheson 2006). This interim analysis after dose-escalation to select the expansion dose was pre-specified. Results:17 MDS pts received SX-682 (median 1 prior therapies; range 1-4) with 6 pts in the 200 mg cohort, 3 pts in each of the 25, 50 and 100 cohorts and 2 pts in the 400 mg cohort (Table). Median age was 76, and pts were low (n=1), intermediate-1 (n=10), intermediate-2 (n=5) and high (n=1) risk by the International Prognostic Scoring System (IPSS). All pts were transfusion-dependent and all had failed prior HMA and 24% lenalidomide. Steady-state PK exhibits increasing drug plasma concentration with dose comparable to pts with solid tumors. The ANC PD marker exhibited a dose-dependent decrease from baseline (ΔANC) that plateaued in the 200 and 400 mg dose cohorts consistent with maximum receptor inhibition (Table). Marrow MDSCs and LSCs were reduced after initiation of SX-682. SX-682 was well-tolerated with no maximally tolerated dose and no pt discontinued treatment for adverse events. Treatment-emergent adverse events > grade 3 were most common in the 200 and 400 mg dose cohorts, and those related to neutrophils are consistent with being related to SX-682. Effects on neutrophils reversed on cessation of drug dosing. There was a dose-dependent increase in overall response rate (ORR) from 0% at 25 mg BID to 50% at 200 mg BID consistent with the observed clinical benefit being related to CXCR1/2 inhibition by SX-682 (Table). Four of the five responders had mutant genes (MGs) involving splicing factors (60% of responders; SF3B1, SRSF2) and/or epigenetic regulation (60% of responders; TET2, ASXL1, IDH2). Across all dose cohorts, 8 of 17 (47%) pts had a reduction in marrow blasts after initiating SX-682 (Figure). The 200 mg dose yielded the most rapid and deep reduction in blasts with 2 of 6 pts (33%) achieving a marrow complete remission (mCR) in keeping with this dose providing maximum receptor inhibition. There was hematologic improvement (HI) in 3 pts with one having a durable near-CR response (on SX-682 >500 days) consisting of trilineage HI (hemoglobin > 10 g/dL) and transfusion independence for over 4 months (pt required 16 transfusions in the 7 weeks before starting SX-682 therapy). Based on ANC PD, ORR and marrow blast responses, the 200 mg BID dose was selected for the expansion phase of the trial. Conclusions: SX-682 is a novel therapy in HMA failure MDS with dual activity against LSCs and MDSCs. SX-682 was well tolerated with encouraging efficacy with a biologically effective oral dose selected at 200 mg BID. An expansion cohort in both lower and higher risk MDS pts is ongoing and will additionally include HMA naïve patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Itacitinib and Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease: Phase 1/2 Results from Gravitas-309

Background: Itacitinib is a potent, selective oral Janus kinase (JAK) 1 inhibitor with broad anti-inflammatory activity. GRAVITAS-309 was designed as a 2-part, multicenter, randomized trial to assess the efficacy and safety of itacitinib in combination with corticosteroids (CS) as first-line treatment for moderate or severe chronic graft-versus-host disease (GVHD). We describe preliminary results from the open-label, dose-finding portion of the study. Methods: The study initially investigated itacitinib at doses of 200 mg once daily (qd; n=11) and 300 mg qd (n=10) in combination with CS. Both doses were well tolerated. The trial was then expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300-mg qd cohort was expanded, and a CS monotherapy cohort was added (Figure 1). The expected CS starting dose was 0.5-1 mg/kg per day prednisone (or methylprednisolone equivalent) with a dose taper initiated on Day 14 or earlier during the second week of treatment and following published recommendations (Flowers and Martin. Blood. 2015;125[4]:606-15). Itacitinib dosage was initially reduced by 100 mg when given concomitantly with a strong CYP3A4 inhibitor (sCYP3A4i; eg, azole antifungals). A total of 140 patients (pts) (35/treatment group) with moderate or severe chronic GVHD were to be randomized 1:1 using chronic GVHD risk status (moderate vs severe) as a stratification factor. The primary objective was to identify the appropriate dose and schedule of itacitinib for further development. The data cutoff was January 31, 2022. Results: 103 pts were enrolled and received at least one dose of itacitinib. The cohorts were well balanced for pt and disease characteristics. Median age was 57 years (range, 23-76) for the itacitinib cohorts and 59 years (range, 28-75) for the CS cohort. Approximately two-thirds of pts had moderate chronic GVHD. At the time of data cut, 39 (38%) pts in the itacitinib cohorts and 10 (28%) pts in the CS cohort continued study treatment. Median duration of study treatment was 27-28 weeks for the itacitinib cohorts (including 13-16 weeks of concomitant CS) and 17 weeks for the CS cohort. The itacitinib 300-mg bid dose cohort was discontinued early due to malignancy relapse occurring in 4/29 (14%) pts and more pts requiring dose reductions compared with the 400-mg qd and 300-mg qd cohorts (28% vs 17% and 8%, respectively), mostly due to cytopenias. Incidence of grade ≥3 treatment-emergent adverse events (AEs) was higher in the itacitinib cohorts than with CS (65% vs 31%) and were reported most commonly in the system organ classes of infections (44% vs 6%) and blood and lymphatic system disorders (23%-34% vs 6%). Cytomegalovirus (CMV) infections occurred in 10%-15% of pts in itacitinib cohorts (including CMV pneumonia [n=3], esophagitis [n=1], enteritis [n=1]) vs 3% with CS. The all-cause mortality rate was 14%-18% in itacitinib cohorts vs 11% with CS, with infections the leading cause. The overall response rate (ORR) at 6 months was 46% (complete response [CR], 14%) with 300-mg qd and 53% (CR, 32%) with 400-mg qd, vs 36% (CR, 18%) with CS. A preliminary exposure-response analysis showed a bell-shaped curve with maximum efficacy decreasing at higher exposures, consistent with increasing incidence of AEs. 60%-70% of patients received coadministration with a sCYP3A4i at any time point during study treatment, which increased itacitinib exposure across all doses, requiring dose reduction by 200 mg qd. Conclusion: Preliminary results for first-line treatment of moderate or severe chronic GVHD showed an increase in ORR and CR rate with itacitinib + CS vs CS alone in both the 300-mg qd and 400-mg qd cohorts, at the expense of increased rates of cytopenias, infections, and mortality. This benefit:risk ratio does not support moving the combination of itacitinib + CS to a later phase of development in first-line therapy of chronic GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Суррогатные конечные точки при платинорезистентных рецидивах рака яичников

Background: overall survival (OS) is the gold-standard primary end point for cancer clinical trials to evaluate the outcome of therapy. However, in some cases the direct assessment of OS can be inappropriate. Therefore, various surrogate endpoints, such as overall response rate (ORR) and progression-free survival (PFS), are used commonly in clinical trials. Aim: to assess the relevance of mentioned endpoints in platinum-resistant recurrent ovarian cancer. Patients and Methods: we used PubMed queries to search for all ovarian cancer studies from 01/01/2000 to 07/01/2019. Key inclusion criteria were: 1) recurrent epithelial ovarian cancer, 2) platinum-free interval ≤6 months, 3) standard chemotherapy (CT) without targeted and/or experimental drugs, 4) reported objective response rate, PFS and OS, as well as response assessment criteria. Correlation and linear regression analysis were conducted to identify the relationship between various markers of therapy efficacy. Trials were weighted according to the number of enrolled patients. Statistical analysis of the data was performed using R and RStudio software. Results: 7156 studies were reviewed, and 157 studies meeting the inclusion/exclusion criteria were selected. PFS and OS data were available in 104 (n=5081) and 99 (n=5089) studies, respectively. The average ORR was 17.2% (non-platinum CT — 13.6%, platinum-based CT — 36.7%; p<0.001), and median PFS was 3.68 months (3.38 and 5.37 months, respectively; p<0.001). A significant correlation was found between ORR and PFS (r=0.62; p<0.001). Linear regression analysis identified 0.5 months increase in median PFS for every 10% increase in ORR (p<0.001). There was no significant correlation between ORR and OS. Conclusions: the meta-analysis results provide valuable information for understanding the role of surrogate biomarkers in platinum-resistant recurrent ovarian cancer. ORR is a reliable predictor of PFS in this patient population. KEYWORDS: ovarian cancer, platinum resistance, chemotherapy, surrogate endpoints, systematic review, meta-analysis. FOR CITATION: Rumyantsev A.A., Tyulyandina A.S., Israelyan E.R. et al. Surrogate endpoints in platinum-resistant recurrent ovarian cancer. Russian Medical Inquiry. 2022;6(6):319–325 (in Russ.). DOI: 10.32364/2587-6821-2022-6-6-319-325

The Clinical Efficacy and Safety of Neratinib in Combination with Capecitabine for the Treatment of Adult Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) positive cancers account for 15–20% of all breast tumors. Several drugs have been approved in the metastatic setting, including monoclonal antibodies, tyrosine kinase inhibitors (TKI) and, more recently, antibody-drug conjugates. Neratinib is a pan-HER, irreversible TKI with potent preclinical activity against trastuzumab-resistant breast cancer models. Based on Phase I and II clinical trials, the combination of neratinib plus capecitabine was compared to lapatinib and capecitabine, an established regimen for trastuzumab-resistant disease, in the randomized, Phase III NALA trial. In this trial, neratinib yielded increased progression-free survival, response duration and a benefit in time to intervention for CNS progression. However, there was no overall survival benefit, no increase in overall response rate and no improvement in QoL. The most frequent adverse event in the neratinib arm was diarrhea, which was manageable with prophylactic treatment with loperamide. Conclusion: Neratinib is a valuable addition to the therapeutic armamentarium to treat metastatic, HER2-positive breast cancer. The current positioning of the combination of neratinib and capecitabine based on the results of the NALA trial needs to consider the rapidly evolving scenario due to the recent introduction of new drugs, like the pure-HER2 TKI tucatinib and the antibody drug-conjugate trastuzumab-deruxtecan.

Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)

Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)

Effects of Micro-Ecological Enteral Nutrition on Systemic Inflammatory Response, Bacterial Translocation, and Immune Function in Patients with Severe Acute Pancreatitis

We have evaluated the effect of early and late micro-ecological enteral nutrition on systemic inflammatory response, bacterial translocation, and immune function in patients with severe acute pancreatitis. Two weeks after treatment, experimental group receiving early nutritional intervention exhibited a significant increase in intestinal lactobacilli and bifidobacteria, fewer staphylococci, and E. coli, and lower levels of serum endotoxin, D-lactic acid, and diamine oxidase than the group receiving late intervention (control group) (P < 0.05). Also, the serum levels of CD3+ and CD4+ and CD4+/CD8+ ratio significantly increase after 2 weeks of intervention. On the other hand, the level of CD8+ and the Acute Physiology and Chronic Health Evaluation II and Modified Computed Tomography Severity Index scores significantly decreased after 2 weeks of treatment (P < 0.05). The early intervention also led to a significant shortening of time needed for abdominal pain relief, anal exhaustion, resumption of peristaltic sound, and hospitalization. Furthermore, there was a significant increase in overall response rate, and decrease in the incidence rate of complications (P < 0.05). Early micro-ecological enteral nutrition therapy can effectively relieve systemic inflammatory response, prevent intestinal bacterial translocation, restore the function of intestinal mucosal barrier, and alleviate nutritional imbalance in severe acute pancreatitis patients leading to improved immune function, mitigation of the disease, and reduced complications benefiting the recovery of patients.

The DIAL Study (Dual Immunomodulation in Aggressive Lymphoma): A Randomized Phase 2 Study of CDX-1127 (Varlilumab) in Combination with Nivolumab in Patients with Relapsed or Refractory Aggressive B-Cell Lymphomas (NCI 10089 / NCT03038672)

Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced aggressive B cell non-Hodgkin lymphoma (B-NHL). Sponsored by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation in the context of T cell receptor (TCR) engagement through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion in pre-clinical models. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies (NCT01460134). We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using immunohistochemistry (IHC), mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry (IMC), and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients are randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered (NCT03038672) and open to participation to members of the Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP). Figure Disclosures Tun: BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding. Bartlett:Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Immune Design: Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding; Gilead: Research Funding. Kline:Merck: Honoraria; Merck: Research Funding. Awan:Janssen: Consultancy; Gilead: Consultancy; Sunesis: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau. Lazaryan:Kadmon: Consultancy. Ansell:Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding.

The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. a Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Recurring mutations have been identified in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) which translate to therapeutic targets. Isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations occur in ~20% of AML, and up to 12% of patients with MDS. Three conserved mutational hotspots in the IDH enzymes alter their function and lead to the production of (R)-2-hydroxyglutarate (2HG), an oncometabolite with numerous downstream effects, including impaired DNA damage repair. Specifically, homologous recombination (HR) is impaired by inhibiting the function of histone demethylases that are critical for HR and recruitment of the HR machinery to sites of DNA damage. In HR deficient tumors poly-ADP ribose polymerase (PARP) enzymes mediate a key salvage pathway. PARP inhibition in HR deficient tumors leads to synthetic lethality via simultaneous inhibition of HR and SSB mediated DNA repair. Our group previously demonstrated synthetic lethality with PARP inhibition in IDH mutant cells lines, and other IDH mutant models including primary patient-derived cell lines and genetically-matched tumor xenografts. Study Design and Methods: The PRIME trial (NCI10264) is a proof of concept, biomarker-driven, multi-institution, phase II open label clinical trial to assess the overall response of IDH1/2 mutant relapsed/refractory AML and MDS to PARP inhibitor monotherapy with olaparib. The clinical trial is executed by the Experimental Therapeutics Clinical Trials Network of the NCI. The Cancer Therapy Evaluation Program will provide olaparib. Eligibility criteria include documented IDH1 or IDH2 mutation in blood or bone marrow within 30 days of enrollment based on mutational testing by PCR or sequencing in a CLIA certified laboratory and willingness to undergo a bone marrow biopsy. Patients will be treated with olaparib 300 mg q12hrs each day of a 28-day cycle, using a tablet formulation, until disease progression, unacceptable toxicity, withdrawal of consent or death. Blood and bone marrow samples for 2-HG analysis will be collected prior to starting therapy and after 1 cycle (28 days), cycle 2, 3, 6, 9, 12 or when there is concern for disease progression (Figure 1). A Simon two-stage optimal design will be used to test the null (ORR=10%) versus the alternative hypothesis (ORR=40%) in each arm. In the first stage, 9 patients will be accrued in each arm. If one or fewer responses are observed in these 9 patients, that arm will be stopped early for futility. Otherwise, 11 additional patients will be accrued for a total of 18 in each arm. We reject the null hypothesis if at least 5 responses are observed in these 20 patients. In each arm, we have approximately 90% power to detect a 30% increase in ORR at a one-sided type I error rate of 0.05. Primary endpoint: Overall response rate (ORR) of 40%, i.e., a 30% ORR improvement (40% vs. historical control ORR = 10%) based on MDS International Working Group 2006 criteria and AML MDS International Working Group 2003 criteria after 6 cycles of treatment. Cumulative ORR will include complete remission, complete remission with incomplete blood count recovery, partial response, and bone marrow complete remission. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up) and overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) for the trial. Exploratory studies: The PRIME trial will also test the utility of 2-HG and DNA damage markers such as γ-H2AX as potential biomarkers of response to olaparib. Using multiple viability assays on leukemia cell lines and bone marrow cultures we will assess synergistic therapeutic combinations to further improve outcomes in this patient population. To confirm efficacy in vivo without undue toxicity, promising combination therapies will be confirmed in cytokine-humanized immunodeficient "MISTRG" mice. We will also examine the impact of PARP inhibitors on the genomic, proteomic, metabolomic and immunologic landscape of IDH 1/2-mutant hematologic malignancies using DNA whole exome sequencing (WES), RNA-Seq, and liquid chromatography-mass spectrometry assessment of oncometabolites. Disclosures Bindra: Cybrexa: Consultancy, Equity Ownership. Prebet:pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; novartis: Honoraria; Genentech: Consultancy; Boehringer Ingelheim: Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; Agios: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria. OffLabel Disclosure: We will be using PARP inhibitors as a novel therapy for patients with relapsed or refractory AML and high risk MDS based on preclinical data.

482P - Tislelizumab exposure-response analyses of efficacy and safety in patients with advanced tumors

BackgroundTislelizumab, an investigational humanized IgG4 monoclonal antibody, was engineered to minimize binding to FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Tislelizumab exposure-response (E-R) relationships for efficacy and safety endpoints in subjects with advanced tumors were evaluated to inform the benefit-risk assessment and to explore the feasibility of alternative dosing schedules. MethodsThe analyses used data from patients with advanced solid tumors (n=745) and classical Hodgkin lymphoma (cHL, n=70) from three clinical studies who received tislelizumab doses ranging from 0.5 to 10mg/kg (including current recommended dose of 200mg Q3W). E-R efficacy analyses were performed for overall response rate (ORR) and E-R safety analyses were performed for immune-related adverse events (irAEs), infusion-related AEs, and AEs ≥ grade 3, AEs leading to dose modification, and drug discontinuation using logistic regression models. Impact of tumor type on E-R efficacy and safety analyses were also investigated. ResultsE-R analysis indicated that there was slight trend for increase in ORR in solid tumors with steady-state maximum concentration, minimum concentration and average concentrations over the dose range tested. However, the increase in ORR over the exposure range was not considered to be clinically significant. Tislelizumab exposure was not associated with ORR in cHL patients. No E-R relationships were observed for safety endpoints irAEs, infusion-related AEs, AEs ≥ grade 3, AEs leading to drug discontinuation or dose modification among tumor types. Predictions with an alternate dose regimen of 400mg Q6W showed that clinically significant differences in ORR and safety were not expected, compared with 200mg Q3W. ConclusionsThere was a lack of clinically significant E-R relationships for ORR and safety endpoints across a variety of advanced solid tumors and cHL for tislelizumab. These findings support the current dose regimen of 200mg Q3W and further clinical testing of alternative dosing schedules that produce comparable exposure (eg, 400mg Q6W). Clinical trial identificationBGB-A317-Study-001: NCT02407990 BGB-A317-203: NCT03209973 BGB-A317-102: CTR20160872. Legal entity responsible for the studyBeiGene, Ltd. FundingBeiGene, Ltd. DisclosureC-Y. Wu: Full / Part-time employment: BeiGene, Ltd. N. Budha: Full / Part-time employment: BeiGene, Ltd. H. Castro: Full / Part-time employment: BeiGene, Ltd. A. Nkobena: Full / Part-time employment: BeiGene, Ltd. Y. Ben: Full / Part-time employment: BeiGene, Ltd. Sahasranaman: Full / Part-time employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

The DIAL Study (Dual Immunomodulation in Aggressive Lymphoma): A randomized phase 2 study of CDX-1127 (varlilumab) in combination with nivolumab in patients with relapsed or refractory aggressive B-cell lymphomas (NCI 10089/NCT03038672).

TPS7570 Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced B cell non-Hodgkin lymphoma (B-NHL). Developed by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies. We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using IHC, mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry, and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients will be randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered and open to participation to members of ETCTN and EDDOP. Clinical trial information: NCT03038672.

Efficacy of Lenalidomide Based Three Drug Versus Two Drug Regimen for Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis of Randomized Trials

Introduction:Survival of patients with multiple myeloma (MM) has improved over the last decade, mainly due to advent of newer drugs, three drug based induction, high dose chemotherapy consolidation and routine use of maintenance therapy for eligible patients. Despite advances in therapy, many cases of MM ultimately relapse and there is need to summarize evidence comparing efficacy and clinical outcome of combination regimens used in relapsed or refractory MM (RRMM) treatment. We performed a systematic review and meta-analysis of randomized controlled trials to compare the efficacy of lenalidomide based three drug regimens versus two drug regimens among relapsed and refractory myeloma (RRMM) patients.Methods:We conducted a literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov which was completed on March 26, 2018. We used keywords like “relapsed multiple myeloma”, “revlimid”, “dexamethasone”, “elotuzumab”, “carfilzomib”, “bortezomib”, “ixazomib”, “daratumumab”, “doxorubicin”, “pembrolizumab”, “thalidomide”, “cyclophosphamide” along with MeSH and Emtree terms. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel method. It was used to calculate pooled risk ratio of objective response rates with 95% confidence interval. Cochrane Collaboration's tool was used for quality assessment of included studies. Systematic reviews, meta-analyses, combination regimen without lenalidomide, newly diagnosed MM patients, and other plasma cell dyscrasias were excluded.Results:Literature search retrieved 11,362 titles. Following initial screening, 72 articles were considered for full text review. Of these only five studies with 2844 patients met inclusion criteria and two studies qualified for meta-analysis. The study arm used daratumumab (Dara), ixazomib, carfilzomib, or elotuzumab in combination with lenalidomide (Len) and dexamethasone (Dex). The control arm used combination of Len and Dex (LenD). There was no difference in overall response rate (ORR) between ixazomib-Len-Dex regimen versus LenD (RR=1.33, 95% CI = 0.83 to 2.17, p= 0.236). However significantly higher complete response (CR) was observed in ixazomib-Len-Dex group compared to LenD (RR = 1.82, 95% CI = 1.14 to 2.93, p = 0.013). An absolute increase in ORR among carfilzomib-Len-Dex, elotuzumab-Len-Dex, and daratumumab-Len-Dex versus LenD was 20.4% (87.1% vs. 66.7%, p <0.001), 13% (79% vs 66%, p <0.001) and 16.5% (92.9% vs. 76.4%, p <0.001) respectively.Conclusion:Daratumumab and carfilzomib in Len based three drug regimens have better clinical efficacy when compared to lenalidomide and dexamethasone based two drug regimens among relapsed and refractory multiple myeloma patients. There was no difference between the ORR of ixazomib based combination regimen and LenD but higher number of patients achieved deeper responses. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MODERN STRATEGIES FOR TREATMENT OF PATIENTS WITH BRAIN METASTASES

Brain metastases are the most common intracranial malignancy accounting for significant morbidity and mortality in cancer patients. The current treatment paradigm for brain metastasis depends on patient’s overall health status, the primary tumor pathology and the number and location of brain lesions. Treatment of brain metastases should be individualized for each patient: in case of single brain metastasis surgery or radiosurgery should be considered as first options of treatment; in case of multiple lesions whole-brain radiotherapy is the standard of care in association with systemic therapy or surgery/radiosurgery. Herein, we review the modern management options for these tumors including surgical resection, radiotherapy. In the last decades TKIs or monoclonal antibodies have showed an increase in overall response rate and overall survival in Phase II-III trials. The aim of this paper is to make an overview of the current approaches in management of patients with brain metastases.

Nursing Implications for Patients with Relapsed and/or Refractory Multiple Myeloma Receiving Combination Therapy with Daratumumab (Darzalex™) and Lenalidomide

November 21, 2016, the United States Food and Drug Administration (FDA) approved DARA in combination with lenalidomide and dexamethasone (DRd). The POLLUX clinical trial has demonstrated an increase in overall response rate from 76% to 93% and an increase in the percentage of patients who experienced a complete response from 19% to 43% when DARA was added to lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone.

RNA Sequencing of Newly Diagnosed Multiple Myeloma to Identify a Predictive Signature for Proteasome Inhibitor-Based Therapy

A major challenge in modern myeloma management is the selection of the best initial treatment from a plethora of available therapies. PAD (bortezomib, doxorubicin, and dexamethasone) is a highly effective regimen which may obviate the need for an upfront high-dose melphalan stem cell transplant (HDSCT). However, it is not clear a priori which patients will benefit from this treatment. In the phase 2 PADIMAC trial, patients with newly diagnosed myeloma were treated with six cycles of PAD and stratified to receive HDSCT in partial remission (PR) or watch and wait in very good partial remission (VGPR) or better. To identify predictive biomarkers, we extracted somatic RNA prior to treatment and performed massively parallel RNA sequencing (RNAseq).Basic quality control metrics suggested a high-quality RNAseq dataset. Furthermore, spiked expression of IgH fusion partners was consistent with fluorescent in situ hybridization (FISH) data for each sample. All t(4;14) and t(4;16) cases were correctly identified by RNAseq on the basis of the relevant fusion transcript. As a final quality control measure, recurrent variants (e.g. NRAS, KRAS, TP53, FAM46C, DIS3) were identified in the expected proportions.We performed a pre-planned analysis of differential gene expression between those patients achieving a VGPR or better, sustained for at least 12 months without HDSCT (excellent responders), and those patients who achieved less than a PR (poor responders). 85 genes were upregulated in poor responders and 225 in excellent responders. Interestingly, there was no significant overlap between our PAD-predictive signature and the Arkansas 70 gene poor prognosis signature, the Arkansas 17 gene poor prognosis signature, or the EMC92 prognostic signature. This is likely to reflect in part, the greater sensitivity of RNAseq for gene expression compared to microarrays. However, it also implies that there is a selective signature for PAD responsiveness.We employed the Gage and Pathview packages to identify non-redundant pathways associated with PAD responsiveness. Significantly upregulated genes in poor responders were those involved in: DNA replication, base excision repair, and the Fanconi anaemia pathway. Genes upregulated in excellent responders included those involved in: several signalling pathways (including RAS, NF-Kappa B, FOXO and JAK-STAT pathways); chemokine and cell adhesion; protein processing in the endoplasmic reticulum; and immune activation pathways such as T-cell receptor signalling and natural killer cell-mediated cytotoxicity.Finally, we investigated the ability of expression signatures to stratify patients on the basis of PAD responsiveness. Our analysis suggests that RNASeq-defined transcriptional profiles could aid in the selection of patients for PAD therapy (leading to an increase in overall response rate from 70% to 86%), as well as the stratification of patients in CR to a non-HDSCT protocol. We anticipate that our current analysis could easily incorporate specific response signatures for other regimens and could make personalized therapy for myeloma a reality in the foreseeable future. DisclosuresYong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Streetly:Guys and St. Thomas’ NHS Trust: Honoraria. Schey:Celgene, Takeda: Honoraria; Celgene: Consultancy; Celgene, Johnson & Johnson: Speakers Bureau. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria. Cook:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees.

Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort.

PurposeTreatment with pembrolizumab, an anti–programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) –positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported.Patients and MethodsPatients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses.ResultsOf 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1–positive versus –negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively.ConclusionFixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.

Neoadjuvant endocrine therapy for resectable breast cancer: A systematic review and meta-analysis

IntroductionThe role of neoadjuvant endocrine therapy for resectable breast cancer is not well established, despite encouraging results obtained in the metastatic and adjuvant settings. This systematic review aims to examine existing medical literature on neoadjuvant hormone therapy (HT). MethodsData from prospective, randomized trials was included if comparing neoadjuvant HT versus surgery alone without adjuvant treatment, or neoadjuvant HT versus chemotherapy (CT), or HT plus CT versus CT alone, or HT plus CT versus HT alone, or two distinct HT. Odds Ratios (OR) were calculated from pooled data. ResultsFive studies compared HT with tamoxifen versus HT with aromatase inhibitors (AI). A meta-analysis of their results demonstrated superiority of AIs in overall response rate (ORR) (OR 1.9; 95% CI 1.17–3.08). Two trials compared HT against CT, and pooled data from them demonstrated a trend favoring CT (OR for ORR 0.75; 95% CI 0.35–1.6). That trend disappeared when only postmenopausal women were considered (OR 1.01; 95% CI 0.62–1.63). One trial compared HT plus CT with no neoadjuvant treatment, and obtained an 83% ORR. One trial compared HT plus CT versus CT alone and found a non-significant increase in ORR for adding HT to CT (OR 1.48; 95% CI 0.58–3.77). No trial compared HT plus CT versus HT alone. ConclusionsNeoadjuvant HT is a safe and feasible option, but it cannot be considered equivalent to CT. If neoadjuvant HT is performed, AIs are preferable over tamoxifen due to higher response rates.

Brain metastases: an overview.

So far brain metastases represent a critical stage of a disease course and the frequency is increasing over the years. The treatment of brain metastases should be individualized for each patient: in case of single brain metastasis, surgery or radiosurgery should be considered as first options of treatment; in case of multiple lesions, whole-brain radiotherapy is the standard of care in association with systemic therapy or surgery/radiosurgery. Chemotherapy should be considered when surgery or radiation therapy are not possible. In the last decades, TKIs or monoclonal antibodies have shown increase in overall response rate and overall survival in Phase II-III trials. The aim of this paper is to make an overview of the current approaches in management of patients with brain metastases.