A phase III,randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer

BackgroundASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor.Patients and methodsThis global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile.ResultsPatients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6–11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8–NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4–39.0) versus 47.9% (95% CI 41.7–54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib.ConclusionsFirst-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib.ClinicalTrial.gov numberNCT02588261.     

Phase I–IIa study of BMS-690514, an EGFR,HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor,in patients with advanced or metastatic solid tumours

PurposeBMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I–IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514.Patients and methodsIn phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD.ResultsIn phase I (n = 28), the MTD was determined to be 200 mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n = 62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n = 4; 4%) and rash (n = 2; 2%). Disease control (?4 months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways.ConclusionThis phase I–IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200 mg/d, including those with EGFR mutations conferring resistance to erlotinib.     

A prospective,multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911

BackgroundLow-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene.MethodsPatients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d.ResultsThirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes.ConclusionThe primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients.     

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry

BackgroundAnti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.Patients and methodsWe conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.ResultsWe studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).Conclusions: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.     

A phase I trial of LY2584702 tosylate,a p70 S6 kinase inhibitor,in patients with advanced solid tumours

BackgroundLY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.MethodsPatients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0.ResultsThirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n = 22) began with 300 mg BID (n = 2). Due to toxicity, this was scaled back to doses of 25 mg (n = 3), 50 mg (n = 8), 100 mg (n = 3), and 200 mg (n = 6) QD. Part B dose escalation (n = 12) included 50 mg (n = 3), 75 mg (n = 3), and 100 mg (n = 6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis.ConclusionThe MTD was determined to be 75 mg BID or 100 mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose.     

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials

BackgroundAfatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials.Patients and methodsTreatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not.ResultsDose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}.ConclusionsTolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy.Clinical trial registrationClinicaltrials.gov identifiers: NCT00949650 and NCT0112393.     

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome

AimTo evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases.Patient and methodsHER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed.ResultsHER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p = 0.026) and in the subgroup of patients with colon cancer stage II (p = 0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r = 0.9, p < 0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r = 0.6, p < 0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis.ConclusionA high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.     

Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug–drug interaction

IntroductionErlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.MethodsEscalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib + 300 mg dovitinib) and cohort -1 (150 mg erlotinib + 200 mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.ResultsTwo of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average C_max 2308 ± 698 ng/ml and AUC _0–24 41,030 ± 15,577 ng × h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib C_max and AUC_0–24 decreased significantly by 93% (p = 0.02) and 97% (p < 0.01), respectively, during dovitinib co-administration.ConclusionsThis small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.     

Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer

IntroductionMaintenance therapy can delay progression and prolong survival in metastatic non-small-cell lung cancer (mNSCLC). As treatment for mNSCLC is non-curative, its impact on patient health-related quality of life (HRQoL) is an important consideration. SATURN (Sequential Tarceva in Unresectable NSCLC) was a randomised, double-blind, placebo-controlled, multicentre study investigating the impact of erlotinib maintenance therapy on HRQoL in patients with locally advanced or recurrent NSCLC.Patients and MethodsEligible patients who had previously completed four cycles of platinum-based chemotherapy were randomised 1:1 to receive erlotinib 150 mg/day or placebo until disease progression, unacceptable toxicity or death. Patient HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung questionnaire, in terms of time to symptom progression (TSP), time to deterioration (TTD) in Trial Outcome Index (TOI) and TTD. Exploratory analysis was based on time to analgesia and appearance of key symptoms (pain, cough and dyspnoea).ResultsCompared with placebo, erlotinib maintenance therapy prolonged progression-free and overall survival by 41% and 23%, respectively. At baseline, HRQoL measures were comparable between the two treatment groups. Maintenance therapy with erlotinib did not impact on deterioration in HRQoL: TSP (hazard ratio [HR] = 0.91 [95% confidence interval (CI) 0.74–1.12]; n = 785), TTD in TOI (HR = 1.06 [95% CI 0.87–1.31]; n = 781) and TTD in HRQoL (HR = 0.96 [95% CI 0.79–1.16]; n = 776). Time to pain and time to analgesic use were significantly delayed in patients receiving erlotinib compared with placebo (HR = 0.61 [95% CI 0.42–0.88]; p = 0.0080 and HR = 0.66 [95% CI 0.46–0.94]; p = 0.0199, respectively). A non-significant trend towards delayed time to cough and time to dyspnoea (HR = 0.77 [95% CI 0.49–1.21] and HR = 0.75 [95% CI 0.48–1.17], respectively) was also observed.ConclusionsErlotinib maintenance therapy significantly extends progression-free survival without compromising patient HRQoL in comparison with placebo, with some improvement in symptoms.     

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy

BackgroundNeratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer.Patients and methodsPhase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m²; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR).ResultsIn phase I (n = 12), neratinib (240 mg) plus vinorelbine (25 mg/m²) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine.ConclusionNeratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients.Trial registrationClinicalTrials.gov #NCT00706030.     

Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer

BackgroundNext to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients.MethodsGermline DNA was isolated from 246 KRAS wild-type mCRC patients who were treated in the phase III CAIRO2 study with chemotherapy and bevacizumab alone or with the addition of cetuximab. Associations of epidermal growth factor (EGF) 61A > G, EGF receptor (EGFR) CA_14–22, cyclin D1 (CCND1) 932G > A, fragment-C gamma receptor (FCGR) 2A 535A > G and FCGR3A 818A > C polymorphisms with progression-free survival (PFS) and cetuximab-related skin toxicity were studied.ResultsIn cetuximab-treated patients, the FCGR3A 818C-allele was associated with decreased PFS compared with the FCGR3A 818AA genotype (median PFS, 8.2 [95%CI, 6.7–10.3] versus 12.8 [95%CI, 10.3–14.7] months, respectively; HR, 1.57 [95%CI, 1.06–2.34]; P = .025). The EGFR ? 20 genotype was associated with decreased PFS compared with the EGFR < 20 genotype (median PFS, 7.6 [95%CI, 6.7–10.0] versus 12.4 [95%CI, 10.3–13.4] months, respectively; HR, 1.58 [95%CI, 1.06–2.35]; P = .024). The FCGR3A and EGFR polymorphisms were not associated with PFS in patients treated without cetuximab. None of the polymorphisms were associated with the incidence of grades 2–3 skin toxicity.ConclusionEGFR and FCGR3A germline polymorphisms are associated with PFS in KRAS wild-type mCRC patients treated with cetuximab, bevacizumab and chemotherapy.     

A phase 1b,open-label study of trebananib in combination with paclitaxel and carboplatin in patients with ovarian cancer receiving interval or primary debulking surgery

AimTo evaluate the tolerability, pharmacokinetics and tumour response of first-line trebananib plus paclitaxel and carboplatin followed by trebananib maintenance in high-risk or advanced ovarian cancer.MethodsIn this open-label phase 1b study, patients received intravenous (IV) trebananib 15 mg/kg administered weekly (QW) plus paclitaxel 175 mg/m² once every 3 weeks (Q3W) and carboplatin 6 mg/mL·min Q3W followed by trebananib 15 mg/kg QW monotherapy for 18 months. End-points were dose-limiting toxicities (DLTs; primary); treatment-emergent adverse events (AEs), anti-trebananib antibodies, pharmacokinetics and tumour response (secondary).ResultsTwenty seven patients (interval debulking surgery [IDS], n = 13) were enrolled. No DLTs occurred. During the combination therapy phase, AEs (>50%) in patients with IDS were nausea, diarrhoea, fatigue, decreased appetite and thrombocytopenia. In patients with primary debulking surgery (PDS), they were nausea, diarrhoea, fatigue and localised oedema. Grade 4 AEs were neutropenia (IDS, PDS; all n = 3) and thrombocytopenia (IDS, PDS; all n = 1). No deaths occurred. Toxicity results pertaining to trebananib maintenance were immature. The treatment combination did not markedly affect the pharmacokinetics across agents. In patients with IDS (n = 14 after one patient was reassigned from PDS to IDS), 12 patients had a partial response (PR), two patients had stable disease. In patients with PDS (n = 4), three patients had a complete response, one patient had a PR.ConclusionsIn women with ovarian cancer receiving IDS or PDS, IV trebananib 15 mg/kg QW plus paclitaxel and carboplatin appears tolerable. Results suggest that the treatment combination followed by trebananib 15 mg/kg monotherapy is associated with antitumour activity.     

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer

BackgroundHER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.Patients and methodsBaseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).ResultsThirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031).ConclusionsOur findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.     

A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer

BackgroundErlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine.MethodsErlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50 mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks).ResultsFifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200–300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17–47%)). Disease control was observed in nine patients (24% (95% CI: 10–38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19–47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival.ConclusionsErlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.     

Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor,in patients with refractory solid tumours

BackgroundOrally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422.MethodsUsing a dose-escalation design, 3–6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3 weeks on/1 week off or QD continuously, with disease assessments every 8 weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined.ResultsIn total, 56 patients were enrolled: QOD 3 weeks on/1 week off, n = 36; QD 3 weeks on/1 week off, n = 17; QD continuous, n = 3. Doses ranged from 4 to 133 mg/m² QOD and 50 to 89 mg/m² QD. The MTDs were defined as 100 mg/m² QOD and 67 mg/m² QD, respectively, with diarrhoea being dose-limiting on both 3 weeks on/1 week off schedules. Overall, treatment-related adverse events were mainly low grade, including diarrhoea (64%), nausea (39%), fatigue (28%), and vomiting (28%). Reversible grade 1–3 nyctalopia (night blindness) was reported by four patients (dose: 50–89 mg/m² QD; 100 mg/m² QOD). Exposure was generally linear, though greater than dose-proportional. Of 32 evaluable patients on QOD dosing, there was one durable complete response (prostate cancer), one confirmed (HER2 + breast cancer) and one unconfirmed partial response (adrenal gland cancer). Three patients (QOD schedule) had stable disease for ⩾6 months.ConclusionsThe dose and schedule recommended for further study with SNX-5422 is 100 mg/m² QOD 3 weeks on/1 week off based on improved tolerability and preliminary evidence of clinical activity.     

Epidermal growth factor receptor polymorphisms and risk for toxicity in paediatric patients treated with gefitinib

PurposeTo investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib.Patients and methodsGefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included –191C>A, –216G>T, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment.ResultsThe analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the –216 GG (n = 51), GT (n = 41) and TT (n = 16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p = 0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p = 0.004, dominant model). The –191C>A, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR –216 and –191 polymorphisms were in linkage disequilibrium (D′ = 0.66, p = 0.01). The haplotype (–191C, –216T) was associated with increased risk for rash (p = 0.049), but was not more predictive of rash than the single –216 polymorphism.ConclusionThese findings indicate that EGFR –216G>T genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted.     

A phase I study of daily afatinib,an irreversible ErbB family blocker,in combination with weekly paclitaxel in patients with advanced solid tumours

BackgroundThis phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.MethodsOral afatinib was combined with intravenous paclitaxel (80 mg/m²; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.ResultsSixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m², which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.ConclusionsThe MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m² (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.Trial registrationClinicalTrials.gov, NCT00809133.     

Comparison of gefitinib and erlotinib efficacies as third-line therapy for advanced non-small-cell lung cancer

PurposeThe epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population.Patients and methodsThe Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox’s proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses.ResultsA total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p = 0.524) and TTF (median, 5.5 versus 3.4 months, p = 0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR] = 1.04, p = 0.629) and treatment failure (adjusted HR = 0.94, p = 0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS.ConclusionsGefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan.     

EORTC study 26041-22041: Phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma

BackgroundGlioblastoma is a highly vascularised tumour with a high expression of both vascular endothelial growth factor (VEGF) and VEGFR. PTK787/ZK222584 (PTK/ZK, vatalanib), a multiple VEGF receptor inhibitor, blocks the intracellular tyrosine kinase activity of all known VEGF receptors and is therefore suitable for long-term therapy of pathologic tumour neovascularisation.Patients and methodsThe study was designed as an open-label, phase I/II study. A classic 3 + 3 design was selected. PTK/ZK was added to standard concomitant and adjuvant treatment, beginning in the morning of day 1 of radiotherapy (RT), and given continuously until disease progression or toxicity. PTK/ZK doses started from 500 mg with subsequent escalations to 1000 and 1250 mg/d. Adjuvant or maintenance PTK after the end of radiochemotherapy was given at a previously established dose of 750 mg twice daily continuously with TMZ at the standard adjuvant dose.ResultsTwenty patients were enrolled. Dose-limiting toxicities at a once daily dose of 1250 mg were grade 3 diarrhoea (n = 1), grade 3 ALT increase (n = 2), and myelosuppression with grade 4 thrombocytopenia and neutropenia (n = 1). The recommended dose of PTK/ZK in combination with radiotherapy and temozolomide (TMZ) is 1000 mg once a day. This treatment is safe and well tolerated.ConclusionIn our phase I study once daily administration of up to 1000 mg of PTK/ZK in conjunction with concomitant temozolomide and radiotherapy was feasible and safe. Prolonged administration of this oral agent is manageable. The planned randomised phase II trial was discontinued right at its onset due to industry decision not to further develop this agent.     

Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment

BackgroundA wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies.Patients and methodsGC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics.ResultsQuantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy.ConclusionsProteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.