Flat Dose Research Articles

Pembrolizumab and Copanlisib for the Treatment of Relapsed or Refractory Mature T-Cell Lymphomas

Pembrolizumab and Copanlisib for the Treatment of Relapsed or Refractory Mature T-Cell Lymphomas

Daratumumab (DARA) Subcutaneous (SC) Delivery in Relapsed or Refractory Multiple Myeloma (RRMM): Population Pharmacokinetics (PPK) and Exposure-Response (E-R) Analysis

Daratumumab (DARA) Subcutaneous (SC) Delivery in Relapsed or Refractory Multiple Myeloma (RRMM): Population Pharmacokinetics (PPK) and Exposure-Response (E-R) Analysis

ATIM-17. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) COMBINED WITH NIVOLUMAB (NIVO), IPILIMUMAB (IPI) AND BEVACIZUMAB (BEV) IN PATIENTS (PTS) WITH RECURRENT HIGH GRADE GLIOMAS

Abstract BACKGROUND There is strong pre-clinical evidence that combining CTLA4 and PD-1/PDL-1 blockade with antiangiogenic agents and HFSRT independently enhance anti-tumor immune responses and tumor regression. METHODS This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 26 pts. Pts with Bev naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior RT is required unless there is a new recurrence outside of the previous RT treatment field. Eligible pts are treated with HFSRT to the recurrent tumor (30 Gy in 5 fractions) and 4 cycles of Nivo (3 mg/kg), Ipi (1 mg/kg) and Bev (15 mg/kg) every 3 weeks followed by Nivo 240 mg and Bev 10 mg/kg every 2 weeks for 4 months. After 4 months, Nivo is administered every 4 weeks at 480 mg flat dose and Bev is continued at every 2 week schedule. The primary study objectives are to determine safety and tolerability of above treatment. Secondary endpoints include response rate, 6 and 9-months survival rates, and exploring tissue and imaging biomarkers. RESULTS As of June 2019, safety cohort has been completed and accrual to dose expansion cohort is ongoing. Combination of HFSRT, Nivo, Ipi and Bev as above is well tolerated. The most common toxicities were grade 1 anorexia, grade 1 diarrhea, grade 1 elevation of alanine aminotransferase, grade 1 elevation of lipase and grade 1 infusion related reaction. One patient had grade 3 confusion which was reversible with use of corticosteroids. No dose limiting toxicity has been observed. CONCLUSIONS Combination of HFSRT with Nivo, Ipi and Bev was considered safe to be studied in expansion cohort. Updated safety and efficacy data will be presented.

RBTT-08. A RANDOMIZED PHASE 2 OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VERSUS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (GBM)

Abstract INTRODUCTION Initial trials with anti-PD1 in recurrent glioblastoma showed limited efficacy. Vascular endothelial growth factor (VEGF) is a highly upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression by inhibition of dendritic cell maturation and antigen presentation, induction of apoptosis of CD8+ T-cells and enhancing Treg activity. Hence, a combination of anti-PD1 and anti-VEGF is promising approach in recurrent GBM. METHOD This is a 90 patient randomized, open-label, phase 2 safety study of Nivolumab and bevacizumab administered according to standard and reduced dosage schedules in patients with first recurrence of GBM. Patients will undergo 1:1 randomization to receive treatment with either Nivolumab (240 mg flat dosing IV every 2 weeks) and bevacizumab administered according to standard (10 mg/kg IV every 2 weeks; Arm A) and reduced (3 mg/kg IV every 2 weeks; Arm B) dosage schedules for recurrent glioblastoma patients. The study will allow patients that require dexamethasone up to 4 mg/day to participate in the study. All subjects will be followed for safety and tolerability, tumor progression and overall survival. Tumor progression or response endpoints will be assessed using the Radiologic Assessment in Neuro-Oncology (RANO) criteria and an exploratory endpoint will evaluate the response endpoints using the Immunotherapy RANO (iRANO). Treatment with study medication will continue until confirmed tumor progression, unacceptable toxicity or death. It is expected that enrollment and follow-up of randomized subjects (45 subjects in each arm) will take approximately 12months. The one-sample log-rank test will be applied to outcomes observed for each arm individually to test the hypothesis that OS has been improved beyond the null 12-month survival rate of 45%. With N=45 patients per arm, a one-sided test provides power=0.80 to detect survival rate of 58% at 12-months following treatment at the 0.10 significance level. The study (NCT03452579) is ongoing and enrolling patients.

212P - Immunotherapy with nivolumab in metastatic renal cell carcinoma patients in India: Bringing a change in clinical practice

BackgroundThe standard practice for management of metastatic renal cell cancer (mRCC) patients in India has been sunitinib or pazopanib in the first line setting, and everolimus at progression. Nivolumab in the second line setting, showed a median overall survival (OS) of 26 months, 2year OS rate of 52% and objective response rate(ORR) of 26%; which was better than everolimus in the Checkmate 025 study. There is sparse data about nivolumab in Indian RCC patients. MethodsThis is a single centre, retrospective analysis, which included mRCC patients who received nivolumab between April 2016 to April 2019. The endpoints were ORR, OS and adverse events (AEs). Results31 patients of mRCC received nivolumab at 3 mg/kg or flat dose of 240mg. Median age was 60 years (22-82 years). There were 27 males and 4 females. 4 patients received first line nivolumab, and 27 patients as second line. 16 patients had earlier received sunitinib, 10 pazopanib, and 1 sorafinib. 3 patients (9.7%) achieved complete response(CR), 8(25.8%) achieved partial response, 8(25.8%)had stable disease and 12(38.7%)had progressive disease. The 3 patients with CR, received 18 doses, after which their treatment was stopped; and they continue to be in CR at followup of 36, 32 and 26 months respectively. 10 patients have completed more than 12 cycles. OS at 1 year is 60% and median OS has not been reached. The common AEs were fatigue in 8(25.8%), hypothyroidism in 6(19.3%), skin rash in 4(12.9%) and pneumonitis in 3(9.7%) patients. Colitis, arthritis, immune retinopathy, and myocarditis was each seen in 1 patient. Treatment was discontinued in 3 patients who developed grade 3 AEs. ConclusionsWith an ORR of 35.5%, nivolumab has replaced everolimus, and has become our standard second line regimen in mRCC. Achieving an OS at 1 year of 60% is the best we have seen in the second line setting. The most exciting impact has been the durable long lasting response seen (duration ranging 2-3 years) even after discontinuing treatment, in our 3 CR patients. This has prompted us to make 1 year of treatment as a standard duration of nivolumab for responding patients at our center; enabling us to reduce cost of treatment. It is very well tolerated; but a careful watch should be kept for immune related AEs. Legal entity responsible for the studyAmit Rauthan. FundingHas not received any funding. DisclosureA. Rauthan: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

PCN105 COST-UTILITY OF NIVOLUMAB FOR RECURRENT OR METASTATIC HEAD AND NECK CANCER (R/M SCCHN) IN FRANCE

Nivolumab is indicated for the treatment of adult patients with R/M SCCHN progressing during or after platinum-based chemotherapy. We conducted a cost-utility analysis to evaluate nivolumab efficiency compared to standard therapies according to methodological guidelines of the French ‘Haute Autorité de Santé’ (HAS). A three-state partitioned survival model was developed to simulate the evolution of a cohort of patients with R/M SCCHN over a lifetime horizon. Clinical data were obtained from pivotal phase III CheckMate 141 comparing nivolumab to investigator's choice (IC) of standard therapies: cetuximab, docetaxel or methotrexate. Progression-free and overall survival extrapolation was based on parametric models. Utility data were from CheckMate 141 (EQ-5D; French tariffs): 0.743 for nivolumab and 0.682 for IC in pre-progression state and, 0.628 for both comparators in post-progression state. Costs of disease management, treatment administration, adverse events, monitoring and palliative care were obtained from recently published real-world data in national health insurance databases. Treatment acquisition cost was based on public prices, flat dose for nivolumab (240 mg per patient) and the IC treatment mix in France: 32% cetuximab, 20% methotrexate, 28% docetaxel. A probabilistic sensitivity analysis (PSA) was performed. In the base-case scenario, nivolumab produced 1.12 life years (LY) and 0.76 Quality Adjusted Life Years (QALY) versus 0.64 LY and 0.42 QALY for standard therapies. Total costs of nivolumab were €58,232 and €29,706 for standard therapies. Incremental cost effectiveness ratios of nivolumab were €59,911/LY and €84,461/QALY versus standard therapies. PSA reported 89% probability that nivolumab would be an efficient strategy at a willingness to pay (WTP) of €100,000 per QALY. Our results suggest that nivolumab would be a cost-effective option to treat patients with R/M SCCHN in France at a WTP of €100 000 per QALY.

287TiP - Neoadjuvant HER2-targeted therapy with or without immunotherapy with pembrolizumab (neoHIP): An open label randomized phase II trial

BackgroundImmune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) is safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, HER2-directed therapy with ICI administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxic backbones; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). This randomized, multicenter, phase II, open-label trial, will evaluate the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K (NCT03747120). Trial design174 patients (pts) ≥18y with previously untreated, clinical stage II-III, HER2+ breast cancer will be randomized 1:1:1 to one of the 3 arms, stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive THP: T at 80mg/m2 weekly for 12 weeks, H day 1 at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P day 1 at 840mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K day 1 at 200mg (flat dose) and then every 3 weeks x 3 doses (THP-K). In arm C, pts receive TH-K. Definitive surgery is 3-6 weeks after the last dose of T. After surgery, pts are treated per the treating physician’s discretion including HER2-directed therapy and radiotherapy per local clinical standards. Pts whose tumors are hormone-receptor positive will receive hormone therapy per local standard-of-care. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Clinical trial identificationNCT03747120. Legal entity responsible for the studyThe authors. FundingBreast Cancer Research Foundation, Merck & Co. DisclosureH.L. McArthur: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Genomic Health; Research grant / Funding (institution): ZIOPHARM Oncology; Travel / Accommodation / Expenses: Puma Biotechnology. J.H.S. Leal: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca. D.B. Page: Honoraria (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy: Syndax; Advisory / Consultancy: Nektar; Advisory / Consultancy: NanoString Technologies; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Puma Biotechnology; Speaker Bureau / Expert testimony: Genentech/Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: MedImmune; Speaker Bureau / Expert testimony: Philips Healthcare. A. Bardia: Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Radius Health; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Innocrin; Advisory / Consultancy, Research grant / Funding (institution): Biothernostics Inc.; Advisory / Consultancy: Spectrum Pharma; Advisory / Consultancy: Taiho; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Daiichi Pharma. L. Spring: Advisory / Consultancy: Novartis; Advisory / Consultancy: Lumicell; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Tesaro. R.K. Basho: Advisory / Consultancy: Puma Biotech; Advisory / Consultancy: Heron Therapeutics. S. Verma: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Puma; Advisory / Consultancy: Novartis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Mylan. All other authors have declared no conflicts of interest.

817P - First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma

BackgroundTrastuzumab stimulates HER2-specific T cell responses and increases tumour PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. MethodsPatients (pts) with previously untreated HER2 IHC 3+ or FISH+ tumours irrespective of PD-L1 status received intravenous P 200mg flat dose, T 6mg/kg (after 8mg/kg load), O 130mg/m2 every 3 weeks and oral C 850mg/m2 2 weeks on/1 week off. 22 pts received 1 cycle of induction P/T prior to initiation of chemotherapy. The primary endpoint was 6-months PFS; with target accrual of 37 pts. Secondary endpoints included safety, OS, ORR, and biomarker analysis. ResultsAccrual completed and 100% of the 37 evaluable pts had tumour regression (ranging from -4% to -100%). The RECIST 1.1 ORR was 81% (27 PR, 3 CRs), and 12 (52%) of pts that received induction P/T x 1 cycle showed reduction in target lesions. Median PFS was 14.2 months (mo), with 70% 6mo PFS. Median follow up was only 8mo. In pts with available material, 14/36 (40%) had PD-L1 CPS >1 and median TMB was 4.4 mut/Mb (0-10.6). There was no correlation between PD-L1 status and PFS or OS. ERBB2 amplification was evident by tissue-NGS in 17/30 (63%) and ctDNA-NGS in 17/30 (58%) pre-treatment, while the remaining pts were ERBB2- by NGS likely due to tumour heterogeneity or low tumour content. CtDNA decreased in 16/24 tested pts after 1 cycle of induction T/P alone. irAEs included interstitial nephritis Gr4 (3%), transaminitis Gr3 (11%), Gr4 (3%), colitis Gr3 (3%). Conclusions40% remain on therapy, and so the primary endpoint should be reached by 9/19. Updated survival, correlative studies and will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial (NCT03615326). Legal entity responsible for the studyMemorial Sloan Kettering Cancer Center. FundingMerck. DisclosureY.Y. Janjigian: Advisory / Consultancy, Research grant / Funding (self): Bristol-Meyers; Advisory / Consultancy, Research grant / Funding (self): Eli Lily; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Merck; Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): Boehringer Ingelhiem; Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Imugene. S. Maron: Non-remunerated activity/ies, Research Collaboration Only: Guardant Health; Shareholder / Stockholder / Stock options: Calithera; Travel / Accommodation / Expenses: Merck; Licensing / Royalties, Non-remunerated activity/ies, Research Collaboration Only: Genentech. G.Y. Ku: Advisory / Consultancy, Research Support: Arog; Advisory / Consultancy, Research Support: Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Research Support: Merck; Advisory / Consultancy, Research Support: Pieris; Advisory / Consultancy, Research Support: Zymeworks. D.H. Ilson: Advisory / Consultancy: Merck; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pieris; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Britsol Myers Squibb; Advisory / Consultancy, Contracted Research: Taiho. D. Solit: Advisory / Consultancy: Pfizer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Loxo Oncology; Advisory / Consultancy: Illumina; Advisory / Consultancy: Vivideon Therapeutics; Honoraria (institution), Speaker Bureau / Expert testimony: Lilly Oncology. J.F. Hechtman: Research grant / Funding (institution): Bayer; Honoraria (institution): Medscape; Advisory / Consultancy: Axiom Healthcare Strategies; Advisory / Consultancy: Cor2Ed. M. Lamendola-Essel: Advisory / Consultancy: Rockefeller University. All other authors have declared no conflicts of interest.

961P - First results of safety profile of nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in II and III line of patients (pts) with metastatic renal cell carcinoma (mRCC) in NIVES study

BackgroundNIVO is an anti-programmed cell death-1 (PD-1) monoclonal antibody; it might work even better when combined with SBRT improving clinical outcomes with a phenomenon known as abscopal effect. To date there are limited data on safety profile of combined SBRT and NIVO in mRCC. We report for the first time the toxicities occurred in phase II NIVES Study. MethodsThis is a phase II, single arm, multicentre study in pts with mRCC with progression disease after≤2 prior anti-angiogenic therapies and with measurable non-brain metastatic sites, at least one of which potentially suitable for SBRT. The pts included received hypofractionated radiation in one lesion at dose of 10Gy/3 fractions after 7 days from the first infusion of NIVO. NIVO will be given as flat dose of 240mg on day 1 every 14 days for 6 months, then switch to 480mg q4-weekly in responding pts until PD or unacceptable toxicity. Descriptive statistics are reported for patient/tumor/treatment characteristics and observed severe Adverse Events (AEs) graded by CTCAE v. 4.03. ResultsSixty-nine pts were enrolled from July 2017 to March 2019 in 11 Italian centers. 79.7% of pts had clear cell histology, median age was 67 years (range 43-85), 82.6% were male. ECOG PS was 0 in 57 pts (82.6%), only 18.8% pts had received 2 previous lines of therapy. The most frequent sites of SBRT were lung (39.4% of pts), lymphonodes (16.7%) and bone (10.6%). Toxicities of grade (G) 3-4 related to NIVO were experienced in 13 pts (18.8%); all G3-4 toxicities were outside of the irradiated area. The most frequently observed G3-4 treatment-related AEs included diarrhea (5.8%), fatigue (4.3%), anemia (2.9%) and increase of amylase/lipase (2.9%). To date no G3-4 pneumonitis were observed. Six pts (8.7%) were hospitalized due to treatment-related SAEs. Overall, 5 of 69 treated pts (7.2%) discontinued therapy because of G3-4 AEs. At the time of this analysis 32/69 pts (46%) are still on treatment. ConclusionsConcurrent NIVO plus SBRT is generally well tolerated, without increased rates of common severe toxicity. Definitive data of toxicities and efficacy of the combination of immunotherapy and radiotherapy are not yet mature. Clinical trial identificationNCT03469713. Legal entity responsible for the studyGOIRC. FundingGOIRC. DisclosureC. Masini: Travel / Accommodation / Expenses: BMS, Janssen, Astellas, Bayer; Advisory / Consultancy: Pfizer, Novartis, Sanofi. U.F.F. De Giorgi: Research grant / Funding (institution): AstraZeneca, Roche, Sanofi; Advisory / Consultancy: Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer, Sanofi; Travel / Accommodation / Expenses: BMS, Ipsen, Janssen, Pfizer. S. Buti: Advisory / Consultancy: BMS, Pfizer, MSD. M. Milella: Speaker Bureau / Expert testimony: AstraZeneca, Pfizer, EUSA Pharma. M.G. Vitale: Speaker Bureau / Expert testimony: Astellas, Ipsen, Janssen, Pierre Fabre, BMS, Pfizer, Novartis; Travel / Accommodation / Expenses: Astellas, Pfizer, Ipsen, Janssen, BMS, Novartis; Advisory / Consultancy: Janssen, BMS. G. Procopio: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer, BMS, Ipsen, MSD, Novartis, Pfizer. F. Nole: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS, Ipsen, Pfizer, Bayer, Novartis, MSD. G. Pappagallo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen, BMS, Astellas, Janssen, Bayer, Pfizer, Novartis. C. Pinto: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche, BMS, MSD, Janssen, Pfizer, Novartis, Ipsen, Lilly, Bayer. All other authors have declared no conflicts of interest.

P1.01-67 Ph I/II Carboplatin, Nab-Paclitaxel and Pembrolizumab for Advanced NSCLC (HCRN LUN13-175): Outcomes by Nab-Paclitaxel Dose

Combination chemotherapy and immunotherapy have significantly improved survival for patients with treatment-naïve advanced non-small cell lung cancer (NSCLC). We sought to evaluate the safety and efficacy of adding pembrolizumab to a standard regimen at the time of study development, nab-paclitaxel and carboplatin. Safety data from phase I have been reported, and phase II commenced with the same chemotherapy doses and flat dosing of pembrolizumab at 200 mg. Patients with treatment-naïve, stage IIIB/IV NSCLC AJCC 7 (all histology), any PDL1, no EGFR or ALK, ECOG 0-1, received carboplatin AUC 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3wks. Co-primary endpoints were progression-free survival (PFS) and response rate (RR). PDL1 was assessed prior to treatment and from biopsies obtained after cycle 4. 46 patients enrolled, 14 on phase I and 32 in phase II, from June 2015–July 2018. Accrual stopped after data was presented from similar phase III trials. 43 were evaluable for the primary endpoints. Median age was 65 years, 48% female, 45% adenocarcinoma, 94% current/former smokers, 9% brain metastases. PDL1 expression (TPS) by <1%, 1-49%, and ≥50% cutoffs was 44%, 28%, and 28%, respectively. ORR was 28%. Median PFS was 5.6 months (CI, 4.2-10.5 mo). Median OS was 15.7 mo (CI 11.1-22.3 mo). There was no statistical differences in PFS or OS outcomes by PDL1 status. Paired PDL1 results from pre- and post-treatment biopsies were available in 8 patients. PDL1 status changed categories in 4/8 samples (n=3, 0% to positive; n=1, 99% to 0%). The most common grade 3-4 adverse events (AEs) were neutropenia (64%), anemia (31%), thrombocytopenia (24%), leukopenia (16%) and fatigue (11%). Other notable AEs included rash (58%), diarrhea (47%), neuropathy (22%), arthralgia (18%), transaminitis (13%), and myalgia (11%). 18% discontinued treatment due to AEs. In an exploratory analysis, there was no difference in median PFS for those receiving total nab-paclitaxel dose of 400–799 mg/m2 compared to ≥800 mg/m2 (6.2 mo vs. 8.2 mo, p=0.62). Although the study did not meet its pre-specified endpoints of PFS 9 months and RR of 50%, results were similar to previously reported phase III Keynote 407 (squamous histology). Despite hematologic toxicity, the combination could safely be administered, and outcomes were similar for those receiving moderate doses of nab-paclitaxel compared to those with an average of at least 200 mg/m2 per cycle.

461P - First in human phase I/IIa study of PEN-866, a heat shock protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumours: Phase I results

461P - First in human phase I/IIa study of PEN-866, a heat shock protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumours: Phase I results

Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.

High Efficacy and Safety of Flat-Dose Ribavirin Plus Sofosbuvir/Daclatasvir in Genotype 3 Cirrhotic Patients.

Background/AimsPatients with genotype 3 hepatitis C virus (G3-HCV) cirrhosis are very difficult to treat compared to patients with other HCV genotypes. The optimal treatment duration and drug regimen associated with ribavirin (RBV) remain unclear. To evaluate the efficacy and safety of daclatasvir (DCV)/sofosbuvir (SOF) plus a flat dose of 800 mg RBV (flat dose) compared to DCV/SOF without RBV or DCV/SOF plus an RBV dose based on body weight (weight-based) in G3-HCV patients with compensated or decompensated cirrhosis.MethodsWe analyzed data for 233 G3 cirrhotic patients. Of these, 70 (30%), 87(37%) and 76 (33%) received SOF/DCV, SOF/DCV/RBV flat dose, and SOF/DCV/RBV weight-based dose, respectively. Treatment duration was 24 weeks. Sustained virological response (SVR) was evaluated at week 12 posttreatment (SVR12).ResultsOverall, SVR12 was achieved in 220 out of 233 patients (94.4%). The SVR12 rate was lower in the DCV/SOF group than in the DCV/SOF/RBV flat-dose group and the DCV/SOF/RBV weight-based group (87.1% vs 97.7% and 97.4%, respectively, p=0.007). A higher incidence of anemia occurred in the DCV/SOF/RBV weight-based group compared to those in the other two groups (p<0.007).ConclusionsWe found that the DCV/SOF/RBV flat-dose regimen is an effective treatment in terms of efficacy and safety in patients with G3-HCV compensated or decompensated cirrhosis. Therefore, antiviral regimens without RBV should be restricted only to naïve patients with G3-HCV compensated cirrhosis who have a clear contraindication for RBV.

Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types.

Bintrafusp alfa, an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, has shown promising antitumor activity and manageable safety. To support the dosing strategy for bintrafusp alfa, we developed a population pharmacokinetics model using a full covariate modeling approach, based on pharmacokinetic and covariate data from 644 patients with various solid tumors who received bintrafusp alfa intravenously in two clinical studies. A two-compartmental linear model best described bintrafusp alfa concentrations, and no time-varying clearance was identified. Using this model, the estimated clearance was 0.0158l/h (relative standard error, 4.1%), and the central and peripheral volume of distribution were 3.21l (relative standard error, 3.2%) and 0.483l (relative standard error, 9.8%), respectively. The estimated mean elimination half-life of bintrafusp alfa was 6.93days (95% CI 4.69-9.65days). Several intrinsic factors (bodyweight, albumin, sex, and tumor type) were found to influence bintrafusp alfa pharmacokinetics, but none of these covariate effects was considered clinically meaningful and no dosage adjustments are recommended. Notably, simulations from the model suggested less variability in exposure metrics with flat dosing versus weight-based dosing. Pharmacokinetic analysis of bintrafusp alfa supports the use of a flat dose regimen in further clinical trials (recommended phase 2 dose: 1200mg every 2weeks). ClinicalTrials.gov identifiers: NCT02517398 and NCT02699515. Merck Healthcare KGaA as part of an alliance between Merck Healthcare KGaA and GlaxoSmithKline.

Abstract LB-268: Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors

Abstract Background: INCMGA00012, a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1, is being developed for the treatment of multiple solid tumor types, both as monotherapy and in combination with other potentially immunoactive agents. Flat dosing is preferred to weight-based dosing for multiple reasons, including convenience of preparation and administration, reduced errors in preparation calculation, and minimization of drug waste. A modeling and simulation approach was employed to support flat doses for later phase studies. Patients and Methods: INCMGA00012 has been administered to approximately 200 participants in a Phase 1 study (Study INCMGA 0012-101) at weight-based doses ranging from 1 to 10 mg/kg Q2W or Q4W and at flat doses of 500 mg Q4W and 750 mg Q4W. PK data from weight-based doses were used for population PK model development and data from flat doses were used for model validation. Simulations were performed to support the selection of RP2 flat dose. Results: The concentrations of INCMGA00012 were adequately described by a 2-compartment model with first-order elimination. Higher clearance was estimated for 1 mg/kg (23.5 mL/h) than the other dose groups (13.5 mL/h). Body weight dependence of clearance and volume of distribution for central compartment were characterized by power relationships with exponents of 0.911 and 0.493, respectively. The model was validated using PK data from participants who received INCMGA00012 500 mg Q4W and 750 mg Q4W, respectively, in the cohort expansion phase. Median steady state trough concentrations of 500 mg Q4W and 750 mg Q4W exceeded the target value. Conclusion: Modeling and simulation provide justification for 500 mg Q4W for further clinical development of INCMGA00012 based upon favorable safety, PK characteristics and presumed flat exposure-response relationships for efficacy. Citation Format: Xuejun chen, Phil Wang, Sanjeev Kaul, Bradley Sumrow, Swamy Yeleswaram. Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors [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 LB-268.

Abstract 1469: Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration

Abstract Background:EnAd is a tumor-selective oncolytic adenovirus with highly selective replication and cell killing in a broad range of carcinoma cell lines. Following intravenous dosing in clinical studies, uptake and replication of EnAd, associated with CD8+ cell infiltration, has been shown. It is currently in combination studies with nivolumab and paclitaxel. Intravenous delivery of EnAd stimulates an acute response characterised by an increase in cytokines in peripheral blood. As previously reported (ESMO IO 2017, abstr 203), the MTD of EnAd (3x1012 viral particles (vp) Days 1, 3 and 5, flat dosing schedule) has been determined primarily based on AEs occurring on first dose (C1D1), with the cytokine response, including interleukin-6 (IL-6), to subsequent doses of EnAd appearing attenuated when delivered within a few days of the first dose. Methods: The effect of the first EnAd dose on subsequent acute particle-mediated cytokine (IL-6) responses in mice was investigated following administration of systemic doses equivalent to between 5.5 x 1012 vp and 5.5 x 1013 vp in humans. Results: The magnitude of IL-6 response to a low first dose, which itself induces very low or undetectable levels of IL-6 cytokine, is sufficient to attenuate the response to subsequent high doses (10 times more vp). When administered as first dose these high doses induced a significant elevation in systemic IL-6. Conclusions: Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. The data from this in vivo pharmacology study support the concept of delivering a lower dose of enadenotucirev on Day 1 and administering higher doses thereafter, with the aim to deliver a higher viral load to tumour tissue and potentially optimise the overall risk:benefit of EnAd administration. This type of dosing regimen (low-high-high) has been successfully implemented in clinical studies of other systemically administered oncolytic viruses (Clin Cancer Res 2006;12:2555-2562) and is under clinical investigation as part of the ongoing combination study with nivolumab. (EudraCT:2013-001276-38). Citation Format: Hilary McElwaine-Johnn, Sam Illingworth, Rochelle Lear, Richard Brown, Brian Champion. Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration [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 1469.

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use.

Protein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed.

PS1535 AUTOLOGOUS STEM CELL TRANSPLANT FOLLOWED BY POST‐TRANSPLANT IMMUNOTHERAPY WITH NIVOLUMAB AND UNSELECTED AUTOLOGOUS LYMPHOCYTES INFUSION AS SALVAGE THERAPY FOR RELAPSED/REFRACTORY HODGKIN LYMPHOMA

Background:About 30% of Hodgkin Lymphoma (HL) patients are refractory to induction therapy or relapse. Standard salvage treatment is often followed by high‐dose chemotherapy and autologous stem cell transplantation (ASCT) if at least a partial remission is achieved. However 30–50% of relapsed‐refractory (R/R) patients fail to achieve PR. Recently the PD‐1 targeting antibody Nivolumab has shown promising activity in HL patients relapsed after ASCT but the expected CR rate is only about 20%. Administration of nivolumab as early post‐ASCT consolidation might improve results However, several reports have highlighted the relevance of patient immune‐competence. In this view, T‐cell count is severely depleted after ASCT.Aims:Here we report the preliminary results of a prospective trial investigating the feasibility, and the efficacy of post‐ASCT Nivolumab with the support of unselected autologous lymphocyte reinfusions (ALI).Methods:HL patients under the age of 60 with active, relapsed/refractory disease who have already failed at least two chemotherapy lines and Brentuximab were eligible for the trial. All enrolled patient underwent lymphocyte aphaeresis, with a minimum target of 5x107 CD3+/kg. All patients then received ASCT with FEAM conditioning. After ASCT, the first ALI wasdelivered 7 days after engraftment. ALI dosing was incremental, one logarithm at each step, starting from 1x104/kg in the first infusion to a maximum of 1x107/kg in the fourth and last infusion. Each ALI was followed after 48 hours by the administration of Nivolumab 240 mg flat dose. The second ALI dose was administered at 14 days after the first one. The third and the fourth were given every 21 days. Lymphocyte subpopulations were extensively studied on peripheral blood samples before and after each ALI and each Nivolumab administration, by 12‐colours flow cytometry. Clinical response was evaluated 21 days after completion of the fourth ALI + Nivolumab.Results:Five R/R HD patient have completed treatment so far and one is currently being treated. All patients failed to achieve CR with first and second line chemotherapy and then progressed during BV therapy. PET scan before ASCT showed progressing disease in all patients, with multiple‐extra nodal involvement in 4 of them. All patients achieved complete engraftment after a median of 10 days (8–12).Overall, ALI allowed to achieve significantly higher lymphocyte counts at day 90 in all patients, if compared to HL patients receiving the same conditioning without ALI (p &lt;0.05), especially in the T‐lymphocyte effector‐memory (CD45RA‐, CD68L‐, CD27+) compartment (p &lt; 0.03). After ALI administration, naïve (CD45RA+, CD62L+, CD27+, CD28+) CD8+ cell (p &lt; 0.03) and cytotoxic (CD56+,CD16+,CD57+) NK cells (Fig. 1, p &lt; 0.05) showed the most consistent and most durable increase. Nivolumab administration determined only a modest and transient increase in T‐effector‐memory population. No grade 3 or 4 adverse events were recorded so far. All treated patients so far achieved negative PET scan after the procedure and are alive and disease free after a median follow‐up of 12 months.Summary/Conclusion:Post‐ASCT ALI proved to be feasible and effective in a heavily‐pre‐treated population, resulting in a quicker immune recovery and in a complete response in all treated patients. Immunotherapy as post‐ASCT consolidation therapy might improve the CR rate expected with anti‐PD1 blockade alone, providing a more effective option for refractory patients, who are usually considered not candidate for ASCT.image

A phase Ia/Ib trial of the anti-PD-L1 human monoclonal antibody (mAb), CS1001, in patients (pts) with advanced solid tumors or lymphomas.

2526 Background: CS1001 is the first full-length, fully human anti-PD-L1 mAb developed by the OMT transgenic rat platform, which mirrors natural IgG4 human antibody with expected PK profiles, and may potentially reduce the risk of immunogenicity and toxicity in pts. This first-in-human Phase Ia/Ib study of CS1001 was conducted to evaluate the safety, tolerability, PK profile, and anti-tumor activity of CS1001 in pts with advanced solid tumors or lymphomas. Methods: Pts with advanced solid tumors or lymphomas were enrolled in the dose escalation Phase Ia, receiving CS1001, Q3W, IV, at escalating doses from 3, to 10, 20, 40 mg/kg and 1200 mg. Dose escalation was aided by a 3+3 dose escalation scheme. DLT was evaluated within 3 weeks after the initial dose. Pts with various tumor types were enrolled in the dose expansion Phase Ib to assess anti-tumor activity and safety, including NSCLC, esophageal carcinoma, GC, HCC, cholangiocarcinoma, etc. Safety was assessed by monitoring AEs and the associated grades per NCI CTCAE v4.03, tumor assessed per RECIST v 1.1 (solid tumors) or Lugano 2014 (lymphomas). Results: As of 30 Nov 2018, 29 pts, median age of 53 (23-75) yrs, were enrolled in Phase Ia, 3 mg/kg (N = 3); 10 mg/kg (4); 20 mg/kg (3); 40 mg/kg (3) and 1200 mg flat dose (16). A total of 20 pts discontinued treatment due to disease progression (14), death (2), withdrawal by pts (2) and AEs (2; Grade [G] 4 hepatic function abnormal and G3 pulmonary tuberculosis, both were not related to treatment). 9 pts remain on treatment. Median treatment duration was 126 (21-408+) days. No DLTs were observed. 27 of 29 pts had TRAEs with the most frequent TRAEs including anaemia (14), proteinuria (13) and blood bilirubin increased (8). G3 TRAEs include anaemia (2) and platelet count decreased (1). SAEs were reported in 6 pts and they were TRAEs. Three G4 AEs were reported: anaemia (1), hypokalaemia (1) and hepatic function abnormal (1), they were not TRAEs as determined by the investigators. irAEs occurred in 7 pts (24%). Among the 29 evaluable pts, 7 pts had PR and 8 had SD, mDoR was not reached. In Phase Ib, 97 pts were enrolled, with 65 pts on treatment and 32 pts discontinued from treatment. The most frequent reason on the discontinuation was disease progression (21). Phase Ib enrollment is still ongoing. Conclusions: CS1001 is well tolerated without DLT across tested dose levels. Evidence of anti-tumor activities was observed. Currently, 1200 mg flat dose Q3W is being explored in various tumor types in Phase Ib, and safety and efficacy results will be displayed in the presentation. Clinical trial information: NCT03312842.

Costs and hazard ratios of commonly used drugs in advanced/metastatic lung cancer at Cancer Free Foundation, Dana Point, California.

e20508 Background: The American Cancer Society of Clinical Oncology used hazard ratios (HR) in its value framework as indicators of clinical response. Bevacizumab (Bev) and Pemetrexed (Peme) were introduced for non-squamous metastatic lung cancer prior to epidermal growth factor recognition. Objective: Analyze drug costs and HR in 1st-line advanced/metastatic lung cancer. Methods: Costs of Bev, Peme, Pembrolizumab (Pembro) and Atezolizumab (Atezo) were calculated x one year. Protocols and HR at 95% confidence intervals were quoted. Results: Median drug HR was 0.73. Bev costs were $132,314 and HR 0.79 (A. Sandler, 2006). Peme costs were $97,947, HR 0.63 (M. Zuchin, 2013) and 0.78 (PARAMOUNT). Costs of Pembro 2mg/Kg x 80 Kg were $125,770 compared with $157,313, the currently used 200 mg flat dose. Proportionate savings were noted over the 90-50 Kg weight. Pembro costs x 35 cycles increased to $317,450. In tumor progression score (TPS) &gt; 50% (KEYNOTR-24), Pembro HR was 0.60. In KEYNOTE-042, HR in &gt; 1.0% was 0.81 and improved to 0.69 in 50% with a net benefit of 14%. In squamous cell (KEYNOTE-407), Pembro+chemo HR was 0.64. Pembro+Peme+chemo costs were $255,160. In KEYNOTE-189, irrespective of program death receptor-ligand-1 (PD-L1), HR was 0.49, &lt; 1.0% 0.59 and &gt; 50% 0.42. The net benefit was 28%. Atezo+Bev combination costs were $287,314 and HR 0.78 (IMPOWER 150). In extensive small-cell, Atezo+chemo costs were $150,604 and HR 0.70 (IMPOWER 133). Conclusions: Pembro weight-adjusted dose resulted in significant cost saving over the fit-all 200mg. In 1st-line advanced/metastatic lung cancer, Pembro-Peme, irrespective of PD-L1, offered incomparable 0.49 HR at yearly costs of $255,160.