SEATTLE (FRONTLINE MEDICAL NEWS) – Many advanced non–small cell lung cancer (NSCLC) adenocarcinomas can now be managed with therapies that target driving mutations, but oncologists must look for these mutations and be aware that they can change over time, Dr. Mark A. Socinski said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

The 2013 College of American Pathology guideline for the molecular testing of lung cancer “was a monumental publication and a beachhead, if you will, for establishing a standard of care [for NSCLC], much like we have in breast cancer for ER, PR, and HER2 measurement,” he said. Furthermore, “we are now in an era where doing subsequent or sequential biopsies with repeat molecular testing is a standard of care in this population.”

Although lung adenocarcinomas are homogeneous histologically, they are diverse with respect to oncogenic drivers ( JAMA 2014;311[19]:1998-2006 ), noted Dr. Socinski, director of the lung cancer section at the University of Pittsburgh Medical Center; clinical associate director of the University of Pittsburgh Lung Cancer SPORE; codirector of the UPMC Lung Cancer Center of Excellence; and coleader of the lung cancer program at the University of Pittsburgh.

“Our major nemesis is KRAS. We still don’t have a good answer for that,” he said. But roughly a third of lung adenocarcinomas have actionable mutations in the genes for EGFR [epidermal growth factor receptor], ALK, ROS1, BRAF, MET, or RET.

“In the year 2015, these are what I look for in our patient population … We test routinely to identify these populations,” he said. “In my clinic this week, I might have had almost all of these patients on targeted TKIs [tyrosine kinase inhibitors] with these sorts of things, getting clinical benefit in this particular setting.”

Common mutations

“The EGFR mutation story really transformed lung cancer,” Dr. Socinski said. In patients whose adenocarcinomas harbor these mutations, targeted therapy with an EGFR inhibitor commonly nets a dramatic response. “If you see this a number of times and you’re a lung cancer doc, you become addicted to oncotype testing. And you certainly don’t want to ever miss this,” he said.

The IPASS trial (First-Line Iressa Versus Carboplatin/Paclitaxel in Asia) comparing the targeted agent gefitinib (Iressa) with chemotherapy in advanced NSCLC adenocarcinoma among never or light smokers was “a transformational trial in lung cancer,” according to Dr. Socinski ( N Engl J Med. 2009;361[10]:947-57 ).

“The lesson from IPASS: phenotype we threw out the door, it’s really about genotype. And if you didn’t have the genotype [EGFR mutation], a TKI was very poor treatment. And if you had the genotype, the TKI was superior to chemotherapy,” with a 52% reduction in the risk of progression or death.

Trials testing the EGFR inhibitors erlotinib (Tarceva) and afatinib (Gilotrif) have likewise shown a progression-free survival benefit in this patient population.

“One of the issues that we struggled with for some time was whether there is any survival benefit,” Dr. Socinski said. A recent combined analysis of two afatinib trials has answered that question affirmatively ( Lancet Oncol. 2015;16[2]:141-151 ), and these agents have therefore become standard of care for EGFR-mutant adenocarcinoma.

“Interestingly, as we say, all EGFR mutants are not created equal, because in the exon 21[–mutated tumors], actually there was no difference relative to chemotherapy, and that survival advantage is really driven by exon 19. So the nature of your mutation is important in this particular analysis,” he cautioned.

When patients on EGFR targeted therapy develop resistance, the cause in about half of cases is emergence of a secondary mutation in exon 20, the T790M mutation ( Sci Transl Med. 2011;3(75):75ra26 ).

“The standard of care is to biopsy at the time of progression,” Dr. Socinski maintained. “The reason why rebiopsy is important and it’s important to diagnose that [new mutation] is that we have a couple of drugs close to [Food and Drug Administration] approval that are highly active in patients with T790M-positive disease after a first- or second-generation TKI.”

Specifically, the investigational third-generation TKIs rociletinib (ASCO 2015. Abstract 8001 ) and AZD9291 (ASCO 2014. Abstract 8009 ) have response rates of about 48% and 53%, respectively, in this setting. “This looks quite promising. And these drugs will likely be commercially available between now and the holidays at the end of the year,” he predicted.

The T790M mutation can appear at different times, he said. “I’ve even got several patients whom we’ve rebiopsied three or four times, and there has been T790M negativity and then emergence of positivity on subsequent biopsy. Given the activity of these drugs, that’s important to know.”

Another fairly common actionable mutation in lung adenocarcinoma is ALK, for which oncologists now have crizotinib (Xalkori). Crizotinib has likewise been tested against combination chemotherapy in a phase III trial in which it yielded superior progression-free survival in patients with advanced nonsquamous NSCLC harboring ALK mutations (ASCO 2014. Abstract 8002 ).

“This is now a second example with a molecular biomarker in which we’ve replaced the standard of care chemotherapy with a molecularly targeted agent,” Dr. Socinski noted.

Second-generation ALK inhibitors such as the investigational agent alectinib are showing promise (ASCO 2015. Abstract 8008 ). “Even in previously crizotinib-exposed patients, these have a great deal of activity and allow another option for sequential therapy in this population of patients,” he said.

Uncommon mutations

Driving mutations of ROS1 are found in about 1%-2% of lung cancers, most often in younger never-smokers with adenocarcinomas, according to Dr. Socinski.

These tumors respond to crizotinib, which is also a ROS1 inhibitor. “In fact I think it may actually be a better ROS1 drug than an ALK drug,” he said.

The drug yields an impressive median progression-free survival of 19.2 months and overall response rate of 72% in this setting ( N Engl J Med. 2014;371[21]:1963-1971 ), “so ROS1 is another biomarker that we go hunting for in this population, even though you won’t see it very commonly.”

Mutations of BRAF are found in about 2% of metastatic adenocarcinomas ( Cancer. 2015;121[3]:448-456 ). The large majority, about fourth-fifths, are of the V600E type.

The BRAF inhibitor dabrafenib (Tafinlar) has been associated with an overall response rate of 32% in patients with this specific mutation (abstract LBA38, Ann Oncol. 2014;25[Suppl 4]. doi: 10.1093/annonc/mdu438.46 ). And preliminary data suggest efficacy increases when it is combined with the Mek inhibitor trametinib (Mekinist) (ASCO 2015. Abstract 8006 ), as has been seen in melanoma.

About 4% of lung cancers have an intermediate or high level of MET amplification. In a small sample of patients with these tumors, treatment with crizotinib appeared to be active (ASCO 2014. Abstract 8001 ). In addition, this agent has efficacy against lung cancers having exon 14 splice mutations in MET (ASCO 2015. Abstract 8021 ). “So this is another genotype not to miss,” Dr. Socinski said.

Finally, mutation of RET is seen about 1%-2% of unselected NSCLCs, also typically in young never-smokers or former smokers with adenocarcinoma. Cabozantinib (Cometriq), a multitargeted TKI having activity against RET, yields a 28% response rate in RET-rearranged adenocarcinomas (ASCO 2015. Abstract 8007 ).

A controversial topic for these uncommon mutations in lung adenocarcinomas is how much evidence should be required for new targeted agents to gain FDA approval, Dr. Socinski said.

“For instance, the ROS1 experience: Do we really need a randomized trial in a rare genotype to approve this drug [crizotinib] for ROS1-positive patients? I would say, absolutely not,” he concluded.

Dr. Socinski disclosed that he receives fees from Celgene and Genentech, and performs contracted research for Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta


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