Camidge Breaks Down Oncogene-Driven NSCLC

Brandon Scalea
Published: Saturday, Nov 10, 2018

Dr. Ross Camidge

D. Ross Camidge, MD, PhD

Although frontline therapy options for patients with EGFR- and ALK-positive non–small cell lung cancer (NSCLC) are well established, challenges remain in deciphering why patients develop resistance to therapy and eventually progress, according to D. Ross Camidge, MD, PhD.

Camidge, director of Thoracic Oncology at the University of Colorado, said osimertinib (Tagrisso) is the best frontline therapy choice for patients with advanced EGFR-positive disease. In ALK-driven NSCLC, frontline treatment with alectinib (Alecensa) should be the standard-of-care.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gained FDA approval in the frontline setting in April 2018 based on data from the phase III FLAURA study in which frontline osimertinib reduced the risk of progression or death by 54% versus standard TKI therapy options erlotinib (Tarceva) or gefitinib (Iressa). The median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).1

In the ALK space, alectinib improved PFS by 47% compared with crizotinib (Xalkori) (HR, 0.53; 95% CI, 0.38-0.73; P <.0001) in the phase III ALEX study for which the FDA approved it use in the frontline setting in November 2017.2

In an interview with OncLive®, Camidge discussed the crowded landscape of oncogene-driven NSCLC at the 13th Annual New York Lung Cancers Symposium hosted by Physicians’ Education Resource®, LLC on November 10, 2018.

OncLive: What have been some of the most significant findings in the EGFR space?

Camidge: In EGFR mutations, the field is pretty much solidified in that osimertinib, a third-generation TKI, is your initial choice. You can line up and say that the median PFS looks very similar to sequential therapy. You can do the algebra and add together all the median PFS [rates]—it probably comes out the same. But if you tell that to a patient, they will look at you like you are crazy. They would probably rather take just 1 oral drug. It opens up the avenue to, "Where do we go next?"

People are looking at adding antiangiogenics like bevacizumab [Avastin] to osimertinib. They are looking at adding chemotherapy to the drug. These are both hard sells, though. If you have a pill that is going to control your disease for a number of years, in some cases, you want a short leash in the infusion center. Another thing we have to understand is why people eventually progress on osimertinib and what [are] rational combinations to overcome this. If you try to do them more upfront, maybe it applies only to a subgroup.

Is there any insight as to why patients become resistant to these targeted agents?

Even though osimertinib is better in the brain than some of the other inhibitors we use, it is not a perfect central nervous system [CNS] drug. It is marketed commercially as a CNS penetrant, but some patients are still progressing in the brain faster than in the body. Opening up that avenue is important. Is it just a dose of osimertinib, or are there better drugs out there?

In the body, if you biopsied somebody who initially responded to osimertinib and then progressed, some of the mechanisms we [would] understand. You can develop an additional mutation called C797S. There was a little excitement here about adding erlotinib and gefitinib; but this works in a petri dish, not in a patient. Researchers are looking at adding antibodies to this such as cetuximab [Erbitux]. This will bring in added toxicity, but [it may] control the disease for a significant period of time. People are looking to get a drug specifically targeting C797S.


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