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My 5 Take Home Msgs from the Santa Monica Targeted Therapies

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My 5 Take Home Messages from the Santa Monica Targeted Therapies Conference

February 25th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/02/25/my ... onference/

I’m heading back now from the”12th Annual Targeted Therapies in Lung Cancer Conference”, three days crammed with over 150 talks, nearly all lasting just 5 minutes, that introduce a new agent or treatment combination that would be considered a targeted therapy for lung cancer. From this large collection, a few may well prove valuable tools, while the majority won’t meet that bar. It’s obviously not possible to relay news on over 150 agents, each introduced over a few brief slides, but I thought I’d share five leading themes that I came away with.

1) Targeted therapies are becoming more and more relevant, while our definitions of distinct treatment populations are shifting and becoming narrower. I think we’ve now moved past the era of trials designed for anybody with advanced NSCLC, with patients being randomized to “chemo backbone X with or without new agent Y for everyone with advanced NSCLC”. It is becoming increasingly apparent that we do a disservice to the patient community and our understanding of lung cancer by pooling patient groups together that are, in actuality, different groups. By doing this, we will overlook meaningfully effective treatments for small groups that are diluted in broad populations of others far less likely to do well with these therapies. For instance, you can readily imagine that if XALKORI (crizotinib) were tested first in everyone and not just in the 4% of patients with NSCLC that features an ALK rearrangement, we’d likely see a 3% response rate and dismiss it, instead of recognizing it as a 60% response rate in a much more narrow population. For that matter, we also risk missing situations in which we are actually helping one subgroup of patients while simultaneously harming another subgroup, as we see in the phase II MetMAb trial, as well as in the “intent to treat” results of the IPASS trial; you see fundamentally different results when they are divided by biomarker status, in which case, it appears we may well be conferring a deleterious effect in one group — and we don’t want to miss that as we develop subsequent trials.

2) The most promising results that we have been able to achieve in molecular marker-defined subgroups unfortunately won’t apply for the majority of people with lung cancer. We know that most of the biomarkers that have been the darlings of the lung cancer world in the last few years, ranging from EGFR and ALK to very new ones like ROS1 and HER2, are most commonly seen in patients with an adenocarcinoma, and in fact most commonly in patients with an adenocarcinoma and who are never-smokers or with minimal prior smoking history. These more genetically simple cancers are the very ones most likely to demonstrate a single driver mutation that can be dramatically inhibited by hitting that Achilles heel. But the lung cancers we tend to see in longtime smokers, even those with an adenocarcinoma tumor but especially squamous or large cell NSCLC, or any SCLC, are characterized most typically by dozens of mutations that each contribute only very incrementally to the biology of the cancer cell. Accordingly, we really don’t tend to see profound improvements by adding a single new therapy in very genetically complex cancers that likely comprise at least 70-75% of the lung cancers in North America and Europe, at least. (In contrast, lung cancer in never-smokers and a unique driver mutation in the cancer are clearly more common in Asia, where the majority of lung cancers may even be able to be effectively suppressed by targeted therapies).

3) Combinations of targeted therapies will be tested and may emerge as a meaningful improvement over the strategy of sequential single agent treatment that we have pursued up to now. The Director of Yale’s Cancer Center, Dr. Tom Lynch, who is a world-renowned expert in lung cancer and one of the members of the team that first identified EGFR mutations, delivered the keynote presentation on the opening evening of the meeting. During this talk, he make the compelling argument that our more challenging medical problems often require multiple angles of attack and a combination approach. Treatments for AIDS, tuberculosis, and many lymphomas, which are typically very effective, are all combinations of effective agents that are given concurrently rather than sequentially. Though Dr. Lynch is quite sanguine about combinations of targeted therapies for patients with particular driver mutations being developed as a cure for these more genetically simple cancers, I’m less sanguine. It may be that giving two or three effective therapies at once will kill the last cancer cell in a treatment-sensitive metastatic lung cancer; but this strategy might just exhaust our treatment options much sooner than applying several effective therapies serially. I completely agree that studies should move from single agents to testing combinations, but I wouldn’t presume that combinations are going to necessarily be a quantum leap.

4) The ground is shifting under our feet as many of our medical truisms fail to work in new models. We now sometimes see EGFR mutation-positive adenocarcinoma re-biopsied after acquired resistance and demonstrating EGFR mutation-positive SCLC (which isn’t supposed to happen), as well as different mutational profiles in biopsies from different areas of a person’s cancer, and even responses when “re-challenging” a patient with a targeted therapy that they had previously progressed on. This is leading us to question some of our central tenets. The molecular markers from a resected lung cancer from 2009 may not represent the biomarker profile for a recurrent cancer a few years later, or even that the metastases developing after a year on Tarceva (erlotinib) will demonstrate the same biology as the initial cancer. Our current practice patterns now lead us to consider continuing an agent on which someone is even showing progression, or returning to it later. Even if we don’t have all of the answers, we’re less convinced that our old answers weren’t actually oversimplifications. We are even starting to debate whether it’s truly possible to cure some patients with metastatic disease, even if the principles of cancer have long dictated otherwise.

5) The gulf between general oncology management and input from a lung cancer specialist is increasing over time. There was a time when the differences between seeing a general oncologist and seeing a specialist in lung cancer didn’t make a critical difference. You can easily imagine that it doesn’t matter much whether you have your appendectomy done by a perfectly good local surgeon or by the Chief of Surgery at the Mayo Clinic: there’s a ceiling to how well you can do. For decades, our limited understanding of lung cancer biology lowered the ceiling of how any of us could do. Because of that, the treatments available at the closest general oncologist’s office were quite comparable to the offerings from the most renowned academic centers. Today, however, new trials for rare mutations like ROS-1 or relatively specialized clinical situations like acquired resistance to an EGFR tyrosine kinase inhibitors are often only available at 3 or 5 centers around the country — or the larger ones might have a couple of locations in your home state. I think there is now a real potential value in recommending that some patients (at least those with the highest “pre-test probability” for a clinically actionable biomarker) consider seeking an opinion at one of just a few very specialized centers where their cancer can be tested for rare or very, very newly identified markers that can’t be tested for commercially elsewhere today, or that these patients investigate enrolling on a clinical trial that might require them to fly to the center to participate. That is only worthwhile if the new therapy holds a potentially very great promise, but I think that some targeted therapies being offered for that specific targeted population fulfill that criterion.

Though not feasible for everyone, but the value proposition between perfectly good general oncology management and a highly specialized perspective, with the additional clinical research opportunities that are also often available from these people, has been increasing as our knowledge increases, leading to a bottleneck effect in the general oncologist’s office.

There will be plenty more to add on targeted therapies in the coming months and years, because we have really now entered into the “molecular oncology era”. Much of the challenge, though, will be trying to translate some of what we learn in these very narrow populations into the groups that are still the majority, who don’t have just a single identifiable molecular target.

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