ESMO 2014 Congress

ROMANA 1 and 2

ROMANA 1 and 2, two phase 3 trials, have assessed the efficacy and safety of anamorelin hydrochloride, a selective ghrelin receptor agonist, in patients with cancer anorexia-cachexia and unresectable stage III/1V non-small-cell lung cancer (NSCLC). Patients were randomly assigned (2:1) to either anamorelin or placebo.

The coprimary endpoints were change in lean body mass from baseline over 12 weeks, and change in handgrip strength. Jennifer Temel (Boston, MA, USA) presented data showing that anamorelin significantly increased lean body mass compared with placebo: in ROMANA 1 (n=484) the median change was 1.10 kg (95% CI 0.76 to 1.42) for anamorelin versus -0.44 kg (-0.88 to 0.20) for placebo (p<0.0001); in ROMANA 2 (n=495) the changes were 0.75 kg (0.51 to 1.00) and -0.96 kg (-1.27 to -0.46), respectively (p<0.0001). There were no significant differences in handgrip score between treatment groups in either study. The most frequent drug-related adverse events were hyperglycaemia and nausea in ROMANA 1, and hyperglycaemia and diabetes in ROMANA 2.

LUX-Head & Neck 1

Jean-Pascal Machiels (Brussels, Belgium) presented data from the phase 3 LUX-Head & Neck 1 trial, in which patients with recurrent or metastatic head and neck squamous-cell carcinoma who had progressed on or after platinum-based therapy were treated either with afatinib or methotrexate. 322 patients were randomly assigned to oral afatinib and 161 to intravenous methotrexate. Progression-free survival, the primary endpoint, was significantly longer for those treated with afatinib (median 2.6 months vs 1.7 months; hazard ratio [HR] 0.80, 95% CI 0.65-0.98; p=0.03); there was no difference in overall survival. The most frequent grade 3-4 drug-related adverse events were rash or acne and diarrhoea in the afatinib group and leukopenia and stomatitis in the methotrexate group.

BRAF and MEK inhibition in melanoma

Grant McArthur (Melbourne, VIC, Australia) presented data supporting the hypothesis that combined BRAF and MEK inhibition has greater efficacy than BRAF inhibition alone in BRAF V600-mutated unresected locally advanced or metastatic melanoma. In a phase 3 trial, McArthur and colleagues randomly assigned 495 patients with to treatment with either vemurafenib and cobimetinib or vemurafenib and placebo. Median progression-free survival—the study's primary endpoint—was significantly longer in the combination group than in the control group (9.9 months vs 6.2 months; HR 0.51, 95% CI 0.39-0.68; p<0.0001). There were more grade 3 or worse adverse events in the combination group than in the placebo group (65% vs 59%). Additionally, Caroline Robert (Villejuif, France) presented the preplanned interim overall survival analysis of the phase 3 COM BI-v trial, in which the combination of dabrafenib and trametinib was shown to improve overall survival and progression-free survival compared with vemurafenib in patients with previously untreated, unresectable or metastatic BRAF V600E mutation-positive cutaneous melanoma. Adverse events were similar between groups.

Rolapitant for CINV

Martin Chasen (Ottawa, ON, Canada) presented data showing that the novel NK-1 receptor antagonist rolapitant reduces the incidence of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy. In this phase 3 trial, patients were randomly assigned 1:1 to receive either oral rolapitant or placebo, plus either granisetron or dexamethasone, before chemotherapy. The proportion of patients who achieved the study's primary endpoint of a complete response (defined as either no emesis or no need for rescue medication 24-120 h after chemo-therapy treatment) was significantly greater with rolapitant than with placebo (72.7% vs 58.4%, p<0.001). No significant difference in quality of life was reported between treatment groups.

Dabrafenib in NSCLC Dabrafenib, a BRAF inhibitor, showed significant activity in patients with stage IV BRAF V600E-mutated NSCLC. David Planchard (Villejuif, France) presented data from a phase 2, single-group study, which enrolled 84 patients to treatment with dabrafenib. Six patients were treatment-naive, 40 had previously received single-line treatment, and 38 had received two or more lines of treatment. Of the 78 patients who had previously received one or more lines of treatment, the proportion achieving an overall response was 32% (95% CI 22-44); of those who were treatment-naive, three patients (50%) achieved a partial response. Adverse events occurring in more than 25% of patients were pyrexia (36%), asthenia (30%), hyperkeratosis (30%), decreased appetite (29%), nausea (27%), cough (26%), fatigue (26%), and skin papilloma (26%). Grade 3 or worse adverse events occurred in 45% of patients, and one patient died from intracranial haemorrhage.

Antenatal irradiation

Antenatal exposure to radiotherapy does not have significant neuro-psychological, cardiac, or general health effects, according to the results of a case-control study by Frederic Amant (Leuven, Belgium) and colleagues. Retrospective and prospective data were collected for 16 children (median age 6 years [range 1.5-9.6]) and ten adults (33 years [22.0-49.0]) who had been exposed to antenatal radiation. Median maternal and fetal irradiation were estimated to be 48 Gy (range 12-70) and 91 mGy (0-1690), respectively. Cardiac function, neuro-logical function, and general health were all within normal ranges for all but one patient (for whom other confounding factors existed), with no linear relation identified between dose of fetal irradiation and cognitive outcomes.

LUX-Lung 8

The results of LUX-Lung 8, presented by Glenwood Goss (Ottawa, ON, Canada), showed that patients with advanced squamous-cell lung carcinoma treated with second-line afatinib had significantly longer median progression-free survival than those treated with second-line erlotinib. The phase 3 trial enrolled patients who had stage 111B/IV disease, had progressed after four or more cycles of platinum-based doublet therapy, and had not received previous tyrosine-kinase inhibitor treatment. 335 patients were randomly assigned to receive afatinib and 334 to receive erlotinib until disease progression. Median progression-free survival was 2.4 months in the afatinib group and 1.9 months in the erlotinib group (HR 0.82, 95% CI 0.68-1.00; p=0.043)• More patients in the afatinib group had grade 3 or worse diarrhoea (9.7% vs 2.4%) and grade 3 stomatitis (3.3% vs none), and more patients in the erlotinib group has grade 3 rash or acne (5.5% vs 9.0%).

Cediranib for cervical cancer

Cediranib significantly increased progression-free survival for patients with metastatic or recurrent cervical cancer compared with those treated with placebo. In the phase 2 CIRCCa trial, patients were randomly assigned to receive cediranib (n=34) or placebo (n=35), in combination with carboplatin and paclitaxel. R Paul Symonds (Leicester, UK) presented data showing that median progression-free survival was significantly longer in the cediranib group (35 weeks, 95% CI 32-38) compared with the placebo group (30 weeks, 29-31; HR 0.61, 80% CI 0.41-0.89; p=0.046). More patients in the cediranib group than in the placebo group had grade 2-4 diarrhoea (50% vs 18%) and hypertension (34% vs 12%).


Johan Vansteenkiste (Leuven, Belgium) presented disease-free survival data from the phase 3 MAGRIT trial, which assessed the efficacy of adjuvant MAGE-A3 recombinant protein plus AS15 (hereafter MAGE-A3) in patients with resected MAGE-A3-positive NSCLC compared with placebo. 2272 patients were randomly assigned (2:1) to receive intramuscular injections of MAGE-A3 or placebo over 27 months. Median disease-free survival was 60.5 months in the MAGE-A3 group and 57.9 months in the placebo group (HR 1.024, 95% CI 0.891-1.177; p=0.7379); there was no difference in adverse events between groups. In the absence of any significant treatment effect, no potentially predictive gene signature—a coprimary endpoint—could be identified.

Nivolumab for melanoma

A significantly greater proportion of patients with previously treated, advanced melanoma achieved an an overall response when treated with nivolumab (a fully human IgG4 PD-1 inhibitor antibody) than with investigator's choice of chemotherapy, the results of a phase 3 trial show. Jeffrey Weber (Tampa, FL, USA) and colleagues randomly assigned patients with metastatic melanoma who had progressed after treatment with anti-CTLA-4 therapy and a BRAF inhibitor 2:1 to receive either nivolumab or chemotherapy until disease progression or unacceptable toxic effects. 268 patients received nivolumab and 102 received chemotherapy. 32% (95% CI 24-41) of patients in the nivolumab group had an objective response compared with 11% (3.5-23) in the chemotherapy group. Grade 3-4 drug-related adverse events were seen in 9% and 31% of patients treated with nivolumab and chemotherapy, respectively.

Pembrolizumab for advanced solid tumours

Results of an ongoing phase lb trial for pembrolizumab, a humanised IgG4 monoclonal antibody that inhibits PD-1, in patients with advanced solid tumours were reported. Eligible patients had to have PD-L1 expression in the stroma or in more than 1% of cells; those enrolled were treated with pembrolizumab until complete response, disease progression, or unacceptable toxic effects. 39 patients with advanced gastric cancer were enrolled; for these patients, the most common treatment-related adverse events were hypothyroidism and fatigue (five [13%] each) and grade 3 or worse adverse events occurred in three patients (hypoxia, peripheral neuropathy, and pneumonitis).

32% of Asian patients and 30% of non-Asian patients achieved an objective response. 61 patients with head and neck cancer were enrolled, of whom 60 received one or more treatment dose. 23 patients were human papillomavirus (HPV)- positive, and 37 were HPV-negative. For these patients, the most common drug-related adverse-events were fatigue (18%), pruritus (10%), and nausea (8%); grade 3 or worse adverse events occurred in 17% of patients. 20% of patients with head and neck cancer achieved an objective response. 33 patients with urothelial cancer were enrolled: for these patients, the most common adverse events were fatigue (18%), peripheral oedema (12%), and nausea (9%). Four (12%) patients reported grade 3 or worse treatment-related adverse events, and 24% of patients had an objective response. A phase 2 trial of pembrolizumab is due to begin early 2015.