Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer.

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.

Proactive monitoring of drug-drug interactions between direct oral anticoagulants and small-molecule inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Small-molecule inhibitors (SMIs) have revolutionised the treatment of non-small cell lung cancer (NSCLC). However, SMI-induced drug-drug interactions (DDIs) with frequently co-administered direct oral anticoagulants (DOACs), increase thromboembolic and bleeding risks. This study investigated and proactively managed the consequences of DOAC-SMI DDIs. METHODS: This prospective, observational study enrolled patients with NSCLC concomitantly using a DOAC and SMI. The primary outcome was the proportion of patients with DOAC plasma trough (Ctrough) and peak (Cpeak) concentrations outside expected ranges. Secondary outcomes included DOAC treatment modifications, incidence of bleeding and thromboembolic events and feasibility evaluation of pharmacokinetically guided DOAC dosing. RESULTS: Thirty-three patients were analysed. Thirty-nine percent (13/33) had DOAC Ctrough and/or Cpeak were outside the expected ranges in 39% (13/33). In 71% (5/7) of patients with DOAC concentrations quantified before and during concurrent SMI use, DOAC Ctrough and/or Cpeak increased or decreased >50% upon SMI initiation. In all patients in whom treatment modifications were deemed necessary, DOAC concentrations were adjusted to within the expected ranges. CONCLUSION: Proactive monitoring showed that a substantial proportion of patients had DOAC concentrations outside the expected ranges. DOAC concentrations were successfully normalised after treatment modifications. These results highlight the importance of proactive monitoring of DOAC-SMI DDIs to improve treatment in patients with NSCLC.

Development and validation of an HPLC-MS/MS method to simultaneously quantify brigatinib, lorlatinib, pralsetinib and selpercatinib in human K2-EDTA plasma.

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.

Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer.

BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers.

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.

Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Several population pharmacokinetic (popPK) studies have been reported that can guide the prediction of osimertinib plasma concentrations in individual patients. It is currently unclear which popPK model offers the best predictive performance and which popPK models are most suitable for nonadherence management and model-informed precision dosing. Therefore, the objective of this study was to externally validate all osimertinib popPK models available in the current literature. METHODS: Published popPK models for osimertinib were constructed using NONMEM version 7.4.4. The predictive quality of the identified models was assessed with goodness-of-fit (GoF) plots, conditional weighted residuals (CWRES) plots and a prediction-corrected visual predictive check (pcVPC) for osimertinib and its active metabolite AZ5104. A subset from the Dutch OSIBOOST trial, where 11 patients with low osimertinib exposure were included, was used as evaluation cohort. RESULTS: The population GoF plots for all four models poorly followed the line of identity. For the individual GoF plots, all models performed comparable and were closely distributed among the line of identity. CWRES of the four models were skewed. The pcVPCs of all four models showed a similar trend, where all observed concentrations fell in the simulated shaded areas, but in the lower region of the simulated areas. CONCLUSION: All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known. CLINICAL TRIALS REGISTRATION: NCT03858491.

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC.

Introduction: Brain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,SS and BM development or progression. Methods: A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group. Results: A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) Cmin,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6-49.0), 31% (95% CI:10.6-53.9), and 31% (95% CI:10.8-54.5) per Cmin,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6-49.0), 52% (95% CI:23.8-74.2), and 57% (95% CI:24.9-79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups. Conclusions: No relation was found between osimertinib Cmin,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.

Validated extended multiplexed LC-MS/MS assay for the quantification of adagrasib and sotorasib in human plasma, together with four additional SMIs.

Recently, two small molecular inhibitors (SMIs) -adagrasib and sotorasib- have been introduced for targeting Kirsten rat sarcoma (KRAS) p.G12C mutations in patients with non-small cell lung cancer (NSCLC). In order to support pharmacokinetic research as well as clinical decision making, we developed and validated a simple and accurate liquid chromatography-tandem mass spectrometry method for the multiplexed quantification of adagrasib and sotorasib. This assay was co-validated with the quantification for brigatinib, lorlatinib, pralsetinib and selpercatinib. Methanol was used for single-step protein precipitation. Chromatographic separation was performed using an Acquity® HSS C18 UPLC column, with an elution gradient of ammonium formate 0.1 % v/v in water and acetonitrile. In K2-EDTA plasma, adagrasib was found to be stable for at least seven days at room temperature and 4 °C, and at least 3 months at -80 °C. Sotorasib was found to be stable for at least three days at room temperature, seven days at 4 °C and at least 3 months at -80 °C. The method was validated over a linear range of 80-4000 ng/mL for adagrasib and 25-2500 ng/mL for sotorasib. The assay is therefore well-equipped for determining plasma concentrations in clinical practice.

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.

BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

Concise drug review: pazopanib and axitinib.

Pazopanib and axitinib are both U.S. Food and Drug Administration approved ATP-competitive inhibitors of the vascular endothelial growth factor receptor. Pazopanib and axitinib have been shown to be effective and tolerable treatment options for patients with metastatic renal cell cancer and therefore have enlarged the armamentarium for this disease. This concise drug review discusses the clinical benefits, clinical use, mechanism of action, bioanalysis, pharmacokinetics, pharmacogenetics, pharmacodynamics, drug resistance, toxicity, and patient instructions and recommendations for supportive care for these two drugs.

Practical recommendations to combine small-molecule inhibitors and direct oral anticoagulants in patients with nonsmall cell lung cancer.

BACKGROUND: The risk for thromboembolisms in nonsmall cell lung cancer (NSCLC) patients is increased and often requires treatment or prophylaxis with direct oral anticoagulants (DOACs). Small-molecule inhibitors (SMIs) to treat NSCLC may cause relevant drug-drug interactions (DDIs) with DOACs. Guidance on how to combine these drugs is lacking, leaving patients at risk of clotting or bleeding. Here, we give practical recommendations to manage these DDIs. METHODS: For all DOACs and SMIs approved in Europe and the USA up to December 2021, a literature review was executed and reviews by the US Food and Drug Administration and European Medicines Agency were analysed for information on DDIs. A DDI potency classification for DOACs was composed and brought together with DDI characteristics of each SMI, resulting in recommendations for each combination. RESULTS: Half of the combinations result in relevant DDIs, requiring an intervention to prevent ineffective or toxic treatment with DOACs. These actions include dose adjustments, separation of administration or switching between anticoagulant therapies. Combinations of SMIs with edoxaban never cause relevant DDIs, compared to more than half of combinations with other DOACs and even increasing to almost all combinations with rivaroxaban. CONCLUSIONS: Combinations of SMIs and DOACs often result in relevant DDIs that can be prevented by adjusting the DOAC dosage, separation of administration or switching between anticoagulants.

Nivolumab exposure in a hemodialysis patient with metastatic melanoma.

The effect of intermittent hemodialysis (IHD) on nivolumab serum concentrations in patients with severe renal impairment is largely unknown. Here, we present a 79-year-old patient with metastatic melanoma and end-stage renal disease on IHD three times a week, treated with 480 mg nivolumab every 4 weeks. A serum trough concentration of nivolumab was determined before the start of the third cycle, and two samples were taken immediately before and after a hemodialysis session during this cycle. All nivolumab serum concentrations were within a similar range as those previously measured among patients without renal insufficiency, after a comparable duration of nivolumab treatment. Therefore, we conclude that IHD does not influence nivolumab exposure. Furthermore, nivolumab treatment was continued without complications and appears to be well tolerated for patients on IHD.

Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer.

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 (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm 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.

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer.

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 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 BRAF-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.Significance: 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 BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. ©2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.

Crizotinib-induced fatal fulminant liver failure.

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.

Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months.

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.

Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors.

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/m2), cisplatin (75 mg/m2), 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.

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1 These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504-15. ©2016 AACR.

Treatment Individualization in Colorectal Cancer.

Colorectal cancer has been characterized as a genetically heterogeneous disease, with a large diversity in molecular pathogenesis resulting in differential responses to therapy. However, the currently available validated biomarkers KRAS, BRAF, and microsatellite instability do not sufficiently cover this extensive heterogeneity and are therefore not suitable to successfully guide personalized treatment. Recent studies have focused on novel targets and rationally designed combination strategies. Furthermore, a more comprehensive analysis of the underlying biology of the disease revealed distinct phenotypic differences within subgroups of patients harboring the same genetic driver mutation with both prognostic and predictive relevance. Accordingly, patient stratification based on molecular intrinsic subtypes rather than on single gene aberrations holds promise to improve the clinical outcome of patients with colorectal cancer.