New Agents Topple Resistance in NSCLC

Acquired Resistance in Non-Small Cell Lung Cancer

Hello. This is Mark Kris from Memorial Sloan Kettering. A lot went on at this year's American Society of Clinical Oncology (ASCO) meeting in Chicago. I would like to highlight developments in the care of patients with lung cancer who have acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. The patients we are talking about have activating mutations in the EGFR gene, and when they receive dovitinib, erlotinib, or afatinib, they have a major prolonged response and then go on to have progressive disease. This situation is called acquired resistance. It is a biological response to the cytotoxic stress on the cancer cell; ways are found to counteract the effects of these initially very effective drugs.

Until this meeting, we didn't have a good way to deal with these patients. We knew the cause in 60% of patients: the development of a second site mutation in the EGFR gene. These patients now had 2 mutations in the EGFR gene. There are some other causes -- amplification of MET, amplification of HER2, and transformation of small cell lung cancer -- but these are rather rare, and 60% had T790M. Finding these second site mutations has prompted an extraordinary degree of research to find drugs that could counteract the effects of these second site mutations. For chronic myelogenous leukemia, new drugs have arrived for patients with acquired resistance to EGFR tyrosine kinase inhibitors.

New Drugs: Effective, and Better Safety Profiles

Remember the scenario: When people with activating mutations are treated with upfront drugs, they develop acquired resistance, which is almost always owing to T790-M. Scientists (and I'll focus on Dana-Farber Cancer Institute, Vanderbilt University, Memorial Sloan Kettering, and Massachusetts General Hospital) developed models for this T790M resistance and specific drugs to target T790M resistance. Three of those drugs were discussed at the ASCO meeting: [AstraZeneca's] AZD9291,^[1] Clovis' CO-1686,^[2] and [Hanmi's] HM61713,^[3] a drug developed in Korea. They are different chemically, but structurally they are very similar to the compounds that have been discovered to be effective in the face of these second site mutations.

The data are extraordinarily consistent. Each of these drugs is designed to target the mutant kinases -- both the single mutants and the double mutants for T790M. All of these drugs are clearly effective. The degree of effectiveness will likely exceed 50%. The numbers are different in different groups, but all showed this degree of effectiveness. When you crunch the confidence intervals, you will find that effectiveness will be 50% or more for these drugs. They clearly work on the mutant kinases [and not as well in] the wild-type kinases. With the wild-type kinase, side effects (rash and diarrhea) are much less severe than with such drugs as afatinib or erlotinib. The side-effect profile is somewhat different. We have seen some changes in QT intervals with the Clovis drug, as well as hyperglycemia requiring treatment with metformin. In general, however, the side effects can be surmounted.

Practice-Changing Drugs

Which of these drugs is best? When I say "best," I mean the drug with the highest chance of shrinking these tumors with 2 mutations in EGFR, and doing so with the fewest side effects. Ongoing research will help us choose the winner, but I'm very happy to say that we have 3 drugs, all of which conclusively show that the promise of developing agents for the second site mutations is coming true. Other drugs are entering the scene as well. There is a drug from Astellas (ASP8273) and a drug from Novartis (EGF816). These are entering clinical trials now and they have the same sort of potential.

I hope that these drugs will be fast-tracked by physicians. Two of them [AZD9291 and CO-1686] have already been given breakthrough status by the US Food and Drug Administration. They also have potential to work as initial therapies. These drugs are very effective against single site mutations, so it is possible that this drug with fewer side effects would be the right drug upfront.

These drugs have changed practice for patients with acquired resistance. Now that we have drugs that clearly work for specific mechanisms of acquired resistance, it is very important to rebiopsy these patients. There was very little evidence that these drugs are as effective for patients who do not have this second site mutation in the acquired resistance setting, so it is very important to know whether the T790M is present. We can also can find other mechanisms of resistance, such as MET amplification and transformation to small cell, which would point to a different therapy. The promise of new agents developed specifically for double mutants (T790M and sensitizing mutant) has been realized, and it is just a matter of getting these drugs through the clinical trials to get them into our pharmacies.

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