Maintenance Erlotinib Research Articles

Approval Summary: Erlotinib Maintenance Therapy of Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)

On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy. In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)(+) tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint. Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62-0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70-0.95). The PFS and OS HRs in patients with EGFR(+) tumors by IHC were 0.69 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.64-0.93), respectively. The PFS and OS HRs in patients with EGFR(-) tumors by IHC were 0.77 (95% CI, 0.51-1.14) and 0.91 (95% CI, 0.59-1.38), respectively. Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs. The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.

Phase II Study of Gemcitabine and Erlotinib as Adjuvant Therapy for Patients with Resected Pancreatic Cancer

There is currently no consensus about the most effective adjuvant therapy for adenocarcinoma of the pancreas. Both gemcitabine and erlotinib have been demonstrated to improve survival in patients with metastatic disease. This study was designed to evaluate the efficacy of gemcitabine and erlotinib as adjuvant therapy, and to explore potential biomarkers associated with response. An institutional review board-approved single-center phase II trial of adjuvant biweekly fixed-dose rate gemcitabine (1500mg/m(2)) and daily erlotinib (150mg/day) for 4months followed by maintenance erlotinib (150mg/day) over 8months was initiated. Primary end point was recurrence-free survival (RFS). Epidermal growth factor receptor (EGFR) expression in the resected tumors was assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). The study completed planned accrual of 25 patients. Median follow-up was 18.2 (range 11.6-23.5) months. Recurrences were observed in 17 subjects (68%). Median RFS was 14.0months (95% confidence interval [95% CI], 8.2-24.5) with 1-year and 2-year RFS of 56% (95% CI, 35-73) and 26% (95% CI, 6-52), respectively. Median overall survival was not reached. Estimated 1-year and 2-year overall survival was 84% (95% CI, 63-94) and 53% (95% CI, 22-76), respectively. Nine patients (36%) had a grade 3 event and only 1 (4%) had a grade 4 (neutropenia). Most toxicities were dermatologic, gastrointestinal, and constitutional. There were nonsignificant trends to longer RFS and lower recurrence rates while receiving therapy in subjects with fluorescence in situ hybridization-positive tumors and greater immunohistochemistry expression. Our phase II results suggest that adjuvant gemcitabine and erlotinib is a promising regimen that merits further investigation.

Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report

BackgroundGallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene.Case presentationA 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found.ConclusionThis case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status.

Phase I trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer.

5561 Background: Concurrent inhibition of EGFR and COX-2 has previously been shown to be an active and well tolerated regimen in recurrent head and neck cancer (Wirth, JCO 23: 6976, 2005). Based on robust preclinical data, we tested concurrent erlotinib and celecoxib as radiosensitizing agents. Methods: Patients with unresectable or high risk adjuvant (microscopic positive margins or extracapsular extension) head and neck cancer and M0 requiring reirradiation were eligible. Eligible patients received celecoxib (200 to 600 mg BID) and erlotinib (150 mg QD) starting 14 days prior to and concurrent with reirradiation (IMRT 60 to 72.4 Gy in 2.2 Gy QD M-F). The primary objective was to determine the safety, tolerability, and maximum tolerated (MTD) dose of celecoxib. The starting dose was celecoxib 200 mg BID escalated to 400 mg BID and 600 mg BID using a 3+3 design with an expanded cohort at the MTD. Results: Between 3/07 to 12/09, 15 pts were enrolled with a median follow-up of 10 months. Patient characteristics include median age 68 (6 age >75); 11 male; 10 with ECOG PS 2, 9 had unresectable disease, 3 with second primaries, 8 received prior chemotherapy and median prior RT dose was 62 Gy. There were no dose limiting toxicities (DLTs) in dose levels (DL) 1 and 2. Two of three patiens at DL3 developed DLTs consisting of gr 3 bone necrosis and trismus. Therefore, celecoxib 400 mg BID was declared the MTD with concurrent erlotinib and reirradiation. Overall gr ≥3 toxicities were uncommon and consisted of gr 3 mucositis (n=3), gr 3 dermatitis (n=2), and gr 3 pain (n=3). At last follow-up, five are alive with no evidence of disease (NED), three developed locoregional progression, three had distant progression, one had both local and distant progression and three are NED but succumbed to comorbid illness. Maintenance erlotinib 150 mg QD until progression was allowed but only 3 patients participated. Conclusions: Concurrent erlotinib, celecoxib and reirradiation is a well tolerated regimen that demonstrates activity in a difficult to treat population of previously irradiated patients. These data suggest that this regimen warrants further study particularly in patients who failed chemoradiation or elderly patients with PS 2. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Genentech, sanofi-aventis OSI, Pfizer

Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinib started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.

Initial Results of a Phase I Dose Escalation Trial of Concurrent and Maintenance Erlotinib and Re-irradiation for Recurrent and New Primary Head and Neck Cancer

Initial Results of a Phase I Dose Escalation Trial of Concurrent and Maintenance Erlotinib and Re-irradiation for Recurrent and New Primary Head and Neck Cancer

SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC

8001 Background: Erlotinib (E), a small-molecule EGFR TKI, is proven to extend survival versus placebo (P) in 2nd/3rd-line advanced NSCLC. The phase III SATURN study (BO18192) was initiated to evaluate E as maintenance therapy after standard 1st-line platinum-based chemotherapy (CT) in advanced NSCLC. Methods: Patients with no evidence of disease progression after 4 cycles of CT were randomized to receive either E 150 mg/day or P until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) in all patients and the co-primary endpoint was PFS in EGFR immunohistochemistry-positive (IHC+) patients. Results: A total of 1,949 patients entered the CT phase, of whom 889 were randomized to E (n=438) or P (n=451). Median age was 60 years for both arms. Baseline characteristics for E and P arms (%): male/female: 73/27 and 75/25; adenocarcinoma + BAC/squamous-cell/other: 47/38/15 and 44/43/13; stage IIIB/IV: 26/74 and 24/76; Caucasian/Asian/other: 84/14/2 and 83/15/2; ECOG PS 0/1: 31/69 and 32/68; current/former/never smoker: 55/28/18 and 56/27/17. PFS (by investigator assessment; confirmed by independent review) was significantly prolonged with E versus P in all patients (HR 0.71 [95% CI 0.62–0.82]; p&lt;.0001) and in EGFR IHC+ patients (HR 0.69 [95% CI 0.58–0.82]; p&lt;.0001). Subgroup analyses will be reported. Response rate was 12% with E versus 5% with P. Disease control rate (complete response + partial response + stable disease &gt;12 wks) was 40.8% with E versus 27.4% with P (p&lt;.0001). OS data are not yet mature. E was well tolerated: the majority of treatment-related adverse events (AEs) were grade 1/2. AEs reported in ≥10% of all patients were rash (60% with E versus 9% with P) and diarrhea (20% with E versus 5% with P); again, most were grade 1/2. Only 2.3% of patients receiving E had a serious treatment-related AE and 2.8% withdrew due to a treatment-related AE. Conclusions: The SATURN study met its primary and co-primary endpoints with high statistical significance. Erlotinib in the 1st-line maintenance setting is well tolerated, and significantly improves disease control and delays progression versus placebo across patient subgroups. [Table: see text]

Biomarker analyses from the phase III placebo-controlled SATURN study of maintenance erlotinib following first-line chemotherapy for advanced NSCLC

8020 Background: The SATURN (BO18192) study investigated whether erlotinib maintenance therapy improved PFS in patients (pts) with advanced NSCLC who had obtained clinical benefit from 1st-line chemotherapy. This study included a prospective analysis of the prognostic/predictive value of several molecular markers. Methods: 889 pts with advanced NSCLC whose disease had not progressed following 4 cycles of 1st-line platinum-doublet chemotherapy were randomized to erlotinib 150 mg/day or placebo. Mandatory tumor specimens were collected at baseline and tested for EGFR protein expression using immunohistochemistry (IHC), EGFR gene copy number using fluorescent in-situ hybridization (FISH), and EGFR and KRAS somatic mutations using DNA sequencing. Pts were stratified according to EGFR IHC status (any membranous staining in ≥10% tumor cells used as cut-off); the co-primary endpoint was PFS in EGFR IHC+ pts. Baseline whole blood samples were obtained for genotyping of EGFR (intron 1 CA-repeat polymorphisms). Results: In the overall population, erlotinib significantly prolonged PFS vs placebo (HR 0.71, p&lt;.0001; primary endpoint). The co-primary endpoint was also met, with erlotinib significantly improving PFS in the EGFR IHC+ group (HR 0.69, p&lt;.0001). Many tumor samples were assessable for molecular marker status (see table). Biomarker data suggest that patients derived a PFS benefit with erlotinib irrespective of EGFR FISH or EGFR intron 1 CA-repeat status. The magnitude of benefit with erlotinib was similar in both KRAS-mutant and KRAS wild-type pts. Conclusions: This is the largest biomarker analysis performed for erlotinib in a randomized, placebo-controlled setting, and answers key scientific questions regarding the prognostic and predictive value of potential biomarkers of efficacy. Full data will be presented. [Table: see text] [Table: see text]

Phase II trial of erlotinib maintenance therapy after platinun-based chemotherapy in advanced non-small cell lung cancer (NSCLC)

e19013 Background: phase II trial-efficacy &amp; toxicity of sequential erlotinib in advanced NSCLC after platinum-based CT Methods: Pts with adv NSCLC, PS 0/1, adequate renal, hepatic and bone marrow function, no PD after CT. Treatment: erlotinib 150 mg/day starting 3–4 weeks after CT until progression. Safety was evaluated monthly and tumor evaluation bimonthly. Results: 47 pts enrrolled:42(89%)stageIV &amp; 5(11%)wet IIIB, all valid for response &amp; toxicity. Median age 62 y(r:39 -77): 39(83%) males and 8(17%) females. Histology: adenocarcinoma 8(61.7%), bronquioloalveolar 3(6.4%), large cell 3(6.4%), squamous12(25.5%). PS 0: 23(49%), PS 1:24(51%). 38(81.9%) completed 6 cycles of CT. Response: CR: 1(2.1%), PR: 2(51.1%), EE: 22 (46%). Sequential erlotinib improved RR in 6 (12.8%), 23 (48.9) prolonged stabilization, 18 (38.3%) had progression. Median TTP and OS were 9.4 m (95% CI, 4.96–13–84), and 19.23 m (95% CI, 8.82–29.64). No significant differences in TTP according to age, sex, PS, histology or previous response to CT, but yes depending on RR to erlotinib: PR: 31.5 m (95% CI 15.37–47.63), EE: 12.8 m (95% CI, 10.58–15.03), PD: 6.3 m (95% CI, 5.36–7.3), p &lt; 0.001; and moreover depending on smoking status: Never: 21.67 m(95% CI, 5.39–37.94), previous smoker &gt; 5 years: 14.03 m(95% CI, 10.77–17.30), previous smoker 1 year: 7.77 m(95% CI, 7.62–7.91), current smoker: 5.9 m(95% CI, 5.12–6.34), p &lt;0.001. In Cox-regression model, smoking status ( p&lt; 0.001), and response to erlotinib (p=0.002) were associated with a significant difference in TTP. Similar results in OS, although in Cox-regression model only never smoker or &gt; 5 years previous smoker pts had a significant better survival. Toxicity: The most frequent was skin rash, grade (g) 1 in 11(23.4%), g 2: 16(34%) and g 3: 3(6.4%). Only 1 p had diarrea g 3, and no other side effects were observed. We found a significant benefit in p with g 2–3 skin toxicity respect g 0–1, in both TTP( p= 0.0003) and OS (p= 0.0014). Conclusions: Erlotinib-maintenance therapy after platinum-based CT had promising results. Pts with the best benefit were those with response to erlotinib, in never or past (&gt; 5 years) smokers and with g 2–3 skin toxicity. No significant financial relationships to disclose.

Phase I Study of Concurrent Whole Brain Radiotherapy and Erlotinib for Multiple Brain Metastases From Non–Small-Cell Lung Cancer

Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non-small-cell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study.

Disruption of the EGFR E884–R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity

Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity towards the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent, and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant fashion, to change downstream signaling, differentially induce MAPK-ERK1/2 signaling and associated cell proliferation, and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific fashion. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity towards preclinical MET inhibitors SU11274 (unchanged), and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome (COSMIC) revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET, FAK) and tumor suppressor gene (LKB1). Targeted therapy using small molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.

Metronomic Chemotherapy in Patients with Advanced Non—Small-Cell Lung Cancer Associated with Long-Term Survival

PurposeMetronomic chemotherapy is defined as lower-dose, more frequent chemotherapy treatments. Herein, we report 14 consecutive patients with advanced non—small-cell lung cancer (NSCLC; 3 patients with stage IIIB disease, 11 patients with stage IV disease) who were treated between 2002 and current time with continuous weekly chemotherapy until disease progression or 1–2 cycles (12–24 weeks) beyond optimal response. Patients and MethodsPatients with disease progression were treated with a salvage weekly chemotherapy regimen until progression. Since 2005, patients who had optimal response were placed on maintenance erlotinib. All patients had Eastern Cooperative Oncology Group performance status of 0–1, initiated first-line treatment at our clinic, and received ≥ 12 weeks of planned chemotherapy. ResultsAll patients had a partial or complete response as their best response during the course of treatment. Median survival of this group of patients was > 30 months. One patient (patient 14) with bronchoalveolar lung cancer had a partial response (PR) in her lungs but developed brain metastasis that progressed soon after whole-brain radiation therapy. She was then placed on erlotinib and survived for 13 months. Another patient (patient 13) died of possible stroke while still in PR. Overall side effects from treatments were mild, with the most common side effects being grade 1/2 fatigue (75%) and peripheral neuropathy (40%), but no grade 3 or 4 neuropathy was observed. ConclusionMetronomic chemotherapy might be associated with long-term survival in patients with advanced NSCLC. Further clinical trials to confirm these findings are warranted.

Whole brain radiotherapy with concurrent erlotinib for brain metastases from non-small cell lung cancer: A phase I study

19122 Background: Whole brain radiotherapy (WBRT), the standard treatment for multiple brain metastases from NSCLC, results in a median survival of 4 months with approximately 50% of patients dying from intracranial progression. We performed a two-phase dose-escalation phase I trial (NCT00536861), evaluating the safety of WBRT with concurrent and maintenance erlotinib. Methods: Pts with untreated brain metastases from pathologically confirmed NSCLC were eligible. Erlotinib (cohort 1: 100mg/day; cohort 2: 150mg/day) was started 1 week prior to, and continued during, WBRT (30 Gy/10 fractions). Maintenance erlotinib (150mg/day) was continued until unacceptable toxicity or disease progression. Serial neuro-imaging was performed at 3-monthly intervals. The primary study end-point was toxicity. Secondary end-points were survival and time to disease progression. Results: 13 pts were enrolled between May 2006-Dec 2007. Two pts withdrew prior to WBRT due to rapid clinical progression and 11 pts (M:F 6:5, median age 65 years) completed WBRT. Median duration of erlotinib treatment was 78 days (range 38–523). No treatment-related toxicity ≥ grade 3 was observed in cohort 1 (4 pts). In cohort 2 (7 pts) grade ≥ 3 toxicity consisted of grade 3 acneiform rash (n=1); grade 3 fatigue (n=1); fatal interstitial lung disease (n=1). No treatment-related neurotoxicity was observed. Median overall survival was 130 days (range 42–557), with 3 pts alive at the time of analysis. Five pts developed an acneiform rash, including all 3 pts surviving > 150 days. Median time till disease progression was 96 days (range 38–523), which was located exclusively extracranially (n=6). No clinical intracranial progression was observed. In the 6 pts with follow-up neuro-imaging, the intracranial response was PR in 4 and SD in 2. Four pts without disease progression had died at the time of analysis: erlotinib- induced interstitial lung disease (n=1); COPD exacerbation (n=1); pulmonary embolism (n=1); congestive cardiac failure (n=1). Conclusions: WBRT (30 Gy/10 fractions) with concurrent erlotinib (150mg/day) is well tolerated in patients with brain metastases from NSCLC. The absence of clinical intracranial progression warrants further study of concurrent erlotinib and WBRT. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche, the Netherlands

Maintenance erlotinib (E) following first-line treatment with docetaxel, carboplatin and erlotinib in patients with ovarian carcinoma

5560 Background: We previously reported on the feasibility of a combination of erlotinib (E; a HER1/EGFR tyrosine-kinase inhibitor) with platinum and taxane chemotherapy (Agarwal et al, Ann Oncol 2004) and reported that almost 1/3rd patients (pts) stopped E during treatment due to toxicities which included intolerable rash, diarrhea and neutropenic sepsis. This update reports on those pts who then received E at 150mg daily as maintenance treatment. Methods: 48 pts initially received docetaxel (75 mg/m2) and carboplatin (AUC 5) following surgery q21d for 6 cycles in combination with daily oral E (50–100 mg) in dose-escalating cohorts. After 6 cycles, pts could continue with E alone (150mg/d) until progression. Results: 27 pts (56%) continued E beyond chemotherapy for a median of 8.6 months (mo) (range 2.3–32.5 mos), and 23/27 were escalated as planned to daily. Subsequently, 12/27 (44%) pts had their dose either reduced or interrupted for toxicity, which was cutaneous in 10/12 (83%) pts. However, the incidence of = grade 2 toxicity was low apart from alopecia (24%), rash (18%) and fatigue (15%). During follow-up (36 mo) 22/27 (81%) pts stopped E due to progressive disease and 3/27 (11%) stopped E due to cutaneous toxicity. Only 2/27 (7%) pts continue to receive E without evidence of progression, both at doses less than 150mg, again due to cutaneous toxicity. Pts receiving maintenance E had a median progression-free survival of 14.8 mo (95% CI 12.6–17.1 mo) and median overall survival 37.0 mo (95% ci 31.6–42.4 mo); for all pts these figures were 12.5 mo (95% CI 9.1–15.9 mo) respectively, and 37.0 mo (95% ci 27.3–46.7 mo). Conclusions: Maintenance E at 150mg daily following initial treatment with E plus docetaxel-carboplatin for ovarian carcinoma is associated with cutaneous toxicity which limits the dose and duration of treatment in a proportion of pts. The potential benefit of this approach can only be addressed in a randomized trial, and this is now underway under the auspices of the EORTC. A parallel translational study will examine the possibility that patients most likely to benefit can be predicted by molecular tumor analysis. [Table: see text]

Erlotinib and Chemoradiation Followed by Maintenance Erlotinib for Locally Advanced Pancreatic Cancer

A phase I trial was conducted to determine the maximally tolerated dose of erlotinib with concurrent gemcitabine, paclitaxel, and radiation for patients with locally advanced pancreatic cancer and to gather preliminary data on maintenance erlotinib after chemoradiation. Patients received gemcitabine, 75 mg/m2, and paclitaxel, 40 mg/m, weekly for 6 weeks with 50.4 radiation to the primary tumor and draining lymph nodes with a 2- to 3-cm margin. Erlotinib was administered over 3-dose levels (50-100 mg/d) with chemoradiation then all patients received 150 mg/d maintenance until disease progression. Seventeen patients were assessable for toxicity; 13 with locally advanced disease and 4 who had undergone resection but had positive margins. At erlotinib dosages > or =75 mg/d with chemoradiation the dose-limiting toxicities were diarrhea, dehydration, rash, myelosuppression, and small bowel stricture. Maintenance erlotinib, 150 mg/d, was well tolerated. The median survival of the 13 patients with locally advanced disease was 14.0 months and 6 of 13 (46%) had a partial response. The maximum tolerated dose of erlotinib with gemcitabine, paclitaxel and concurrent radiation is 50 mg/d for patients with locally advanced pancreatic cancer. Full dose maintenance erlotinib is well tolerated. Promising preliminary activity and overall survival were demonstrated.

Phase I trial of neoadjuvant and postoperative paclitaxel (P), carboplatin (C) and erlotinib with concurrent accelerated hyperfractionation radiation (AHFR) followed by erlotinib maintenance therapy in stage III non-small cell lung cancer (NSCLC)

2091 Background: Erlotinib (E), a potent reversible Her1/EGFR tyrosine kinase inhibitor is a radiosensitizer in preclinical studies. Our study was conducted to determine the recommended dose of E when given with P, C and AHFR before/after surgery in patients (pts) with potentially resectable stage III NSCLC. Methods: Pts had biopsy-proven Stage III NSCLC, and ECOG performance status of 0/1. Treatment Plan was: 1) Induction AHFR (30 Gy/1.5 Gy BID), with concurrent P [50 mg/m2] C (AUC 2), weekly x 3, and E at 3 dose levels (DL); I: 50, II: 100, and III: 150 mg, orally once daily (qd) for 4 weeks (wks); 2) Surgery after 4 wks; 3) a second identical course of chemoradiotherapy (CRT) 4–6 wks postoperatively; 4) 2-year maintenance of a fixed dose of E (150 mg qd). 3 to 6 pts were treated at each DL of E. A dose level was deemed intolerable if greater than or equal to 2 of 6 pts develop a dose-limiting toxicity (DLT). Results: Between 8/03 and 11/04, 6 male and 3 female pts were enrolled, 4 at DL I, 3 at DL II, 2 at DL III. Median age was: 61(range 33–68) years. All pts completed induction treatment. 7 pts had surgery (3 lobectomy; 4 pneumonectomy). One patient (pt) progressed; 1 pt was deemed unresectable. 6 of 9 pts received postoperative CRT + E. No DLT was observed at DL I or DL II. One pt at DL 3 had prolonged postoperative recovery from respiratory failure (grade IV toxicity). Common grade I-II toxicities were, rash (6 pts), diarrhea (3 pts), and esophagitis (3 pts). One pt at DL I had reversible posterior leucoencephalopathy, thought to be unrelated to treatment. There were no unexpected surgical complications, and no treatment-related mortality. 4 pts were downstaged at surgery; to stage I: 1 pt, stage II: 2, and 1 pt had complete pathologic response. Maintenance E was started in 6 pts. 7 of 9 pts are progression free at a mean follow-up of 9.1 months (range: 5–15). Additional pts are being treated at DL III to further characterize toxicity. Conclusion: Erlotinib in combination with concurrent weekly P/C/AHFR is well tolerated. The recommended dose of E has not yet been determined. A phase II study is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Genentech, Lilly Oncology, Pfizer, Bayer, Antigenics Amgen, Pfizer, Eyetech, Genentech, Genentech Genentech, Pfizer, Celgene, Antigenics, Amgen, Wyeth