Multicenter randomized, open-label phase II trial of sequential erlotinib and gemcitabine compared with gemcitabine monotherapy as first-line therapy in elderly or ECOG PS two patients with advanced NSCLC.

AIM: The potential beneficial interaction between erlotinib and chemotherapy may require sequencing or pharmacodynamic separation. The aim of this study was to evaluate the efficacy and tolerance of sequential erlotinib and gemcitabine versus gemcitabine monotherapy as first-line therapy in elderly or ECOG PS-2 patients with advanced non-small cell lung carcinoma. METHODS: The primary objective of this multicenter randomized Phase II study was progression-free survival (PFS). Secondary objectives were overall response rate (ORR), disease control rate, response duration, overall survival and safety. Patients were randomized to either gemcitabine (1250 mg/m2 Day 1, 8 q28 days) followed by erlotinib (150 mg/day on day 15 through day 28), (EG-arm), or gemcitabine monotherapy (1000 mg/m2 Days 1, 8, 15 q28 days), (G-arm) for up to six cycles. RESULTS: Fifty-four patients were recruited, 28 G-arm and 26 EG-arm. Overall, efficacy results were not significantly different between study arms. Median PFS and ORR for the G- versus EG-arms were 8.0 versus 10.3 weeks (hazard ratio 1.3; 95% confidence interval [0.63;2.68]; P=0.48) and 7.1 versus 3.8 percent respectively (difference -3.30; 95% confidence interval [-17.5;10.9]). The majority of adverse events (AEs) in both arms were Grade 1-2. The commonest AEs recorded in the EG- and G-arms were rash-like events (65 percent) and nausea (42 percent) respectively. Four patients (17 percent) in EG-arm and five (16 percent) in G-arm experienced at least one treatment-related serious AE. CONCLUSIONS: In this study, patients with non-small cell lung carcinoma at ECOG PS-2 or aged ≥70 years derived no efficacy advantage from sequential erlotinib in combination with gemcitabine relative to gemcitabine alone. No unexpected safety findings were noted.

A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer.

BACKGROUND: Mucin 1 antigen, highly expressed by epithelial ovarian cancer (EOC), is a potential target for immunotherapy. A previous successful phase 1 trial was conducted in patients with adenocarcinoma who were injected with Cvac, autologous monocyte-derived dendritic cells (DCs) incubated with mannosylated mucin 1 protein (M-FP). The present study was a phase 2 trial of Cvac in patients with advanced EOC. METHODS: Eligible patients had EOC with progressive disease, defined as an increase in CA125 of ≥ 25% in 1 month. The primary endpoint was CA125 response or stabilization. Peripheral blood mononuclear cells were collected by leukapheresis and cultured to generate DCs. The DC were incubated with M-FP, and after washing were prepared for injection into the patient intradermally every 4 weeks for 3 doses, then every 10 weeks for up to 12 months. RESULTS: All 28 patients recruited were evaluable for safety and 26 for efficacy. All had undergone surgery and platinum-based chemotherapy, and 57% of patients received ≥ 3 chemotherapy regimens. There were no Grade 3 or 4 toxicities considered related to Cvac. Four patients showed CA125 response or stabilization (2 patients with major responses, 1 minor response, 1 stabilization) of median duration 10.3 months (5.3-16.3 months). An additional patient had > 25% CA125 reduction (not confirmed). CONCLUSIONS: Cvac immunotherapy was well tolerated. Clinical activity in EOC was evident based on decline or stabilization of CA125 in some patients, supporting ongoing development of Cvac in ovarian carcinoma and planning of additional trials of patients in remission is currently underway.

The role of Cancer-Testis antigens as predictive and prognostic markers in non-small cell lung cancer.

BACKGROUND: Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. METHODS: We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. RESULTS: NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. CONCLUSIONS: NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.

Paraneoplastic leukocytoclastic vasculitis as an initial presentation of malignant pleural mesothelioma: a case report.

INTRODUCTION: Vasculitis has been associated with malignancies, more commonly hematological rather than solid malignancies. Due to the rarity of these conditions and the lack of a temporal association, the relationship between vasculitis and malignancy remains unclear. Paraneoplastic vasculitis as a phenomenon of lung cancer has been described in the literature. To the best of our knowledge, this is the first case report of leukocytoclastic vasculitis being an initial presentation of malignant pleural mesothelioma. CASE PRESENTATION: We report the case of an 84-year old Greek man who presented to our facility with an erythematous, pruritic and purpuric rash affecting his limbs. This was biopsy-proven to be leukocytoclastic vasculitis and treated conservatively with topical corticosteroids as well as oral prednisolone, with good results. Six months later, he was diagnosed as having malignant pleural mesothelioma. As he remained asymptomatic from his malignancy, no systemic chemotherapy was instituted. He had a recurrence of biopsy-proven leukocytoclastic vasculitis two months after he was diagnosed as having mesothelioma, which again settled with conservative measures. CONCLUSIONS: It is important to remain vigilant with regard to the association between leukocytoclastic vasculitis and malignancies. A diagnosis of vasculitis requires a search for malignancies as well as other possible etiologies. This is particularly of relevance when the vasculitis becomes chronic, recurrent or treatment is no longer effective. Should our patient have experienced refractory vasculitis, we would have instituted systemic chemotherapy to treat the underlying malignancy.