Mutation May Affect PFS in Lung Cancer

Mutant KRAS status in non-small cell lung cancer (NSCLC) correlated with significantly worse progression-free survival (PFS) and resistance to platinum-based chemotherapy, data from a randomized trial showed.

KRAS mutations were associated with almost a 40% decrement in PFS compared with patients who had wild-type KRAS.

The outcome was consistent across all platinum-containing combinations the patients had received as first-line therapy, although patients treated with gemcitabine did worse than others, Marina C. Garassino, MD, reported here at the European Lung Cancer Conference.

"KRAS is a strong prognostic factor in first-line treatment of non-small cell lung cancer patients," said Garassino, of the Fatebenefratelli and Ophthalmic Hospital of Milan.

"The numbers are too small to determine whether there is a mutation with worse prognosis than others," she added. "It is of major importance to develop new strategies for patients with KRAS mutations."

KRAS is the most frequently mutated gene in humans, and the mutation rate is especially high in pancreatic, colon, and lung cancers. Mutant KRAS is a necessary step for tumor initiation and progression in several preclinical models, and is widely considered to be "undruggable," said Garassino.

An Italian trial of second-line chemotherapy in NSCLC included prespecified substudy of EGFR and KRAS mutations and their impact on treatment (Clin Lung Cancer 2011; 12: 138-141). Garassino presented results of the KRAS analyses.

Eligible patients who had received first-line platinum-based chemotherapy were randomized to second-line treatment with either erlotinib (Tarceva) or docetaxel. The primary endpoint of the parent trial was overall survival, and secondary endpoints included PFS and response rate.

PFS was the primary endpoint of the substudy, and the secondary endpoint was the impact of the three most common KRAS mutations (G12C, G12V, and G12D) on prognosis.

The 306 evaluable patients received first-line therapy consisting of cisplatin or carboplatin paired with gemcitabine, vinorelbine, or pemetrexed (Alimta). The most commonly used doublets were cisplatin-gemcitabine (N=135), cisplatin-pemetrexed (N=70), and carboplatin-gemcitabine (N=52).

Analysis of KRAS mutations showed that G12C occurred in 36.56% of specimens, G12V in 22.58%, and G12D in 15.05%. The next most frequent mutation was G12A (9.68%).

A majority of patients (253) had adenocarcinoma histology, followed by squamous in 80 cases. Overall, 93 tumors harbored KRAS mutations, most of which (71 tumors, or 76.34%) occurred in adenocarcinomas. Mutations were uncommon in squamous-cell tumors (5 of 80, 5.38%).

Data on tumor grade were available for 249 patients, including 60 patients with KRAS mutations. Garassino reported that 40 of the 60 mutations were associated with grade 3 disease.