Extension Of Progression-free Survival Research Articles

A randomized phase II study of apalutamide with or without carotuximab (ant-CD105) in metastatic, castration-resistant prostate cancer.

TPS5107 Background: CD105 (endoglin) is a co-receptor for the transforming growth factor-beta (TGF-β) receptor family. TGF-β signaling is activated in response to castration and is a determinant of PCa epithelial cell death in response to castration. In prostate cancer, silencing of TGF-ß receptor type 2 (Tgfbr2) in cancer-associated fibroblasts (CAF) potentiates tumor progression and castrate resistance primarily by paracrine signaling mechanisms mediated by the bone morphogenic protein (BMP)-SMAD axis. Upregulation of CD105 is observed in the face of progression through AR suppression and can drive pro-survival, pro-metastatic pathways BMP-SMAD signaling. This is accompanied with an increase in neural differentiation and the generation of AR-splice variants. In model systems, suppression of CD105-mediated signaling reversed these behaviors and resorted sensitivity to AR suppression. Carotuximab is a humanized monoclonal antibody that potently inhibits CD105-mediated signaling. It was originally developed for clinical use as an anti-angiogenic agent and was found to have an acceptable toxicity profile. Given our previous work, we hypothesized that use of CD105 will restore sensitivity to AR inhibition in men who have developed early resistance to an AR signaling inhibitor (ARSI) that would result in a synthetic lethality from combination treatment that will manifest as an extension of progression free survival when compared to ARSI therapy alone. Methods: This study (NCT05534646) is open to men with metastatic, castration-resistant prostate cancer who have progressed on previous ARSI therapy. Patients with recent thrombotic and/or cardiovascular events are excluded. Patients are allowed to have had prior docetaxel only in the setting of castration sensitive disease. The study includes a safety lead-in of 10 patients on combination therapy based on our previous work with carotuximab with other ARSI in NCT03418324. This will ensure that the probability of starting the phase 2 dose with a safe dose is sufficiently high. The study then proceeds to a (1:1) randomized study of apalutamide with or without carotuximab (n = 90). Patients randomized to apalutamide alone are permitted to cross over to combination therapy at the time of radiographic progression. The primary endpoint of the study is radiographic progression free survival (rPFS) and is designed to detect a 45% difference in rPFS in the two arms with 81% power and two-sided alpha of 0.10. This study also includes extensive correlative studies focusing on circuating tumor cells and extracellular vesicles which will be enriched and studies using novel nanotechnology enabled methodologies from our group as well as cell free DNA studies which will be used identify those patients with the greatest benefits from this form of therapy to expedite the development of this therapeutic approach. Clinical trial information: NCT05534646 .

1772P Characterisation of a DNA repair deficiency (DRD) biomarker phenotype in metastatic urothelial carcinoma (mUC) within the ATLANTIS clinical trial platform

A subset of mUC exhibits a DRD phenotype predicting benefit from platinum based chemotherapy (PBC). We previously reported switch maintenance therapy with the PARP inhibitor rucaparib, following PBC, in patients with mUC harbouring a DRD biomarker. Rucaparib extended progression free survival (Crabb et al, J Clin Oncol 40, 2022 (suppl 6; abstr 436)). We undertook an exploratory analysis of the phenotypic and genomic characteristics of the DRD biomarker allocated cohort, involving all patients from the ATLANTIS clinical trial where next generation sequencing (NGS) was possible.

Real-world effectiveness of first-line maintenance olaparib in women with BRCA-mutated advanced ovarian cancer: U.S. retrospective cohort study.

5518 Background: Following cytoreductive surgery and first-line (1L) platinum based chemotherapy, 70% of patients (pts) with newly diagnosed advanced ovarian cancer (AOC) experience relapse within 3 years. 1L maintenance treatment (tx) with olaparib monotherapy, a poly (ADP-ribose) polymerase inhibitor, extended progression free survival in pts with BRCA mutated (BRCAm) AOC in the SOLO-1 (NCT01844986) randomized controlled trial (RCT). We aimed to describe real world characteristics, tx patterns, and clinical outcomes of pts with newly diagnosed, BRCAm AOC. Methods: Data were collected from 457 pts via electronic case report forms in the US. Pt eligibility criteria were positive BRCAm test result between Jan-June 2019 (6 months post 1L olaparib FDA approval), newly diagnosed AOC (no maintenance tx prior to index), aged ≥18 years, no RCT enrollment, no active neoplasia, no prior tx for metastatic/stage IV cancer. Pt follow up was until July 2021. Kaplan-Meier (KM) estimation was used for time to event analysis using progression proxies: Time to subsequent therapy and discontinuation (or death for both) from initiation of 1L maintenance olaparib monotherapy. Results: Pt mean age (±SD) at index was 62 (±10) years, 64% of pts were white and 18% African American; further clinical characteristics are in the table. 95% of pts received ≥1 pharmacological tx. At 1L, 36% of pts (156/433) received maintenance tx after chemotherapy, with 64% of pts (277/433) receiving routine surveillance (no maintenance tx). Olaparib was the most common maintenance tx (67%, 105/156), with 67% of pts (70/105) prescribed olaparib monotherapy. At 24 months, the KM model estimated 91% of pts (95% confidence interval: 82, 96) would not progress to their subsequent therapy, with a median discontinuation of olaparib monotherapy of 25.0 (interquartile range [IQR]: 21.0, not estimable) months, over a median follow-up of 22.0 (IQR: 20.6, 24.0) months. Conclusions: This real world study complements SOLO-1 RCT data by demonstrating prolonged benefit of 1L olaparib in newly diagnosed pts with BRCAm AOC in terms of lower likelihood of progression (tx switch/death). To assess real world tx effectiveness globally, data collection across further eight countries is due to be completed in 2022. [Table: see text]

Engineered Cell-Derived Vesicles Displaying Targeting Peptide and Functionalized with Nanocarriers for Therapeutic microRNA Delivery to Triple-Negative Breast Cancer in Mice.

Polymeric nanocarriers (PNCs) can be used to deliver therapeutic microRNAs (miRNAs) to solid cancers. However, the ability of these nanocarriers to specifically target tumors remains a challenge. Alternatively, extracellular vesicles (EVs) derived from tumor cells show homotypic affinity to parent cells, but loading sufficient amounts of miRNAs into EVs is difficult. Here, it is investigated whether uPAR-targeted delivery of nanococktails containing PNCs loaded with therapeutic antimiRNAs, and coated with uPA engineered extracellular vesicles (uPA-eEVs) can elicit synergistic antitumor responses. The uPA-eEVs coating on PNCs increases natural tumor targeting affinities, thereby enhancing the antitumor activity of antimiRNA nanococktails. The systemic administration of uPA-eEV-PNCs nanococktail shows a robust tumor tropism, which significantly enhances the combinational antitumor effects of antimiRNA-21 and antimiRNA-10b, and leads to significant tumor regression and extension of progression free survival for syngeneic 4T1 tumor-bearing mice. In addition, the uPA-eEV-PNCs-antimiRNAs nanococktail plus low dose doxorubicin results in a synergistic antitumor effect as evidenced by inhibition of tumor growth, reduction of lung metastases, and extension of survival of 4T1 tumor-bearing mice. The targeted combinational nanococktail strategy could be readily translated to the clinical setting by using autologous cancer cells that have flexibility for ex vivo expansion and genetic engineering.

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer.

Niraparib (Zejula™) is a PARP inhibitor which is approved for maintenance therapy in adults with advanced ovarian cancer in complete or partial response to platinum-based chemotherapy. In a placebo-controlled phase III trial in patients with newly diagnosed advanced ovarian cancer, niraparib significantly extended progression free survival in two predefined populations, namely a patient population with altered homologous-recombination DNA repair pathways [i.e. homologous-recombination deficiency positive (HRd)] and the overall trial population. A prespecified exploratory subgroup analysis indicated that niraparib was also efficacious in patients who were homologous recombination deficiency negative or homologous recombination proficient (HRp). Niraparib has a manageable tolerability profile with myelosuppression as the main safety concern. Haematological reactions were managed with monitoring and dose reduction or interruption. A weight- and platelet count-based individualised dosage regimen introduced during the trial (and subsequently approved) appeared to improve haematological tolerability. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer in adults who responded to platinum-based chemotherapy, regardless of homologous-recombination deficiency status and is a promising option for HRp patients, for whom maintenance treatment options are limited.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00841-2.

Rapid Progress in the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma.

Simple SummaryDue to the complex mechanism of actions, immunomodulatory drugs (IMiDs) are one of the primary drug classes used to treat multiple myeloma (MM). IMiDs are the backbone of treatment for both newly diagnosed, post-transplant maintenance, and relapsed/refractory MM. The standard of care is a combination of IMiDs, corticosteroids (e.g., dexamethasone) with either a proteasome inhibitor or a monoclonal antibody. Future management will include a quadruplet of all four drug classes. Recent clinical trials have shown that another class of cereblon inhibitors in development, Cereblon E3 ligase modulators (CELMoDs), have significant activity in MM even when refractory to approved IMiDs.Over the past two decades, the improvement in our understanding of the biology of MM and the introduction of new drug classes, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies (MoAb), have significantly improved outcomes. The first IMiD introduced to treat MM was thalidomide. The side effects observed during treatment with thalidomide initiated work on the synthesis of IMiD analogs. Subsequently, lenalidomide and pomalidomide were developed, both with different safety profiles, and they have better tolerability than thalidomide. In 2010, the cereblon (CRBN) protein was discovered as a direct target of IMiDs. By binding to CRBN, IMiDs change the substrate specificity of the CRBN E3 ubiquitin ligase complex, which results in the breakdown of internal Ikaros and Aiolos proteins. Most clinical trials conducted, both in newly diagnosed, post-transplant maintenance and relapsed/refractory MM, report a beneficial effect of IMiDs on the extension of progression-free survival and overall survival in patients with MM. Due to side effects, thalidomide is used less frequently. Currently, lenalidomide is used at every phase of MM treatment. Lenalidomide is used in conjunction with other agents such as PIs and MoAb as induction and relapsed therapy. Pomalidomide is currently used to treat relapsed/refractory MM, also with PIs and monoclonal antibodies. Current clinical trials are evaluating the efficacy of IMiD derivatives, the CRBN E3 ligase modulators (CELMoDs). This review focuses on the impact of IMiDs for the treatment of MM.

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer.

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73-3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

Azacitidine Maintenance Versus No Maintenance after Standard Therapy in Patientswith Acute Myeloid Leukemia, a Mexican Center Experience

INTRODUCTION Achieving complete remission (CR) is an important goal for patients with acute myeloid leukemia (AML)undergoing treatment with the intent to cure. However, even after consolidation and/or hematopoieticcell transplantation (HCT), many patients will experience disease recurrence. Because of this there has long been an interest in the use of maintenance therapies after the intensive treatment phase to prolong the duration of remission and improve survival and the likelihood of cure. Although the concept of maintenance therapy in AML has been present since the 1960s, it is still a matter of controversy.Azacitidine (AZA) is a hypomethylating agent that acts by incorporating itself into DNA, reversiblyinhibiting DNA methyltransferase, thereby blocking its methylation and activating silenced tumor suppressor genes, resulting in an antitumor effect.Maintenance chemotherapy had not been able to demonstrate improvement in survival. However, in the results of the HOVON-97, Huls et al. showed a 12-month progression free survival (PFS) in 64% of older AML patients who received AZA as maintenance therapy for a maximum of 12 cycles, thus opening the door for new research in this field. OBJECTIVE To know if there is an impact of maintenance treatment with 5-Azacitidine on disease-free survival and progression-free survival, in Acute Myeloid Leukemia in complete remission, in patients who are and are not candidates for bone marrow transplant. PATIENTS AND METHODS We conducted a longitudinal, cohort, analytical, descriptive and single-center study, in the time period between January 2016 and December 2019 (designated the AZA group). Data obtained from patients receiving maintenance was compared with a historic patient cohort (designates as the no-AZA group).This study was approved by the ethics committee of CMN 20 de Noviembre. RESULTS A total of 21 patients were analyzed in the AZA group, of which 53% (n = 12) were women and 37% (n =9) were men, the median age was 54 years with a range of 19 to 65. The median of leukocytes,hemoglobin and platelets of the AZA-group at diagnosis was 22.8x109, 9.3 g/dL, and 44,000 mm3, respectively. Thirty percent had an intermediate cytogenetic risk. In the no-AZA group a total of 18 patients were analyzed, of which 73% (n=11) were female and 26% (n=7) were male, the median age was 57 years with a range of 18 to 64. The median of leukocytes, hemoglobin and platelets at diagnosis was 29.5 x109, 9.5 g/dL, and 57,000 mm3, respectively. In the no-AZA group 8% and 22% had intermediate and high cytogenetic risk, respectively. The median follow up in the no-AZA group was 32 months (10-96). The median of cycles of maintenance with AZA was 12 cycles (1-24); the follow up median, in months, was 19 (range 7-59). The response to maintenance therapy was evaluated after the completion of the first 6 treatment cycles, in which 71.4% maintained a negative minimal residual disease (MRD), and 23.8% experienced a relapse. In the no-AZA group the median time to progression was approximately 8 months, with a PFS median of 15 months; time to progression in the AZA group was approximately 15 months. At the closing of this study the AZA group has not reached the median for PFS (p=0.011) (Figure 1); 42.8% are still in maintenance therapy and in remission, 19% received a bone marrow transplant and are still in remission, 14.4% experienced relapse, 4.8% are in elective suspension of treatment and continue in remission, 9.5% are in observation and palliative care respectively CONCLUSIONS Azacitidine used as maintenance treatment in Acute Myeloid Leukemia can extend progression free survival. Disclosures De La Peña: Janssen:Speakers Bureau;Novartis:Speakers Bureau;Amgen:Speakers Bureau.Alvarez:Amgen:Speakers Bureau;Roche:Speakers Bureau;Celgene:Speakers Bureau;Novartis:Speakers Bureau;Janssen:Speakers Bureau.Perez:Novartis:Speakers Bureau;Roche:Speakers Bureau;Celgene:Speakers Bureau.Alvarado:Novartis:Speakers Bureau;Amgen:Speakers Bureau;Celgene:Speakers Bureau;Alexion:Speakers Bureau;Roche:Speakers Bureau. OffLabel Disclosure: azacitidine as maintenance for AML it is not approved yet in Mexico

Economic challenges of oncological diseases’ pharmacotherapy

Oncological diseases rank high in the structure of population morbidity and mortality. They entail considerable direct and indirect economic costs. In the past decades, the cost of oncotherapy has increased significantly, which is largely conditioned by high prices of antitumor drugs, which on average increased by ten times in the past ten years. At the same time, many innovative medications have only minor advantages over cheaper old medications because they are registered based on the data on the achievement of the surrogate endpoint – extension of progression-free survival. The high cost of oncotherapy is associated with financial toxicity that affects negatively the patients’ quality of life, their adherence to treatment and consequently survival. To reduce the cost of oncotherapy, it is necessary to conduct pharma-economic analysis, the results of which can serve as the basis to negotiate price-cutting with the manufacturers, as well as to use high-quality generics and biosimilars as effective and safe as their originals, and to monitor effectiveness and safety of all antitumor drugs within the pharmacovigilance framework.

RTHP-28. TTFIELDS TREATMENT AFFECTS TUMOR GROWTH RATES: A POST-HOC ANALYSIS OF THE PIVOTAL PHASE 3 EF-14 TRIAL

Abstract INTRODUCTION The pivotal EF-14 trial showed that Tumor Treating Fields (TTFields) extend Progression Free Survival (PFS) in newly Diagnosed Glioblastoma (ndGBM) patients. This leads to the hypothesis that TTFields therapy leads to local control of tumors, yielding a significant decrease in tumor growth rates. Here we present an analysis testing this hypothesis in biopsy-only patients who participated in the EF-14 trial. METHODS Biopsy patients of the EF-14 trial who exhibited radiological progression were included in this study (treatment: N=37/60, control: N=12/29). Volumes of enhancing tumor were segmented on T1c MRIs at baseline and at progression. Tumor growth rate was calculated as: growth_rate=(ln(v0)-ln(v1))/dt. (v0- tumor volume at baseline), v1- Tumor volume at progression, dt- days to progression), which models tumor volume as increasing exponentially over time. Median growth rates in the treatment and control arms were compared. RESULTS The median growth rate was lower in the treatment arm than in the control. (control: 0.14±0.12 mL/month, TTFields -0.011±0.11 mL/month, p< 0.008 Wilcoxon rank-sum) DISCUSSION AND CONCLUSIONS This study shows that tumor growth rates are slower in patients treated with TTFileds+Temozolomide (TMZ) than in patients treated with TMZ alone. This analysis was restricted to biopsy-only patients since the definition of tumor volume is ambiguous in patients that underwent resection since a large portion of the tumor has been removed. The negative median growth rate for patients in the treatment arm may indicate that a significant number of TTFields-treated patients a decrease in tumor volume was observed, suggesting that TTFields enhances local tumor control.

EXTH-34. IN VITRO TUMOR TREATING FIELDS (TTFIELDS) APPLIED PRIOR TO RADIATION ENHANCES THE RESPONSE TO RADIATION IN PATIENT-DERIVED GLIOBLASTOMA CELL LINES

Abstract Tumor treating fields are FDA-approved for treatment of newly-diagnosed and recurrent glioblastoma. Adding TTFields therapy to standard-of-care extended progression-free survival and overall survival in newly-diagnosed glioblastoma patients. In this study, cell lines generated from newly-diagnosed glioblastoma patients were treated in vitro with TTFields prior to irradiation to determine if the response to radiation would be altered. This study was approved by the WSU Institutional Review Board and written consent obtained from the patients. Single-cell suspensions generated from tumor tissues obtained from newly-diagnosed patients were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields initiation, cells were plated on plastic coverslips (5×104cells/coverslip) and incubated overnight. Then, TTFields were applied at 200 kHz with a field intensity of ~1.6 V/cm for 3 days. After TTFields application, cells were irradiated with 2, 4, or 6 Gy, or were untreated. After radiation delivery, cells were harvested and replated in a clonogenic assay. From each group, 3 coverslips were each replated in triplicate. After 3 days (3 doubling times), cells were stained with crystal violet and plates were scanned to determine cell counts. Treatment groups were compared to their control group with t-test. For both patient-derived GBM cell lines tested, TTFields prior to radiation decreased the number of crystal violet-stained cells in the clonogenic assay plates. In cell line 15–037, pretreatment with TTFields decreased cell counts by 16, 29, and 56% after 2, 4, or 6 Gy radiation, respectively, compared to the control cells with no TTFields pretreatment (p< 0.05). The response in 14-015S cells was less radiation dose-dependent, with the decrease in cell counts ranging from 33–47% control across the radiation doses (p< 0.05). These data suggest that the use of TTFields therapy prior to radiotherapy may enhance the response to radiotherapy in GBM patients.

Abstract 3361: A prescription for new trial designs for drug development focused on the neoadjuvant setting: Save lives, resources, and time

Abstract Background: Traditionally, new drug combinations are first tested for safety and efficacy in the stage 4 setting. The I-SPY 2 TRIAL has focused on bringing promising new combinations into the phase 2/3 high-risk setting once safety is established. I-SPY 2 is an adaptive neoadjuvant platform trial for women with stage 2/3 breast cancer at high risk for early recurrence. In this setting, complete pathologic response (pCR) is the primary endpoint. We and others have demonstrated that pCR is highly predictive of distant recurrence free survival at 3 years. In I-SPY 2 the hazard rate is 0.2 (Confidence Interval 0.11-0.37), regardless of subtypes or agent. Agents that extend progression free survival in the metastatic setting, can be lifesaving when given at an earlier stage setting. Methods: The health economic benefits of achieving pCR were investigated using a Markov model describing the risk of recurrence, progression and death. The risk of recurrence was informed by I-SPY 2 and the risk of cancer progression and the associated treatment costs were based on literature values. We assumed constant recurrence rate without accounting for subtype specific rates in this first version of the model. Results: For each additional patient with pathologic complete response a net monetary benefit of $170,000 (Credible Interval 95% 100,000—250,000) and a gain of 4 life-years (CrI 95% 2—6) was predicted. The ICER for pCR is -$45,000. This represents the aggregate benefit across all I-SPY cancers. Modeling accounting for cancer subtype is in process and will be presented also. Conclusion: A short term endpoint, response to chemotherapy in the neoadjuvant setting, which is highly correlated with long term outcome, provides the opportunity to focus drug development on improving that endpoint. Enabling more patients to achieve a pCR would provide enormous benefit in terms of lives and resources saved. The economic modeling, along with the findings from I-SPY 2 suggests that we should shift drug development to the high risk early setting and evolve drug designs to improve every patient’s outcome. In I-SPY 2, we are shifting our platform trial design to increase every patient’s chance to achieve pCR. Platform adaptive trials in the early stage neoadjuvant setting are ideal for advancing the field and maximizing benefit for patients. Citation Format: Andreas Karlsson, Yiwey Shieh, Andre Dempsey, Christina Yau, Angela Dmichele, Doug Yes, Laura van't Veer, Nola Hylton, Martin Eklund, Laura Esserman. A prescription for new trial designs for drug development focused on the neoadjuvant setting: Save lives, resources, and time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3361.

Characterisation of Long-Term Responders to First-Line Myeloma Therapy - Results from the UK Myeloma IX and XI Trials

INTRODUCTION Features of high risk myeloma (MM) have been studied in detail but patients with longer term responses to first-line therapy are less well characterised. Identification of common features of this group may support optimised management. Here we analysed clinical and genetic characteristics of long-term responders of 4,249 trial patients from the UK MRC Myeloma IX (M-IX) and NCRI Myeloma XI (M-XI) trials. PATIENTS AND METHODS In M-IX patients were randomised between alkylating therapy (CVAD or MP) and thalidomide-based induction therapy (CTD). M-XI patients were randomised between thalidomide and lenalidomide based induction (CTD vs CRD) and a response-based bortezomib (CVD) intensification. Fitter patients received HD-Mel+ASCT consolidation. Patients were then randomised to thalidomide (M-IX) or lenalidomide (M-XI) maintenance or observation. Trials included symptomatic, newly diagnosed patients based on CRAB criteria. This analysis included 1,921 My-IX and 2,328 My-XI patients with median follow-up of 73 and 61 months (m), respectively. Genetic profiling was available for 1,866 patients. Patients with a long-term response post induction (PFS≥48m) were identified and their baseline characteristics, responses and treatment compared to those with PFS RESULTS In M-IX, 283 (25.8%) of transplant-eligible (TE) patients had PFS ≥48m whereas 58 (7%) of transplant non-eligible (TNE) patients reached PFS≥48m. In M-XI 410 (34.2%) patients had PFS≥48m for TE and 116 (10.2%) for TNE. Extended progression free survival translated to overall survival (OS) benefit with a median post progression OS of 36.9m for PFS≥48m vs 16.7m for PFS Clinical factors including ISS I (P The proportion of patients with a high risk lesion (Adverse translocation, Gain(1q) or Del(17p)) were lower in the PFS≥48m group than The majority of patients with PFS ≥48m showed ≥VGPR after induction +/- consolidation: 211 (76.4%) and 340 (84%) of PFS ≥48m patients in the TE arms and 26 (49.1%) and 87 (76.3%) in the TNE arms of M-IX and M-XI, respectively. 86.7% of patients who achieved a ≥VGPR had a PFS ≥48m in the absence of high risk lesions compared to 72.8% with any high risk lesion present (P=0.004). Some patients with PFS≥48m had only reached PR after induction; 56 (20.3%) and 57 (14.1%) of PFS ≥48m patients in the TE arm and 15 (28.3%) and 24 (21.1%) in the TNE arms of M-IX and M-XI, respectively. Baseline factors that were associated with still being able to achieve PFS≥48m from induction after only achieving a PR included the lack of high risk genetic lesions (P CONCLUSIONS Response assessment after induction+/-HD-Mel consolidation with baseline factors can define a patient group with superior outcomes in both TE and TNE patients and may influence future treatment strategies of MM patients undergoing first line therapy. Further analyses including modelling of predictors of response duration are ongoing and will be presented at the conference. Disclosures Shah:Celgene: Other: Travel, Accommodation expenses; Sanofi: Other: Travel and Accommodation expenses. Striha:Janssen: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; MSD: Research Funding; Amgen: Research Funding. Hockaday:Celgene: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; MSD: Research Funding; Millenium: Research Funding. Pawlyn:Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support. Jenner:Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Drayson:Abingdon Health: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel Support; Janssen: Consultancy, Other: Travel Support. Gregory:Celgene: Consultancy, Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding; Janssen: Honoraria; Amgen: Research Funding. Morgan:Janssen: Research Funding; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene: Research Funding; Amgen: Research Funding; Merck Sharp and Dohme: Research Funding. Jackson:Roche: Consultancy, Honoraria, Speakers Bureau; Merck Sharp and Dohme: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau. Kaiser:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: travel support; Janssen: Consultancy, Honoraria; Chugai: Consultancy; Bristol-Myers Squibb: Consultancy, Other: travel support; Celgene: Consultancy, Honoraria, Research Funding.

Abstract 2856: Targeting OXPHOS with IACS-010759 to eliminate standard of care resistant tumor cells

Abstract Tumors are comprised of heterogenous populations of tumor cells that rely on both glycolysis and oxidative phosphorylation (OXPHOS) for bioenergy and synthetic processes in support of cell proliferation. Over the past few years, we and others have reported that there is a subpopulation of tumors cells that are resistant to standard of care treatment or targeted therapies, and that these so-called persistent tumor cells possess stem cell like properties. Of note, these cells have elevated levels of mitochondria and are dependent on OXPHOS for survival. We have previously disclosed the discovery of IACS-010759, a potent, selective inhibitor of complex I of the electron transport chain, which is orally bioavailable and has excellent PK and physicochemical properties in preclinical species. IACS-010759 is currently in phase I clinical trials in relapsed/refractory AML and solid tumors where initial safety, pharmacokinetics, efficacy and pharmacodynamic impacts on tumor cell biology are being evaluated. As part of the development of IACS-010759, we were interested to explore the impact of the compound to target the persistent tumor cells, in particular by treating AML, TNBC and PDAC PDX models post-chemotherapy with IACS-010759. For all three contexts, IACS-010759 extended progression free survival, consistent with IACS-010759 targeting the recently described metabolically adapted residual tumor cells. For solid tumor indications, we have utilized innovative barcoding and clonal tracking strategies to confirm dependency of a specific subpopulation of tumor cells on OXPHOS. We show that OXPHOS inhibition extends survival and limits AML growth in secondary transplantation by stimulating terminal differentiation of putative stem cells. Taken together, these data provide rationale for multiple Phase II/III clinical trials where IACS-010759 will be used to target persistent tumor cell population and extend survival. Citation Format: Joseph R. Marszalek, Sahil Seth, Denise Corti, Qi Zhang, Gloria V. Echeverria, Lina Han, Yuting Sun, Jennifer Molina, Sonal Gera, Edward Chang, Tin O. Khor, Mikhila Mahendra, Ningping Feng, Jason P. Gay, Timothy McAfoos, Virginia Giuliani, Xi Shi, Sabrina Jeter-Jones, Sarah Loponte, Chieh-Yuan Li, Christopher A. Bristow, Maria Emilia Di Francesco, Helen Piwnica-Worms, Marina Konopleva, Alessandro Carugo, Andrea Viale, Philip Jones, Timothy P. Heffernan, Giulio F. Draetta. Targeting OXPHOS with IACS-010759 to eliminate standard of care resistant tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2856.

Prospective multicenter trial: Hormonal changes by switching from GnRH agonist to GnRH antagonist in patients with early stage of castration resistant prostate cancer as a second line hormonal therapy.

e17030Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. H...

Genetic and Epigenetic Features of Rapidly Progressing IDH-Mutant Astrocytomas.

IDH-mutant astrocytomas are significantly less aggressive than their IDH-wildtype counterparts. We analyzed The Cancer Genome Atlas dataset (TCGA) and identified a small group of IDH-mutant, WHO grade II-III astrocytomas (n = 14) with an unexpectedly poor prognosis characterized by a rapid progression to glioblastoma and death within 3 years of the initial diagnosis. Compared with IDH-mutant tumors with the typical, extended progression-free survival in a control group of age-similar patients, the tumors in the rapidly progressing group were characterized by a markedly increased level of overall copy number alterations ([CNA]; p = 0.006). In contrast, the mutation load was similar, as was the methylation pattern, being consistent with IDH-mutant astrocytoma. Two of the gliomas (14%) in the rapidly progressing, IDH-mutant group but none of the other grade II-III gliomas in the TCGA (n = 283) had pathogenic mutations in genes (FANCB and APC) associated with maintaining chromosomal stability. These results suggest that chromosomal instability can negate the beneficial effect of IDH mutations in WHO II-III astrocytomas. The mechanism of the increased CNA is unknown but in some cases appears to be due to mutations in genes with a role in chromosomal stability. Increased CNA could serve as a biomarker for tumors at risk for rapid progression.

Multicenter prospective study of switching from GnRH agonists to GnRH antagonist for patients with early stage of castration resistant prostate cancer as a second-line hormonal therapy.

183 Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. However, the usefulness of switching from GnRH agonist to GnRH antagonist as a second hormonal therapy remains obscure. We performed a multicentral prospective study to investigate whether the switching from GnRH agonist to GnRH antagonist (degalerix) for patients with castration resistant prostate cancer (CRPC) as the 2nd line hormonal therapy was effective. Methods: 37 patients who were pathologically diagnosed as prostatic adenocarcinoma and developed CRPC after 1st line hormonal therapy with GnRH agonist plus anti-androgens were enrolled. After confirming anti-androgen withdrawal syndrome, they were treated with switching from GnRH agonists to degalerix. The primary endpoint was PSA response (PSA decline or up to 10% over baseline PSA). Secondary endpoints were the time to 25% PSA increase from the baseline (PSA response time), PSA progression free survival (PPFS), the time to treatment failure, cancer specific survival, radiographic PFS (rPFS), and safety. Results: Mean age was 76 years old, super high risk; 20 cases (54.1%), high risk; 11 cases (29.7%), intermediate risk; 5 cases (13.5%), low risk; one case (2.7%). PSA responder rate was 24.3% (9 cases). In responders, the median PSA response time was 5.75 months, the median PPFS was 1.77 months, and rPFS rate at 3 months was 96%. Regarding safety, only 2 cases (5.4%) showed G3 of AE. The PSA response had no relationship with the change of serum testosterone, LH nor FSH. Conclusions: The effectiveness of switching from GnRH agonist to GnRH antagonist showed to be limited. Although no predictive factor of the switching was recognized, some long-term responders were seen. We expect the possibility of switching to GnRH antagonist for patients in the early stage of CRPC, especially non-metastatic status. Clinical trial information: UNKNOWN.

Estimation of The Health Benefit Associated With A Potential Denosumab-Induced Extension of Progression Free Survival In Multiple Myeloma Patients

The efficacy of Denosumab in the prevention of skeletal-related events in multiple myeloma (MM) patients, and its non-inferiority to Zoledronic Acid, was demonstrated in a randomized, double blind phase 3 trial (IMW 2017 and ASCO 2017). Preliminary analyses of trial survival data suggested that patients treated with Denosumab may have a longer progression free survival (PFS) compared to patients treated with Zoledronic Acid (IMW 2017 and ASCO 2017). The objective of this study was to quantify the potential incremental health benefit associated with a Denosumab-induced extension of PFS, in MM patients. Parametric statistical models were fitted on individual failure time data from the primary data analysis of the trial to extrapolate long-term trends for PFS. Multiple scenarios, based on the 5 best fitting parametric models (unrestricted exponential, Weibull, log-normal, log-logistic, and generalized gamma) were generated. A partitioned survival cohort model was used to calculate the quality-adjusted life gains associated with the extended PFS on top of anti-myeloma therapy. Model results showed that the delay in disease progression observed in the trial may translate into a lifetime health benefit equivalent to living between 1.5 and 2.3 extra months in perfect health, 1.9 and 2.8 extra months with the same quality of life as in the MM pre-progression state, and between 2.3 and 3.5 extra months with the same quality of life as in the MM post-progression state. In all MM patients, Denosumab use is potentially associated with a significant incremental health benefit, compared to Zoledronic Acid.

Abstract 2343: The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer

Abstract Background: The effectiveness of palbociclib (CDK4/6 inhibitor) for estrogen receptor positive breast cancer has been demonstrated by large-scale clinical studies, with the drug garnering attention as a key drug for breast cancer subtypes with endocrine sensitivity in the future. According to PALOMA-3 trial, palbociclib has been demonstrated to contribute to the extension of progression-free survival in patients with advanced hormone receptor-positive and HER2-negative metastatic breast cancer after endocrine therapy. On the other hand, in the case of triple-negative breast cancer (TNBC), luminal AR (LAR) related to androgen signaling is believed to have endocrine activity. Previous clinical data revealed that palbociclib shows high sensitivity in luminal breast cancer cell lines with endocrine activity, with effectiveness also expected in LAR. In this study, we created TNBC cell lines that forcibly express AR and examined the effectiveness of palbociclib for TNBC. Materials and Methods: MCF-7 and T-47D were used as luminal breast cancer cell lines, while MDA-MB-231 and BT-549 were used as TNBC cell lines. In addition, we created TNBC cell lines that forcibly express AR, called AR-MDA-MB-231, by the transfection of pEGFP-C1-AR Plasmid Vector using Lipofectamine® 3000 Reagent. We confirmed the expression of AR by qRT-PCR as well as Western blotting and examined the impact of palbociclib on proliferation as well as apoptosis of breast cancer cell lines. Results: AR was found to have been expressed only in luminal breast cancer cell lines but not TNBC cell lines. It was confirmed that AR was expressed in AR-MDA-MB-231 which are stable cell lines with the properties of LAR. In a CCK assay, palbociclib showed high sensitivity in AR-MDA-MB-231 as in luminal breast cancer cell lines. Furthermore, in an apoptosis assay using FACS and cell cycle assay, apoptosis was induced in AR-MDA-MB-231 and cell cycle arrest at the G1S check point was confirmed. Conclusion: palbociclib (CDK4/6 inhibitor) showed effectiveness for TNBC cell lines that compulsively express AR, suggesting it may be one treatment option for TNBC in the future. Citation Format: Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Koji Takada, Tsutomu Takashima, Tamami Morisaki, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira. The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2343. doi:10.1158/1538-7445.AM2017-2343

Abstract 2351: The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer

Abstract Background: The effectiveness of palbociclib (CDK4/6 inhibitor) for estrogen receptor positive breast cancer has been demonstrated by large-scale clinical studies, with the drug garnering attention as a key drug for breast cancer subtypes with endocrine sensitivity in the future. According to PALOMA-3 trial, palbociclib has been demonstrated to contribute to the extension of progression-free survival in patients with advanced hormone receptor-positive and HER2-negative metastatic breast cancer after endocrine therapy. On the other hand, in the case of triple-negative breast cancer (TNBC), luminal AR (LAR) related to androgen signaling is believed to have endocrine activity. Previous clinical data revealed that palbociclib shows high sensitivity in luminal breast cancer cell lines with endocrine activity, with effectiveness also expected in LAR. In this study, we created TNBC cell lines that forcibly express AR and examined the effectiveness of palbociclib for TNBC. Materials and Methods: MCF-7 and T-47D were used as luminal breast cancer cell lines, while MDA-MB-231 and BT-549 were used as TNBC cell lines. In addition, we created TNBC cell lines that forcibly express AR, called AR-MDA-MB-231, by the transfection of pEGFP-C1-AR Plasmid Vector using Lipofectamine® 3000 Reagent. We confirmed the expression of AR by qRT-PCR as well as Western blotting and examined the impact of palbociclib on proliferation as well as apoptosis of breast cancer cell lines. Results: AR was found to have been expressed only in luminal breast cancer cell lines but not TNBC cell lines. It was confirmed that AR was expressed in AR-MDA-MB-231 which are stable cell lines with the properties of LAR. In a CCK assay, palbociclib showed high sensitivity in AR-MDA-MB-231 as in luminal breast cancer cell lines. Furthermore, in an apoptosis assay using FACS and cell cycle assay, apoptosis was induced in AR-MDA-MB-231 and cell cycle arrest at the G1S check point was confirmed. Conclusion: palbociclib (CDK4/6 inhibitor) showed effectiveness for TNBC cell lines that compulsively express AR, suggesting it may be one treatment option for TNBC in the future. Note: This abstract was not presented at the meeting. Citation Format: Yuka Asano, Shinichiro Kashiwagi, Wataru Goto, Katsuyuki Takahashi, Tsutomu Takashima, Satoru Noda, Naoyoshi Onoda, Shuhei Tomita, Kosei Hirakawa, Masaichi Ohira. The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2351. doi:10.1158/1538-7445.AM2017-2351