Prior Anticancer Therapy Research Articles

A phase I trial of aerosol gemcitabine for the treatment of patients with solid tumors and lung metastases.

TPS3645 Background: Pre-clinical studies of aerosol gemcitabine (GCB) in mice and dogs with osteosarcoma (OS) lung metastases demonstrated therapeutic efficacy. Aerosol GCB administered once weekly proved to be safe in adults with lung cancer. Direct delivery of GCB to the lungs via inhalation may offer higher drug concentration in the tumor with fewer side effects. We initiated a Phase I study to evaluate the feasibility and safety of aerosol GCB treatment in patients >12 years with solid tumors and lung metastases (2015-0720- NCT03093909). Methods: Eligibility criteria: 1) Diagnosis of solid tumor with lung metastases, 2) willing to comply with protocol therapy, 3) adequate organ function, 4) patient age > 12 and < 50 years, 5) good performance status, 6) resolution of all acute toxic effects of any prior anti-cancer therapy, and 7) no radiotherapy within 2 weeks. Patients who previously received systemic GCB are eligible. Objectives: To determine the maximum tolerated dose (MTD) and toxicities of aerosol GCB, to evaluate for drug spillover into the circulation, and to preliminarily assess the anti-tumor activity. Correlative studies include effect of aerosol GCB on immune cell infiltration in the lung, autophagy, apoptosis, heat shock protein 27, evidence of DNA strand breaks (gH2AX) and expression of human equilibrative nucleoside transporter-1.Aerosol GCB is administered via a breath-induced nebulizer twice a week in 28-day cycles. A maximum of 6 dose levels will be studied; the starting dose is 0.75 mg/kg twice weekly. If no progressive disease or unacceptable treatment-related toxicity, patients may continue for 12 cycles. The study uses the accelerated titration method for the first 2 dose levels then the 3+3 design for the remaining dose levels. After determining the MTD, we will evaluate the defined MTD in an expansion cohort of 14 patients with relapsed OS. Symptoms, pulse oximetry, and pulmonary function are assessed prior to each nebulized dose using remote spirometry that allows raw numbers and flow-volume curves to be uploaded and transmitted via bluetooth to an android tablet provided to patients. Data is transmitted to a web portal and captured in a HIPAA-compliant web-based database (REDCap) that is accessible to the research team. Results: To date, the study enrolled 4 patients and accrual is ongoing at dose level 3. Conclusions: This study will provide information on the feasibility and safety of aerosol GCB. If proven to be feasible and safe, it can potentially offer a novel approach to treat metastatic OS to the lungs while minimizing systemic toxicity. Clinical trial information: NCT03093909 .

Everolimus plus exemestane in hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: incidence and time course of adverse events in the phase IIIb BALLET population

The addition of everolimus to exemestane therapy significantly improves progression-free survival in postmenopausal patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant breast cancer. However, the safety profile of this schedule still might be optimized. Patients included in the BALLET trial were assessed. The objectives of this analysis were to provide additional information on the safety profile of this schedule depending on prior anticancer therapies and to characterize the time course of adverse events (AEs) and serious AEs (SAEs) of clinical interest throughout the study period. Non-infectious pneumonitis (NIP), stomatitis, asthenia and weight loss were selected as AEs of clinical interest. The safety population of this analysis comprised 2131 patients. There were similar incidences of AEs and SAEs of clinical interest regardless of previous anticancer therapies. Most stomatitis and asthenia events occurred within the first three months. Incidence of weight loss appeared to plateau except in the case of grade 3-4 events, which occurred rarely. The incidence of any grade NIP (between 2 to 6%) and grade 3-4 NIP (between 0 to 1%) was low across the study, but steady. Everolimus plus exemestane is a well-known therapeutic option for aromatase inhibitor pretreated advanced breast cancer patients, and its toxicity profile is similar to that described in previous studies. Close monitoring, especially within the first three months, early intervention with preventive measures and patient education to help recognize the first signs and symptoms of AEs, will help to reduce their incidence and severity.

Safety and Effectiveness of Aflibercept + Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) for the Treatment of Patients with Metastatic Colorectal Cancer (mCRC) in Current Clinical Practice: OZONE Study

For patients with metastatic colorectal cancer (mCRC) that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. This prospective, observational, noncomparative, post-authorization safety study (OZONE) evaluated the safety and effectiveness of aflibercept plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with mCRC treated in daily practice after failure of an oxaliplatin-based regimen. Patients were grouped by age, renal impairment, hepatic impairment, race, number, and type of prior anticancer therapy. Of 766 treated patients enrolled, 59.5% were male, 94.8% had an Eastern Cooperative Oncology Group performance status of 0–1, all received previous chemotherapy (97.8% including oxaliplatin), and 58.6% had prior exposure to bevacizumab. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 68.3% of patients. Neutropenia, hypertension, diarrhea, and asthenia were the most frequently occurring grade ≥ 3 TEAEs. Antivascular endothelial growth factor class events were infrequent. Subgroup analyses did not reveal major differences in the safety profile according to age, renal and hepatic status, race, or prior anticancer therapy. For the total population, median overall survival was 12.5 months, median progression-free survival was 6.1 months, and overall response rate was 16.3%. Aflibercept in combination with FOLFIRI is a safe and efficacious regimen administered in current clinical practice to patients with mCRC previously treated with oxaliplatin. The study results, conducted in real-world clinical practice with a less selected patient population, are aligned with the VELOUR (NCT00561470) trial and no new safety issues were identified.

Abstract P1-19-17: Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer

Abstract Approved CDK4/6 inhibitors have demonstrated significant improvements in progression free survival when combined with fulvestrant in patients with HR+/HER2- advanced breast cancer, though limited by neutropenia and gastrointestinal side effects. Lerociclib is a potent selective CDK4/6 inhibitor with a differentiated PK/PD profile from currently approved CDK4/6 inhibitors that has demonstrated clinical proof-of-concept (Phase 1b data ASCO 2018). This Phase 1b/2a study assesses lerociclib dose escalation in combination with 500 mg fulvestrant using a 3+3 design followed by dose expansion in patients with metastatic or locally advanced HR+/HER2- breast cancer that had progressed following endocrine therapy. Up to two prior chemotherapies in Phase 1b and one prior in Phase 2a in the advanced setting are allowed. Prior fulvestrant was excluded for all patients; prior CDK4/6 inhibitors were excluded in Phase 2a only. Lerociclib is administered daily without a drug holiday. The objectives are to evaluate DLTs, safety, tolerability, PK, and tumor response and to determine the recommended dose and schedule (QD or BID) of lerociclib administered with fulvestrant for randomized trials. The BID dosing regimen demonstrated optimal safety, tolerability, and antitumor activity. To date, 35 patients (6 patients @ 100 mg BID, 9 patients @ 150 mg BID, 17 patients @ 200 mg BID, and 3 patients @ 250 mg BID) with mean age of 54 years, ECOG of 0 (86%) or 1 (14%), and a median of two prior anticancer therapies in the advanced setting have received lerociclib + fulvestrant for up to 804 days. A dose proportional increase in drug exposure has been observed. The most common lerociclib-related adverse events were neutropenia (63%), leukopenia (57%), nausea (37%), anemia (29%), diarrhea (20%), and thrombocytopenia (20%). The rates of lerociclib-related Grade 3 and Grade 4 neutropenia were 29% and 9%, respectively. Following an initial decline, ANC plateaued beginning at week 4. There were no reports of Grade 3 or greater nausea, vomiting, or diarrhea. One DLT of dose interruption due to Grade 2 fatigue and nausea was observed at 200 mg BID. There have been no reports of venous thromboembolism, QT prolongation or drug-induced liver injury. Twenty patients were evaluable for tumor response based on RECIST v1.1. Five patients (25%) had a confirmed PR; 8 patients (40 %) had stable disease; 6 patients (30 %) had PD. The CBR (CR + PR + SD ≥ 24 weeks) was 67% (12 of 18 patients either had SD at the week 24 tumor assessments or achieved an objective response). A population PK/PD/efficacy model was developed, and simulation data are concordant with existing clinical results. Additional patients are being enrolled at 150 mg BID and 200 mg BID, and updated data will be presented. Lerociclib, dosed BID with no drug holiday, has a favorable safety profile with low rates of gastrointestinal AEs and Grade 3/4 neutropenia, as well as encouraging antitumor activity in patients with HR+/HER2- advanced breast cancer. Phase 2b is ongoing to confirm the BID dose (150 mg or 200 mg) for randomized clinical trials. Clinical trial information: NCT02983071. Citation Format: Iurie Bulat, Marina Maglakelidze, Carmen Murias, Boris Krastev, Richard D Baird, Andrew M Wardley, Rebecca Roylance, Adrian Crijanovschi, Maia Gogiladze, Yili Pritchett, Amy McCullough, Chao Li, Jessica A Sorrentino, Rajesh Malik, Andrew P Beelen. Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-17.

Abstract OT1-04-06: Evaluation of cognitive functioning in patients with metastatic breast cancer treated with endocrine or combined therapy

Abstract Background: A subset of patients with breast cancer is vulnerable to treatment-related cognitive problems. However, relatively little is known about the cognitive effects of endocrine treatment and the novel cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors in the metastatic setting. Research on possible cognitive effects of these therapies is needed, since cognitive impairment can affect role functioning, independence and quality of life. Trial design: The current study is a side study of the SONIA (Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer) trial: a multicenter, randomized phase III study. The side study is an observational study with nine months of follow-up, comparing two intervention groups (first line non-steroidal aromatase inhibitor + CDK4/6 inhibition vs. single agent non-steroidal aromatase inhibitor) and a reference group of people without a history of cancer. Cognition will be measured at start of treatment (T0) and nine months later (T1), using the Amsterdam Cognition Scan, a validated online neuropsychological test battery that is completed at home without supervision. It includes tests of among others attention, memory, and executive functioning, and two questionnaires on anxiety and depression, and fatigue. Specific aims: The main objective is to evaluate if there is a difference in cognitive functioning over time in patients with metastatic breast cancer who will undergo first line endocrine treatment + CDK4/6 inhibition vs. endocrine treatment alone. Eligibility criteria: All patients who participate in the main SONIA study will be eligible for participation: adult women (≥ 18 years of age) with proven diagnosis of hormone receptor-positive, human epidermal growth factor receptor 2 negative adenocarcinoma of the breast with evidence of loco-regional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent, for whom chemotherapy is not clinically indicated and who have not received any prior systemic anti-cancer therapy for metastatic disease. Participants in the reference group are patients’ female relatives/friends without a history of cancer and without neurological/psychiatric symptoms influencing cognition, who have a sufficient level of Dutch and access to a computer with internet. Statistical methods: We will use a mixed effects modeling approach to examine changes in cognition from baseline to follow-up between the two intervention groups and the reference group, adjusting for non-ignorable drop-out patterns. The primary endpoint will be the change from baseline to follow-up on the total score of cognition. Present accrual and target accrual: With an accrual period of 21 months and 9 months of follow-up, inclusion of 260 patients is required. In addition, our already existing reference group (n=157) will be expanded by recruiting participants’ female relatives/friends without a history of cancer. As of June 2019, 435 patients have enrolled in the main SONIA study. Target accrual is 1050 patients. Contact information Study coordinator: Philippe Lee Meeuw Kjoe, Netherlands Cancer Institute, p.lee.meeuw.kjoe@nki.nl PI: Elsken van der Wall, MD, PhD, UMC Utrecht Cancer Center, E.vanderWall@umcutrecht.nl PI: Sanne Schagen, PhD, Netherlands Cancer Institute, s.schagen@nki.nl Citation Format: Philippe Lee Meeuw Kjoe, Elsken van der Wall, Inge Konings, Agnes Jager, Gabe Sonke, Annemiek van Ommen-Nijhof, Sanne Schagen. Evaluation of cognitive functioning in patients with metastatic breast cancer treated with endocrine or combined therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-06.

Abstract P5-11-02: Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer

Abstract Background: Selective estrogen receptor (ER) degraders (SERDs) result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor, palbociclib, in ER-positive (+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). We previously presented preliminary results (ASCO 2019). Here we describe safety, pharmacokinetics (PK), ER gene (ESR1)profiling and updated antitumor activity for SAR439859 monotherapy dose escalation. Methods: Part A of this open-label, Phase 1/2 first-in-human study (NCT03284957; TED14856) assessed SAR439859 dose escalation (3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Dose levels ranged from 20-600 mg once daily (QD). Primary objectives: dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended dose. Secondary objectives: safety, PK, tumor response (RECIST v1.1), pharmacodynamic (PD) inhibition of ER occupancy (18F-fluoroestradiol positron emission tomography[18F-FES PET] scan). Exploratory objective: mutation profiling of ESR1 (circulating tumor DNA was assessed for 12 ESR1 mutations at baseline and end of Cycle 2 using multiplex droplet digital polymerase chain reaction). Results: As of May 29, 2019, 16 patients were treated. Median age: 59.5 years (range 40-79); ECOG performance status: 0 (62.5%) or 1 (37.5%); median prior anticancer therapies in the advanced setting: 3 (range 1-8). All patients had ≥ 1 treatment-emergent adverse event (TEAE), mostly grade 1-2; most frequent were hot flushes, diarrhea, constipation, nausea (all 37.5%) and decreased appetite (31.3%). Most frequent TEAEs related to treatment were hot flushes (31.3%), diarrhea, nausea (both 25%), decreased appetite, constipation, night sweats, asthenia (all 18.8%), arthralgia and fatigue (both 12.5%); no event was grade ≥ 3. There were no DLTs at any of the five dose levels (maximum administered dose 600 mg QD); MTD was not reached. In 18F-FES PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. PK profile showed rapid SAR439859 absorption (median tmax ~ 3 hours) and an apparent terminal half-life of ~ 8 hours after first administration. After repeated QD administration, there was no or low accumulation and exposure (Cmax/AUC0-24h) increased with doses up to 600 mg. Food intake did not have a major effect on exposure. Best overall response (BOR) was confirmed partial response (PR) in one patient at 150 mg QD (6.3%) and stable disease (SD) in eight patients (50.0%) including seven (43.8%) with long-term SD (≥ 24 weeks). Seven had progressive disease (43.8%). Tumor shrinkage > 10% was seen in eight patients (50.0%), without any dose dependency. ESR1 mutations were detected at baseline in 11 patients (68.8%), with five patients harboring > 1 mutation. Similar BOR was seen regardless of ESR1 mutation status with SD seen in 54.5% (6/11) of patients with ESR1 mutations and SD/PR seen in 60.0% (SD: 2/5; PR: 1/5) of patients with wild-type ESR1. Conclusions: SAR439859 demonstrated a favorable safety profile and high ER occupancy in pretreated patients with ER+/HER2- mBC. Most patients had ESR1 mutations. Preliminary antitumor activity was encouraging in both ESR1 mutated and wild-type patients. With no DLTs and no MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK. Additional data on PK, PD, antitumor activity and the ESR1 mutational profile, and any correlations, will be presented. Funding: Sanofi. Citation Format: Mario Campone, Aditya Bardia, Gary A Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Jeffrey Ming, Marina Celanovic, Hannah M Linden. Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-02.

Abstract P5-05-01: Novel mechanisms of action of selective androgen receptor modulator RAD140 in AR+/ER+ breast cancer models

Abstract Background: Recurrence after standard-of-care estrogen receptor α (ER)-targeted therapy presents challenges in management of metastatic ER positive (ER+) breast cancer (BC). The high prevalence of androgen receptor (AR) in ER+ BC, along with preclinical and clinical evidence showing anti-tumor activity of AR agonists in AR+/ER+ BC, suggest an opportunity to address resistance to ER-targeted agents by targeting AR. Significant anti-tumor activity has been reported with RAD140, an oral selective AR modulator (SARM), in estrogen-dependent and -independent AR+/ER+ BC models. Mechanistic investigation revealed that inhibition of tumor growth by RAD140 was in part through AR-mediated reduction of ESR1 mRNA and subsequent suppression of ER signaling, independent of ESR1 alterations. Here, we present new observations on RAD140 mechanisms of action in in vitro and in vivo models of endocrine-independent BC models. Methods: HCC1428-long term estrogen deprived (LTED) line was established by passaging cells in steroid-depleted media for > 6 months. HCC1428-LTED-palbociclib resistant (-palboR) BC cell line was generated from LTED by long-term passaging in the presence of 500 nM palbociclib. Fluorescence-microscopy was used to assess annexin V/propidium iodide (PI) and phospho- H2A.X expression. The endocrine-independent BC PDX model was established in nude mice without supplemental estradiol. Prior anti-cancer therapy of the donor patient included tamoxifen, exemestane, fulvestrant and multiple lines of chemotherapy. RAD140 (3 mg/kg twice daily), elacestrant (30 mg/kg once daily), and palbociclib (10 mg/kg once daily) were administered via oral gavage for the duration of study. Fulvestrant (3 mg/mouse) was given once weekly subcutaneously. Results: In a hormone-independent BC PDX model harboring the ESR1 D538G mutation, RAD140 treatment led to 80% tumor growth inhibition (TGI) compared to the vehicle. The selective ER degrader (SERD) fulvestrant had TGI of 7%, while the oral SERD elacestrant (RAD1901) had TGI of 60%. The combination of RAD140 with elacestrant exhibited enhanced anti-tumor activity greater than that of each agent alone (93% TGI). These in vivo findings suggest the activity of the AR-targeting RAD140 may be mediated through mechanisms beyond its AR-mediated inhibition of ER signaling. We then sought to identify additional mechanisms of action of RAD140 in two hormone-independent AR+/ER+ BC cell line models, HCC1428-LTED and HCC1428-LTED-palboR. After prolonged treatment (2 weeks) at 100 nM, RAD140 induced morphological changes related to apoptosis, along with increased number of annexin V/PI-positive cells. This was further supported by increases in cleaved PARP/caspase3/caspase7 proteins by western blot analysis. A decrease in the pro-survival protein BCL-2 was also seen. These results collectively suggest that RAD140 induced apoptosis in endocrine-resistant BC cells. In line with these findings, an increase in phospho-H2A.X, a sensitive marker for DNA damage, was also observed in RAD140-treated cells. Similar changes were observed with the positive control AR agonist dihydrotestosterone (DHT), but not with fulvestrant. The AR antagonist apalutamide was found to partially reverse the apoptosis induced by RAD140 and DHT, further supporting the on-target effect. Conclusion: Our data suggest the anti-tumor activity of RAD140 may be mediated through suppression of ER signaling as well as additional mechanisms. The effect of RAD140 on DNA damage and apoptosis implies the potential for combination therapy with agents targeting cell survival and DNA damage repair pathways. RAD140 is being studied in a Phase 1, first-in-human trial in postmenopausal women with hormone receptor positive BC (NCT03088527). Citation Format: Suqin He, Maureen G Conlan, Heike Arlt, Charles Morris, Ziyang Yu. Novel mechanisms of action of selective androgen receptor modulator RAD140 in AR+/ER+ breast cancer models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-01.

173TiP PECan Study, Imaging PD-L1 in Cancer: A Tool for Measuring Response to Immunotherapy?

Abstract Background Cancer evades immune detection and destruction via upregulation of immune checkpoint molecules, such as programmed death-1 (PD-1). Signalling from these molecules can be inhibited by antibodies targeting them or their ligands (e.g. PD-L1). Durable responses have been demonstrated, for example, in subsets of patients with melanoma or non-small cell lung cancer (NSCLC). Identifying potential ‘responders’ remains challenging, with immunohistochemical PD-L1 expression the only validated biomarker to date. Biopsies are however invasive, do not account for intratumoural heterogeneity nor are practical for serial measurement, and therefore cannot be used to measure response to immunotherapy reliably. Radioisotope labelling and imaging of PD-L1 antibodies has been shown in preclinical (indium-111) and phase I clinical trials (technetium-99m (99mTc)) to demonstrate PD-L1 expression in tumours. It has the potential to capture heterogenous expression, as well as spatiotemporal variance which would permit quantitative assessment of expression and serve as a companion diagnostic and monitoring tool to improve patient stratification and outcomes. Trial Design The PECan (PD-L1 Expression in Cancer) study aims to determine whether PD-L1 expression measured using 99mTc-labelled PD-L1 single-domain antibody single photon emission computed tomography (SPECT) in melanoma and NSCLC correlates with, and thus can predict treatment response in those having anti-PD1/PD-L1 immunotherapy. 99mTc-PD-L1 SPECT will be compared with standard FDG-PET/CT at 0, 12 and 24 weeks in 15 patients with melanoma and FDG-PET/CT and standard CT at 0, 9 and 18 weeks in 15 patients with NSCLC. Imaging will be analysed centrally by an experienced nuclear medicine physician and correlated with clinical data. PD-L1 expression, assessed using SPECT, will also be correlated with baseline immunohistochemistry to determine intertumoural PD-L1 heterogeneity. Patients will require confirmed histological status, PD-L1 assessment and not have received any prior systemic anti-cancer therapy nor radiotherapy. This study is now open to recruitment with reporting expected late 2020. Clinical trial identification UK IRAS ID 256684. Legal entity responsible for the study King's College London and Guy's and St Thomas' NHS Foundation Trust. Funding Department of Cancer Imaging, King's College London, UK with funding from NanoMab Technology Limited, China. Disclosure G. Chand: Advisory / Consultancy, Shareholder / Stockholder / Stock options: NanoMab Technology Limited. H.H. Ting: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NanoMab Technology Limited. G. Cook: Research grant / Funding (institution): NanoMab Technology Limited. All other authors have declared no conflicts of interest.

Abstract B055: Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors

Abstract Background: Rebastinib is an orally administered, kinase inhibitor targeting the switch pocket of tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells, playing a role in angiogenesis. In addition, TIE2 is expressed in a subset of macrophages, TIE2 expressing macrophages (TEMs), which have pro-angiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as paclitaxel, increase the recruitment and activity of TEMs, leading to chemotherapy resistance. This study aims to investigate the efficacy of anti-TIE2 therapy against chemo-resistant advanced solid tumors. Methods: This is an open-label, Phase 1b/2, multicenter study with two parts. Part 1 evaluated two doses of rebastinib at 50 and 100 mg twice daily (BID) with paclitaxel administered weekly at 80 mg/m2 to determine the recommended phase 2 dose (RP2D) by enrolling at least 15 pts in each arm. The objective of Part 1 is to identify a recommended Phase 2 dose. Pts with locally advanced or metastatic solid tumors for which paclitaxel was considered appropriate treatment were enrolled. Part 2 has four disease-specific cohorts: triple-negative breast cancer, inflammatory breast cancer, platinum-resistant ovarian cancer and metastatic endometrial cancer to further evaluate the safety, tolerability and efficacy of the RP2D. This abstract focuses on data from Part 1. Results: A total of 43 pts were enrolled in Part 1 (24 pts at 50 mg BID and 19 pts at 100 mg BID) as of June 21, 2019. The median age was 61 years; 79% were female. Most frequent diagnoses were ovarian (11 pts), breast (8 pts) and endometrial cancer (7 pts). The median number of prior anti-cancer therapies was four (4). Median duration of treatment is 56 days. Treatment-emergent adverse events (TEAEs) were reported for 41 pts. Most TEAEs were previously observed in the rebastinib first-in-human study or were known AEs of paclitaxel. TEAEs >10% include mostly Grade (Gr) 1 or 2 fatigue (30%), constipation (21%), dry mouth (21%), nausea and alopecia (19% each), anemia and UTI (16%), hypokalemia, hypomagnesemia, peripheral neuropathy, and dyspnea (14% each), diarrhea, stomatitis, vomiting, sepsis, dysgeusia, rash and ALT elevation (12% each). Twenty-four pts experienced at least one ≥Gr 3 TEAE. Six pts had ≥Gr 3 AEs related to rebastinib. No significant difference in TEAEs was observed between the two dose levels. The RP2D was determined for rebastinib at 100 mg BID in combination with weekly paclitaxel at 80 mg/m2. Exposure of rebastinib was dose-proportional. Plasma TIE2 and its ligand, ANG2, were induced in a dose-dependent manner. Evidence of observed preliminary clinical activity in heavily pre-treated patients will be presented. Conclusion: Preliminary results demonstrated that the combination of rebastinib and paclitaxel was generally well tolerated. This combination is currently under evaluation in four disease-specific cohorts in Part 2. Clinical trial information: NCT03601897. Citation Format: Filip Janku, Michael Birrer, Debra Richardson, Christina Chu, Sanjay Goel, Ying Su, Bahar Matin, Keisuke Kuida, Rodrigo Ruiz-Soto, Erika Paige Hamilton. Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B055. doi:10.1158/1535-7163.TARG-19-B055

A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Entospletinib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Entospletinib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Idelalisib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Idelalisib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030)

BackgroundPatients with metastatic, recurrent, or persistent cervical cancer not amenable to local control and/or distant metastases have a very poor prognosis, only being candidates for palliative-systemic therapy. First line standard...

Antitumor activity of TAK-788 in NSCLC With EGFR exon 20 insertions

Abstract Background We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Methods Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with ≥1 disease assessment was PR, n = 14; SD, n = 9; and PD, n = 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥ 3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. Conclusions In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs.

LBA87 - INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥ 4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753)

LBA87 - INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥ 4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753)

1473P - First-line ceritinib versus chemotherapy in patients (pts) with advanced ALK rearranged (ALK+) non-small cell lung cancer (NSCLC): ASCEND-4 Asian subgroup analysis

BackgroundIn global phase III ASCEND-4 study (NCT01283516), ceritinib 750mg/day (fasted), demonstrated statistically significant and clinically meaningful improvement in PFS by BIRC (median, 16.6 mos [95% CI: 12.6, 27.2] vs 8.1 mos [95% CI: 5.8, 11.1]; HR=0.55; p<0.001) compared to chemotherapy (pemetrexed 500mg/m2 + cisplatin 75mg/m2 or carboplatin AUC 5-6, followed by pemetrexed maintenance) in untreated pts with advanced ALK+ NSCLC. Here, we report the efficacy and safety of ceritinib in Asian pts from ASCEND-4 study. MethodsPts with stage IIIB/IV, ALK+(centrally tested IHC), nonsquamous NSCLC, ≥1 measurable lesion per RECIST v1.1, and WHO PS 0–2 were eligible. Efficacy and safety were evaluated in Asian pts who had not received prior systemic anticancer therapy except neo-/adjuvant therapy. Data cutoff: June 24, 2016. ResultsAmong 376 pts randomized (1:1) in the study, 158 pts were Asian, with 76 in ceritinib arm and 82 in chemotherapy arm. Of these, 25 pts (32.9%) in ceritinib arm and 21 (25.6%) in chemotherapy arm had brain metastases at baseline. Median duration of treatment exposure: 64.5 wks (ceritinib, N=76) and 35.0 wks (chemotherapy, N=75). Median duration from randomization to data cutoff: 18.3 mos. Ceritinib demonstrated superior PFS by BIRC (median, 26.3 mos; 95% CI: 8.6, NE; HR=0.66) compared to chemotherapy (Table). Most common (≥50%; all grades; all-causality) AEs in ceritinib arm: diarrhea (85.5%), ALT increased (73.7%), vomiting (73.7%), AST increased (69.7%), and nausea (69.7%). Incidence of grade 3/4 AEs was <6%, except ALT increased (38.2%), GGT increased (22.4%), AST increased (21.1%), fatigue (7.9%), amylase increased (6.6%), and hyperglycemia (6.6%). Only 7 pts (9.2%) discontinued ceritinib due to AEs.Table1473PTableBy BIRC (N*=158)Ceritinib 750mg N=76Chemotherapy N=82Overall response rate (ORR), % [95% CI]65.8 [54.0, 76.3]29.3 [19.7, 40.4]Best overall response, n (%) Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Non-CR/Non-PD Unknown0 50 (65.8) 11 (14.5) 11 (14.5) 2 (2.6) 2 (2.6)0 24 (29.3) 38 (46.3) 6 (7.3) 3 (3.7) 11 (13.4)Disease control rate (DCR), % [95% CI]82.9 [72.5, 90.6]79.3 [68.9, 87.4]M‡=50M‡=24Median DOR, months [95% CI]NE [24.7, NE]16.4 [7.8, NE]n/N (%)14/50 (28.0)8/24 (33.3)% Event-free probability estimates [95% CI]9 months81.2 [67.0, 89.8]76.1 [48.0, 90.4]12 months79.0 [64.5, 88.1]50.8 [22.5, 73.5]15 months70.4 [54.0, 81.9]50.8 [22.5, 73.5]Median PFS, months [95% CI]26.3 [8.6, NE]10.6 [6.7, 15.0]n/N (%)32/76 (42.1)45/82 (54.9)% Event-free probability estimates [95% CI]9 months61.0 [48.4, 71.5]54.7 [41.8, 65.8]12 months61.0 [48.4, 71.5]49.8 [37.1, 61.2]15 months55.9 [43.2, 66.9]39.0 [26.9, 51.0]*Total number of patients included in the full analysis set.‡Total number of patients with confirmed complete response or partial response. n: Total number of events included in the analysis. N: Total number of patients included in the analysis. ConclusionsIn Asian pts with ALK+ NSCLC, ceritinib demonstrated durable and clinically meaningful efficacy and a safety profile consistent with overall ASCEND-4 study results. Clinical trial identificationNCT01828099. Editorial acknowledgementShilpa Garg, Novartis Healthcare Pvt Ltd. Legal entity responsible for the studyNovartis Pharmaceuticals Corporation. FundingNovartis Pharmaceuticals Corporation. DisclosureD.S. Tan: Honoraria (self): Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli-lily, Loxo; Research grant / Funding (self): Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer; Travel / Accommodation / Expenses: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche,Takeda. S. Geater: Advisory / Consultancy: Boehringer Ingelheim; Honoraria (institution): AstraZeneca, Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Roche, Novartis, Boehringer Ingelheim; Full / Part-time employment: Prince of Songkla Univerisity. C.J. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim. T.C. Hsia: Advisory / Consultancy: Norvatis, Lilly, AZ, Roche local speaker. M.C. Lin: Advisory / Consultancy: AZ, Novartis, BI, Roche. V. Sriuranpong: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Novartis, Roche, Pfizer, Eisai, Boehringer, Taiho, MSD, BMS, Amgen; Research grant / Funding (institution): AstraZeneca, Novartis, Roche, Pfizer, Boehringer, Eisai, Taiho, Lilly, MSD. P. Sen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. F. Branle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Shi: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Y.L. Wu: Honoraria (self): AZ, Roche, Eli Lilly, Pfizer, MSD, BMS, BI; Advisory / Consultancy: AZ, Roche, BI; Research grant / Funding (institution): AZ, Roche. All other authors have declared no conflicts of interest.

602P - Safety and effectiveness of aflibercept + FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC): OZONE secondary analyses

BackgroundFor patients with mCRC that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. In these secondary analyses of the OZONE study, aflibercept + FOLFIRI safety and efficacy was evaluated for sub-populations of patients with mCRC. MethodsOZONE is a prospective, multicentre, observational, non-comparative study evaluating patients receiving aflibercept + FOLFIRI in the clinical setting, for 24 months from aflibercept initiation or until death. Patients were grouped according to: age (≥ 65 years vs<65 years); renal (CrCl ≤ 80mL/min) or hepatic (bilirubin > UNL or AST/ALT > 1.5 UNL) impairment; number and type of prior anti-cancer therapy. ResultsFrom the overall population (N=766), there were 370 patients aged ≥ 65 years. All grade asthenia (43.5% vs 35.9%) and decreased appetite (25.4% vs 20.2%) occurred more frequently (≥ 5%) in patients aged ≥ 65 vs<65 years. There were 256 patients with CrCl ≤ 80mL/min, of which 43 had CrCl < 50mL/min. Renal function did not influence treatment-emergent adverse events (TEAEs). Grade ≥ 3 TEAEs were reported in 76.7%, 67.1% and 67.9% of patients with CrCl < 50mL/min, CrCl 50–80mL/min, and CrCl > 80mL/min, respectively. There were 129 patients with impaired liver function. All grade constipation and haemorrhage were more frequent in patients with impaired liver function vs those without (23.3% vs 14.2% and 37.2% vs 30.1%, respectively). There were 449 patients previously treated with bevacizumab. Only fatigue occurred more frequently in patients with prior bevacizumab vs those without (23.8% vs 17.0%). Efficacy multivariate analyses showed that treatment with aflibercept + FOLFIRI favoured patients without vs with hepatic impairment (median overall survival [OS] 13.7 vs 8.7 months; p<0.001) and without vs with prior use of bevacizumab (median OS 16.6 vs 10.6 months; p<0.001). ConclusionsSubgroup analyses of the OZONE study did not reveal major differences in the safety profile according to age, renal or hepatic status, or prior bevacizumab status. These results suggest that aflibercept may be a treatment option for these subgroups of patients. Funding: Sanofi. Clinical trial identificationENCEPP/SDPP/4836. Legal entity responsible for the studyThe authors. FundingSanofi. DisclosureI. Chau: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eli-Lilly; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (self): Janssen-Cilag; Research grant / Funding (self): Sanofi Oncology. P. García-Alfonso: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Sanofi Oncology; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Servier. Z. Linke: Advisory / Consultancy, Advisory Board- Oncologic days in Bratislava, Slovakia, 2016, 2017, 2018 and Prague in 2018.: Sanofi; Speaker Bureau / Expert testimony, Lecture- Prague Onco 2019: Merck; Non-remunerated activity/ies, ESMO 2017: Roche. A. Ruiz-Casado: Research grant / Funding (self): Sanofi; Research grant / Funding (self): Servier; Research grant / Funding (self): Amgen; Research grant / Funding (self): Merck; Research grant / Funding (self): Lilly; Research grant / Funding (self): Roche; Research grant / Funding (self): Medtronic; Research grant / Funding (self): BTG. E. Polo Marques: Research grant / Funding (self): Roche; Research grant / Funding (self): Amgen; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Merck. T. Cartwright: Research grant / Funding (self): Amgen; Research grant / Funding (self): Taiho. All other authors have declared no conflicts of interest.

Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer.

Angiogenesis plays a critical role in the neoplastic growth, progression, and metastasis of colorectal cancer (CRC) in a process regulated by vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR). Several small-molecule anti-VEGFR tyrosine kinase inhibitors (TKIs), such as regorafenib, famitinib, axitinib and apatinib, have been shown to be effective in treating metastatic colorectal cancer (mCRC). Fruquintinib (ELUNATE®) is a novel oral anti-VEGFR TKI, originated and developed by Hutchison MediPharma. Fruquintinib is a potent and highly selective small-molecule inhibitor of VEGFR-1, -2 and -3. In the Phase 3 FRESCO trial, fruquintinib improved both overall survival (OS) and progression-free survival (PFS) in patients with mCRC, compared with placebo. Fruquintinib also showed an acceptable safety and tolerability profile. Based on the data from this trial, fruquintinib was approved by the China Food and Drug Administration (CFDA) in 2018, for the treatment of patients with mCRC who had undergone at least two prior standard anticancer therapies. The existing clinical trials and future prospects of fruquintinib in mCRC will be discussed in this article. In addition, to better understand the role of fruquintinib in this setting, recent advances in other anti-VEGFR TKIs for mCRC treatment are also reviewed herein.

Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).

1054 Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy (18FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18FES-PET scans, signal inhibition &gt; 87% occurred with plasma concentrations &gt; 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average Ctrough was reached after repeated 400 mg QD allowing 90% of 18FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.

Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.

1040 Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.

Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.

9007 Background: TAK-788 is an oral investigational EGFR/HER2 inhibitor under evaluation in NSCLC patients (pts) with EGFR exon 20 insertions. We report results of a phase 1/2 open-label, multicenter study (NCT02716116). Methods: Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results: As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (median 3.6 mo on treatment; median 3.8 treatment cycles); 24 pts remain on treatment. Antitumor activity in pts with EGFR exon 20 insertions is shown in Table. At data cutoff, 7/14 responses were confirmed with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Rate of treatment discontinuation due to AEs was 10.7% in pts treated at 160 mg. Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥3 TEAEs (≥5%) were diarrhea (26%) and hypokalemia, nausea, and stomatitis (7% each). Median dose intensity for pts treated with 160 mg qd was 93%. There is no clear trend that response to TAK-788 is enriched in particular EGFR exon 20 insertion variants. Conclusions: In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. Clinical trial information: NCT02716116. [Table: see text]