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The Evolution of Therapy for Non-Small-Cell Lung Cancer:


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An Expert Interview With Mark R. Green, MD

Posted 12/29/2004

Editor's note:

The approval of gefitinib and erlotinib in 2003 and 2004, respectively, for the treatment of advanced non-small-cell lung cancer (NSCLC) represents the latest addition to a growing armamentarium of effective agents used in the fight against this disease. To gain some perspective on how the therapeutic landscape has changed over the past decade, Medscape spoke with Mark R. Green, MD, Professor of Medicine at the Medical University of South Carolina in Charleston.

Medscape: Let's go back a few years. What was going on in the management of advanced lung cancer in the 1990s?

Dr. Green: For the decade of the 1990s, we had a general awareness that chemotherapy improves survival over best supportive care (BSC). We had new agents that impacted front-line treatment in people with advanced disease -- improving their median survival, improving their 1-year survival, improving their overall survival. We had a variety of 2-drug combinations that appeared in the aggregate to improve response rates and probably somewhat improve survival compared with the single agents. And we had a clearer view of what the standard approach to treatment might have been.

We've learned something about the treatment of "special populations." Older individuals, who, probably based on bias alone, were previously excluded from treatments, have now been shown prospectively to be able to tolerate chemotherapy and garner benefit. In performance status 2 (PS2) patients, we found the same thing. They might not do as well as PS0 or PS1 patients, but they can benefit from treatment. People have begun to look at the difference between PS2 patients who are deteriorating rapidly because of disease-related limitations compared with those who are PS2 because of multiple preexisting comorbidities.

We had a number of 2-drug combinations, almost exclusively a platinum plus one of a number of "partner drugs," which produced beneficial outcomes in terms of symptoms management, quality of life, and duration of survival. That's where we were in the first-line setting.

In 1997, in the ASCO guidelines, it stated that there was no second-line therapy of proven efficacy. Then we saw the 2 docetaxel trials, and they both demonstrated benefit. When comparing docetaxel with BSC, you saw a clear survival advantage. And we didn't need to use supratolerable doses, but we could use a reduced dose -- 75 mg/m2 vs the 100 mg/m2 that was routinely used in breast cancer -- and still show a survival benefit. There also seemed to be an increase in the frequency of 1-year survival when using 75 mg/m2 docetaxel vs vinorelbine or ifosfamide. Over the last few years, we've seen another cytotoxic agent, pemetrexed, come to the fore and be approved for second-line therapy. It appears to be quite similar in efficacy, and may have some advantages in terms of the toxicity profile. Some physicians now feel comfortable using pemetrexed in the second line, especially those who use taxanes in the first line, while those who use gemcitabine in the first line may choose to use a taxane in the second line.

So in patients with "wet" stage IIIB disease and stage IV disease, we've gone from just barely having data showing that chemotherapy is better than BSC to a series of doublets that showed small but real increments in 1-year, 2-year, and median survival rates.

In stage III disease, we first found that chemotherapy followed by radiation was better than radiation alone; we then found that chemotherapy concurrent with radiation therapy appears to be a little bit more effective, albeit more acutely toxic, than the sequence of chemotherapy and radiotherapy.

So we've now seen incremental benefits in survival in stage III patients, and incremental benefits in response and survival in stage IV patients. We've gotten more sophisticated in terms of modifying dose schedules and using supportive-care medications, so the quality of life of the patients is improved. We have second-line therapy in advanced disease with conventional cytotoxic therapies, and improvements in staging and imaging.

That sets the stage as we get into the later 1990s for the emergence of targeted therapies as elements to add to, to combine with, or, in some settings, to potentially supplant conventional cytotoxic therapy.

Medscape: Why are targeted therapies an attractive option?

Dr. Green: Cancer chemotherapy has been seen as relatively nonspecific, in that the "target" might be expressed in normal tissue as well as in tumor tissue. This made for a less specific killing of cells, and one that was associated with more side effects. Targeted therapy, in theory, is designed to focus on molecular targets or signaling pathways that are either unique or largely confined to neoplastic tissue.

And for those tumors that have the target, and where the target is part of the driving mechanism of growth, you have superb benefit at relatively low cost. So when you look at some of these agents, they're more specific, perhaps less effective across the spectrum of patients, but also less toxic. Look at chronic myeloid leukemia. Because BCR-ABL is pretty much a sine qua non of the disease, imatinib is effective in a very large percentage of patients. Or in the HER-2 subset of patients with breast cancer -- if they're HER-2-positive, trastuzumab is very frequently effective.

With that in mind, the early targeted therapies in solid tumors were rather broad-based. In a sense, the first targeted therapy was hormonal treatment in breast cancer. We could measure the frequency of ER and PR positivity, and target the receptor in those patients who had positive tumors, so the response rates were reasonably high. Not everyone is responsive, but a large percentage of patients have the marker and those who do are pretty likely to respond to hormonal manipulation. For HER-2-positive breast cancer, a smaller percentage of patients are amplified for HER-2, but in those individuals, there's a high likelihood of benefit with trastuzumab.

In lung cancer, some of the optimum targets are relatively infrequent, such as the EGFR mutation, but even those with the wild-type EGF receptor have some chance of benefit, although usually with stable disease rather than broad regression. So the model continues to apply, although it depends on the frequency of the specific abnormality.

In addition to these very targeted therapies, you have agents such as bevacizumab, which is more broadly involved in the biology of tumor proliferation, based on concepts of vasculogenesis and angiogenesis, which are thought to be a core process of tumor growth and development and therefore may have a broader application.

We're moving toward an increasing level of sophistication in identifying the mutations or targets so we can better select patients more likely to respond. We're not only doing this with these therapies, we're also trying to do this with chemotherapy, to identify molecular characteristics that make patients more or less sensitive to the different drugs, and making even the cytotoxic, more conventional agents more targeted. And finally, we're also looking at subgroups of patients, phenotypically, who seem to be more likely to respond to different agents. For example, women and never-smokers are 2 groups in whom the likelihood of an EGFR mutation is enriched, and who therefore might benefit more from EGFR-targeted therapies, so researchers are now looking at using these agents in these groups in the first-line setting.

Looking at the evidence, we have first-line and second-line cytotoxic therapies that improve survival, and even third-line targeted therapies that can improve survival as well, across many different patient groups: men, women, smokers, nonsmokers, adenocarcinomas, squamous-cell carcinomas, etc. We have evidence that the survival benefit is statistically significant and clinically meaningful, for responders as well as for those with stable disease.

As we think about agents that have independent activity, we're thinking about how these agents might be useful in earlier-stage disease, and maybe even as an adjunct to adjuvant therapies.

But it's also not limited to the small molecules. The proteasome inhibitor bortezomib has shown activity in the third line, and we're waiting on results of the bevacizumab trials. We're looking at combinations of these agents, targeting multiple pathways in those tumors that don't have unique growth drivers, but that learn to develop resistance and find another growth pathway -- combinations of agents that don't have overlapping toxicity, that have different mechanisms of action. By attacking several different pathways, or several steps in a highly relevant pathway, you avoid the evolution of resistance, increase the likelihood of response, and get responses that are more durable. So, for example, there's a trial now looking at bevacizumab and erlotinib; there's good biology, good preclinical data, good theoretical rationale, and early evidence of activity in renal cell cancer.

Medscape: What are the odds that we'll be able to find something like BCR-ABL and imatinib in NSCLC? If you look at the data from the studies of EGFR mutations in gefitinib responders, it's great to be able to identify such a mutation, but if an agent is limited to only 10% of the population, is it worth studying?

Dr. Green: We're not yet in the position in the large majority of patients with NSCLC to expect to find a single molecular abnormality. There are some people who have genetic susceptibility, and we'll need to explore that. In Asian women, in whom only a small fraction are smokers, the incidence of the EGFR mutation is increasingly frequent, 25% to 30% or higher, and the response rate to oral EGFR inhibitors in some populations of nonsmokers is in the 50% range. But in the carcinogen-induced setting of lung cancer, it's going to be harder to find a single mutation.

If you think about it, some leukemias and other hematologic disorders are diseases that can come to clinical awareness with one mutation, and therefore are susceptible to control in a large percentage of patients because they have a single driver. Solid tumors are much more complex when they're clinically apparent, especially when you come to stage III and stage IV disease. But if you go back to where it started, somewhere early, the number of gene-change drivers is going to be smaller, finite, and approachable.

It will be quite a while before we have the "answer" to the common solid tumor, but until then, we'll need to continue studying targets and targeting agents, and to look at strategies such as their use in chemoprevention and in the adjunctive settings, to go back and find a seminal event in the development of the tumor that we could target.

Supported by an independent educational grant from Genentech.

Shira Berman, Site Editor, Medscape Hematology-Oncology

Mark R. Green, MD, Clinical Professor of Medicine, Medical University of South Carolina, Charleston, South Carolina

Disclosure: Shira Berman has no significant financial interests or relationships to disclose.

Disclosure: Mark R. Green, MD, has reported that he has received grants for educational activities from Aventis and Genentech. Dr. Green has served as an advisor or consultant for Aventis, Genentech, and Lilly. He has received honoraria from Aventis, Genentech, AstraZeneca, and Lilly.

Medscape Hematology-Oncology 7(2), 2004. © 2004 Medscape

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