TARGETED AGENTS FOR NSCLC

SYDNEY — Data from the Lung Cancer Mutation Consortium (LCMC) add to evidence that using targeted agents improves survival, something that has been very difficult to show in clinical trials.

Conducted across 14 top cancer centers across the United States, the LCMC used multiplex testing for 10 different genetic mutations or other oncogenic drivers, and then used that information to assign in "real time" patients to a targeted therapy in clinical trials.

The latest results from over 1000 patients with adenocarcinoma were presented here at a presidential session at the 15th World Conference on Lung Cancer by Mark Kris, MD, from the Memorial-Sloan Kettering Cancer Center in New York City.

Oncogenic drivers were identified in 63% of patients, and 23% of these were treated with a targeted agent.

Patients with an oncogenic driver who are treated with targeted therapies live longer than patients with an oncogenic driver who are not treated with targeted therapies, he said.

Among 938 patients with follow-up, the median survival was 3.5 years for patients with an oncogenic driver treated with targeted therapy, 2.4 years for patients with an oncogenic driver not treated with targeted therapy, and 2.1 years for patients with no driver identified (P < .0001).

Median survival in this study was measured from the time of diagnosis of metastatic disease, he noted, whereas in most studies, the survival is measured from the start of treatment.

The longest survival (4.3 years) was seen in patients with ALK-positive tumors, followed by those withEGFR (sensitizing) tumors (4.0 years), EGFR (other) tumors (3.3 years), and KRAS mutations (2.4 years).

The most common mutations found were KRAS (in 25% of tumors), EGFR (sensitizing) in 15%, ALK in 8%, EGFR (other) in 6%, BRAF in 2%, HER2 in 2%, while the other mutations were found in 1% of tumors.

Direct Patients to Targeted Therapy

"This study showed that it is feasible to test for multiple genetic mutations in lung cancer patients, and that it is important to direct patients to appropriate targeted therapies, because a key finding of this presentation was that patients who had identified oncogenic drivers who get the appropriate treatment have the best outcomes," Ben Solomon, MBBS, PhD, from the University of Melbourne, Australia, toldMedscape Medical News.

"As much as local circumstances allow for this, all lung cancer patients should be tested and, where appropriate, should be treated with targeted agents," he added.

At present, outside of clinical trials, there are 2 oncogenic drivers that are related to targeted therapies available in many countries worldwide: ALK rearrangement targeted by crizotinib (Xalkori), and EGFRmutations targeted by erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Giotrif).

Mounting Evidence of Improved Survival

Dr. Solomon acted as discussant of this study, and pointed out several limitations. This was a retrospective analysis of prospectively collected data in a selected population, and the groups were not matched with respect to the molecular driver, he noted. For instance, in the EGFR (sensitizing) group, 129 patients had the driver and were treated with a targeted therapy but only 29 patients had the driver and were not.

Despite these caveats, the survival of 3.5 years seen in patients with an oncogenic driver treated with a targeted therapy was "very impressive" and was significantly better than the survival seen in patients with drivers not treated with targeted therapy and those without oncogenic drivers.

"These are really important data because we have precious little data regarding the impact on survival with targeted therapies in lung cancer," he said.

A number of prospective clinical trials have shown large improvements in progression-free survival with targeted agents, compared with chemotherapy, but there has not been a significant difference shown in overall survival, likely because of the confounding from crossover of patients from the control group to the targeted therapy on progression of the disease, he explained.

There are some data on survival from retrospective studies, he said, and there is also some evidence from another consortium, the Network Genomic Medicine group, based in Cologne, Germany. This group has just published results from 3000 patients with adenocarcinoma and squamous cell lung cancer showing improved survival in patients with tumors that were EGFR-positive or ALK-positive treated with targeted agents (Siedel et al. Sci Transl Med. Published online October 30, 2013).

Dr. Kris reports consultancy for Pfizer, Roche, Boehringer Ingelheim, Novartis, and Genentech/Roche, and receiving research/grant support from Pfizer. Dr. Solomon reports consultancy for Roche, Pfizer, Lilly, Clovis, Boehringer, and Novartis, and receiving research/grant support from Pfizer Oncology.

15th World Conference on Lung Cancer (WCLC): Abstract PL03. Presented October 29, 2013.