Novel RCT With Treatment Based on Tumor Characteristics

Roxanne Nelson

September 12, 2013

The goal of personalized medicine might be one step closer for cancer patients. A new study has found that about 40% of patients with a variety of primary tumor types had molecular abnormalities that could be targeted by existing drugs.

Even though the clinical data are early and the study is ongoing, the researchers conclude that establishing a comprehensive molecular tumor profile to guide treatment is safe, feasible, and compatible with clinical practice.

Preliminary results of the study will be presented at the 2013 European Cancer Congress, which begins September 27 in Amsterdam.

This is the first randomized trial to evaluate outcomes after treatment chosen on the basis of a tumor's molecular profile, and the first to encompass a variety of tumor types, according to the researchers.

Currently, 320 patients from 7 comprehensive cancer centers in France are enrolled in the SHIVA trial. The aim of this proof-of-concept randomized phase 2 trial is to compare 2 treatment strategies for patients with refractory cancer.

A molecular profile is established with a tumor biopsy. If an abnormality is identified for which an approved targeted agent is available, patients are then randomized to 1 of 2 treatments: targeted therapy chosen on the basis of the molecular profile of the tumor; or standard treatment chosen by the investigator.

To date, 60 patients with solid tumors have been randomized, all have recurrent/metastatic disease, and all have either failed standard treatments or are not candidates for them.

All Tumors Included

"Our goal is to have 200 randomized patients," said lead author Christophe Le Tourneau, MD, head of the phase I program at the Institut Curie in Paris. "Although 40% of the 320 patients have a tumor for which targeted drugs are available, some are still on the chemotherapy that was started at the time of the biopsy; therefore, we will have to randomize them later."

"Because we are looking for an effect in different kinds of tumors, we have ruled out the inclusion of any particular type of tumor if this brings the number of randomized patients with this type to over 20% of the total," Dr. Le Tourneau said in a statement. "We have also allowed the inclusion of patients with rare tumors."

The researchers note that previous work has suggested that selecting targeted therapies on the basis of an individual molecular tumor profile improves patient outcomes. "But the lack of randomization versus standard of care in these studies did not allow for drawing robust conclusions," they write in their abstract.

Study Details

SHIVA was designed to compare targeted therapy, selected on the basis of molecular tumor profiling, with conventional treatment in patients with any type of refractory cancer. The primary outcome is progression-free survival. Secondary outcomes include overall response rate, overall survival, adverse effects, and variations in treatment effect.

At the time of abstract submission, results for the feasibility part of the study were available for 53 patients. A biopsy was performed in 50 (94%) of these patients, mutation status was obtained in 32 (64%), gene copy-number alterations were obtained in 34 (68%), and immunohistochemistry profile was obtained in 45 (90%).

Patients randomized to targeted therapy are receiving a variety of agents, including imatinib (Gleevec), everolimus (Afinitor), sorafenib (Nexavar), erlotinib (Tarceva), abiraterone (Zytiga), and tamoxifen.

Challenges and Changes Ahead

The researchers note that these targeted therapies were developed largely on the basis of the histology and primary location of the tumor. A number of potentially promising targeted therapies might have failed in early clinical trials because a response was not observed in a sufficient number of patients.

Dr. Le Tourneau pointed out how the history of breast cancer treatment "changed beyond recognition" when role of the ErB2/HER2 gene was identified.

"We also know that patient outcomes in the few trials to date where the choice of treatment is based on a molecular abnormality are better than those where the treatment is not matched to the abnormality," he explained. "What was missing is a histology-independent randomized trial comparing molecular targeted treatment with conventional therapy. This is why I decided to set up the SHIVA trial."

Currently, according to the researchers, cancer patients continue to receive molecularly targeted therapy on the basis of the location of the primary tumor. The results of this trial, primarily the end point of progression-free survival, might help change that practice.

But this would present a challenge for physicians. Currently, "we have no data on the efficacy of drugs in patients with the same molecular abnormality but different tumor types. We suspect that a treatment effect would not depend on the presence of a single molecular abnormality, but more likely on several," said Dr. Le Tourneau. "However, we believe that it is most likely that, in the future, tumor location and histology will no longer be the primary criteria for the prescription of molecularly targeted agents; rather, tumor biology will be the deciding factor."

The SHIVA trial is supported by a grant from the French Agence Nationale de la Recherche (Investissements d'Avenir) and the Site de Recherche Intégré sur le Cancer (SIRIC).

2013 European Cancer Congress (ECC): Abstract 950. To be presented September 28, 2013.

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