D. Ross Camidge, MD, PhD, discusses the crowded landscape of oncogene-driven non­–small cell lung cancer.
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.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.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.
The other actionable area is MET amplification. We knew this was a resistance mechanism to first- and second-generation TKIs. It could be [occurring in] up to 30% of patients on osimertinib. It becomes more prominent here. The one challenge is that it is a continuous variable. Where do we determine that MET is a true second driver, and that you need combination therapy?Dacomitinib is a second-generation, irreversible inhibitor in the same class as afatinib (Gilotrif). The ARCHER 1050 trial led to this FDA approval, and technically it was a positive study.3 Median PFS was [14.7 months versus 9.2 months in patients treated with gefitinib]. This is a very toxic drug, [and 66% of] patients needed dose reductions.4 I can tell you honestly that when this approval came out and our on-site pharmacists asked who wanted to set up a treatment care plan for dacomitinib, not a single person said yes. It is too little too late.In EGFR-positive NSCLC, immunotherapy is going through some growing pains. Initially in second-line studies [examining] pembrolizumab (Keytruda), nivolumab (Opdivo) and atezolizumab (Tecentriq) compared with pretty poor chemotherapy regimens of docetaxel, it could not even beat the docetaxel. We are seeing response rates as high as 12% and as low as 3% or 4%.
You could say there is a very small subset of EGFR-positive patients who will benefit from immunotherapy, but it is obviously less than the general lung cancer population. The patients who benefit may also have severe side effects.There are really 3 different categories here. One is somebody who is already on crizotinib, and there are plenty of these patients who progress. Post crizotinib, the response rates under the next-generation inhibitors all look pretty much the same. Where they differ is in the median PFS. Brigatinib (Alunbrig) is the standout winner. We may not understand why, and the preclinical modeling suggests this should not be happening. But that tells us the model is not perfect.
The second group are the ones who walk out the door with ALK-positive disease—what do they start therapy on? The drugs with a first-line license are crizotinib, ceritinib [Zykadia], and alectinib. We already know alectinib beats crizotinib head to head. Ceritinib has only been tested against chemotherapy, and it did better than chemotherapy. I think it is clear that alectinib is the first-line choice.
The third category is [for those patients who progress] on a next-generation inhibitor. Very recently, lorlatinib [Lorbrena] got a license for someone who progresses on 1 or more next-generation inhibitors.
The really exciting thing about this field is that these hazard ratios can mature over time. We now understand why. The hazard ratio is determined by controlling the disease in the CNS amongst those with baseline CNS disease. The maturation is coming from controlling differences in extra CNS penetration. It takes 7 or 8 months to even start out separating the curves.If you walk through the door with an EGFR mutation, we are starting you on osimertinib. The real challenges [lie in] how patients become resistant and tailoring therapies based on that. MET is the standout mechanism we can target. For ALK patients, if you are post-crizotinib, you are taking brigatinib. Newly diagnosed patients get alectinib.