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BackgroundCombined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.Patients and methodsROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsAt data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.ConclusionsThese updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

TPS870 Background: Approximately 96% of CRCs have an MSS phenotype, which results in more immunologically quiescent tumors for which immunotherapies are largely ineffective (Lee et al. 2015; Overman et al. 2016). Pts with MSS CRC and activating RAS mutation (35%–45% of CRCs) have treatment options limited still further because anti-EGFR monoclonal antibodies (eg, cetuximab) are ineffective owing to dominant activation of RAS in the MAPK pathway (Douillard et al. 2014). However, preclinical and preliminary clinical data suggest that MAPK pathway inhibition enhances antigen presentation and T-cell cytotoxicity to positively modulate the efficacy of checkpoint inhibitors (Brea et al. 2016; Bendell et al. 2014). The main objective of this open-label multicenter phase 1b/2 study is to evaluate whether the potential positive modulation of NIVO or NIVO plus IPI, when combined with BINI, translates into clinically meaningful overall response in pts with MSS mCRC and RAS mutation. Methods: The study will enroll ~90 previously treated pts (1 or 2 prior regimens), ~42 in phase 1b and ~48 in phase 2. The primary objective of phase 1b will be to determine the recommended phase 2 dose (RP2D) of BINI in combination with NIVO ± IPI. Dose finding in the doublet arm will begin with BINI 45 mg BID + NIVO 480 mg Q4W; the triplet arm will begin with the BINI RP2D from the doublet arm + NIVO 480 mg Q4W + IPI 1 mg/kg Q8W. In phase 2, pts will be randomized 1:1 to doublet or triplet arms, incorporating the BINI RP2Ds found in phase 1b; treatment will continue in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, loss to follow-up, or death. The primary objective for phase 2 will be to assess response by RECIST version 1.1. The study will also characterize safety and PK. CT.gov Identifier: Clinical trial information: NCT03271047.

AimsPreviously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice. MethodsOne thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens. ResultsSunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h(-1) and 17.1 (RSE 7.4%) l h(-1), respectively for 70kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy. ConclusionsA semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects.

Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug resistance (,MDR1) P-glycoprotein, multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). The presence of BCRP has thus far been reported solely using mRNA data. In this study, me describe a BCRP-specific monoclonal antibody, BXP-34, obtained from mice, immunized with mitoxantrone-resistant, BCRP mRNA-positive MCF-7 MR human breast cancer cells. BCRP was detected in BCRP-transfected cells and in several mitoxantrone- and topotecan-selected tumor cell sublines. Pronounced staining of the cell membranes showed that the transporter is mainly present at the plasma membrane, In a panel of human tumors, including primary turners as well as drug-treated breast cancer and acute myeloid leukemia samples. BCRP was low or undetectable. Extended studies will be required to analyze the possible contribution of BCRP to clinical multidrug resistance.

The multidrug resistance protein BCRP (breast cancer resistance protein) is a member of the ATP-binding cassette family of drug transporters. Overexpression of BCRP caused by exposure of cells to mitoxantrone (MX) or doxorubicin/verapamil resulted in a resistance pattern that is different from what is generally seen in the case of P-glycoprotein and MRP1 overexpression. Recently, the BCRP gene has been described in ovarian, breast, colon, and gastric cancer and fibrosarcoma cell lines. Our human tumor cells T8 and MX3, derived from the ovarian cancer cell line IGROV1 by stepwise increased exposure to topotecan and MX, are resistant to topotecan, CPT11, SN38, and 9-aminocamptothecin as well as MX. Increased energy-dependent efflux of affected drugs was noted. BCRP is a very efficient transporter of topotecan. Our recent studies, using the monoclonal antibody (mAb) BXP34, revealed that BCRP is located in the plasma membrane of the T8 and MX3 cell lines. Preliminary results of staining of human tumor cells showed low or absent levels of BCRP in a panel of solid tumors and acute myeloid leukemia cells.