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Video Presentation on Timing of Chemo after First Line for Advanced NSCLC
With special thanks to Harvey and Bernice Janssen for providing support to make it possible, I’m pleased to post a new video presentation on the topic of Timing the Transition to Maintenance/Second Line Chemotherapy for Advanced NSCLC. We can expect new information to emerge in the coming months and years, but here is the current snapshot of what we know, along with a little describing what I think (noted as such), about this important topic today.
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Lung Cancer and the Enzyme Connection
Erlotinib (Tarceva) was approved for treatment of progressive non-small cell lung cancer (NSCLC) after the BR21 study that showed that tarceva not only improved survival but also improved lung cancer symptoms and quality of life. This study and others have also taught us that the benefit of tarceva is much better in those who had never smoked and less effective in current smokers. It is important to note, however, that even those who currently smoke obtain a benefit from treatment with tarceva, albeit smaller.
In the wake of the BR.21 trial, it became known that certain EGFR mutations in the tumor are associated with a dramatic benefit with tarceva, as well as the other EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa).We also began to realize that these EGFR mutations were found most commonly in never smokers and rarely in current smokers.
There it was: the reason why tarceva worked better in never smokers. But in fact that was not the whole story. Tarceva, like many other drugs, is broken down in the body by an enzyme group called CYP 1A1/1A2. Enzymes are proteins that help to break down and digest our food, but enzymes can break down and digest many other things as well. The products in inhaled tobacco smoke stimulate this enzyme CYP, which then further breaks down tarceva in the body before it has a chance to work.
EGFR Mutations Demystified
It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR). However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.
The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done. In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive. In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients. This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.
However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients. In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.
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A Case of a 36 Year-Old Never-Smoking Woman with Metastatic Adenocarcinoma of the lung
With all this recent talk about never-smokers with lung cancer, and the interest in stories of patients with so-called “oligometastatic” cancer (minimal metastatic burden to perhaps a single site), I thought I would describe a recent case in my clinic as an illustration of how I use this information in everyday decision making.
Mrs. D, a very fit 36 year-old woman with a young child at home, presented to her family doctor last year with back pain. It didn’t seem to be getting better, so her doctor ordered an x-ray of the back which showed a very nasty-looking spot in the lower spine. An MRI confirmed that there was a large tumor in the lower spine, and a surgeon went in and took a piece of the bone to determine the cause. The result was a metastatic adenocarcinoma, with special tests pointing to a primary site from the lung.
She had never smoked, nor had her spouse. A PET scan showed a very small spot in her lung, with no evidence of spread to local lymph nodes, and no evidence of metastatic disease outside of the single metastasis in the spine. An orthopedic surgeon opined that she probably could resect the entire vertebrae involved, but this would be a major undertaking.
This type of case, aside from the heartbreaking anguish of having to tell a young mother she has lung cancer, causes all of us in the oncology world fits. How could such a small tumor, less than 1cm in size, be the cause of the spine tumor? Was it worthwhile to discard what we intellectually know about metastatic lung cancer (incurable) and treat her aggressively for cure, and if so would we be putting her through Hell only to make ourselves feel better about not giving up on such a young patient?
How Much Does Treatment Sequence Matter in Lung Cancer?
One of the general rules in oncologist is that we typically use our most effective treatments first, and often early, though there are certainly exceptions. Women with metastatic breast cancer may have a higher response rate by receiving combination chemotherapy than single agent chemo, but when a gentle single drug chemotherapy or hormone therapy option will do very well and provide fewer side effects, that’s usually the approach we recommend until bigger guns are needed. Similarly, patients with slow-growing cancers like chronic lymphocytic leukemia (CLL) often do well for many years and sometimes forever without needing treatment, so we often hold on initiating any treatment unless there’s a good reason to (and I think the same argument can be made for some lung cancers, most commonly indolent bronchoioloalveolar carcinoma, or BAC). So we don’t want to treat patients with less therapy than they need, but we’d also prefer not to treat them with more.
When you have multiple potential treatments to pursue, one question that becomes relevant is whether the sequnce matters. If you have choices A, B, and C, does it matter if you give AB followed by C, or C followed by AB or even A followed by B and then C? First, we need to take a step back and recognize that this is a good dilemma to have, because 10 years ago we didn’t have multiple effective treatments to try to position. For advanced NSCLC, the value of giving chemo for metastatic disease was debated until about 10-12 years ago, when the survival benefit of platinum-based doublet chemo regimens became a clear standard. In 2000 or so, second line taxotere emerged as a second line treatment option that improved survival and was approved by the FDA in that setting. A few years later, additional treatment options for previously treated patients with advanced NSCLC were approved, ushering in agents like alimta and EGFR inhibitors (initially iressa and then tarceva, with iressa removed from the US marketplace. These all became viable options, and over the last few years all of these agents have also been studied as first line treatments. Taxotere and alimta are now both FDA approved as first line combination therapy with platinum, and the EGFR inhibitors have also been studied as first line treatment and have appeared particularly attractive in certain subsets of patients, such as those with an EGFR mutation or patients with advanced BAC.
EGFR Tyrosine Kinase Inhibitors for Patients with EGFR Mutations
Back when I first started doing this, one of my earliest posts (see here) was on the question of whether EGFR tyrosine kinase inhibitors (TKIs) (see introduction to this work in prior post). My point, which is still true, is that EGFR TKIs aren’t only effective in a narrow population of patients, whether identified based on molecular or clinical variables. But in the more limited number of patients who have the “activating mutation” in the actual receptor, who might be expected to do especially well with an EGFR TKI, how do they do? How does a targeted therapy do in a precisely targeted population?
There are several studies that have now tested this by identifying patients who have an EGFR mutation and received an EGFR TKI. As shown in the table below, the results are very clear and consistent.
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Tarceva (Erlotinib) in the Elderly
One of the initial appeals of targeted therapies like tarceva (erlotinib) was that they may have fewer side effects and emerge as an alternative to standard chemo for some people. And one of the most appealing areas for offering a good alternative to standard chemo has been in the setting of older patients, who may be more wary of side effects and/or have additional medical problems than younger patients.
A theme that has emerged very consistently in studies of elderly patients in lung cancer, and largely in oncology in general, is that fit older patients without many medical problems are very likely to do every bit as well as younger patients. Although studies of older patients with lung cancer have largely paired the elderly and “poor risk”/frailer patients (performance status of 2, corresponding to being symptomatic, a little limited in activities, but spending more than half of the day in bed or a chair) in pooled trials. More recently, though, we’ve come to recognize that these are overlapping but definititely distinct groups. We also learned in a prior post that unselected patients (not singled out by things like having never smoked, or having an EGFR mutation, for instance), with a marginal performance status who receive tarceva instead of standard chemo clearly do less well than patients who get standard chemo. But how well do older patients do with tarceva, independent of performance status? This is an important question now that more than half of all newly diagnosed lung cancer patients are over 70. A couple of trials help shape our thinking here.
Erlotinib (Tarceva) in Previously Treated NSCLC
In a recent post, I described the approval of taxotere as a second-line chemotherapy with a modest but survival benefit for patients previously treated with one line of chemo, usually a platinum-based doublet. Two years ago, erlotinib/tarceva, an inhibitor of a target on many NSCLC tumors called the epidermal growth factor receptor, was approved by the FDA as an additional treatment option for previously treated patients with advanced NSCLC, based on a large randomized clinical trial led by the National Cancer Institute of Canada that was published in the New England Journal of Medicine (BR.21 abstract here), demonstrating the importance of the results.
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