Co-clinical Modeling of the Activity of the BET Inhibitor Mivebresib (ABBV-075) in AML.

BACKGROUND/AIM: The therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML). MATERIALS AND METHODS: Co-clinical modeling involves taking the patient's biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG-EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%). RESULTS: Results from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with >60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively). CONCLUSION: These findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment.

Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). METHODS: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. RESULTS: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. CONCLUSION: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma.

The NovoTTF-100A System (NovoTTF™ Therapy, Novocure Inc.) is a device that delivers alternating electric fields (TTFields) to tumor cells and interferes with mitosis. It is approved for use as monotherapy for the treatment of recurrent glioblastoma (rGB). TTFields are delivered through insulated transducer arrays applied onto the shaved scalp and connected to a battery-operated field generator. The occurrence of dermatologic adverse events (dAEs) is primarily due to the continuous contact between the array-related components and the scalp for periods of 3-4 days (together with other risk factors). These dAEs may include allergic and irritant dermatitis, mechanical lesions, ulcers, and skin infection. The incidence of dAEs in the phase III trial (n = 116) was 16% (2% grade 2, 0% grade 3/4); the post-marketing surveillance program (n = 570) revealed 156 (21.8%) dAEs with some patients reporting more than one event. Prophylactic strategies for dAEs include proper shaving and cleansing of the scalp and array relocation. Treatment-based strategies are AE-specific and include topical or oral antibiotics, topical corticosteroids, and isolation of affected skin areas from adhesives and pressure. The addition of skin care strategies to the NovoTTF-100A System use will maximize adherence to therapy while maintaining quality of life, all of which contribute to the therapeutic benefit of NovoTTF Therapy in rGB.

Phase I/II trial of pemetrexed plus nab-paclitaxel in advanced solid tumor patients with emphasis on non-small cell lung cancer.

BACKGROUND: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in non-small cell lung cancer (NSCLC). Based on preclinical demonstration of additive cytotoxicity, we evaluated the safety and efficacy of combining pemetrexed and nanoparticle albumin bound (nab) paclitaxel with a focus on NSCLC for phase II expansion. METHODS: A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: pemetrexed 500 mg/m(2) day 1 and nab-paclitaxel day 1 at 180, 220, & 260 mg/m(2) every 21 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. RESULTS: Planned dose escalation was completed without reaching the MTD. The RP2D was pemetrexed 500 mg/m(2) and nab-paclitaxel 260 mg/m(2). The phase II portion accrued 37 pts before early closure due to increasing first-line pemetrexed/platinum doublet use in non-squamous NSCLC. In 31 assessable phase II patients there were 5 partial responses, 12 stable disease, 14 progressive disease. The median overall survival was 8.8 months; progressive disease 4.4 months and disease control 15.6 months. CONCLUSIONS: Pemetrexed 500 mg/m(2) day 1 with nab-paclitaxel 260 mg/m(2) was feasible and well tolerated. The phase II component demonstrated activity in second/third-line therapy of advanced NSCLC; response rate 14% and disease control rate 46%. Treatment practice patterns of advanced NSCLC have evolved; further trials of this regimen are not planned.

Tumor treating fields: a new frontier in cancer therapy.

Tumor treating fields (TTFields) is a noninvasive, regional antimitotic treatment modality that has been approved for the treatment of recurrent glioblastoma by the U.S. FDA and has a CE mark in Europe. TTFields therapy delivers low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz), alternating electric fields to the tumor using transducer arrays placed on the skin around the region of the body containing the tumor. TTFields therapy affects metaphase, by disrupting mitotic spindle formation, and anaphase, by dielectrophoretic dislocation of intracellular constituents, resulting in apoptosis. TTFields therapy is frequency tuned to specific cancer cell types. The antimitotic effect of TTFields therapy has been demonstrated in multiple cell lines when the appropriate frequency was utilized. A phase III trial of TTFields monotherapy compared to active chemotherapy in recurrent glioblastoma patients established that TTFields therapy is associated with minimal toxicity, better quality of life, and comparable efficacy to chemotherapy. Ongoing and future trials will evaluate TTFields in newly diagnosed glioblastoma, solid tumor brain metastases, nonsmall cell lung cancer, and ovarian and pancreatic cancers.

Southwestern oncology group phase II trial (S0526) of pemetrexed in bronchioloalveolar carcinoma subtypes of advanced adenocarcinoma.

BACKGROUND: Pemetrexed, a multitargeted antifolate drug, is an active agent in non-small-cell lung cancer (NSCLC), especially adenocarcinomas. Based on preclinical data supporting the relevance of alpha-folate receptors in adenocarcinoma of the bronchioloalveolar carcinoma (BAC) subtype, this trial was designed to assess pemetrexed in patients with this pathologic subtype of lung adenocarcinoma. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV adenocarcinoma with BAC features or pure BAC were eligible. Treatment consisted of pemetrexed, 500 mg/m(2), administered intravenously every 21 days. RESULTS: Of 27 patients enrolled, 24 were eligible and assessable for adverse events: Toxicity was primarily hematologic, consisting of leukopenia/neutropenia, thrombocytopenia, and anemia. The median follow-up among patients still alive (n = 8) was 35 months (range, 26-47 months). Among 17 patients with measurable disease, the response rate was 23% (all partial responses; 95% confidence interval [CI], 10%-56%). The median progression-free survival (PFS) and overall survival (OS) were 6 and 25 months, respectively. CONCLUSION: Pemetrexed is active and well tolerated and, in patients with adenocarcinoma BAC subtypes, likely related to its underlying mechanism of action as a multitargeted antifolate drug.

Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/II trial.

INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. METHODS: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. RESULTS: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2%, and the disease control rate was 64.1%. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≥3 toxicities were neutropenia (36%) and diarrhea (18%). CONCLUSIONS: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.

Bortezomib for patients with advanced-stage bronchioloalveolar carcinoma: a California Cancer Consortium Phase II study (NCI 7003).

BACKGROUND: Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor, has demonstrated objective responses in patients with BAC in early-phase clinical trials. We conducted a phase II study of bortezomib in patients with advanced-stage BAC. METHODS: Patients with advanced BAC, adenocarcinoma with BAC features or BAC with adenocarcinoma features, and less than two prior regimens were eligible. Prior epidermal growth factor receptor (EGFR) inhibitor therapy was allowed. Bortezomib was administered intravenously at 1.6 mg/m on days 1 and 8 of every 21-day cycle until disease progression or unacceptable toxicity. The primary end point was response rate. The Simon two-stage design was used. RESULTS: Forty-two patients were enrolled, and the study was halted early for slow accrual. Patient characteristics were female 55%, median age 68 years, and Eastern Cooperative Oncology Group performance status of 0 and 1 in 31 and 11 patients, respectively. Twenty-six (62%) patients had received prior therapy with an EGFR inhibitor. A median of four cycles of therapy were administered. Objective responses were noted in 5%, whereas 57% had disease stabilization. The median progression-free survival and overall survival were 5.5 and 13.6 months, respectively. Grade 3 diarrhea and fatigue were noted in three and five patients, respectively. CONCLUSIONS: Bortezomib is tolerated well and is associated with modest anticancer activity in patients with advanced BAC, including patients who progressed on EGFR inhibitor therapy.

Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.

HYPOTHESIS: To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer. METHODS: In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively. RESULTS: Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1-9), KRAS mutant (7 months; 1.5-10), ALK positive (9 months; 3-12), and triple negative (4 months; 3-5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17-0.73], p = 0.0051). CONCLUSIONS: In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.

Escalating weekly doses of cetuximab and correlation with skin toxicity: a phase I study.

BACKGROUND: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m² intravenously (IV) followed by a weekly maintenance dose of 250 mg/m². It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods Four dose levels were tested: Cetuximab 400 mg/m² IV loading dose and 250, 300, 350, 400 mg/m² weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. RESULTS: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m²). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m²) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. CONCLUSIONS: Cetuximab administered at 400 mg/m² IV as a loading dose with weekly maintenance dose of 400 mg/m² is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.

EGFR mutations detected in plasma are associated with patient outcomes in erlotinib plus docetaxel-treated non-small cell lung cancer.

PURPOSE: Activating mutations in the epidermal growth factor receptor (EGFR) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), whereas KRAS mutations translate into poor patient outcomes. We hypothesized that analysis of plasma for EGFR and KRAS mutations from shed tumor DNA would have clinical utility. METHODS: An allele-specific polymerase chain reaction assay using Scorpion-amplification refractory mutation system (DxS, Ltd) was used to detect mutations in plasma DNA from patients with advanced stage NSCLC treated as second- or third-line therapy on a phase I/II trial of docetaxel plus intercalated erlotinib. RESULTS: EGFR mutations were detected in 10 of 49 patients (20%). Six (12%) had single activating mutations in EGFR, associated with improved progression-free survival (median, 18.3 months), compared with all other patients (median, 3.9 months; p = 0.008), or those with wild-type EGFR (median, 4.0 months; p = 0.012). Four of 49 patients harbored a de novo T790M resistance mutation (median progression-free survival, 3.9 months). EGFR mutational status was associated with clinical response (45 assessable, p = 0.0001); in the six patients with activating mutations, all achieved complete (33%) or partial (67%) response. All CR patients had E19del detectable in both tumor and plasma. KRAS mutations were detected in two of 49 (4%) patients, both of whom had rapid progressive disease. CONCLUSIONS: Activating EGFR mutations detected in shed DNA in plasma are significantly associated with favorable outcomes in patients with advanced NSCLC receiving docetaxel plus intercalated erlotinib. The addition of docetaxel in this schedule did not diminish the efficacy of erlotinib against patients with EGFR activating mutations.

Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation.

INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. METHODS: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. RESULTS: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status >or=90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. CONCLUSIONS: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

Bortezomib plus gemcitabine/carboplatin as first-line treatment of advanced non-small cell lung cancer: a phase II Southwest Oncology Group Study (S0339).

INTRODUCTION: Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. This phase II study of bortezomib in combination with gemcitabine/carboplatin was conducted in chemotherapy-naive advanced NSCLC patients to assess efficacy and safety. METHODS: Patients with selected stage IIIB/IV NSCLC, performance status 0-1, and no history of brain metastasis received up to six 21-day cycles of gemcitabine 1000 mg/m, days 1 and 8, carboplatin area under curve 5.0, day 1, and bortezomib 1.0 mg/m, days 1, 4, 8, and 11. RESULTS: One-hundred-fourteen patients (52% adenocarcinoma, 85% stage IV) received a median of 3.6 treatment cycles. Median follow-up was >3 years. Median overall survival was 11 months; 1-year and 2-year survival rates were 47% and 19%, respectively. Median progression-free survival was 5 months; 1-year progression-free survival rate was 7%. Response rate was 23%, and disease control rate (responses + stable disease) was 68%. The most common grade 3/4 toxicities were thrombocytopenia (63%) and neutropenia (52%). One patient experienced febrile neutropenia. Grade 3/4 neuropathy occurred in 4%, and a further 6% experienced grade 2 sensory neuropathy. CONCLUSIONS: Bortezomib plus gemcitabine/carboplatin resulted in a notable survival benefit in patients with advanced NSCLC, with the anticipated primary toxicity of myelosuppression. Further studies designed to investigate the role of bortezomib in advanced NSCLC are warranted.

Erlotinib: applications in therapy and current status of research.

Erlotinib, a small-molecule tyrosine kinase inhibitor targeted against the EGF receptor, has demonstrated survival benefit as a single agent in advanced non-small-cell lung cancer and in pancreatic cancer in combination with gemcitabine. Erlotinib has been studied extensively as a single agent as well as in combination with chemotherapy, radiation and other targeted agents. Despite its distinct target, biomarkers for selecting patients most likely to benefit from therapy are still under investigation. While EGF receptor mutations are present in approximately 10% of North American patients, that alone does not explain the benefit observed in patients with advanced non-small-cell lung cancer. With the therapeutic landscape becoming more crowded and challenging, the role of biomarkers to individualize therapy for patients is becoming increasingly more important. We summarize the current database of knowledge with regard to erlotinib pharmacology, clinical efficacy, toxicity and biomarkers.

Early clinical trial experience with vaccine therapies in non-small-cell lung cancer.

Cancer immunotherapy has made great progress because of advances in immunology and molecular biology. Increased understanding of mechanisms by which lung cancer cells escape the immune system and recognition of key tumor antigens and immune system components involved in tumor ignorance have led to the development of a variety of lung cancer vaccines. Immunotherapy has advanced from using nonspecific immunomodulatory agents to lung cancer-specific tumor antigens and tumor cell-derived vaccines. While understanding of immune processes and malignancy has improved, there is great opportunity for further research of vaccine therapies in non-small-cell lung cancer. Herein, we review the development and evolution of early lung cancer vaccine trials.

The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: a California Cancer Consortium Phase I study.

INTRODUCTION: Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. The combination of gemcitabine and carboplatin is an accepted first-line treatment for advanced NSCLC. We conducted a phase I study of gemcitabine and carboplatin in combination with bortezomib. METHODS: Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m2/gemcitabine 800 mg/m2, bortezomib 1.0 mg/m2/gemcitabine 1000 mg/m2, and bortezomib 1.3 mg/m2/gemcitabine 1000 mg/m2, in combination with carboplatin AUC 5.0. RESULTS: Twenty-six patients with advanced NSCLC were treated; 21 were chemotherapy-naive. The median age was 59 years (range, 34-74), and 23 patients were stage IV. The Karnofsky performance score was 80% in 16 patients. Dose-limiting toxicities were grade 3 thrombocytopenia with bleeding and febrile neutropenia accompanied by grade 4 thrombocytopenia and grade 3 hyponatremia. The maximum-tolerated dose was defined as bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved partial response, and eight patients had stable disease. CONCLUSIONS: The combination of bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.

Pharmacogenomic approaches to individualizing chemotherapy for non-small-cell lung cancer: current status and new directions.

At present, selection of chemotherapy regimens for individual patients remains largely an empirical process. Nevertheless, developing pharmacogenomic approaches for selection of chemotherapy through predictive biomarkers now appears feasible because of improved understanding of underlying molecular mechanisms. Although diverse terminology has been applied to such pharmacogenomic approaches (individualizing, customizing, or personalizing therapy), all rely on commonly shared principles for assessing tumor- or host-related factors. Herein, we summarize emerging data regarding pharmacogenomic approaches to treatment selection for non-small-cell lung cancer, focusing primarily on biomarkers relevant to 2 important chemotherapeutic drug classes: platinum compounds and antimicrotubule agents. The results of pilot studies and the first randomized prospective trial testing this concept are described, including limitations in the clinical setting of advanced-stage disease. Methodologic and technical aspects of pharmacogenomic approaches are elucidated, recommendations for clinical application are provided, and new directions in this field are projected.

Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer.

INTRODUCTION: Bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors. METHODS: Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500-600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7-1.3 mg/m2 on D1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0-1.6 mg/m2 on D1 and 8). RESULTS: We treated 27 patients on four dose levels in arm A and three dose levels in arm B. Tumor types included lung (n = 16), adenoid cystic carcinoma (n = 2), prostate (n = 2), sarcoma (n = 2), breast (n = 1), thymus (n = 1), head and neck (n = 1), and gastrointestinal(n = 2). Dose-limiting toxicities were seen in arm A only; grade 3 asthenia (n = 2), grade 3 transaminitis and dehydration (n = 1). The most common grade 3/4 toxicity was neutropenia. Of 26 evaluable patients, 2 patients had partial response (1 in arm A and 1 in arm B), 13 had stable disease (7 in arm A and 6 in arm B), and 11 had progression (6 in arm A and 5 in arm B). Of the 16 patients with non-small cell lung cancer, 2 (12.5%) had partial response and 9 had stable disease, for a disease control rate of 68.8%. Recommended phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly. CONCLUSIONS: Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses. Based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.

Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer.

PURPOSE: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER2's dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUVmax) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. RESULTS: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUV max. These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. CONCLUSIONS: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC.