Emerging Gene Mutation Targets in Lung Cancer

Clinical Advances in Hematology & Oncology
December 2015, Volume 13, Issue 12

Bruce E. Johnson, MD
Professor of Medicine
Harvard Medical School
Boston, Massachusetts

H&O How common are mutations in EGFR, ALK, and ROS1 in lung cancer, and how does identifying these alterations affect treatment?

BJ We routinely test for mutations in EGFR and rearrangements in ALK in nonsquamous non–small cell lung cancer (NSCLC), as stated in guidelines from the National Comprehensive Cancer Network (NCCN). This is important to do because EGFR mutations predict response to erlotinib (Tarceva, Genentech/Astellas), gefitinib (Iressa, AstraZeneca), and afatinib (Gilotrif, Boehringer Ingelheim), and ALK rearrangements predict response to crizotinib (Xalkori, Pfizer) and ceritinib (Zykadia, Novartis). Although crizotinib does not have an indication from the US Food and Drug Administration (FDA) for use in patients with ROS1 rearrangements, oncologists generally want to get patients with ROS1 rearrangement on crizotinib or on an investigational agent. The NCCN’s guidelines say that we should consider testing for ROS1 rearrangements, and we generally do so.

Mutations in EGFR and rearrangements in ALK and ROS1 are all much more common in lung adenocarcinoma than in squamous cell carcinoma or small cell lung cancer. They are also much more common in nonsmokers and light smokers than in heavy smokers. In addition, patients with ALK or ROS1 rearrangements tend to be younger than patients without these alterations. EGFR mutations typically occur in 10% to 15% of patients with NSCLC who are of Western European ancestry, and in 30% to 40% of those with NSCLC who are of Asian ancestry—specifically those from China, Korea, Taiwan, and Japan.

One advantage of afatinib is that it improved overall survival compared with chemotherapy among patients with EGFR exon 19 mutations in an analysis of LUX-Lung 3 and LUX-Lung 6 (Afatinib Versus Cisplatin-Based Chemotherapy for EGFR Mutation-Positive Lung Adenocarcinoma). By contrast, erlotinib and gefitinib have been shown to increase only progression-free survival compared with chemotherapy in patients with EGFR mutations.

Among patients who had ALK rearrangements, progression-free survival was 4 months longer with crizotinib than with chemotherapy as first-line therapy, according to a study published in the New England Journal of Medicine in 2014 by Solomon and colleagues. This study also found a trend toward improved survival with crizotinib, but the data were immature because most patients were still alive. Among patients with ROS1 rearrangements, a single-arm study published in the New England Journal of Medicine in 2014 by Shaw and colleagues found that progression-free survival was 19 months with crizotinib, which is dramatically better than what we typically see with chemotherapy.

H&O How common are BRAF mutations in lung cancer, and what is their potential role in treatment?

BJ Most of the work on BRAF mutations has been done in melanoma. The majority of patients with melanoma have mutations in BRAF, and in most of these patients the mutation is located in V600E. Both dabrafenib (Tafinlar, Novartis) and vemurafenib (Zelboraf, Genentech/Daiichi Sankyo) are FDA-approved to treat patients with melanoma who have BRAF V600E mutations.

BRAF mutations occur in approximately 2% of patients with lung cancer, and about half of those patients have the mutation located in V600. The response rate to dabrafenib or vemurafenib among patients with lung cancer who have a V600 BRAF mutation is approximately 30% to 35%. In a basket study by David Hyman and colleagues that was published in the New England Journal of Medicine in 2015, the response rate to vemurafenib among the 20 patients with NSCLC was 42%, and median progression-free survival was 7.3 months.

In another study, a combination of dabrafenib and the MEK inhibitor trametinib (Mekinist, Novartis) was shown to produce response rates in excess of 60%, with a response duration that is yet to be determined. I presented these results at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO); David Planchard is listed as the first author on the abstract.

H&O What are some of the other mutations in lung cancer that may become targets for treatment?

BJ A number of attempts have been made to target MET, using both antibodies and tyrosine kinase inhibitors that inhibit MET. MET amplification of 2- to 5-fold, which is considered low-level amplification, is present in approximately 4% of lung cancers. MET amplification of 5-fold or greater, which is considered high-level amplification, is present in approximately 1% of lung cancers. As such, MET positivity is relatively rare in lung cancer.

In a trial that was presented at the 2014 ASCO annual meeting by Ross Camidge, 1 of 6 patients with low-level amplification had a response to crizotinib monotherapy, and 3 of 6 patients with high-level amplification had a response. So we can see that the degree of amplification appears to be important in determining how well these patients respond to crizotinib.

Regarding agents to target MET in patients with evidence of MET overexpression documented by immunohistochemistry, the antibody onartuzumab (MetMAb) looked promising in the randomized phase 2 METLung trial of onartuzumab/erlotinib vs erlotinib alone in late-stage NSCLC, but it failed in the phase 3 trial. David Spigel was the presenting author of this study at the ASCO annual meeting in 2014.

Efforts also have been made to target exon 14 skip mutations in MET, which are present in approximately 3% to 4% of lung cancers. Crizotinib appears to have antitumor activity in these patients. The researchers in the original crizotinib study identified a cohort of patients with exon 14 mutations. My colleague Mark Awad has a paper in press in which he identifies the frequency of exon 14 skip mutations and our ability to target them. There is also a case report with David Barbie as the senior author and Russell Jenkins as the first author that has been published in Clinical Lung Cancer showing a response to crizotinib in a patient with an exon 14 skip mutation. We think this is pretty promising.

H&O Do the exon 14 skip mutations overlap with MET amplification?

BJ The skip mutations overlap with MET amplification approximately 20% of the time. About 20% of the skip mutations also have MET amplification.

H&O How common are RET fusions, and what is their potential role in treatment?

BJ RET fusions also occur in 1% or 2% of patients with lung cancer. We are not as good at targeting this oncogenic driver as we are with the previous drivers we have discussed. The drugs directed against RET are not very potent or specific, and so far the therapeutic results have not been as encouraging.

Alexander Drilon presented results at the 2015 ASCO annual meeting of a study of patients with RET fusions in which 5 of 20 patients responded to cabozantinib (Cometriq, Exelixis), and the response duration was relatively short. So there was some effect, but not as dramatic as we see with the agents targeting ALK or ROS1 rearrangements. We probably need a more specific drug than cabozantinib for patients with RET fusions.

H&O What other mutations are emerging as possible targets in lung cancer?

BJ Researchers are working on agents that target NTRK1 fusions, which affect approximately 1% to 2% of people with lung cancer. We are very early in our research aimed at this oncogenic driver. Robert Doebele from the University of Colorado is one of the researchers who has examined these mutations. In 2015, he reported on a patient with sarcoma and an NTRK1 fusion who responded to LOXO-101.

H&O Could describe your work with the Lung Cancer Mutation Consortium, and explain why this project was undertaken?

BJ Paul Bunn and I discussed this idea during the 2008 meeting of the American Association for Cancer Research after learning that grants for multicenter research would be made available through the American Recovery and Reinvestment Act of 2009. Paul led the effort to put the grant together and was our principal investigator.

Our proposal was to test 1000 patients with carcinoma for a series of 10 genomic changes. We had several reasons for wanting to do this. First, we wanted to determine the true frequency of these mutations. Second, we wanted to find out how many people would be eligible for targeted treatment. Third, we wanted to see what the outcomes would be with targeted treatment. Finally, we wanted to find out how patients would fare who had more than 1 of these mutations.

One of the things we learned is that multiple fluorescence in situ hybridization tests require a fair amount of tissue; somewhere between 5 and 10 slides are needed to carry out all the tests. We simply did not have enough tumor tissue for testing in one-third of the patients. As a result, we needed to begin with approximately 1500 patients in order to do the sequencing on 1000 patients, and we obtained information on all 10 genes in 733 patients.

Another thing we learned is that, as we had suspected, people generally had only 1 of those 10 genes activated by mutation, amplification, or translocation. Just 2% of the patients had more than 1 mutation. Approximately half of the 733 patients had an oncogenic driver, and of those, half were able to receive targeted treatment. We found that overall survival was more than 1 year longer in people who received targeted treatment than in those who were not eligible for targeted treatment. The survival advantage persisted even when patients with a mutation in EGFR or a rearrangement in ALK were taken out of the equation. We published our results in 2014 in the Journal of the American Medical Association, with Mark Kris as the first author.

Our results do not prove that conducting this sequencing and giving targeted treatments will make people live longer, but our findings are consistent with this hypothesis. That was very encouraging to see.

Another encouraging effect of our study is that it helped prompt industry to begin developing drugs to treat tumors with rare genotypes.

Suggested Readings

Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550.

Doebele RC, Davis LE, Vaishnavi A, et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 2015;5(10):1049-1057.

Doebele RC, Vaishnavi A, Capelletti M, et al. NTRK1 gene fusions as a novel oncogene target in lung cancer [ASCO abstract 8023]. J Clin Oncol. 2013;31(15)(suppl).

Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726-736.

Jenkins RW, Oxnard GR, Elkin S, Sullivan EK, Carter JL, Barbie DA. Response to crizotinib in a patient with lung adenocarcinoma harboring a MET splice site mutation. Clin Lung Cancer. 2015;16(5):e101-e104.

Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.

Liu X, Jia Y, Shen Y, et al. Detection of frequent MET exon 14 skipping events in pulmonary sarcomatoid carcinoma and response to targeted inhibition [ASCO abstract 8020]. J Clin Oncol. 2015;33(15)(suppl).

Planchard D, Groen HJ, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC) [ASCO abstract 8006]. J Clin Oncol. 2015;33(15)(suppl).

Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963-1971.

Solomon BJ, Mok T, Kim DW, et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177.

Spigel DR, Edelman MJ, O’Byrne K, et al. Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial [ASCO abstract 8000]. J Clin Oncol. 2014;32(5)(suppl).