Single-agent Maintenance Therapy Research Articles

TRLS-07. PNOC016: INTRATUMORAL PHARMACOKINETICS AND PHARMACODYNAMIC (PK/PD) RESULTS FROM A TARGET VALIDATION STUDY OF A NOVEL PAN-HDAC AND PI3K INHIBITOR, FIMEPINOSTAT, IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG), RECURRENT MEDULLOBLASTOMA (MB), AND RECURRENT HIGH-GRADE GLIOMA (HGG)

Abstract BACKGROUND An intact blood-brain barrier is a limitation to effective therapies for pediatric brain tumors. PNOC016 investigated the tumor penetration of an orally available, promising pan-HDAC and PI3K-inhibitor, fimepinostat, in high-risk pediatric brain tumors, including DIPG, MB, and HGG. Fimepinostat is active as a primary drug and via its metabolite, M2, which exhibits PI3K inhibition. METHODS Patients between 3 and 39 years old with newly diagnosed DIPG (stratum A), recurrent MB (stratum B), or recurrent HGG (stratum C) were eligible. Disease-based strata enrolled independently up to 10. Patients received 3 neoadjuvant doses before standard-of-care resection/biopsy and underwent tissue collection for PK/PD analysis. Patients continued single-agent maintenance therapy for up to 12 months with ongoing collection of circulating tumor DNA (ctDNA) from blood, quality of life (QOL) measures, survival, and response outcomes. RESULTS Thirty-one patients enrolled between August 2019 and August 2022 (n=1 replaced due to disease progression before treatment started). All patients with completed PK analysis had detectable fimepinostat (n=18), metabolite M1 (n=23), or metabolite M2 (n=24) in tumor. Median intratumoral levels of fimepinostat, M1, and M2 (nM) by stratum were as follows: stratum A-2.6, 4.9, 28.3; stratum B-9.5, 6.5, 32.4; stratum C-9.9, 10.7, 15.9. The lowest intratumoral levels were seen in stratum A. Pre-surgical blood PK positively trended with intratumoral PK. Phosphorylation and acetylation PD analyses are underway. The most common grade 3 or above related adverse events were hematologic, with platelet decrease being the most frequent (n=9). Median OS from the diagnosis for stratum A was 13 months. PFS from surgery for stratum B and C was 3 and 3 months. CONCLUSION Fimepinostat crossed the blood-brain barrier in newly diagnosed DIPG and recurrent MB and HGG. PD assessment is underway to correlate PK with biological effects. PD correlation, survival analyses, ctDNA, and QOL will be presented.

Dose Titration of Ixazomib Maintenance Therapy in Transplant-Ineligible Multiple Myeloma: Exposure-Response Analysis of the TOURMALINE-MM4 Study.

Ixazomib has been approved in several countries as single-agent maintenance therapy in newly diagnosed multiple myeloma, in both posttransplant and transplant-ineligible settings, based on two phase III studies. In these maintenance studies, patients were initially administered 3 mg ixazomib, escalating to 4 mg if the initial dose level was well tolerated through Cycles 1-4. Here, we report the results of exposure-response analyses of TOURMALINE-MM4, wherein relationships between exposure and clinical response, dose adjustments, and selected adverse events were evaluated. Similar progression-free survival benefits were observed across the range of ixazomib exposures achieved in the study. Moreover, increased ixazomib exposures corresponded to a higher probability of maintaining complete response. Exposure was not a significant predictor (P > 0.05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy; however, higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue. While ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) were correlated with a reduced likelihood of escalating to the 4 mg dose. Thus, the dose titration approach balanced patient benefit and risk; it ensured that only patients for whom the 3 mg dose was safe/tolerable escalated to the higher dose, while maximizing the fraction of patients (85%) who were able to derive additional clinical benefit at 4 mg. Collectively, these results highlight the value of safety-driven personalized dosing to maximize patient benefit/risk.

Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer

To compare estimated survival times of patients who had received maintenance monotherapy with gemcitabine (GEM), or an immuno-oncology (IO) drug (i.e., pembrolizumab or avelumab) or both therapies (one after the other) following platinum-based combination chemotherapy for metastatic urothelial carcinoma (UC) in a real-world setting. For this retrospective study, we included consecutive patients with metastatic UC who had received first-line platinum-based chemotherapy followed by second-line treatment at our centre from March 2008 to June 2020. Of the 74 patients identified, 58 had received monotherapy as second line treatment, and 16 had received combination chemotherapy (i.e., non-monotherapy). The estimated median duration of survival was significantly longer in the monotherapy group compared with the non-monotherapy group (29 vs 7 months). Multivariate analysis showed that the outcome of the first-line chemotherapy treatment was the most important prognostic factor for survival. There was no significant difference in survival times between monotherapy with GEM or IO drugs. In addition, survival was significantly prolonged when GEM therapy was administered following IO drugs compared with GEM therapy alone. Monotherapy following primary chemotherapy for advanced UC significantly prolonged survival times, and IO drug therapy remained effective when followed by GEM single agent maintenance therapy.

Early Response Assessment in Advanced Stage Melanoma Treated with Combination Ipilimumab/Nivolumab.

BackgroundStandard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma followed by nivolumab single-agent maintenance therapy. While many patients receive less than 4 doses due to immune-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and assess if fewer doses of I/N can lead to similar survival outcomes.MethodsWe performed a retrospective analysis on a cohort of patients with advanced melanoma who w0ere treated with standard I/N. Cox regression of progression-free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 1 or 2 vs 3 or 4 doses of I/N adjusted by known prognostic variables in advanced melanoma.Results199 patients were evaluated. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.16, 95% CI 0.08-0.33; p<0.001) and OS (HR: 0.12, 0.05-0.32; p<0.001) compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.09, 0.05-0.16; p<0.001) and OS (HR: 0.07, 0.03-0.14; p<0.001). There was no survival risk difference comparing 1 or 2 vs 3 or 4 doses of I/N for PFS (HR: 0.95, 0.37-2.48; p=0.921) and OS (HR: 1.04, 0.22-4.78; p=0.965).ConclusionsEarly interval imaging with response during induction with I/N may be predictive of long-term survival in advanced stage melanoma. CBR after 1 or 2 doses of I/N is associated with favorable survival outcomes, even in the setting of fewer I/N doses received. Further studies are warranted to evaluate if electively administering fewer combination I/N doses despite tolerance in select patients may balance the benefits of therapy while decreasing toxicities.

Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031.

High allelic ratio (HAR) FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population. Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients. The maximum tolerated dose of sorafenib was 200 mg/m2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, P = .010). Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.

Midostaurin Plus Intensive Chemotherapy for Younger and Older Patients with Acute Myeloid Leukemia and FLT3 Internal Tandem Duplications

Midostaurin Plus Intensive Chemotherapy for Younger and Older Patients with Acute Myeloid Leukemia and FLT3 Internal Tandem Duplications

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Chidamide Maintenance Therapy after Induction or Salvage Treatment in Patients with Peripheral T-Cell Lymphoma Ineligible for Autologous Stem Cell Transplantation

BackgroundPeripheral T-cell lymphoma (PTCL) is a set of rare and heterogeneous clinically aggressive mature T- and natural killer cell neoplasms, all of which are associated with poor prognosis. PTCL treatments are usually associated with a high failure rate and frequent relapses. To improve the poor clinical outcomes of PTCL, novel agents that target various pathways have been intensively studied and developed. Histone deacetylase (HDAC) inhibitors are among the most significant improvements made in recent years. Chidamide, a novel benzamide class of HDAC inhibitor, showed significant efficacy in relapsed/refractory PTCL patients in previous studies. In China, a high percentage of PTCL patients are elderly and not suitable for transplantation, and many patients cannot afford transplantation. There is an urgent medical need for maintenance therapy for PTCL patients, and chidamide single-agent maintenance therapy may benefit PTCL patients ineligible for autologous stem cell transplantation (ASCT) with its proven outstanding antitumor effects.MethodsIn this prospective, single-center, single-arm study, a total of 43 patients with PTCL, including angioimmunoblastic T-cell lymphoma (AITL) (44.2%), anaplastic large-cell lymphoma, ALK − (ALCL, ALK −) (11.6%), PTCL-not otherwise specified (PTCL-NOS) (14.0%), extranodal NK/T-cell lymphoma (NKT) (16.3%), and other PTCL subtypes (14.0%), were enrolled from January 2016 to March of 2021. All patients were ineligible for transplantation. They had a median age of 59 years (22-80). Thirty-six patients (83.7%) received chidamide maintenance after induction treatment, and 7 patients (16.3%) started chidamide maintenance treatment after salvage treatment. Endpoints included progress-free survival (PFS), overall survival (OS), and safety assessment.ResultsUntil April 2021, the median follow-up time was 10.1 months (2-64.5). The complete remission rate (CR) was 44.2% and overall response rate (ORR) was 79.1%. The median PFS was 24.3 m, and the 1-year PFS rate was 68.1%. The median OS has not yet been reached, and 1-year OS rate was 84.3%. Stratified analyses of PFS and OS showed no significant differences. Grade 3/4 adverse events were mainly hematological toxicities, including neutropenia, leukopenia, thrombocytopenia, and anemia, and they were well tolerated.When used a first-line/1.5-line treatment, i.e., for patients who had achieved CR after introduction treatment (12 cases) or who did not achieve CR but received chidamide + chemotherapy consolidation treatment (24 cases), chidamide maintenance therapy was found to maintain the effect of CR (in all 12 patients) or improve the clinical outcomes to CR/PR (partial remission) (9 out of the 24 patients). Even when used after salvage treatment, chidamide maintenance was found to achieve PR and better efficacy in 4 out the 7 patients.ConclusionsChidamide maintenance treatment achieved significantly high CR and ORR rates for PTCL patients. This therapy may improve PFS and OS with a manageable safety profile for PTCL patients. This treatment thus may benefit PTCL patients who are ineligible for or cannot afford ASCT, which is an especially severe problem in China. Further large-scale, multi-center, randomized studies are required to extensively examine the efficacy and safety of chidamide maintenance therapy in PTCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML

BackgroundOverall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial.Methods/DesignThis is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial statusProtocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st.Trial registrationClinicalTrials.govNCT04093505; EudraCT 2019-003913-32. Registered on October 30, 2018.

The efficacy and toxicity of maintenance therapy with bevacizumab plus pemetrexed versus bevacizumab/pemetrexed alone for stage IIIB/IV nonsquamous non-small cell lung cancer: A meta-analysis of randomized controlled trials.

Whether maintenance therapy with bevacizumab (Bev) + pemetrexed (Pem) can achieve greater clinical benefits than Bev or Pem alone for stage IIIB/IV nonsquamous non-small cell lung cancer (NSCLC) remains unclear. We assessed the antitumour effect and toxicity of maintenance Bev+Pem versus maintenance with single-agent Bev/Pem in this meta-analysis. Appropriate randomized controlled trials (RCTs) were screened using electronic databases (Google Scholar, PubMed, Embase, Scopus, ScienceDirect, Ovid MEDLINE, Cochrane and Web of Science). The endpoints were progression-free survival (PFS), overall survival (OS) and adverse events (AEs). We included six RCTs that contained 2,447 patients receiving induction therapy with platinum-based combination therapies. The maintenance therapy Bev+Pem group had prolonged PFS (HR=0.74, 95% CI 0.69-0.80, p<0.00001) and OS (HR=0.91, 95% CI 0.83-0.99, p=0.02) compared with the Bev/Pem group. Moreover, we further analysed the PFS rate (PFSR) and OS rate (OSR) and found that the Bev+Pem group exhibited improved PFSR-0.5y, PFSR-1y, PFSR-1.5y, PFSR-2y and OS-2y, with preferable trends in OS-1y, OS-3y and OS-4y compared with the Bev/Pem single-agent maintenance therapy. In addition, subgroup analyses indicated that the Bev+Pem group had greater PFS and OS among patients aged <65years, patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, and patients who never smoked. Regarding adverse events (AEs), the Bev+Pem group exhibited an increased occurrence of anaemia, fatigue, thrombocytopenia and anorexia. For stage IIIB/IV nonsquamous NSCLC patients, maintenance therapy with Bev+Pem offers an increased survival outcome (PFS, OS) compared with monotherapy. However, the increased incidence of AEs should not be neglected.

Concomitant Use of Midostaurin with Strong CYP3A4 Inhibitors: An Analysis from the Ratify Trial

Introduction: Midostaurin is an oral multikinase inhibitor with activity in FMS-like tyrosine kinase 3 (FLT3 )-mutated acute myeloid leukemia (AML), including internal tandem duplications and tyrosine kinase domain mutations. The phase 3, double-blind, placebo-controlled, randomized RATIFY/CALGB (Alliance) 10603 trial investigated the effect of midostaurin in combination with standard chemotherapy and as single-agent maintenance therapy on outcomes in patients with newly diagnosed FLT3 -mutated AML. When added to standard chemotherapy, midostaurin improved both event-free survival (EFS) and overall survival (OS) (Stone et al, N Engl J Med. 2017 Jun 23. [Epub ahead of print]). Midostaurin is metabolized into 2 metabolites (CGP62221 and CGP52421) by cytochrome P450 3A4 (CYP3A4). We evaluated the effects of strong CYP3A4 inhibitors on midostaurin exposure, activity, and safety based on clinical data from the RATIFY trial.Methods: Patients received placebo or midostaurin 50 mg twice daily on days 8 to 21 of each 28-day induction or consolidation cycle, followed by 50 mg twice daily as a single agent on days 1 to 28 during the 12-cycle maintenance phase. Concomitant medication use was recorded for patients throughout all 3 treatment phases (induction, consolidation, and maintenance). Plasma levels of midostaurin and its metabolites were measured in a subset of 188 patients. Data on grade ≥3 adverse events (AEs) were collected at all sites; all grade 1/2 AE data were collected by sites outside the United States while only 13 prespecified grade 1/2 AEs were recorded at North American sites. The effect of CYP3A4 on efficacy was assessed using multiple endpoints including complete response, EFS, and OS.Results: Concomitant medication use was balanced between the midostaurin and placebo groups. Strong CYP3A4 inhibitors concurrently administered most frequently were the antifungal medications posaconazole and voriconazole. Strong CYP3A4 inhibitors were used in 60.8%, 45.6%, and 10.8% of patients during induction, consolidation, and maintenance, respectively.A 1.44-fold increase in midostaurin exposure (Cmin) was observed in patients receiving coadministration of strong CYP3A4 inhibitors compared with patients not receiving strong CYP3A4 inhibitors (number of patients: n=55 vs n=112, respectively). No relevant effect was observed with CGP62221 and CGP52421. Because the protocol did not include any recommendations for dose modifications when strong CYP3A4 inhibitors were administered, the median relative dose intensity of midostaurin was >94% of the intended dose in both treatment arms. There was no notable increase in midostaurin-related AEs in patients receiving strong CYP3A4 inhibitors. Exposure-safety analyses showed a slightly shorter time to occurrence of grade 3 or 4 clinically notable AEs with increasing exposure, with an overall acceptable safety profile for midostaurin. Exposure-response analyses indicated that a higher dose intensity was associated with a larger benefit to patients, namely through complete response, EFS and OS. This observation was generally not affected by demographic covariates or presence/absence of CYP3A4 perpetrators during the cycle where the PK sample was used for the analysis.Conclusions: Overall, co-administration of midostaurin with strong CYP3A4 inhibitors, without midostaurin dose adjustment, led to a balanced safety and efficacy profile. Because strong CYP3A4 inhibitors can increase the plasma concentration of midostaurin, caution is required when concomitantly prescribing these with midostaurin. Alternative medicinal products that do not strongly inhibit CYP3A4 activity should be considered. In situations in which satisfactory therapeutic alternatives do not exist, patients should be closely monitored for midostaurin-related toxicity.Support: U10CA180821, U10CA180882, U24CA196171; ClinicalTrials.gov identifier, NCT00651261. DisclosuresOuatas:Novartis: Employment. Duval:Novartis: Employment. Sinclair:Novartis: Employment. Berkowitz:Novartis: Employment.

Primary Analysis of the Tegar Study: A Phase II Study Exploring the Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab or Rituximab in Patients with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), or Waldenstrom Macroglobulinemia (WM)

Primary Analysis of the Tegar Study: A Phase II Study Exploring the Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab or Rituximab in Patients with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), or Waldenstrom Macroglobulinemia (WM)

A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation–positive acute myeloid leukemia: the RADIUS-X expanded access program

Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation–positive acute myeloid leukemia, was based on the phase 3 RATIFY trial results. RADIUS-X (NCT02624570) was an expanded access program providing access to midostaurin during regulatory review and extending the understanding of the safety and tolerability of midostaurin. Patients aged ≥18 years received midostaurin with 1–2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of high-dose cytarabine consolidation chemotherapy or as single-agent maintenance therapy. The study enrolled 103 patients. No new safety events were observed; toxicities were not influenced by age, anthracycline choice, or coadministration of CYP3A4 inhibitors. The most common adverse events (AEs) were febrile neutropenia, nausea, and diarrhea. During maintenance, 46% of patients reported AEs. Midostaurin demonstrated a manageable safety profile and was associated with high transplant and low on-treatment relapse rates.

Abstract CT130: Evidence for synergistic immune responses in the first-in-human (FIH) combination of B cell-activating immunotherapy (IO) with anti-PD1 immune checkpoint inhibitor nivolumab (N) as 2nd-line therapy in patients (pts) with advanced non-small cell lung cancer (aNSCLC)

Abstract Introduction: While combined immunotherapeutic activation of B and T cells is predicted to synergistically enhance both humoral and cell-mediated immunity, this has not been previously tested in human cancer patients. To assess this, we conducted the FIH trial combining B cell-activating IO (CIMAvax-EGF (C)) with T cell-activating IO (PD-1 blockade with nivolumab (N)). C activates B cells to produce endogenous anti-epidermal growth factor (EGF) antibodies (Abs) that deplete EGF from circulation. As a single agent maintenance therapy in aNSCLC, C prolonged overall survival (OS) in a randomized phase III trial. We now present immune correlates of improved OS with this novel combination. Methods: We reported safety and preliminary efficacy data from 13 pts from the phase I study of C+N (AACR 2019). Serial blood samples were analyzed by Luminex for dynamic changes in circulating cytokines and proteins implicated in EGF signaling, and by flow cytometry for peripheral blood mononuclear cell immunophenotype. Cox regression analysis was used to analyze association with OS. Results: 71% of pts achieved anti-EGF Ab titers of &amp;gt;1:4000 after 3 doses of C, compared to historical controls of 39% with C alone. Baseline increase in CD8+ naive T cells, memory B cells, and decrease in MDSC and Th17 T cells all significantly correlated with better OS. Baseline increase of inflammatory cytokines/markers (IL7, IL15, IFNα, IL8, sCD40L and CRP) significantly correlated with worse OS. Despite enrichment for pts with tumor proportion score (TPS) PD-L1 0%, median OS (mOS) of the intent-to-treat population (pts who received at least 1 dose of C+N, n=13) was 13.7 months (mo) vs. 9.9 mo in Checkmate 057 aNSCLC pts with tumor proportion score (TPS) PD-L1 &amp;lt;10%. mOS of per-protocol pts (all 4 loading doses of C+N given over 8 weeks, n=11) was 18.5 mo. In contrast to Checkmate 057 results, where OS benefit of N favored aNSCLC with KRAS mutation (KRASm), C+N showed better mOS of 22.4 mo in EGFR/ALK/KRAS wildtype (wt) pts versus 12.3 mo in KRASm/STKwt pts. Conclusion: This study provides evidence for synergistic effects of combining B and T cell activating IO in aNSCLC pts. C+N generated higher anti-EGF titers in more pts at an earlier time point vs. C alone, which is the first demonstration in pts of enhancement of Ab responses by immune checkpoint blockade. Immune analysis identified new specific immune cell populations and inflammatory markers that significantly correlate with OS with C+N that have not been previously identified with C or N as single agents. C+N improved OS compared to historical controls of aNSCLC pts receiving N in phase III trials. Of particular note, C+N showed better OS in pts with EGFR/ALK/KRAS wt aNSCLC versus KRASm/STKwt pts. The Phase II portion of the study is ongoing. Citation Format: Tania Crombet, Jason Muhitch, Circe Mesa, Rachel Evans, Danay S. Hernandez, Patricia L. Luaces, Zaima Mazorra, Orestes Morales, Carlos Cedeno, Aileen Cinquino, Daniel T. Fisher, Kelvin Lee, Mary Reid, Grace Dy. Evidence for synergistic immune responses in the first-in-human (FIH) combination of B cell-activating immunotherapy (IO) with anti-PD1 immune checkpoint inhibitor nivolumab (N) as 2nd-line therapy in patients (pts) with advanced non-small cell lung cancer (aNSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT130.

Doublet vs Single-Agent Maintenance Therapy in the Treatment of Non-Small-Cell Lung Cancer: A Meta-Analysis.

BackgroundSeveral published meta-analyses have confirmed that single-agent maintenance therapy in advanced non-small-cell lung cancer (NSCLC) can prolong time to disease progression and potentially increase overall survival (OS) in comparison to placebo. However, whether doublet maintenance therapy can improve the survival of advanced NSCLC remains undetermined.MethodsWe searched several databases for relevant trials. Prospective randomized controlled trials comparing doublet vs single-agent maintenance therapy in NSCLC patients were included for analysis. Outcomes of interest were OS, progression-free survival (PFS), and incidence of grade 3/4 toxicities.ResultsA total of 1,950 advanced-NSCLC patients from six trials were included for analysis. Our results showed that doublet maintenance therapy in NSCLC patients significantly improved PFS (HR 0.74, 95% CI 0.59–0.93; P=0.010), but not for OS (HR 0.95, 95% CI 0.85–1.07; P=0.40) in comparison with single-agent maintenance therapy. Subgroup analysis by maintenance regimen showed that pemetrexed plus bevacizumab maintenance therapy significantly improved PFS, but not OS. In addition, there was no significant risk difference between doublet and single-agent maintenance therapy in terms of grade 3/4 hematologic and nonhematologic toxicities.ConclusionOur study suggests that doublet maintenance therapy in advanced-NSCLC patients demonstrates PFS benefits, but not OS benefits, in comparison with single-agent maintenance therapy. Future trials are suggested to assess the long-term clinical benefit of doublet maintenance treatment in NSCLC patients and its impact on health-related quality of life.

Sorafenib in Combination with Standard Chemotherapy for Children with High Allelic Ratio FLT3/ITD+ AML Improves Event-Free Survival and Reduces Relapse Risk: A Report from the Children's Oncology Group Protocol AAML1031

INTRODUCTION Sorafenib, a multi-kinase tyrosine kinase inhibitor (TKI) targets FLT3 internal tandem duplication (FLT3/ITD) mutations and has efficacy in adult FLT3/ITD+ AML. High allelic ratio (HAR) FLT3/ITD mutations (allelic ratio of &amp;gt; 0.4, referred to as FLT3/ITD+) confer poor prognosis in de novo pediatric AML. COG AAML1031 Arm C studied the feasibility and efficacy of adding sorafenib to standard chemotherapy and as a single agent maintenance therapy in pediatric HAR FLT3/ITD+ patients. METHODS The AAML1031 primary randomization (Arm A vs. B) has been previously reported (Aplenc et al. Blood 2016;128:899). Patients with FLT3/ITD+ AML were offered secondary enrollment on Arm C and toxicities were monitored on respective treatment arms. An initial safety phase (Cohort 1, C1; N=12) defined the maximum tolerated dose (MTD) of sorafenib when added to induction II chemotherapy and subsequent courses. Following completion, the study was amended (Cohort 2; C2) to start sorafenib on day 11 of induction I and concomitantly with chemotherapy in subsequent cycles. A year of sorafenib maintenance was also added. Due to concerns for cardiac toxicity on interim analyses, the study was amended (Cohort 3; C3) to initiate sorafenib after chemotherapy completion in all courses. Sorafenib pharmacokinetics (PK) and plasma inhibitory activity (PIA) were measured in a subset of patients. Clinical outcome analysis was limited to cohorts 2/3 given lack of induction I sorafenib exposure in C1. Arm C results were compared to N=34 HAR FLT3/ITD+ AML patients on the control arm of COG AAML0531 (Arm A), a group that received comparable chemotherapy without sorafenib. Complete remission (CR), event-free survival (EFS), overall survival (OS) and relapse risk (RR) of patients with HAR FLT3/ITD AML enrolled on the 2 trials were compared to assess the impact of sorafenib use. Cox proportional hazards were used for multivariable analyses. RESULTS In the dose finding phase (C1), 12 patient were enrolled and the MTD of sorafenib defined as 200 mg/m2; dose limiting toxicities included rash (N=2; 1 grade III, 1 grade II), grade II hand foot syndrome and grade III fever. For the evaluation of efficacy, 80 C2/C3 (C2: N=33, C3: N=47) patients were enrolled. 30/80 (37.5%) received at least 1 maintenance cycle; 20/80 (25%) completed all courses. As outcomes were compared to N=34 HAR FLT3/ITD+ AML patients enrolled on the preceding trial AAML0531 Arm A as a historical comparison, clinical characteristics were described for the 2 groups (Table 1). For AAML1031 C2/C3, rates of induction I CR were 73% vs. 56% for AAML0531 Arm A (p=0.078). Following induction II, CR rates were 91% and 70% respectively (p=0.007). 3 year EFS from study entry was 57.5% for Arm C vs. 34.3% for AAML0531 Arm A; (p=0.007) whereas 3 year OS from study entry was not significantly different (63.9% vs. 54.1%, p=0.375, Figure 1A). RR from CR was reduced with sorafenib treatment (Arm C 18.2% vs. historical 52.5%, p=0.006, Figure 1B). The improvement in EFS and RR observed with sorafenib was retained in those with wild-type nucleophosmin (NPM-) FLT3/ITD+ AML but lacked statistical significance compared to historical in NPM+ FLT3/ITD+ disease (Figure 2A/2B). As 21/34 (62%) patients in the historical control did not undergo HSCT there was concern that the improved outcome observed for Arm C reflected increased use of HSCT in AAML1031. Multivariable analysis that adjusted for HSCT resulted in significantly lower EFS and higher RR for FLT3/ITD+ patients on AAML0531, suggesting that increased use of HSCT on Arm C did not explain the improved outcomes observed (EFS: HR 2.04, CI 1.18 - 3.53; p=0.01, RR: HR 3.09, CI 1.28 - 7.49; p=0.012). While dose modifications were more frequent for FLT3/ITD+ patients on Arm C versus arms A/B of AAML1031, targeted toxicity rates were otherwise no higher (Table 2). PIA assays demonstrated median trough FLT3 inhibition of 92% (n=29, 95% CI 79-94%), 91% (n=84, 95% CI 87-94%) and 81% (n=70, 95% CI 76-90%) for induction I, induction II and intensification I, respectively. CONCLUSION Addition of sorafenib to Arm C of AAML1031 was safe and resulted in potent FLT3 inhibition, particularly early in therapy. Sorafenib improved rates of induction II CR as well as 3 year EFS and reduced RR from CR compared to historical controls. These data support use of sorafenib in pediatric patients with HAR FLT3/ITD+ AML. Disclosures Fisher: Pfizer: Research Funding; Astellas: Other: Data Safety Monitoring Board Chair for an antifungal study; Merck: Research Funding. Levine:Viracor: Patents &amp; Royalties: biomarker patent; Biogen: Other: non-financial support; Ironwood: Consultancy; Bluebird Bio: Consultancy; National Cancer Institute: Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Kamada: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. OffLabel Disclosure: sorafenib for high allelic ratio FLT3/ITD+ AML

Panobinostat As a Maintenance Therapy after Autologous Hematopoietic Cell Transplantation for Patients with Multiple Myeloma

Background: Autologous hematopoietic cell transplantation (HCT) followed by maintenance therapy with an immunomodulatory agent or a proteasome inhibitor remains an important strategy for upfront treatment in multiple myeloma (MM) with progression-free survival (PFS) and overall survival (OS) advantage. We designed a two-arm, open-label prospective study to examine the safety and tolerability of two different dosing schedules of an oral pan-histone deacetylase inhibitor, panobinostat (pano) as an alternative maintenance therapy option in patients with MM (NCT02722941). Methods: A total of 30 MM patients who underwent autologous HCT within the preceding 90 to 180 days were enrolled at Moffitt Cancer Center using a sequential alternating allocation to starting dose of either Cohort A: 20 mg PO 3/week, q 2 weeks on a 28-day cycle, or Cohort B: 10 mg PO daily for 7 days, q 2 weeks on a 28-day cycle, for 12 cycles. Dose level -1 was cohort A: 15 mg 3/week; and cohort B: 10 mg 4/week. Patients with clinically significant cardiac diseases, bradycardia, QTc &gt; 470 msec, bifascicular block were ineligible. EKG was performed on pre- and post-dose on day 1 &amp; 5 of cycle 1, and pre-dose on day 1 of cycles 2-4. Relative dose intensity (RDI), a ratio of amount of drug actually delivered in mg over the amount of planned dose in mg, was calculated to evaluate the treatment feasibility as a surrogate measure. Results: The median age of the entire cohort was 60 (range, 40-73) years with a male/female = 18/12. Disease characteristics are summarized in the Table. Patients initiated pano maintenance at a median of 131 (range 91 - 178) days after autologous HCT. As of 8/1/2019, 16 patients (8 in each cohort) completed full 12 cycles of pano. The RDI for the entire cohort, cohort A, and cohort B was 94.1% (33,750mg/35,860, 98% (16,350mg/16,680mg), and 90.7% (17,400mg/19,180mg), respectively. One patient in cohort A had dose reduction, and 6 patients in cohort B had dose reductions with cytopenias (43%) and GI toxicities (43%) being the most common reasons. No patients required dose modifications due to QT prolongation thus far. There were 3 possibly treatment-associated serious adverse events (pneumonia=2; colitis=1) but all patients successfully resumed pano. Three patients progressed while on pano maintenance. No mortality has been observed thus far. Ten patients are still on pano treatment. The median follow-up is 11 (range, 1-29) months. Conclusions: RDI is 90% overall and panobinostat as a single oral maintenance agent either at 20 mg three times per week or 10 mg po daily for 7 days on alternating weeks appears to be overall well tolerated. There were more dose reductions required in the 10 mg starting dose (cohort B). Panobinostat is a safe alternative for maintenance therapy after autologous HCT. Longer follow-up is needed to confirm the utility of this approach and updated results will be presented at the meeting. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Baz:Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shain:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Panobinostat single agent maintenance therapy after autologous hematopoietic cell transplantation for multiple myeloma

Comparison of bortezomib versus lenalidomide maintenance therapy in newly-diagnosed, transplant-eligible multiple myeloma: Results from the phase III GMMG-HD4 and -MM5 trials

Maintenance therapy (MT) in newly-diagnosed, transplant-eligible multiple myeloma (MM) is a standard of care. Comparisons of single agent MT from distinct substance classes are not available. The present retrospective study analyzed post-transplant MT for 2 years with either bortezomib (BTZ) or lenalidomide (LEN) from two subsequently conducted, multicenter phase III trials (HD4/MM5) of the German-speaking Myeloma Multicenter Group (GMMG). Patients and

The therapeutic effect of capecitabine single drug maintenance therapy in the advanced breast cancer

Objective: To analyze the efficacy of capecitabine (referred to as Cap) single-agent maintenance therapy in the advanced breast cancer. Methods: The subjects of the study were 50 patients with advanced breast cancer who were admitted to the hospital between March 2016 and March 2019. They were divided into groups A and B with 25 cases each. The subjects of these two groups were treated with Cap and conventional method, respectively to compare the efficacy. Results: The efficacy of group A was 96.0% compared to that of group B was 76.0%. The complication rate of group A was 12.0% compared to that of group B was 40.0% (P &lt; 0.05). Conclusion: The patients with advanced breast cancer who received Cap maintenance therapy were benefited from better curative effect and controllable complications, which has high promotion value.