TARGETED TREATMENT FOR NSCLC

HOLLYWOOD, Florida — Mutations are driving the management of metastatic non-small cell lung cancer (NSCLC), the National Comprehensive Cancer Network (NCCN) guidelines suggest.

The treatment of NSCLC has changed dramatically over the past 2 decades. A better understanding of cancer biology has led to a shift from histologic-based subtyping to molecular subtyping and to the recognition of multiple mutations as therapeutic targets, said guidelines codeveloper Leora Horn, MD, MSc, from the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

"We really have made progress in our evaluation of non-small cell lung cancer patients, moving from just 'adeno' and 'squamous' into specific molecular cohorts for adenocarcinoma, where we've really had the greatest improvement in the past decade in patient outcomes. And we're slowly getting there with patients with squamous cell carcinoma," she said here at the NCCN 20th Annual Conference.

That progress is reflected in results from clinical trials. Median overall survival has improved from 7 months in 1976 to 28 to 31 months in the last 6 years, when treatment has been directed by genotype, she noted.

Dr Horn discussed the current approach to targeted therapies in NSCLC, but did not touch on immunotherapy with checkpoint inhibitors, which are still largely in the investigational stage.

"When we think about the different molecular subsets of lung cancer, the most common that we see are the 25% of patients who are KRAS-mutant positive. Unfortunately, at this time, we have no good therapeutic options" for these patients, she said.

The other most frequently seen driver mutations in NSCLC occur in the genes encoding for the epidermal growth-factor receptor (EGFR), the anaplastic lymphoma kinase (ALK), and the v-raf murine sarcoma viral oncogene homolog B1 (BRAF). There are other potentially targetable mutations, such as the gene encoding for human epidermal growth-factor receptor 2 (HER2) in a small percentage of patients with NSCLC, Dr Horn explained.

The NCCN guidelines for patients with metastatic NSCLC have a category 1 recommendation for EGFR and ALK mutation testing for patients with adenocarcinoma, large cell cancer, or NSCLC not otherwise specified. The testing should be conducted as part of multiplex/next-generation sequencing.

For patients with squamous cell carcinomas, the guidelines recommend considering testing for ALK and EGFR mutations in never-smokers, small biopsy specimens, and mixed histology specimens.

EGFR

EGFR mutations are seen in 10% to 15% of all patients with NSCLC in North America. For these patients, the standard of care is first-line therapy with an EGFR-target tyrosine kinase inhibitor (TKI). Both erlotinib (Tarceva, Genentech) and afatinib (Gilotrif, Boehringer Ingelheim) are approved in the United States for this indication.

T790M is the most common mechanism of acquired resistance to EGFR-directed TKIs, but several experimental agents are currently being explored in this population, Dr Horn reported.

"There is no role at this time for continuing the TKI when initiating chemotherapy," she said. She explained that because some patients are known to have disease flare when stopping TKI therapy, she will typically stop the TKI on a Sunday and then start the patient on chemotherapy the next day.

"There is no role, in my mind, for an EGFR TKI in the adjuvant setting at this time," she said.

The large multicenter Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) currently being conducted in the United States is designed to evaluate both EGFR and ALK inhibitors in the adjuvant setting, Dr Horn reported.

ALK

ALK rearrangements are seen in about 3% to 5% of North American patients. First-line crizotinib (XALKORI, Pfizer Oncology) is the standard of care. For patients who experience disease progression while on crizotinib, the US Food and Drug Administration has approved ceritinib (Zykadia, Novartis Pharmaceuticals) for second-line therapy. There are ongoing clinical trials evaluating multiple second-generation ALK inhibitors and combination therapy, Dr Horn said.

BRAF

Mutations in BRAF are found in about 1% to 4% of NSCLC, and are negative prognostic indicators. In general, BRAF mutations do not overlap with other oncogenic driver mutations in NSCLC, and are typically found in patients with adenocarcinoma and, more commonly, in smokers.

HER2

Approximately 2% of patients with NSCLC have somatic HER2 mutations. These mutations, seen primarily in adenocarcinomas, appear to be to mutually exclusive to other driver aberrations, including ALK, EGFR, and KRAS.

In NSCLC, "HER2 mutations behave very differently from the HER2 amplifications you see with breast cancer," Dr Horn explained.

Variations on a Gene

After Dr Horn's presentation, a pathologist thanked Dr Horn for focusing her discussion on genetic variants rather than genes themselves.

"I think that is the biggest problem we have today, that people are presenting and talking about this process at the gene level and not at the variant level," said Carl Morrison, MD, from the Roswell Park Cancer Institute in Buffalo, New York, who was not involved in the guidelines development.

He noted that with a few exceptions, the NCCN guidelines focus on the whole gene and not on specific variants that may require specific treatment approaches.

"When will the NCCN or some other group take on the task of trying this process at the variant level, which influences reimbursement, treatment decisions, and everything downstream from that?" Dr Morrison asked.

Dr Horn explained that her center has a database of approximately 5000 patients with more than 180 mutations, many of which are still of uncertain significance, and that investigators ask for feedback from other groups about treatment choices and patient responses to help them enrich their understanding of which mutations may be clinically important and which are more or less innocent bystanders.

On a personal level, however, "I will very smartly defer from anything political with the NCCN on when they are going to add this for reimbursement," she said.

Dr Horn reports relationships with Astellas Pharma US, Bayer HealthCare, Genentech, Merck & Co., and Xcovery. Dr Morrison has disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 20th Annual Conference. Presented March 13, 2015.