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Consolidation Tarceva after Chemo/Radiation for Locally Advanced NSCLC: At Least It Isn’t Significantly Harmful
Perhaps the most unexpected clinical trial result in lung cancer over the past 5 years was the finding in the large Southwest Oncology Group (SWOG) 0023 trial that randomized several hundred patients to maintenance therapy with either the oral EGFR inhibitor Iressa (gefitinib) or a placebo after chemo/radiation concurrently and then consolidation taxotere (docetaxel). While just about everyone in the lung cancer community expected to see either a significant benefit or, at worst, no real effect from maintenance Iressa, the actual trial was stopped early and demonstrated a statistically and I would say clinically significant decrease in overall survival with maintenance Iressa. The median overall survival (OS) in the final publication was a full 12 months lower in patients who received Iressa compared with those who received the placebo .
To me, not only did this study demonstrate that giving consolidation EGFR inhibitor therapy was probably a bad idea, at least outside of a clinical trial, it also suggested that we don’t necessarily know as much as we presume we do about how trials will turn out, so it makes sense to do the studies rather than just start a new strategy without the evidence to back it up.
EGFR Inhibitors: Personalization by “Snips”
What we are striving for in cancer care today is personalized medicine. So, if a patient with newly diagnosed NSCLC has an activating epidermal growth factor receptor (EGFR) mutation, we give that patient Tarceva (erlotinib), a tyrosine kinase inhibitor (TKI). Right? Well, yes — but it doesn’t always work (the response rate is in the 70-75% range). Why not? We’re not sure, but it would be nice to learn why we don’t see near a 100% response rate among patients with EGFR mutations, so that we can know to recommend other alternatives. On the other hand, if a patient does not have the mutation, we don’t really expect much in the way of a dramatic response. Again, only partly right. In fact, some studies show a significant minority of patients with normal (“wild type”) EGFR will have at least some response to Iressa (gefitinib) or Tarceva. So, what’s going on here?
A recent study out of China looked at blood rather than tumor in 84 patients with advanced NSCLC who were all treated with Iressa. The analysis looked at naturally occurring single-nucleotide polymorphisms (SNPs, and pronounced “snips”), in the EGFR gene. A polymorphism, which basically means “many forms”, can be thought of as small part of a gene which has a different part (nucleotide) from the general population, but is otherwise normal, as best we can tell. A minority of individuals will have the different nucleotide (polymorphism) while the general population will have the same gene but with a different nucleotide.
In these patients, it was found that having a particular SNP could predict for a better response to Iressa and longer survival than the rest of the group, while different SNP could predict for a poorer response and shorter survival with the drug. Still another SNP could predict for a greater risk of developing a rash, which we know is also associated with a benefit from these TKIs. This has also been seen with Tarceva.
Tarceva for Advanced Squamous NSCLC: Recalibrating Expectations
When most oncologists think about the EGFR inhibitor tarceva (erlotinib), they think of the uncommon but very memorable patient who has a spectacular response within a few weeks of starting it, then continues to do well on it for a year or more. These patients are most commonly never-smokers, often Asian, and almost invariably have an adenocarcinoma. In contrast, many oncologists perceive there to be little to no value in giving tarceva to patients with squamous tumors, and many don’t even bother to offer it to these patients. However, it’s worth highlighting the evidence that suggests a meaningful survival benefit, even if it falls short of the “swinging for the fences” idea we have when we give tarceva to some patients. At the same time, we need to remember that agents like Alimta (pemetrexed) and Avastin (bevacizumab) are not generally indicated or used for patients with squamous NSCLC tumors, due to efficacy or safety concerns, respectively. Options in advanced NSCLC are limited, but more so for patients with squamous tumors, so we need to ensure that we don’t leave good alternatives unused.
Throughout all of this work it’s important to underscore here the difference between response rate and survival, something that many oncologists still forget when they dismiss a drug for not having a high enough response rate against a certain type of cancer. But it’s become increasingly clear in the past few years that patients with lung cancer can receive a significant survival benefit in the absence of major tumor shrinkage, and that’s not hard to imagine: if the cancer would otherwise be growing, maintaining stability is a relatively good thing, even if it falls short of major shrinkage. And to fulfill the clinical trial criteria for even a partial response, a tumor needs to shrink by about 50% of its volume. When I tell a patient that his or her tumor has shrunk by about 30%, a “minor response” that is still generally considered stable disease in clinical trials, we’re all pretty happy with that and don’t toss that treatment aside just because the tumor didn’t shrink by 50% or more.
Iressa vs. Chemo in First Line Treatment of Korean Never-Smokers: The First-SIGNAL Trial
I would consider the recently published IPASS trial that compared Iressa (gefitinib) to standard chemo of carbo/taxol (paclitaxel) to be an extremely influential trial in lung cancer that has essentially ushered in a new era of molecularly-defined guidance of our treatment for many patients with advanced NSCLC, and we can expect that this is how we’ll be approaching a much broader population of lung cancer patients. But there was actually another very similar trial done in Korea that was presented in the Plenary Session of the World Conference on Lung Cancer a couple of months ago in San Francisco that provides another opportunity to directly compare chemo to an EGFR inhibitor.
The First-SIGNAL trial (First-line Single Agent Iressa versus Gemcitabine and cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung) randomized 313 Korean never-smokers with previously untreated stage IIIB or IV lung adenocarcinoma to either Iressa at 250 mg by mouth daily to standard chemo with cisplatin/gemcitabine as initial therapy. It asked whether first line Iressa would be associated with a significant improvement in overall survival (OS) and also looked at progression-free survival (PFS), response rate (RR), side effect profile, and quality of life between the two treatment arms. This trial had a rather ambitious goal of showing a 40% improvement in survival and enrolled only about ¼ the number enrolled on the IPASS trial, so the statistics reported here need to be taken with a grain of salt because the study is pretty underpowered to show many meaningful statistical differences.
Alimta for Brain Metastases in NSCLC?
Brain metastases from NSCLC is almost a field of its own. This is because of the relatively high frequency with which metastases appear, the fact that they may return, even after treatment with whole brain radiation therapy (WBRT), and that our chemotherapy has long been considered to be ineffective against them. In fact, the extent of them as a problem is reflected in the number of thread questions on this subject in the GRACE forum. At the same time, there has also been work devoted to prophylactic whole brain radiation therapy (WBRT) in selected NSCLC patients considered to be at high risk. For unknown reasons, adenocarcinomas (ADC) seem to be the most likely to appear in the brain, at times the first/only site outside of the lung.
For this reason, a recent study of Alimta, published on-line in Lung Cancer, by Bearz and colleagues from several hospitals in Italy, may be of interest. Of a subset of 22 patients with brain metastases who either recurred after WBRT (11 patients) or had never received radiation (11 patients), and then received Alimta (pemetrexed), a remarkable 68% had what the authors called a “cerebral benefit.” Of the 22, 5 had a partial response, 9 had stable disease, while only 7 had progressive disease.
That being said, the study had several limitations. First, although half of the 22 had prior WBRT, the authors did not say how each of the 2 groups fared. The implication is that some of the 14/22 who benefited from Alimta had prior WBRT. Next, it would have been good to see how those few with squamous cell carcinomas (SCC) responded. In the entire group of 39 patients, only 4 had SCC, a subtype not generally felt to respond well to Alimta. Finally, this was a small study, with presumably a relatively homogeneous population, and the results may not reflect what might happen elsewhere. On the other hand, of the 39 patients with brain mets treated with Alimta, the median survival was 10 months, a pretty encouraging result considering what we had historically expected.
More Evidence from Asia on Where EGFR TKIs Fit into NSCLC Treatment
As more and more oncologists become aware of the importance of testing for at least the EGFR mutation in tumor, and soon, perhaps, in blood, it seems likely that more patients will have their first systemic treatment for advanced non-small cell lung cancer (NSCLC) be an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), usually Tarceva (erlotinib), until Iressa (gefitinib) is re-approved (perhaps). This is because the presence or absence of the mutation seems more important than clinical features in predicting a benefit from the TKI, as Dr. West described in the wake of the evidence from the IPASS trial. In that regard, a recent paper from a group of investigators in Taiwan discusses what second-line treatment should be considered after progresssion following first line Iressa in patients with advanced NSCLC. A total of 195 patients were included in this retrospective analysis, of whom 95 had tissue for testing for the EGFR mutation (61 with a mutation, 34 without). Although these findings may not be directly transferable to a North American or European population who would be receiving the very similar TKI, Tarceva, they are still of some interest.
Those with the EGFR mutation who progressed while on Iressa got a greater survival benefit with Gemzar (gemcitabine) plus a platinum-containing regime than any other regimen, including single-agents Navelbine (vinorelbine), a taxane (such as Taxol (paclitaxel) or Taxotere (docetaxel)), or any of those combined with a platinum, or Tarceva was given in some patients. However, it is of interest that none received an Alimta (pemetrexed)-containing regimen, so this remains an unknown. On the other hand, those patients who did not have an EGFR mutation did just as well with a single chemotherapeutic agent as with a doublet containing a platinum, and no one treatment emerged as especially better than another.
Integrating EGFR Inhibitor Therapy with Chemotherapy: Should We Treat Advanced NSCLC Like a Sprint and Not a Marathon?
Dr. Tony Mok, a friend who lives and works in Hong Kong and is an international leader in lung cancer, has just published not only the IPASS trial in the New England Journal of Medicine but also another trial called FAST-ACT (for First Line Asian Sequential Tarceva and Chemotherapy trial) in the Journal of Clinical Oncology. While the IPASS trial directly compares first line chemo alone to the EGFR inhibitor Iressa (gefitinib), the FAST-ACT trial was a randomized trial (phase II, so smaller and less definitive than a phase III randomized trial) that directly compared chemo alone to chemo with the oral EGFR inhibitor Tarceva (erlotinib). Importantly, however, in recognition of the justifiable concern that chemo and oral EGFR tyrosine kinase inhibitors given concurrently may well interfere with each other, the investigators gave chemo and either Tarceva or placebo on an alternating basis during a 28-day cycle, in which cisplatin or carboplatin was given on day 1, gemcitabine on days 1 and 8, and then Tarceva or a placebo was given on days 15-28, before chemo restarted. This way, chemo and Tarceva didn’t overlap, which should reduce the risk of a negative interaction between them.
(click on image to enlarge)
Managing Locally Advanced NSCLC: Summary from a Talk to Patients & Caregivers
Here is the third portion of a talk I did at the Seattle-based non-profit Cancer Lifeline in May, and this section focuses on our current standards for managing unresectable locally advanced (stage III NSCLC). This covers theissues of sequential vs. concurrent chemo with radiation and the important issue of whether additional consolidation chemo after the radiation is feasible and advisable. It also covers the emerging key trials being done in this treatment setting.
Here is the presentation in video format, the audio version, transcript, and a pdf file of the figures.
Cancer Lifeline Part 3 Locally Advanced NSCLC Audio Podcast
Podcast: Play in new window | Download (0.3KB) | Embed
Clinical versus Pathologic Staging of Non-Small Cell Lung Cancer
When oncologists and surgeons talk about staging, we often distinguish between clinical and pathologic staging. Many in the health care field don’t understand or know the difference. Even more, why do we “stage” a cancer (NOT the patient!) at all? These are important questions, because they tell those of us involved in the treatment and care of such patients what is the extent of the disease, what the prognosis might be, and what the treatment plan should entail. That way, the caregivers are all “on the same page”.
It is quite important to know that staging is done, by tradition, ONLY at the discovery of the disease and a tissue diagnosis (by biopsy) obtained, and before the start of treatment. When and if there is a recurrence of the cancer, we do not give the cancer a new stage. It is then just that, a recurrence. Thus, the term “re-staging” is really a misnomer; the process would be better termed a “re-evaluation”. Another common misconception in staging and diagnosis among patients is related to the spread of the cancer from one organ to another: if a lung cancer has spread to the bone or liver, it’s still one process. It isn’t called a bone or liver cancer, but rather, it is lung cancer metastatic to those places.
A Disturbing Case of Needle Track Seeding from Biopsy of a Previously Resected NSCLC Tumor
Several days ago, I had a new patient referred to me who has something I’ve never seen before. Though patients will occasionally ask about the risk of their lung cancer being spread by a biopsy or surgery, I’ve not seen and have heard of this only very, very rarely with lung cancer — though it’s not uncommon to see growth through the needle track of a biopsied mesothelioma.
The man in question had undergone resection of a left upper lobe tumor in early 2007, for which he underwent a lobectomy after a CT-guided biopsy demonstrated a moderately differentiated adenocarcinoma. His thorough mediastinoscopy followed by resection demonstrated no nodal involvement, and his scans were fine for two years. Nevertheless, he developed left shoulder pain a few months ago and eventually underwent a CT that demonstrated a soft tissue mass toward the top of his left chest, as well as enlarged to 1.5-2 cm behind his left collarbone (which would drain from the area where the chest was mass was found). He saw his surgeon, who thought it unlikely to be metastatic spread, or locoregional recurrence. Nevertheless, a biopsy of one of the supraclavicular nodes revealed an adenocarcinoma remarkably similar to his original cancer and with proteins present that indicate that they started as lung cells.
Looking at his imaging from today compared to his biopsy from 2007, it seems extremely likely that this local recurrence represents a new tumor in the needle track, along with nearby nodal drainage.
(click on image to enlarge)
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