New ALK Agents: Lung Cancer's 'Second Miracle'?

Giorgio V. Scagliotti, MD, PhD; D. Ross Camidge, MD, PhD


October 07, 2013

In This Article

Will Chemotherapy Just Fade Away?

Dr. Scagliotti: You are a visionary physician. Let's imagine ourselves talking at this table 5 or 6 years from now. How many patients with lung cancer will be treated on the basis of genomic information, because we won't be able to deliver targeted therapy to 100% of our patients? Where do you see the boundary of these targeted therapies?

Dr. Camidge: Let me draw an analogy with chronic myeloid leukemia. There was a very interesting presentation on the first day of this conference by Bill Sellers[13] from Novartis, the company that first developed imatinib (Gleevec®). He showed that, over time, following the introduction of imatinib, the mortality rate for chronic myeloid leukemia was declining. The incidence was staying the same, but because these patients are living longer, the prevalence was going up. So one answer to your question is, the number of people who are living with oncogene-addictive disease will go up because we are keeping them alive, so they will actually start to dominate more than they have in the past.

The other answer to your question is that you can probably sequence every bit of the cancer genome, but in some people (as many as 40%) you are not going to find a gene rearrangement, and you are not going to find a nice kinase domain mutation. Something else is driving those cancers. People are starting to look very aggressively at what those things are, but we are just starting to scratch the surface. One theory is increased wild-type signaling through receptor ligand pairing that won't be seen with standard exome sequencing platforms, but if we find other ways of looking at that, we will be able to find actionable drivers. We probably won't be able to treat 100% of patients with targeted therapy; it will probably be about 50% for adenocarcinomas. Squamous cell is a work in progress, and small cell is really complex.

Dr. Scagliotti: What do you see as the future of chemotherapy?

Dr. Camidge: We are going to need it. You can do all these things but eventually you will run out of options, and chemotherapy works. It may not be fashionable, and it's certainly not nontoxic, but if your back is against the wall, you are always going to go back to chemotherapy.

Dr. Scagliotti: Let's jump back to one of the papers that you reviewed this morning at this meeting, about what I call "mutant selective inhibiting agents." We saw some preliminary data at ASCO,[14] and this morning you reviewed the data about the AstraZeneca compound that targets not only common activating EGFR mutations but also T790M, which is one of the main mechanisms of acquired resistance to EGFR-TKI in the EGFR mutants. Do you see a future for these mutant-selective agents?

Dr. Camidge: Yes. Even though the T790M mutation is a more indolent form of disease (when you get the second mutation in the EGFR kinase, the function of the kinase is not quite as oncogenic), the cancer still progresses. You can get crushed by a building even if it's falling very slowly, so T790M is a major clinical problem for 50%-60% of people with an EGFR mutation. Drugs called "third-generation EGFR inhibitors" have been developed that essentially have the same IC-50 (ie, maximal concentration of drug to cause 50% inhibition of biological activity) against T790M as against the standard activating mutations. We saw data at ASCO on the first of those agents, called Clovis 1686, which had minimal activity at the lower doses, but at a higher dose (900 mg twice a day) it produced 3 out of 4 responses in proven T790M patients.[14] The dataset is still very small but looks promising. Here, we saw the next example of a third-generation inhibitor, AstraZeneca's AZD9291,[15] which produced responses even at the very lowest doses -- about a 56% response rate in proven T790M patients. They are going to be game changers.

Dr. Scagliotti: I was interested in the relatively low toxicity profile of the compound, but it needs to be further investigated.


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