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ESMO Congress

Ezra E.W. Cohen, MD, Associate Professor, Section of Hematology/Oncology, Department of Medicine, Co-Director, Head and Neck Cancer Program, Director, Hematology/Oncology Fellowship Program, University of Chicago Medical Center, discusses an analysis of the phase III EXAM trial that examined the efficacy and pharmacokinetics of cabozantinib (XL184) for patients with advanced medullary thyroid cancer (MTC).

Cohen explains that one of the aspects of the study was to examine if the presence of mutations in the proto-oncogene 

 effected the activity of cabozantinib, an active inhibitor of the RET tyrosine kinase, which is theorized to be one of the main drivers in MTC. Regardless of the presence of 

 mutations all patients benefited from treatment with cabozantinib and only a slight difference was observed between those with or without a 

The pharmacokinetics of cabozantinib are fairly well understood; however, the impact of dose size and drug exposure on efficacy was further examined in the EXAM trial. Cohen explains that evidence from this study seems to suggest that exposure levels did not alter the efficacy of cabozantinib. Overall, this agent demonstrates very robust activity across multiple patient groups.

Ezra E.W. Cohen, MD, from the University of Chicago Medical Center, on the pharmacokinetics and efficacy of cabozantinib for medullary thyroid cancer. 

Dr. Ezra Cohen on the Pharmacokinetics of Cabozantinib

In Asian patients with previously untreated advanced or recurrent gastric cancer, overall survival (OS) and progression-free survival (PFS) were significantly improved when docetaxel was added to S-1, an oral fluoropyrimidine that is a standard treatment for this malignancy in East Asia and parts of Europe.

At the European Society for Medical Oncology (ESMO) 2012 Congress, investigators from the START trial (S-1 plus Docetaxel versus S-1 for advanced gastric cancer) presented an update to the survival analysis previously reported at the 2011 Gastrointestinal Cancers Symposium.Â  Kazuhiro Yoshida, MD, of Gifu University Hospital, Gifu, Japan, presented the findings at ESMO for the Japan Clinical Cancer Research Organization and the Korean Cancer Study Group Intergroup trial.

In the previous analysis, no statistically significant difference in overall survival was observed with the combination (HR 0.88; 

“However, an independent biostatistician pointed out that there was a large number of censored cases, which led to an insufficient number of events for a proper [survival] analysis,” Yoshida said. “According to this recommendation, we performed further confirmation to resolve the censored cases to analyze the START trial properly.”

The current intention-to-treat analysis included 635 patients with advanced or relapsed gastric cancer randomly assigned to S-1 80 mg/m

 on days 1-28 every 6 weeks or S-1 80 mg/m

 on day 1 every 3 weeks. Patients received treatment until disease progression, for a median number of 5 cycles for the combination and 2 cycles for single-agent S-1. Patients were followed an average time of 11.4 months.

Median OS was 12.5 months in the docetaxel/S-1 group and 10.8 months in the S-1 group (HR = 0.837; 

 = 0.0319). PFS was 5.3 months versus 4.2 months, respectively (HR = 0.765; 

 = 0.001). The overall response rate in patients with measurable disease was 38.8% with the combination and 26.8% with S-1 alone (

Several subsets derived a particular survival benefit from the combination: the Japanese cohort (versus Korean) (HR = 0.810), patients with non-measurable (versus measurable) disease (HR = 0.649), patients with ECOG performance status of 0 (HR = 0.780), and patients with no lymph node metastasis (HR = 0.688).

“Adding docetaxel to S-1 significantly improved OS, PFS and response rates, nevertheless it resulted in some increase proportion of hematological toxicities,” he said. Neutropenia grade 3 and higher was observed in 29% of patients, and febrile neutropenia in 3%, compared to 4.2% and 0%, respectively, with S-1 alone.

The findings point to docetaxel plus S-1 as a new treatment option for patients with untreated advanced gastric cancer, Yoshida concluded.

Gunnar Folprecht, MD, of the University Cancer Center in Dresden, Germany, discussed the findings. He said that the findings presented at ESMO “would be taken as positive.” Folprecht concluded that docetaxel plus S-1 is more effective than S-1 alone “if there had not been the analysis presented at the Gastrointestinal Cancers Symposium.”

Folprecht emphasized that the primary analysis was negative. That analysis showed 1-year survival to be 52.5% with the combination versus 46.0% with the single agent. Two-year survival showed 23.7% versus 20.6%, respectively; and 3-year survival was 13.0% versus 12.3% (HR 0.88; 

S-1 is approved by the European Medicines Agency for advanced gastric cancer when given in combination with cisplatin, and the START trial suggests there may be a less toxic, platin-free way to give the drug, he added.

However, Folprecht stayed firm on his own views.

“My personal opinion is that docetaxel plus S-1 is not a new standard of care,” Folprecht said.

Two analyses, two different conclusions in Asian START trial when docetaxel was added to S-1 for patients with previously untreated advanced or recurrent gastric cancer.

Does Docetaxel Add Benefit to the Oral Fluoropyrimidine S-1 in Gastric Cancer?

Combining the new drugs dabrafenib and trametinib provided a clinically meaningful improvement in patients with melanoma that had 

 V600 mutations, according to results of a phase II study presented on Saturday at the 2012 ESMO Congress in Vienna, Austria.

Full-dose combination of a novel BRAF inhibitor (dabrafenib) and a novel MEK 1/2 inhibitor (trametinib) improved progression-free survival (PFS), response rate, and duration of response, said lead investigator Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney. In addition, the combination reduced the side effects associated with BRAF inhibitor monotherapy, which is highly unusual.

Both drugs act on the RAS kinase pathway, dabrafenib at an earlier point than trametinib. About 50% of patients with metastatic melanoma have a 

 mutation. “Dabrafenib attacks that abnormality and works for about 5 to 7 months, and patients develop resistance to the drug. The rationale for adding a MEK 1/2 inhibitor is that it blocks the ‘escape route’ for the BRAF inhibitor and allows continued response,” Long explained.

—positive metastatic melanoma to one of three treatment arms: monotherapy with dabrafenib 150 mg/bid; combination of dabrafenib 150 mg/bid with once-daily trametinib 1 mg; or full doses of both drugs (ie, dabrafenib 150 mg/bid; once-daily trametinib 2 mg).

Median time to follow-up was 14 months. Median PFS was 9.2 months for the full dose combination versus 5.8 months for the monotherapy arm (

 <.0001), representing a 61% reduction in risk of disease progression. Median PFS was 9.2 months for the arm using half-dose trametinib, which was also significantly better than monotherapy (

 = .005). At 12 months, 41% of the patients who received full-doses of both drugs had not progressed versus 9% of the monotherapy arm.

Analysis showed PFS benefit from full doses of both drugs for every category: age, sex, baseline disease stage, baseline LDH, or presence of brain metastasis

Looking at patients with the most common 

, PFS was 6.5 months with monotherapy, 7.3 months for the combination with half-dose trametinib, and 10 months for the full-dose combination (

Median overall survival (OS) had not been reached in any of the three arms at the time of the data were presented at ESMO. Twelve-month OS was 70% in the monotherapy arm, 68% in the combined therapy arm with half-dose trametinib, and 78% in the full-dose combination arm.

“This has never been seen before in metastatic melanoma,” Long noted.

Confirmed response rates were 54% for monotherapy, 50% for the combination of dabrafenib with half-dose trametinib, and 76% for the full-dose combination.

Median duration of response was 5.6 months for monotherapy, 9.5 months for the combination of full-dose dabrafenib and half-dose trametinib, and 10.5 months for the full dose combination of both drugs.

“Using one road block [ie, dabrafenib] and then adding an exit block [ie, trametinib] improves response and duration of response,” said Long.

Hyperproliferative skin toxicities (ie, alopecia hyperkeratosis, skin papilloma, and squamous cell carcinoma) associated with BRAF inhibition were reduced in both combination arms. Squamous cell carcinoma occurred in 10 patients on monotherapy, one patient in the combination arm that included half-dose trametinib, and four patients in the full-dose combination arm.

“This has never been seen before in the history of chemotherapy,” Long noted.

Pyrexia and nausea and vomiting were increased in the combination arm. The rate of pyrexia was 67% in the full-dose combination arm and 23% in the monotherapy arm. Long said that during the evolution of the study, it became clear that prophylaxis with corticosteroids was effective in preventing pyrexia, and going forward, that will be the practice. The median time to first episode of pyrexia was less than 6 weeks and only three patients in the full-dose combination arm developed grade 3 pyrexia. “The majority of patients develop only 1 episode of pyrexia,” explained Long.

The incidence of vomiting in the full-dose arm was 35%, but these were grades 1 and 2 and easily managed, said Long.

The distribution of other adverse events was similar in the three treatment arms.

Two phase III trials of this combination are now ongoing in metastatic melanoma: One comparing the full-dose combination versus dabrafenib alone and the other comparing the full-dose combination to trametinib alone.

Combining the new drugs dabrafenib and trametinib provided a clinically meaningful improvement in patients with melanoma that had BRAF V600 mutations.

BRAF Inhibitor Plus MEK Inhibitor Encouraging in Metastatic Melanoma

Gefitinib improved progression-free survival (PFS) and some quality of life measures when used as second-line therapy for esophageal cancer. However, the PFS benefit did not extend to improved overall survival (OS), the primary endpoint of the trial. These were the findings of the first randomized controlled trial to address a second-line treatment for esophageal cancer. The study was presented by David Ferry, MD, New Cross Hospital, Wolverhampton, UK, at the 2012 ESMO Congress in Vienna.

“At the moment, there is no therapy for esophageal cancer that has progressed on first-line therapy. The standard of care after progression is palliative therapy,” Ferry told listeners at an official ESMO press conference September 29.

The Phase III, multicenter, double-blind, study was conducted at 51 centers in the UK. Participants were 450 patients with esophageal cancer or cancer of the esophageal junction who progressed on first-line treatment with up to two previous chemotherapy regimens; they were randomized to the epidermal growth factor receptor (EGFR)-inhibitor gefitinib 500 mg/day versus placebo and treated until disease progression, as documented on regular CT scans.

At baseline, median age was 64 years and 83% were male; 76% had adenocarcinoma, and 78% had esophageal cancer. Twenty-five percent were performance status (PS) 0; 54% were PS 1, and 21% were PS 2.

A small but statistically significant difference in PFS was observed in favor of gefitinib: median PFS was 49 days on gefitinib versus 35 days for placebo (

“The improved PFS on gefitinib did not translate to an overall survival benefit. But these patients treated second-line have a very dire prognosis with an overall survival of 2 months,” Ferry said.  “We saw durable responses.”

At 8 weeks, disease control was observed in 25.5% of gefitinib-treated patients versus 16% of the placebo group (

The investigators found that PS was a prognostic marker for survival in this trial. Patients with PS 0 had a median OS of 6.03 months; those with PS 1 had median OS of 3.93 months; and those with PS 2 had a median OS of 1.97 months.

Both dysphagia (difficulty swallowing) and odynophagia (pain while swallowing) were significantly improved for patients taking gefitinib versus placebo (

 = .004). Ferry said that these two symptoms are important indicators of quality of life in patients with esophageal cancer.

The UK investigators are planning an associated study called TRANSCOG to analyze biopsies of more than 300 patients enrolled in the trial to identify molecular characteristics associated with enriched benefit of gefitinib.

When questioned as to why OS was selected as the primary endpoint of the trial, Ferry said, “A drug that doesn’t produce an overall survival benefit is unlikely to get approved. We need to put our new drugs through these tough tests [i.e., overall survival]. Otherwise, no new drugs will be approved for out patients for our patients.

At present, gefitinib should not be used outside of a clinical trial setting. Ferry said: “There is not sufficient benefit of gefitinib in unselected patients. That’s why will do the TRANSCOG translational study to identify biomarkers.”

He and his colleagues are planning a new placebo-controlled trial “with another active drug” using biomarkers for selection. Ferry did not name the new drug to be studied.

“That would be telling a secret,” he commented.

Gefitinib improved progression-free survival and some quality of life measures when used as second-line therapy for esophageal cancer.

Gefitinib: Small Benefit as Second-Line Therapy in Esophageal Cancer

OncLive presents live coverage from the 2012 European Society for Medical Oncology (ESMO) congress, held at the Austria Center Vienna from September 28 to October 2, in Vienna, Austria.

ESMO is a large European professional organization committed to furthering oncology care and treatment through the dissemination of research and data.The 2012 installment of the ESMO meeting highlights advances in multiple tumor types, including information on targeted agents for lung cancer, melanoma, and gastrointestinal cancers.

OncLive’s conference coverage features video interviews with leading oncologists and articles discussing the latest breaking news and clinical trial results presented at the meeting.

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View coverage from the 2012 ESMO Congress

Coverage from the 2012 European Society for Medical Oncology congress, held at the Austria Center Vienna from September 28 - October 2, in Vienna, Austria.


ESMO Congress | Conference

Dr. Ezra Cohen on the Pharmacokinetics of Cabozantinib

Does Docetaxel Add Benefit to the Oral Fluoropyrimidine S-1 in Gastric Cancer?

BRAF Inhibitor Plus MEK Inhibitor Encouraging in Metastatic Melanoma

Gefitinib: Small Benefit as Second-Line Therapy in Esophageal Cancer

Conference Coverage From the 2012 ESMO Congress