Dose Of Erlotinib Research Articles

Suppression of mesenchymal phenotype in inflammatory breast cancer by EGFR tyrosine kinase inhibitor erlotinib: a novel approach to suppressing metastasis.

Abstract Abstract #2042 Background: Inflammatory breast cancer (IBC) is a rare subtype well known for its propensity for rapid metastasis. The cause of this rapid metastasis in IBC is unknown. An immunohistochemical analysis of 44 cases of IBC showed HER2 overexpression in 48% of patients and epidermal growth factor receptor (EGFR) overexpression in 30% of patients. EGFR overexpression was the only poor prognostic factor: the 5-year overall survival rate was significantly lower for women with EGFR-positive disease than for women with EGFR-negative disease (P=0.01). HER2 overexpression was not a prognostic factor. The association between EGFR overexpression and increased risk of death indicated that EGFR may represent a potential therapeutic target in IBC. We hypothesized that suppression of the EGFR pathway inhibits proliferation and metastasis of IBC.
 Methods: SUM149 IBC cells, which express low levels of HER2 and high levels of EGFR, were treated with siRNA against EGFR and with the EGFR tyrosine kinase inhibitor erlotinib.
 Results: EGFR siRNA knockdown (but not non-targeting siRNA control) inhibited the proliferation of SUM149 cells. SUM149 cells were sensitive to EGFR tyrosine kinase inhibitor erlotinib in a 2-dimensional (2-D) culture system (median inhibitory concentration [IC50] = 0.90 µM). When we activated ERK by transfecting constitutively active MEK1 in SUM149 cells, the cells showed more resistance to erlotinib. Moreover, ERK siRNA knockdown sensitized SUM149 cells to erlotinib. Further, when we cultured the SUM149 cells in matrigel by using the 3-D culture system (100% matrigel in the bottom layer and cultured medium with 5% FBS and 2% matrigel in the top layer), erlotinib treatment changed the molecular phenotype of SUM149 cells from mesenchymal (a phenotype characterized by low beta-catenin expression and high vimentin and fibronectin expression) to epithelial (recovery of beta-catenin to the sites of cell-cell contacts; downregulation of fibronectin). This reversal of the mesenchymal phenotype, a hallmark of inhibition of epithelial-to-mesenchymal transition (EMT), was ERK dependent. Interestingly, the erlotinib concentration that inhibited the mesenchymal phenotype (0.1 mcM) was one log lower than the concentration that inhibited proliferation (1 mcM).
 Conclusion: Inhibition of tumor growth and EMT in SUM149 IBC cell lines is dependent on the ERK pathway through the EGFR pathway. The erlotinib dose needed to produce an anti-mesenchymal effect is much lower than the cytotoxic dose. Thus, we speculate ERK pathway to be important in inhibiting metastasis in IBC. We are currently investigating the effects of erlotinib in a xenograft model of IBC. Our study provides a rationale for developing novel treatment strategies targeting the EGFR and ERK pathways to inhibit the growth and metastasis of IBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2042.

Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response. Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials. Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival. Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI

The purpose of this study was to demonstrate the beneficial effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of leptomeningeal metastasis (LM) for a select group of non-small cell lung cancer (NSCLC) patients who had a sensitive EGFR mutation or good predictive clinical factors for EGFR TKI treatment. Eleven patients with NSCLC and LM were treated with a standard dose of erlotinib ( n = 9), or higher than standard dose of gefitinib followed by erlotinib ( n = 2). They were treated with various therapies including whole brain radiotherapy or intrathecal chemotherapy for CNS lesion previously and concurrently with EGFR TKI. Nine of 11 patients showed overt improvement in ECOG performance status. Six patients were alive >6 months, and 2 additional patients were alive 2.5+ and 4.4+ months with clinical improvement. Two patients showed responses to higher than standard dose of gefitinib. The median overall survival was not reached. In conclusion, EGFR TKIs are effective in the treatment of LM from NSCLC when patients were selected properly.

Our Experiences with Erlotinib in Second and Third Line Treatment Patients with Advanced Stage Iiib/ Iv Non-Small Cell Lung Cancer

HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV open-label, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).

Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib

Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification. Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.

Phase I Trial of Erlotinib Combined with Cisplatin and Radiotherapy for Patients with Locally Advanced Cervical Squamous Cell Cancer

This phase I trial was aimed to determine the maximum tolerated dose and related toxicity of erlotinib (E) when administered concurrently with standard chemoradiation (CRT) for cervical cancer. In a modified Fibonacci design, the study aimed to study three cohorts of at least three patients receiving escalating doses of erlotinib (50/100/150 mg) combined with cisplatin (40 mg/m(2), weekly, 5 cycles) and radiotherapy (external beam 4,500 cGy in 25 fractions, followed by 4 fractions/600 cGy/weekly of brachytherapy) in squamous cell cervical carcinoma patients, stage IIB to IIIB. Fifteen patients were enrolled, 3 at dose level (DL) 50 mg, 4 at DL 100 mg, and 8 at DL 150 mg. Patients presented median age 47 (36-59), stage IIB (46.2%) and IIIB (53.8%). Overall, E+CRT was well-tolerated. Three patients did not complete the planned schedule. One patient at DL 100 mg withdrew informed consent due to grade 2 rash; at DL 150 mg, 1 patient presented Raynaud's Syndrome and had C interrupted, and another patient presented grade 4 hepatotoxicity. The latter was interpreted as dose limiting toxicity and a new cohort of 150 mg was started. No further grade 4 toxicity occurred. Grade 3 toxicity occurred in 6 cases: diarrhea in 3 patients, rash in 2 patients, and leukopenia in 1 patient. E+CRT did not lead to limiting in-field toxicity. E+CRT is feasible to locally advanced squamous cell cervical cancer and is well tolerated. The maximum tolerated dose has been defined as 150 mg. To the best of our knowledge, this is the first report of a combination of erlotinib, cisplatin, and pelvic radiotherapy.

Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors

Complex interrelationships exist between the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor pathways. EGFR activation elicits cell proliferation and increased VEGF expression. To maximally inhibit EGFR and then downstream VEGF activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of erlotinib with fixed-dose cetuximab, and then combine with bevacizumab in patients with advanced malignancies. Patients with advanced malignancies likely to express EGFR were treated with a full dose of cetuximab intravenous weekly, combined with various doses of oral erlotinib daily (Part 1). Once the MTD was determined in Part 1, escalating doses of bevacizumab were administered intravenously biweekly (Part 2). Forty patients were enrolled and received 155 courses over four dose levels. In Part 1, dose-limiting grade 3 rash occurred in two patients administered with erlotinib at 100 mg daily, and the MTD of erlotinib for this combination was 50 mg daily with standard-dose cetuximab (11 patients treated). Other adverse events included rash, diarrhea, fatigue, and hypomagnesemia. In Part 2, bevacizumab at 10 mg/kg intravenous every 2 weeks was safely added, with additional nondose-limiting headache, proteinuria, and hypertension. There was one partial response in a patient with renal cell carcinoma. Durable stable disease was observed in five patients for 6-11 months. The MTD for Part 1 was 50 mg daily of erlotinib combined with standard cetuximab. Bevacizumab at 10 mg/kg biweekly can be safely administered with the MTD for erlotinib and cetuximab combination.

Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study

We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors. Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed. Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response. The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide.

Sunitinib plus Erlotinib for the Treatment of Metastatic Non—Small-Cell Lung Cancer: A Novel VEGFR—EGFR Co-Inhibition Treatment Strategy

BackgroundVascular endothelial growth factor receptor (VEGFR) and human epidermal growth factor receptor (EGFR/HER1) are 2 important targets in non—small-cell lung cancer (NSCLC) that share common downstream signaling pathways affecting tumor vasculature. Co-inhibition of VEGFR and EGFR in preclinical models showed significantly greater antitumor activity over inhibition of either pathway alone, and clinical data support this co-targeting. Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, platelet-derived growth factor receptors, KIT, RET, CSF-1R, and FLT3 that has shown single-agent antitumor activity in refractory NSCLC. Sunitinib with erlotinib is a novel VEGFR—EGFR treatment strategy that might confer additive/synergistic clinical benefit in patients with advanced NSCLC. We will present preliminary results from 2 ongoing trials (SUN 1058 and SUN 1087) assessing the efficacy/tolerability of sunitinib with erlotinib in NSCLC after failure of platinum-based therapy. Patients and MethodsSUN 1058 is a randomized, multicenter phase II trial evaluating the safety and tolerability of once-daily sunitinib (37.5 mg per day) with erlotinib 150 mg per day versus placebo with erlotinib 150 mg per day. The trial design included a nonrandomized lead-in cohort to evaluate the safety of the combination. SUN 1087 is a global, randomized, multicenter, pivotal phase III trial in which 956 patients with NSCLC will be randomized to sunitinib 37.5 mg per day CDD with erlotinib 150 mg per day or placebo with erlotinib 150 mg per day, given in 4-week cycles. The primary endpoints are progression-free survival (SUN 1058) and overall survival (SUN 1087); secondary endpoints include objective response rate, 1-year survival, duration of confirmed response, safety, and patient-reported outcomes. Patients with NSCLC aged ≥ 18 years with stage IIIB/IV disease, Eastern Cooperative Oncology Group performance status 0/1, and previous treatment with 1 or 2 chemotherapy regimens (including a platinum-based regimen) are eligible for both trials. Enrollment is ongoing in both trials. ResultsTo date, in the lead-in cohort on the SUN 1058 trial, 2 of 12 patients enrolled have had durable partial responses, and 2 patients have had stable disease. Furthermore, there is no evidence of pharmacokinetic interaction of sunitinib on erlotinib. Preliminary pharmacokinetic data (n = 3) indicate that Cmax for sunitinib/erlotinib = 1660.7 ± 1259.3. Sunitinib/erlotinib is well tolerated. Adverse events (AEs) were generally mild to moderate in severity (grade 1/2). The most frequent AEs were diarrhea and fatigue (each n = 7). Four patients reported grade 3 diarrhea, and 2 patients reported grade 3 fatigue. Two patients developed a dose-limiting toxicity (DLT), both of which were grade 3 fatigue, lasting for ≥ 7 days, but these accounted for fewer than the prespecified number of DLTs that would preclude enrollment into the randomized portion of the study at these doses of sunitinib and erlotinib. The randomized phase II portion of this study is ongoing. ConclusionSunitinib 37.5 mg per day with erlotinib 150 mg per day appears well tolerated in this patient population.

Reverse-phase protein array marker evaluation of protein expression patterns related to anti-angiogenesis treatment in renal cell carcinoma

16016 Background: Renal carcinoma patients treated with anti-VEGF therapy (bevacizumab) typically exhibit 10–15% partial responses with detectable primary tumor shrinkage in 70% of the cases (Rini B.I., Clin Cancer Res, 2007). It is not well known which factors determine response or are modulated by therapy. In this study, primary tumors from patients treated with bevacizumab-erlotinib were screened for protein expression of markers representing a broad spectrum of signaling pathways, including AKT, MAPK, angiogenesis, cell growth and apoptosis pathways. Methods: 32 patients with metastatic clear-cell renal carcinoma received bevacizumab 10mg/kg IV Q14 days for a total of 4 infusions plus erlotinib 150mg PO daily for 8 weeks. Nephrectomies were performed 2 weeks after last dose of erlotinib, 4 weeks after last dose of bevacizumab. Tumor and matched normal renal tissue specimens were histologically confirmed and subjected to protein extraction. Lysates were serially diluted and spotted on protein array slides. The arrays were stained with 47 specific antibodies for protein detection. Data were normalized and analyzed according to unsupervised hierarchical clustering approaches, for detecting patterns of protein expression across samples. VHL status (deletions and mutations) was also assessed for each tumor. Results: The protein array method clearly separated normal renal tissue from tumor samples according to their protein expression patterns, as demonstrated by unsupervised hierarchical clustering. Furthermore, duplicate and replicate preparations clustered tightly with their tumor specimen of origin, demonstrating marked reproducibility of the technique, and limited intra-tumor heterogeneity of the biomarkers being analyzed. Treated primary tumors with more than or equal to 10% shrinkage grouped into a distinct protein expression cluster. This cluster was driven mainly by 8 factors (p<0.001) with PTEN being the most prominent (increased expression in the ≥10% shrinkage cluster, p<1.3*10-7). This response group correlated with VHL copy loss (p<0.02). Conclusions: Bevacizumab-erlotinib treated renal tumors reveal distinct protein expression signatures according to the degree of primary tumor response. No significant financial relationships to disclose.

Erlotinib as 1st-line therapy for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)

19016 Background: The prognosis for elderly pts with advanced NSCLC is generally poor due to significant co-morbidities that limit treatment options. Furthermore, aggressive treatments are often contra-indicated due to poor performance status. Erlotinib is approved as a 2nd-line therapy for pts with NSCLC, and is a useful treatment option for elderly pts due to its favorable toxicity profile. However, experience with 1st-line erlotinib in chemo-naïve elderly pts is currently limited. Methods: The global open-label TRUST study investigated erlotinib in >6000 pts with advanced stage IIIB/IV NSCLC. Pts were eligible if they had either failed standard treatment or were unsuitable for chemotherapy/radiotherapy. This report focuses on a subgroup of elderly pts (>70 y), who received erlotinib (150 mg/day) as a 1st-line therapy for advanced NSCLC. Results: By August 2007, eligible pts had received at least one dose of erlotinib and interim analysis data were available for 451 pts. Median age was 78 yrs and baseline characteristics (%) were as follows: male/female 57/43; never smoker/current or former smoker/no data 30/69/1; stage IIIB/V 31/68; adenocarcinoma/BAC/ squamous-cell/other 51/12/22/15; Caucasian/Asian/other 76/15/9. Grade 3–5 adverse events (AEs) of any cause were reported by 49% of pts. However, only 7% had ≥1 treatment-related AE, and only 3 pts (<1%) died due to a treatment-related AE (1 as a result of bleeding, 1 from pneumonitis, and 1 from community-acquired pneumonia). Dose reductions were necessary in 16% of pts. Five complete (1%) and 34 partial responses (8%) were noted. Stable disease was seen in 45% of pts for an overall disease control rate of 54%. Progression-free survival (PFS) was 16.4 wks (95% CI: 14.6- 20.0). This compares favorably with recent data, which demonstrated PFS of around 14 wks for pemetrexed or pemetrexed/gemcitabine in chemo-naïve pts >70 yrs [Gridelli et al, J Thorac Oncol 2007;2:221–9]. Overall survival data will be presented. Conclusions: Erlotinib as 1st-line treatment for elderly pts with NSCLC has encouraging efficacy. These results indicate that erlotinib is a valuable 1st-line treatment option for the management of advanced NSCLC in this subgroup and warrants further investigation in the 1st-line setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim, Hoffmann-La Roche, Lilly Bayer HealthCare, Boehringer Ingelheim, Hoffmann-La Roche, Lilly

Lack of efficacy of erlotinib in most EGFR mutated non-small cell lung cancers (NSCLCs) with acquired resistance to gefitinib

8105 Background: The majority of NSCLC patients (pts) with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib, however acquired resistance to this tyrosine kinase inhibitor (TKI) ensues. The secondary resistant T790M mutation has been identified in 50% of progressing pts. The amplification of the MET oncogene occurs in 20% of TKI-resistant pts and sometimes concomitantly with T790M. Very few other secondary mutations (D761Y, L747S) exist. Our goal was to determine the effects of erlotinib 150mg/d in EGFR mutated pts who became resistant to gefitinib 250mg/d, since the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Methods: We followed radiographic responses of 18 EGFR mutated pts from 4 academic medical centers that were given gefitinib and subsequently erlotinib. All pts, but one, had either exon 19 deletion or L858R mutations. 4 pts had tumor re-sampling after becoming resistant to TKI therapy. Results: Most pts achieved a response to gefitinib monotherapy (14/18, 77.7%) and median time to progression (TTP) was 11 months (95%CI, 4–16.5). After the tumors became gefitinib-resistant, most of the pts exposed to erlotinib had progressive radiographic disease (14/18, 77.7%) and median TTP was 2 months (95%CI, 2–3.8). The 3 pts with exon 19 deletions that acquired the T790M gefitinib-resistant mutation progressed on erlotinib. Only 1 gefitinib-resistant pt achieved a radiographic partial response and this patient had acquired L858R-L747S EGFR, which in vitro is sensitive to serum levels of erlotinib 150mg/d. Conclusions: In EGFR mutated tumors that become resistant to gefitinib, a switch to another reversible EGFR TKI given at higher biological doses - erlotinib - does not lead to responses in most pts. These findings were expected since the two most common mechanisms of gefitinib resistance (T790M and MET amplification) in vitro lead to high-grade resistance to clinically achievable doses of gefitinib and erlotinib. A gefitinib to erlotinib switch may only be beneficial in the rare EGFR mutated pt who acquires atypical “partial” resistance secondary EGFR mutations. Continued clinical development of novel EGFR and MET inhibitors for pts with EGFR mutated TKI resistant tumors is warranted. No significant financial relationships to disclose.

A phase II study of first-line erlotinib in patients (pts) with stage IIIB/IV non-small-cell lung cancer (NSCLC) including dose escalation to toxicity in current and former smokers (C/FS)

8111 Background: Skin rash has been associated with increased activity of erlotinib in retrospective analyses and plasma levels of erlotinib are lower in current vs former or non-smokers (NS), potentially due to tobacco-induced enzyme activation. This parallel phase II study was initiated to determine the efficacy of erlotinib in chemonaïve pts with advanced NSCLC, at a fixed dose in NS, and a toxicity- driven dose in C/FS. The study is still accruing pts. Methods: Oral erlotinib (150mg/d) was given once daily to all pts; this was increased by 50mg increments to a maximum of 300mg/d in C/FS. Each dose was given for 2 wks; if no treatment-related toxicity (TRT) ≥ gr 3 occurred, the dose was escalated. The primary endpoint was non-progression rate (NPR) after 8 wks. Secondary endpoints included response, disease control rate (DCR; CR+PR+SD), safety, and correlative efficacy analyses. Results: Data are available for 41 pts: 21 NS and 20 C/FS. NS were more likely to be women than men (81% vs 19%, compared with 45% vs 55% in C/FS) and there were no cases of squamous-cell carcinoma among NS, compared with 2 cases in C/FS. Dose escalation was possible in the majority of C/FS (16/18 pts with data available), including 5 pts who were escalated to 300mg/d and a further 7 pts escalated to 250mg/d. NPR (n=34) was 59% in all pts after 8 wks; NPR was 50% for C/FS (n=16) and 67% for NS (n=18). Data on best response are available for 8 C/FS and 13 NS. 4 NS had partial responses (PR) and 8 had stable disease (SD) (DCR 92%). 3 C/FS had a PR (1 at 200mg/d, 1 at 250mg/d and 1 at 300mg/d) and 4 had SD (1 at 250mg/d and 3 at 300mg/d) (DCR 88%). In safety analyses (evaluable n=38), 20% of pts reported a gr 3/4 TRT. 28 pts reported rash (12 C/FS, 16 NS; no gr 3/4) and 18 pts reported diarrhea (8 C/FS, 10 NS; 1 gr 3). Conclusions: Erlotinib is a well-tolerated and effective treatment option in first-line NSCLC, with a NPR of ≥50% and a DCR of >85% in all evaluable pts. Increasing the dose of erlotinib in pts with a history of smoking can potentially increase the activity of this agent in these pts. Pharmacokinetic and predictive biomarker analyses will be carried out. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche

A phase I, dose escalation study to determine the maximum tolerated dose of erlotinib when combined with pertuzumab in previously treated non-small-cell lung cancer patients

19134 Background: Pertuzumab (P), a monoclonal antibody, targets the HER2 receptor and prevents dimerization of HER2 and HER2, HER2 and HER1 or HER2 and HER3. P is active against HER2 overexpressing breast cancer (Baselga et al, ASCO 2007) but has no meaningful single agent activity against non-small-cell lung cancer (NSCLC). Erlotinib (E) inhibits HER1 tyrosine kinase signalling, is active against a number of tumour types and is widely registered for the treatment of relapsed NSCLC. By combining E and P signaling via HER1, HER2 and HER3 are inhibited. Inhibition of multiple HER signaling pathways could prove to be clinically useful. Methods: This is a phase I, dose escalating study. Consenting NSCLC patients (pts) with ECOG performance status of 0 or 1, progression after previous chemotherapy and adequate cardiac reserve (baseline LVEF ≥55%) were recruited in 2 cohorts. All pts had tumour specimen for evaluating biomarkers potentially associated with response. The 1st cohort received P at the full dose of 840mg iv loading dose with 420mg iv maintenance every 3 weeks plus E at a dose of 100mg orally daily. If the maximum tolerated dose (MTD) was not reached, a 2nd cohort was to be recruited (these pts were to receive the full dose of P plus E at the full dose of 150mg orally daily). Dose limiting toxicity (DLT) was initially defined as any adverse event (AE) ≥ grade 3; an incidence of DLT in 2 out of 6 pts was defined as MTD. Based on experience with the 1st cohort, the protocol was modified to exclude rash as a DLT (rashes encountered were manageable and responded to interruption or reduction of E). Subsequently a 2nd cohort (9 pts) has been recruited. Results: In the 1st cohort tolerability was good, the common AEs being diarrhea in 3 pts (50%) which was generally mild and self-limiting and rash which was reported by all 6 pts (100%). Rash was severe (grade 3) in 3 pts, but responded to either dose reduction of E to 50 mg orally daily or to withdrawal of treatment. In the 2nd cohort, the combination has been well tolerated with no DLTs reported to date. Conclusions: For Phase II evaluation, a full dose of E (150mg orally daily) with full dose of P appears to be suitable. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Clinical Trial Costs

Final survival and safety results from a multicenter, open‐label, phase 3b trial of erlotinib in patients with advanced nonsmall cell lung cancer

Erlotinib is an orally available, reversible inhibitor of epidermal growth factor receptor (EGFR) with a proven survival advantage for patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) who have failed a prior chemotherapy. This phase 3b, multicenter, open-label trial of erlotinib in patients with advanced NSCLC who had progressed after standard chemotherapy treatment was conducted to examine the efficacy and safety of erlotinib monotherapy in patients with advanced NSCLC who had developed disease progression after previous chemotherapy and to characterize the duration of survival and the response rate of erlotinib-treated patients in subpopulations defined by other patient characteristics before U.S. Food and Drug Administration approval. A total of 229 patients were enrolled and treated with the standard dose of erlotinib (150 mg once daily). The coprimary objectives were to characterize the overall response rate (ORR) and overall survival (OS) associated with erlotinib therapy in this group and in patient subsets defined by tobacco history. Secondary objectives were to assess safety, to characterize OS and ORR in patient subpopulations, and to determine duration of time on treatment. Patients could remain on study up to 9 months after approval. The ORR was 8.3% (95% confidence interval [95% CI], 5.2-2.4%). The ORR in never-smokers, previous smokers, and current smokers was 28.6% (95% CI, 13.2-50.6%), 6.0% (95% CI, 3.0-10.4%), and 7.3% (95% CI, 2.0-19.0%), respectively. The median OS for all patients was 6.3 months (95% CI, 4.7-8.0 months). In previous and current smokers, the median survival was 5.2 months (95% CI, 4.2-7.3 months) and 6.3 months (95% CI, 3.6-9.2 months), respectively, and was not reached in never-smokers. The median duration of treatment was 10.6 weeks. One (0.4%) interstitial lung disease-like event was reported. No new safety signals were noted. The observed ORR and survival data are consistent with results from the pivotal trial BR.21.

High efficacy of erlotinib in Taiwanese NSCLC patients in an expanded access program study previously treated with chemotherapy

Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which has demonstrated a survival benefit in non-small-cell lung cancer (NSCLC) patients. An open label phase II study was conducted in Taiwanese patients with NSCLC to evaluate its efficacy. Patients with proven stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy were enrolled into this study. All patients were given oral erlotinib, 150mg/day till disease progression. From May 2005 to July 2006, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of erlotinib. The best response rates were a 29% partial response and 44% stable disease in 273 patients who had response data available. Non-smoking (p=0.033), adenocarcinoma/BAC (p=0.0027), female (p=0.0013), aged less than 65 years (p=0.0115), stage IV (p=0.0492), patients with skin rash (p=0.0216), and a higher grade of skin rash (p=0.003) were significantly correlated with response to treatment. Skin rash was a common adverse event (any grade: 84%, Gr 3-4: 16%). The median time to disease progression was 5.6 months. Cox regression model for progression free survival showed patients most at risk of early progression were males of low performance status having squamous cell carcinoma. This was the largest multicenter prospective clinical study of NSCLC in Taiwan. The results demonstrated the excellent response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese NSCLC patients who had been previously treated with chemotherapy or radiotherapy.

A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients

BackgroundDysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. Patients and methodsPatients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1–14) and i.v. oxaliplatin (day 1 of a 21-day cycle). ResultsThe first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m2 twice daily, oxaliplatin 130 mg/m2) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m2 twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). ConclusionThe MTD for this combination in MCRC is capecitabine 825 mg/m2 twice daily days 1–14, oxaliplatin 130 mg/m2 day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.

Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals

The effects of food on the pharmacokinetics of erlotinib were investigated in two open-label, randomized studies. In a single-dose crossover study (n = 18), 150 mg of erlotinib was administered under either fasting or fed conditions. In the first period, an approximate doubling in the area under the plasma concentration-time curve was evidenced by the geometric mean ratio (GMR) of 2.09 observed under fed conditions; whereas, in the second period there was a decrease, with a GMR of 0.93. In a multiple-dose parallel study (n = 22), 100 mg of erlotinib was administered daily for 8 days, either 7 days of fasting followed by feeding on day 8, or the reverse sequence. In this study, food resulted in an increase in the plasma concentration-time curve on day 1, with a GMR of 1.66 (P = 0.015). In contrast, there was only a 37% increase on day 7, with a GMR of 1.34 (P = 0.252). These studies indicate that food can substantially increase plasma exposure to erlotinib. Given the maximum tolerated dose of erlotinib used in clinical practice, we recommend that erlotinib be taken under conditions of fasting.

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma

PurposeTo determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. MethodsPatients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m2/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m2 on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. ResultsThree patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. ConclusionIn combination with fixed dose gemcitabine at 40 mg/m2 twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.

PD3-2-3: Randomized phase I pharmacokinetic study of two doses of Erlotinib after failure of prior chemotherapy in patients with advanced NSCLC who continue to smoke

PD3-2-3: Randomized phase I pharmacokinetic study of two doses of Erlotinib after failure of prior chemotherapy in patients with advanced NSCLC who continue to smoke