Lung Cancer Mutation Consortium Finds Oncogenic Drivers in Majority of Metastatic Lung Adenocarcinomas

Genotype-Directed Therapy Shown to Prolong Survival


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Mark G. Kris, MD, and colleagues

Oncogenic Drivers in Lung Cancer

The survival of patients was associated with the type of oncogenic driver detected in their tumor specimen, giving doctors a powerful tool to select therapies and estimate prognosis.

—Mark G. Kris, MD, and colleagues

The Lung Cancer Mutation Consortium (LCMC) was formed to test adenocarcinomas of the lung for 10 oncogenic drivers in order to enable clinicians to select targeted treatments and enroll patients into suitable clinical trials. As recently reported in JAMA by Mark G. Kris, MD, William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center, New York, and colleagues in the LCMC, oncogenic drivers were identified in nearly two-thirds of patients with metastatic disease.1 Median overall survival was extended by more than 1 year in patients with an oncogenic driver who received genotype-directed therapy vs those who did not.

Study Details

From 2009 through 2012, 14 U.S. LCMC sites enrolled patients with metastatic lung adenocarcinoma and Southwest Oncology Group (SWOG) performance status of 0 to 2 and attempted to test their tumors for 10 oncogenic drivers. The drivers consisted of alterations in EGFR, KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, PIK3CA, ALK, and MET.

Sites performed multiplex genotyping for mutation detection using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, multiplexed single-nucleotide extension sequencing, or Sanger sequencing with peptide nucleic acid probes. All sites performed sizing electrophoresis to detect ERBB2 insertions and EGFR deletions.

Results were used to select matched targeted therapies. LCMC clinical committee members solicited industry-sponsored trials for nine drivers, with these trials subsequently being reviewed and approved by representatives from the 14 LCMC sites. Treating physicians decided whether to recommend a targeted therapy to a patient with a tumor with an oncogenic driver.

The primary objective of the study was to determine the frequency of the 10 oncogenic drivers. Secondary objectives were to assess as many tumors as possible for all 10 genes to define the co-occurrence of drivers in a single tumor, document the ability to use the data to select treatment or a clinical trial targeting the identified driver, and assess survival.

Oncogenic Drivers in Majority

Overall, tumors from 1,007 patients were tested for at least 1 gene and 733 were tested for 10 genes. The primary reason for the inability to test for all 10 genes was insufficient tissue.

Among all 1,007 patients, median age was 63 years, 60% were women, SWOG performance status was 0 or 1 in 89%, 34% were never smokers and 58% were former smokers, stage at diagnosis was I in 10%, II in 7%, III in 17%, and IV in 64%, and prior therapy included surgery in 43%, radiotherapy in 20%, and chemotherapy in 59%.

An oncogenic driver was identified in 466 (64%) of the 733 patients with full genotyping: 182 tumors (25%) had the KRAS driver, 122 (17%) had sensitizing EGFR mutations, 57 (8%) had ALK rearrangements, 29 (4%) had other EGFR mutations, 24 (3%) had aberrations in two or more genes, 19 (3%) had ERBB2 alterations, 16 (2%) had BRAF mutations, 6 (< 1%) had PIK3CA mutations, 5 (< 1%) had MET amplifications, 5 (< 1%) had NRAS mutations, 1 (< 1%) had MEK1 mutations, and 0 had AKT1 mutations.

Genotype-Directed Therapy

Results were used to select a targeted therapy or clinical trial for 275 (28%) of the total 1,007 patients and for 44% of patients with identified drivers. Of the 175 patients with EGFR sensitizing mutations, 146 (83%) were treated with targeted therapy, including 130 with erlotinib alone and 16 with another EGFR inhibitor alone or in combination.

Of the 35 patients with other EGFR mutations, 23 (66%) were treated with an EGFR inhibitor alone, another targeted agent, or a combination. Of 80 patients with ALK rearrangements, 52 (65%) were treated with crizotinib (Xalkori). Of the 23 patients with ERBB2-mutant disease, 11 (48%) received an ERBB2-targeted agent. Of the 245 with KRAS mutations, 22 (9%) were treated with investigational targeted agents.

Survival Data

Among the 1,007 patients tested for at least one driver, 93% had sufficient information to be included in the survival analysis, at which time 456 were alive and 482 had died; in this group, median follow-up was 1.7 years. Median overall survival for all 938 patients with adequate data was 2.7 years (95% confidence interval [CI] = 2.4–2.9 years). The median survival of individuals with each of the five most common oncogenic drivers ranged from 2.0 years (mutations in two genes) to 4.3 years (ALK), with a significant difference across groups (P < .001).

Median overall survival was 3.49 years (interquartile range [IQR] = 1.96–7.70) among the 260 patients with an oncogenic driver and genotype-directed therapy, 2.4 years (IQR = 0.88–6.20) among the 318 patients with any oncogenic driver who did not receive genotype-directed therapy, and 2.08 years among the 360 patients with no driver (P < .001 overall). For the comparison of patients with an oncogenic driver who did vs did not receive genotype-directed therapy, propensity score-adjusted analysis adjusting for sex, age, performance status, smoking history, stage, prior therapy, and time from diagnosis of metastatic disease to enrollment yielded a hazard ratio of 0.69 (P = .006).

Among patients with the five most common oncogenic drivers who received genotype-directed therapy, median overall survival was 2.69 years in patients with oncogenic drivers in two genes, 2.70 years in those with other EGFR mutations, 3.78 years in those with EGFR sensitizing mutations, 4.85 years in those with KRAS mutations, and not reached in those with ALK mutations. There was no significant difference in overall survival across the groups (P = .32).

The investigators concluded, “Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.” ■

Disclosure: The study was entirely supported by a grant from the National Cancer Institute. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference

1. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014.

 


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