Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated ...dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback ...activation of epidermal growth factor receptors (HER).
In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336).
Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC.
Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, ...pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m
), cisplatin (75 mg/m
), or carboplatin (area under the curve, 5 mg/mL⋅min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue. Results Two hundred two patients were enrolled onto the study, including nine patients in part 1, 43 in part 2A (including eight rollover patients from part 1), and 158 in part 2B. AZD1775 monotherapy given as single dose was well tolerated, and the maximum-tolerated dose was not reached. In the combination regimens, the most common adverse events consisted of fatigue, nausea and vomiting, diarrhea, and hematologic toxicity. The maximum-tolerated doses and biologically effective doses were established for each combination. Target engagement, as a predefined 50% pCDK1 reduction in surrogate tissue, was observed in combination with cisplatin and carboplatin. Of 176 patients evaluable for efficacy, 94 (53%) had stable disease as best response, and 17 (10%) achieved a partial response. The response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33). Conclusion AZD1775 was safe and tolerable as a single agent and in combination with chemotherapy at doses associated with target engagement.
Purpose
KRAS
oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in
KRAS
-mutant (
KRAS
...m) and
PIK3CA
wild-type tumors, in vitro and in vivo
.
In this phase I study, patients with advanced
KRAS
m and
PIK3CA
wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R).
Methods
Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively.
Results
Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (
n
= 2), rash (
n
= 2), nausea (
n
= 1), multiple grade 2 toxicities (
n
= 1), and aspartate aminotransferase elevation (
n
= 1), resulting in the inability to receive 75% of planned doses (
n
= 2) or treatment delay (
n
= 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected.
Conclusion
Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.
Osimertinib is prescribed to patients with metastatic non‐small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib ...exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan‐Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR‐mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first‐line (40%), second‐line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4‐19.3), 13.9 (95% CI: 11.3‐16.1) and 8.7 months (95% CI: 4.6‐12.7), respectively. Patients with low BMI (<20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; >271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13‐4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45‐0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36‐0.92). A trend towards longer PFS was seen for TP53 wild‐type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.
What's new?
Patients with non‐small cell lung cancer (NSCLC) and a sensitizing epidermal growth factor receptor mutation (EGFRm+) potentially benefit from treatment with the third‐generation tyrosine kinase inhibitor osimertinib. Here, the authors evaluated the impact of NSCLC patient characteristics on outcomes associated with osimertinib. In osimertinib‐treated patients with metastatic EGFRm+ NSCLC, male sex, low body mass index and high steady state osimertinib plasma trough concentration were associated with shorter survival. Meanwhile, increased progression‐free survival was linked to female sex and primary EGFR exon 19 deletion, suggesting that osimertinib treatment strategies can be tailored to improve outcomes among EGFRm+ NSCLC patients.
Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in
colorectal cancer models. Patients with ...refractory
-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (
= 28) or without (
= 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with
-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.
Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with
-mutant mCRC.
.
Aims
The enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important for the tolerability and efficacy of the fluoropyrimidine drugs. In the present study, ...we explored between‐subject variability (BSV) and circadian rhythmicity in DPD and TS activity in human volunteers.
Methods
The BSVs in DPD activity (n = 20) in peripheral blood mononuclear cells (PBMCs) and in plasma, measured by means of the dihydrouracil (DHU) and uracil (U) plasma levels and DHU : U ratio (n = 40), and TS activity in PBMCs (n = 19), were examined. Samples were collected every 4 h throughout 1 day for assessment of circadian rhythmicity in DPD and TS activity in PBMCs (n = 12) and DHU : U plasma ratios (n = 23). In addition, the effects of genetic polymorphisms and gene expression on DPD and TS activity were explored.
Results
Population mean (± standard deviation) DPD activity in PBMCs and DHU : U plasma ratio were 9.2 (±2.1) nmol mg−1 h−1 and 10.6 (±2.4), respectively. Individual TS activity in PBMCs ranged from 0.024 nmol mg−1 h−1 to 0.596 nmol mg−1 h−1. Circadian rhythmicity was demonstrated for all phenotype markers. Between 00:30 h and 02:00 h, DPD activity in PBMCs peaked, while the DHU : U plasma ratio and TS activity in PBMCs showed trough activity. Peak‐to‐trough ratios for DPD and TS activity in PBMCs were 1.69 and 1.62, respectively. For the DHU : U plasma ratio, the peak‐to‐trough ratio was 1.43.
Conclusions
BSV and circadian variability in DPD and TS activity were demonstrated. Circadian rhythmicity in DPD might be tissue dependent. The results suggested an influence of circadian rhythms on phenotype‐guided fluoropyrimidine dosing and supported implications for chronotherapy with high‐dose fluoropyrimidine administration during the night.
A liquid chromatography–tandem mass spectrometry method was developed and validated to quantify the small‐molecule inhibitors (SMIs) brigatinib, lorlatinib, pralsetinib and selpercatinib, which are ...used in patients with oncogenic‐driven non‐small cell lung cancer. Chromatographic separation was performed on a HyPURITY® C18 analytical column with a gradient elution using ammonium acetate in water and in methanol, both acidified with formic acid 0,1%. Detection and quantification were performed using a triple quad mass spectrometer with an electrospray ionization interface. The assay was validated over a linear range of 50–2,500 ng/ml for brigatinib, 25–1,000 ng/ml for lorlatinib, 100–10,000 ng/ml for pralsetinib and 50–5,000 ng/ml for selpercatinib. All four SMIs were stable for at least 7 days under cool conditions (2–8°C), and at least 24 h at room temperature (15–25°C) in K2‐EDTA plasma. Under freezing conditions (−20°C), all SMIs were stable for at least 30 days, except for the lowest quality control (QCLOW) of pralsetinib. The QCLOW of pralsetinib was stable for at least 7 days at −20°C. This method provides an efficient and simple way to quantify four SMIs with a single assay in clinical practice.
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