Joan Lucca

Phase II Clinical Trial of Chemotherapy-Naïve Patients ≥ 70 Years of Age Treated With Erlotinib for Advanced Non–Small-Cell Lung Cancer

PURPOSE This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement. PATIENTS AND METHODS Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS. RESULTS Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival. CONCLUSION Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.

Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non–Small-Cell Lung Carcinoma

PURPOSE We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma

We conducted a phase 2, multicenter, open‐label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non–small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity.

Preliminary results from a phase II study of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in patients > 70 years of age with previously untreated advanced non-small cell lung carcinoma

7080 Background: Chemotherapy for patients ≥ 70 years of age with advanced NSCLC can be associated with greater toxicities than in younger patients. The identification of an efficacious therapy with minimal systemic toxicity would be particularly beneficial to elderly subjects. Erlotinib (Tarceva™) has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We thus chose to conduct a single center phase II trial of erlotinib in patients ≥ 70 with previously untreated advanced NSCLC. METHODS Patients: chemotherapy naïve, IIIB (w/malignant effusion)/IV, PS 0-2; treated with erlotinib, 150 mg p.o. q.d., until evidence of disease progression or toxicity. Primary endpoint: median survival; secondary endpoints: response rate, quality of life (using LCSS), changes in FDG-PET, and analysis of EGFR signaling pathway from pre-treatment tumor specimens. RESULTS From 3/03 to 12/03, 36 pts were treated; 30 evaluable for toxicity and response; 1 for toxicity only; 5 too early. M/F: 19/17; median age 76 (70-86); PS 0/1/2:6/28/2; Path: adeno, 56%; squamous 14%; adeno w/BAC features, 11%; BAC, 11%; NSCLC unclassified 11%, large cell, 2%. Smoking: current/former/never: 2/30/4. TOXICITY rash 77%(grade 1/2: 92%, grade 3: 8%, grade 4:0%), diarrhea 61% (grade 1/2: 100%, grade3/4:0%). Other ≥ grade 3 toxicities: pneumonitis 2/31 (6.5%) and lacrimation 1/31 (3.2%). One patient died from drug toxicity (pneumonitis); 3/31 (9.6%) were dose reduced; 2/31 (6.5%) discontinued. RESPONSE CR:0; PR: 4 (13.3%; 95% CI 5 - 29%); SD: 14 (46.6%; 95% CI 31-64%); PD:12 (40%). Median duration of response and stable disease: 6.8 (range 3.5-7.5+) and 3.5 months (range 1.5-8.0+), respectively. Survival and FDG-PET imaging are too early to evaluate. CONCLUSIONS Erlotinib appears to be well tolerated and demonstrates encouraging activity in patients ≥ 70 years of age with previously untreated advanced NSCLC. Accrual is continuing to 60 patients and updated response, survival and FDG-PET data will be presented. [Table: see text].

A Structured Nursing Intervention to Address Oral Chemotherapy Adherence in Patients With Non-Small Cell Lung Cancer.

PURPOSE/OBJECTIVES To evaluate a nurse-led intervention to enhance medication knowledge and adherence using the Multinational Association for Supportive Care in Cancer Oral Agent Teaching Tool (MOATT). DESIGN Longitudinal, descriptive feasibility study. SETTING An ambulatory thoracic oncology disease center located at the Dana-Farber Cancer Institute in Boston, MA. SAMPLE 30 adult patients with lung cancer who received the oral agent erlotinib. METHODS Structured, nurse-led education sessions using the MOATT were provided, with a 72-hour follow-up telephone contact. Participants completed a Knowledge Rating Scale (KRS) and adapted Morisky Medication Adherence Scale-8 (MMAS-8) at the end of the first cycle of oral chemotherapy. MAIN RESEARCH VARIABLES Knowledge and adherence; feasibility. FINDINGS Twenty-seven participants completed the study outcome measures reporting high knowledge levels and MMAS-8 scores. Structured, nurse-led education and follow-up monitoring sessions ranged from 14-30 minutes. Several participants also initiated contact for assistance with prescription procurement and symptom management. Participants reported a median of two side effects. CONCLUSIONS The structured, nurse-led teaching, using the MOATT tool, and follow-up nurse contacts were feasible as integrated into the thoracic oncology setting. Adherence and knowledge outcomes were encouraging. Additional studies should include objective adherence measures and strategies for delivering supportive care to patients at home. IMPLICATIONS FOR NURSING Structured teaching with patients is important to enhance proper oral anticancer medication knowledge and adherence, including follow-up monitoring of administration and side effects at 72 hours.

Abstract A254: A phase 1 safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in combination with erlotinib in patients (pts) with advanced solid tumors

Background: XL765 is an oral, selective inhibitor of Class I PI3Ks, as well as TORC1 and TORC2. The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical studies, XL765 has demonstrated dose‐dependent target modulation in tumor xenograft models. In an ongoing Phase 1 single agent clinical study, XL765 has exhibited robust pharmacodynamic activity in diverse solid tumors. Methods: Pts with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL765 in combination with erlotinib. Cycles consist of 28 days of XL765 and erlotinib, each given qd. During the ongoing dose‐escalation phase of the study there is a 14‐day run‐in period of erlotinib monotherapy. Cycle 1 safety data determine dose limiting toxicities (DLTs). Tumor response is evaluated every 8 weeks. Results: As of 24Aug2009, 14 pts with advanced solid tumors have been enrolled: NSCLC (11), CRC (1), liposarcoma (1), and endometrial adenocarcinoma (1). Most of the NSCLC pts have been previously treated with erlotinib before entering the study. Pts have been treated at 2 dose levels of XL765 (30 and 50 mg) administered once‐daily in combination with 100 mg erlotinib. No DLTs or study treatment‐related SAEs have been reported. As of 03Aug2009, AEs have been reported for 7 pts. Grade 3 adverse events of nausea, vomiting, and anorexia considered related to study treatment were observed in one pt dosed at 30 mg qd. The PK of XL765 given in combination with erlotinib is consistent with that observed for XL765 given alone (Exelixis study XL765‐001). Likewise, XL765 does not appear to alter the PK of erlotinib. In skin biopsies, substantial post‐dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, and EGFR. For example, progressive pharmacodynamic effects were evident in serial skin biopsies from a pt with EGFR‐mutant NSCLC previously treated with erlotinib who has remained on study through 26 weeks, culminating in decreases in pAKT‐T308 (72%), p4EBP1 (57%), pERK (73%), and pEGFR (50%) at Day 85 post‐start of combination dosing (50 mg XL765/100 mg erlotinib). Pharmacodynamic analyses of paired tumor biopsies are in progress. Of the first 9 patients enrolled, five have remained on study for at least 12 weeks. Conclusions: XL765 in combination with erlotinib is generally well tolerated at doses up to 50 mg XL765/100 mg erlotinib, with no apparent drug‐drug PK interaction, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A254.