A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours.

BACKGROUND: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy. METHODS: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed. RESULTS: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks). CONCLUSIONS: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours.

AIMS: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS: Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. CONCLUSION: Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen.

The Impact of Mismatch Repair Status in Colorectal Cancer on the Decision to Treat With Adjuvant Chemotherapy: An Australian Population-Based Multicenter Study.

BACKGROUND: Testing for mismatch repair (MMR) status in colorectal cancer (CRC) may provide useful prognostic and predictive information. We evaluated the impact of such testing on real-world practice regarding adjuvant chemotherapy for patients with resected CRC. PATIENTS AND METHODS: A total of 175 patients with stage II and III mismatch repair-deficient (MMRD) CRC were identified from an Australian population-based study of incident CRCs. Their treatment decisions were compared with those for a cohort of 773 stage-matched patients with mismatch repair-proficient (MMRP) CRCs. The effect of MMR status, age, and pathologic characteristics on treatment decisions was determined using multiple regression analysis. RESULTS: Overall, 32% of patients in stage II and 71% of patients in stage III received adjuvant chemotherapy. Among the stage II patients, those with MMRD cancer were less likely to receive chemotherapy than were MMRP cases (15% vs. 38%; p < .0001). In this group, the treatment decision was influenced by age, tumor location, and T stage. MMR status influenced the treatment decision such that its impact diminished with increasing patient age. Among patients with stage III tumors, no difference was found in the chemotherapy rates between the MMRD and MMRP cases. In this group, age was the only significant predictor of the treatment decision. CONCLUSION: The findings of this study suggest that knowledge of the MMR status of sporadic CRC influences treatment decisions for stage II patients, in an era when clear recommendations as to how these findings should influence practice are lacking. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair found in 15% of sporadic colorectal cancers. Until recently, expert guidelines on the role of MSI as a valid biomarker in the selection of stage II patients for adjuvant chemotherapy were lacking. Conducted at a time when the clinical utility of routine MSI testing was unclear, this study found that clinicians were influenced by MSI status in selecting stage II patients for chemotherapy. Furthermore, the impact of MSI on treatment decisions was greatest in younger patients and declined progressively until age 80 years, when no effect was found.

Durvalumab in combination with chemoradiotherapy in patients with head and neck squamous cell carcinoma: Results from the Phase 1 CLOVER study.

BACKGROUND: The Phase 1 CLOVER study (NCT03509012) assessed durvalumab in combination with concurrent chemoradiotherapy (cCRT) in patients with advanced solid tumors; we report results from the head and neck squamous cell carcinoma (HNSCC) cohort. METHODS: Patients with histologically/cytologically confirmed locally advanced HNSCC, eligible for definitive cCRT and not considered for primary surgery, received durvalumab plus cisplatin and concurrent external beam radiation. Objectives were to assess safety/tolerability and preliminary efficacy. RESULTS: Eight patients were enrolled. The most frequent any-cause adverse events (AEs) were nausea and radiation skin injury (each n = 5); most frequent grade 3/4 AEs were lymphopenia and stomatitis (each n = 3). No patients had dose-limiting toxicities. Objective response rate was 71.4% (5/7 patients; four complete responses, one partial response); disease control rate was 85.7% at 18 weeks and 83.3% at 48 weeks. CONCLUSIONS: Durvalumab plus cCRT was tolerable and active in patients with unresected, locally advanced HNSCC.

Design and Rationale for a Phase III, Randomized, Placebo-controlled Trial of Durvalumab With or Without Tremelimumab After Concurrent Chemoradiotherapy for Patients With Limited-stage Small-cell Lung Cancer: The ADRIATIC Study.

Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, double-blind, placebo-controlled, multicenter, global study (ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018.

Prospective analysis of 895 patients on a UK Genomics Review Board.

BACKGROUND: The increasing frequency and complexity of cancer genomic profiling represents a challenge for the oncology community. Results from next-generation sequencing-based clinical tests require expert review to determine their clinical relevance and to ensure patients are stratified appropriately to established therapies or clinical trials. METHODS: The Sarah Cannon Research Institute UK/UCL Genomics Review Board (GRB) was established in 2014 and represents a multidisciplinary team with expertise in molecular oncology, clinical trials, clinical cancer genetics and molecular pathology. Prospective data from this board were collated. RESULTS: To date, 895 patients have been reviewed by the GRB, of whom 180 (20%) were referred for clinical trial screening and 62 (7%) received trial therapy. For a further 106, a clinical trial recommendation was given. CONCLUSIONS: Numerous challenges are faced in implementing a GRB, including the identification of potential germline variants, the interpretation of variants of uncertain significance and consideration of the technical limitations of pathology material when interpreting results. These challenges are likely to be encountered with increasing frequency in routine practice. This GRB experience provides a model for the multidisciplinary review of molecular profiling data and for the linking of molecular analysis to clinical trial networks.

Dynamics of Neutrophils-to-Lymphocyte Ratio Predict Outcomes of PD-1/PD-L1 Blockade.

INTRODUCTION: Baseline neutrophil-to-lymphocyte ratio (NLR) has been repeatedly reported as a significant prognostic factor in advanced cancer patients. We explored whether changes in NLR may predict outcome of advanced cancer patients enrolled into phase 1 trials and treated with PD-1/PD-L1 inhibitors. PATIENTS AND METHODS: Advanced cancer patients enrolled into phase 1 trials between September 2013 and May 2016 and treated with anti-PD-1/PD-L1 agents were included in this retrospective study. NLR was calculated at baseline and after 2 cycles of treatment. Royal Marsden Hospital (RMH) prognostic score and Eastern Cooperative Group (ECOG) performance status (PS) were determined at baseline. Kaplan-Meier estimation and Cox regression analyses were used to assess the impact of NLR dynamics on PFS. RESULTS: Among the 55 patients eligible, 26 (47%) were treated with anti-PD-L1 monotherapy, 22 (40%) received single agent anti-PD-1, and 7 (13%) were given a tyrosine kinase inhibitor (TKI) plus a PD-1 inhibitor. Neither ECOG PS nor RMH prognostic score was significantly associated with PFS in our cohort, whereas changes in NLR significantly impacted on PFS. CONCLUSION: Changes in the NLR may be a useful predicting factor in advanced cancer patients treated with anti-PD-1/PD-L1 agents. Further prospective trials are needed to verify these findings.

Dabrafenib and trametinib activity in a patient with BRAF V600E mutated and microsatellite instability high (MSI-H) metastatic endometrial cancer.

BACKGROUND: Targeting BRAF V600E mutation has been proven effective in the treatment of several types of cancer. In endometrial adenocarcinoma, the BRAF V600E mutation has been rarely reported. Whether targeting BRAF oncogene may represent a plausible therapeutic strategy for the rare patients with BRAF-mutated endometrial cancer remains to be ascertained in prospective studies. CASE PRESENTATION: We report herein the case of a heavily pre-treated patient with recurrent microsatellite instability high (MSI-H) BRAF V600E mutated endometrial adenocarcinoma, which was successfully treated with the V600E targeting agent dabrafenib. After developing resistance to this agent, the MEK targeting agent trametinib was added to dabrafenib achieving again a therapeutic response. CONCLUSIONS: This case shows that dabrafenib both as monotherapy and when combined with trametinib may exert significant therapeutic activity in heavily pretreated BRAF V600E mutated endometrial adenocarcinoma, and highlight potential benefits of personalized treatment in this disease.

Resistance surveillance in a BRAF mutant melanoma patient on long-term BRAF-inhibitor treatment.

Treatment responses of BRAF mutant melanoma to BRAF inhibitors are often limited by the development of resistance. This case report describes the use of multiplatform molecular profiling in sequential surgical samples of a treatment-resistant tumour site subjected to ongoing treatment with dabrafenib in a patient with metastatic cutaneous BRAF mutant melanoma. Next-generation sequencing showed the presence of the V600E, fibroblast growth factor receptor 2 (FGFR2), phosphatase and tensin homologue (PTEN) and p53 gene mutations. With a continuous presence of the BRAF V600E, FGFR2 and PTEN mutations and appearances of new mutations in the PTEN gene at R137H and T321fs and p53 R273C genes during ongoing treatment, this case report indicates intratumoural clonal evolution as a resistance mechanism. Two new mutations, the G542E exon 12 mutation variant of the FGFR2 gene and the R273C mutation variant of the p53 gene, are reported for the first time in BRAF mutant melanoma.

Cutaneous metastasis of prostate carcinoma treated with radiotherapy: a case presentation.

BACKGROUND: Prostate cancer is a commonly diagnosed and treated malignancy, although it rarely presents with cutaneous metastases. In this case presentation, we describe the diagnosis and treatment with radiotherapy of a patient who presented with cutaneous metastases on his chest wall secondary to prostate cancer. CASE PRESENTATION: In 2006, a 73-year-old Caucasian gentleman with metastatic castration resistant prostate cancer treated with mitoxantrone and prednisolone presented with cutaneous nodules on his chest wall. A punch biopsy diagnosed cutaneous metastases, with histological confirmation with positive staining for cytokeratin, PSA (prostate specific antigen) and PAP (prostatic acid phosphatise). Systemic treatment was ceased due to progressive disease; radiotherapy was used to treat these nodules with a durable clinical response. The patient died five months after initial diagnosis of cutaneous metastases. CONCLUSIONS: In this report, a rare metastatic manifestation of a common malignancy is presented. Whilst dermal metastases carries a poor prognosis from reported literature, this is the first report of radiotherapy providing a durable clinical response with relief from bleeding and pain.

Use of neostigmine in capecitabine-induced paralytic ileus.

Paralytic ileus is a recognised side effect of the oral agent capecitabine. We present this report on a patient with metastatic colorectal cancer who was treated with capecitabine and presented with persistent paralytic ileus which did not respond to standard conservative measures. Neostigmine was administered safely, resulting in resolution of the paralytic ileus. This approach merits further investigation.