Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non-Small Cell Lung Cancer Patients (SAKK 19/05 trial).

PURPOSE: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome. RESULTS: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001). CONCLUSIONS: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.

A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer.

BACKGROUND: Low intensity, intermediate frequency, alternating electric fields (Tumor Treating Fields; TTFields) exhibit anti-mitotic activity in cancer cells. Promising preclinical data have led to a single arm phase I/II trial in NSCLC patients. METHODS: Forty-two inoperable stage IIIB (with pleural effusion) and IV NSCLC patients who had had tumor progression received pemetrexed 500 mg/m(2) iv q3w together with daily TTFields therapy until disease progression. The primary endpoint was time to "in-field" progression. RESULTS: Median age for all patients was 63 years, 76% had stage IV disease, 78% had adenocarcinoma and 17% had performance status of 2. The median time to in-field progression was 28 weeks and the median time to systemic progression was 22 weeks. Six patients (14.6%) had a partial remission (PR) and 20 had stable disease (SD) (48.8%). Median overall survival was 13.8 months and 1 year survival rate was 57%. There were no TTFields-related serious adverse events. CONCLUSIONS: The combination of TTFields and pemetrexed as a second line therapy for NSCLC is safe and potentially more effective than pemetrexed alone. TTFields improved disease control within the treatment field and a phase III study is planned to further investigate its role as a novel treatment in NSCLC.

Bevacizumab and erlotinib (BE) first-line therapy in advanced non-squamous non-small-cell lung cancer (NSCLC) (stage IIIB/IV) followed by platinum-based chemotherapy (CT) at disease progression: a multicenter phase II trial (SAKK 19/05).

PURPOSE: This phase II trial aimed to evaluate feasibility and efficacy of a first-line combination of targeted therapies for advanced non-squamous NSCLC: bevacizumab (B) and erlotinib (E), followed by platinum-based CT at disease progression (PD). METHODS: 103 patients with advanced non-squamous NSCLC were treated with B (15 mg/kg day 1 of each 21-day cycle) and E (150 mg daily) until PD or unacceptable toxicity. Upon PD patients received 6 cycles of CT (cisplatin/carboplatin and gemcitabine). The primary endpoint was disease stabilization rate (DSR) after 12 weeks of BE treatment. RESULTS: 101 patients were evaluable. Under BE, DSR at week 12 was 54.5%. 73 patients had at least stable disease (SD), including 1 complete remission and 17 partial responses (PR). No unexpected toxicities were observed. Median time to progression (TTP) under BE was 4.1 months. 62 patients started CT; 35 received at least 4 cycles (6 PR, 32 SD). At a median follow-up of 36 months, median overall survival (OS) was 14.1 months. CONCLUSIONS: First-line BE treatment followed by a fixed CT regimen at PD is feasible with acceptable toxicity and activity. In a non-squamous NSCLC population unselected for EGFR status, we found OS rates similar to standard CT.

Efficacy of cetuximab in metastatic castration-resistant prostate cancer might depend on EGFR and PTEN expression: results from a phase II trial (SAKK 08/07).

PURPOSE: The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer. EXPERIMENTAL DESIGN: Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m(2) every 3 weeks or 35 mg/m(2) on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m(2) on day 1 and then 250 mg/m(2) weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted. RESULTS: Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%-52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3-15.4). Seven patients (20%) had a confirmed ≥ 50% and 11 patients (31%) a confirmed ≥ 30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN. CONCLUSIONS: EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further.

A phase I study of the oral platinum agent satraplatin in sequential combination with capecitabine in the treatment of patients with advanced solid malignancies.

BACKGROUND: The broad spectrum of antitumor activity of both the oral platinum analogue satraplatin (S) and capecitabine (C), along with the advantage of their oral administration, prompted a clinical study aimed to define the maximum tolerated dose (MTD) of the combination. PATIENTS AND METHODS: Four dose levels of S (mg/m(2)/day) and C (mg/m(2)/day) were evaluated in adult patients with advanced solid tumors: 60/1650, 80/1650, 60/2000, 70/2000; a course consisted of 28 days with sequential administration of S (days 1-5) and C (days 8-21) followed by one week rest. RESULTS: Thirty-seven patients were treated, 24 in the dose escalation and 13 in the expansion phase; at the MTD, defined at S 70/C 2000, two patients presented dose limiting toxicities: lack of recovery of neutropenia by day 42 and nausea with dose skip of C. Most frequent toxicities were nausea (57%), diarrhea (51%), neutropenia (46%), anorexia, fatigue, vomiting (38% each). Two partial responses were observed in platinum sensitive ovarian cancer and one in prostate cancer. CONCLUSION: At S 70/C 2000 the combination of sequential S and C is tolerated with manageable toxicities; its evaluation in platinum and fluorouracil sensitive tumor types is worthwhile because of the easier administration and lack of nephro- and neurotoxicity as compared to parent compounds.

Non-small-cell lung cancer: multimodality approach in stage-III resectable disease.

The long-term results of surgery +/- radiotherapy in patients with operable disease of locally advanced non-small-cell lung cancer are discouraging. In the vast majority, disseminated microscopic disease, resulting in the later occurrence of distant metastases, contributes substantially to this poor long-term outcome. The further development of multimodality treatment approaches in randomised trials, including effective systemic therapy, is necessary. These approaches and the current status of multimodality treatment strategies of resectable locally advanced non-small-cell lung cancer are discussed.