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Maintenance Tarceva: Ready for Prime Time? Part 1: The SATURN Trial
About a week ago, as most of you are now aware, the annual American Society of Clinical Oncology (ASCO) meeting was held in Orlando, Florida. Tens of thousands of oncologists, nurses, radiation oncologists, pulmonologists, surgeons, radiologists, pathologists, financial advisors, and pharmaceutical representatives descended on Mickey Mouse-land for schmoozing and sunshine… I mean, for the presentation of the most up to date research in the cancer world.
Certainly from the standpoint of lung cancer, the most relevant and potentially standard-of-care changing presentations related to maintenance therapy. This has been extensively discussed on this site in the past, but for the newbies this means giving immediate therapy (chemotherapy or targeted drugs) after patients with advanced NSCLC have completed first-line chemotherapyand show no signs of progression. In the past, patients typically would stop all treatment and observe the cancer for signs of progression prior to starting a new treatment, called “second-line” treatment. However, at least 4 major trials in the last few years have tested whether patients would benefit from NOT stopping, but instead moving right on to the second-line agents immediately, before the cancer recurs.
The trial of maintenance Alimta (pemetrexed) has already been covered by Dr. Pinder earlier this week. For this post I will cover the first of 2 major phase III trials that tested the concept of maintenance Tarceva (erlotinib), the so-called SATURN (Sequential Tarceva in Unresectable NSCLC) trial.
For this trial, nearly 2000 patients with advanced/metastatic NSCLC were given platinum doublet chemotherapy for 4 cycles. After completing 4 cycles, 889 patients who had not progressed were randomized to either single agent Tarceva or to placebo. The primary goal of the trial was to show that maintenance Tarceva improved progression-free survival (PFS).
SATURN Trial Study Design
(Click on figure to enlarge)
How Helpful are EGFR Inhibitors in Frail, Poor Performance Status Patients with Advanced NSCLC?
Among the many challenges in clinical oncology is the fact that a very significant proportion of our patients are quite a bit more debilitated than the vast majority of patients in clinical trials that test our anti-cancer therapies. Approximately a third of the patients with advanced NSCLC have what would be considered a poor performance status (PS) of 2 or 3 (0 to 5 scale, 0 being asymptomatic, and 5 being dead), but they are extremely under-represented on our clinical trials. Because our anti-cancer therapies, whether standard chemo or targeted therapies, have challenging side effects for many patients, we struggle to balance between fighting the cancer and harming the patient. In the absence of much evidence, we need to rely on our judgment when we make treatment recommendations.
Many physicians and patients have looked upon so-called targeted therapies as a potential alternative to standard chemotherapy drugs that could allow us to treat the cancer more selectively, with less collateral damage to a person’s normal tissues. The oral epidermal growth factor receptor (EGFR) inhibitors like Iressa (gefitinib) and Tarceva (erlotinib) have been the first agents that have been widely used as single agents, and they certainly have activity and can improve survival. Nevertheless, we’ve seen evidence that Tarceva was convincingly inferior to standard chemotherapy for poor performance status patients (at least “unselected” patients who hadn’t been particularly singled out by having an EGFR mutation, being a never-smoker, etc.); another study compared Iressa to the widely used single agent approach of Navelbine in elderly patients (not synonymous with poor performance status) and showed very comparable efficacy. Patients with both good and poor performance status were included in the important clinical trial that showed a survival benefit for Tarceva compared with placebo as a second or third line therapy, dicussed further below.
We get some additional information from a newly reported trial that randomized 201 poor performance status patients (considered to be “unfit for chemotherapy”) to either Iressa or placebo (plus general supportive care for all patients). The study was conducted in several centers in North America and Europe (so very few Asian patients were enrolled, a significant issue because results with EGFR inhibitors are often very different in Asian vs. Western populations). The majority of patients were also older, about half 75 or older, and most of the rest in the 65-74 age range. Importantly, this trial included not only patients with a PS of 2, who are still up and out of bed more than 50% of the time, but also PS 3 patients, who are pretty debilitated and spend more than half of the day in bed (enrollment was an approximately 60/40 split of PS 2 vs. 3 patients). Our experience in studying such frail patients is extremely limited.
The Unsettling Evidence of Tumor Heterogeneity
We know that cancer cells mutate over time — in fact, that’s how they became cancer cells. In fact, oncologists see the heterogeneity of cancer cells in our daily practice every day. Although there are certainly many reasons why patients have some of their cancer cells respond and others not (blood supply, local microenvironmental factors, etc.), one of the important factors is genetic heterogeneity within the cancer cell population — some cells die and others don’t. Moreover, the typical gradual shift from a cancer responding to a treatment and then showing an acquired resistance and progression after several cycles is presumably mediated by an ongoing evolution of the tumor itself to selective survival of cancer cells with a new resistance mechanism.
I suppose it should come as no surprise, then, that EGFR mutations are also subject to tissue heterogeneity. This is demonstrated by a paper in this month’s Annals of Oncology by Gow and colleagues, out of Taiwan.This paper checked for EGFR mutations in tumor tissue from 67 patients who underwent some form of surgery of biopsy or resection of NSCLC in Taiwan that included removal of some tissue from both the primary tumor and a metastatic lesion. Those 67 paired patient samples came from a pool of over 900 surgical samples over an 8 year period; none had received an EGFR inhibitor at the time that tissue was collected.
VeriStrat Test for EGFR Test: Initial Impressions after Sending a Few
A few weeks ago I described a blood test for predicting survival after getting an oral epidermal growth factor receptor (EGFR) inhibitor that is just becoming commercially available. This is called the Veristrat test and from company called Biodesix. As I noted previously, this technique looks at the protein patterns in a patient’s serum and reportedly can reliably predict whether a patient is likely to have a prolonged survival after receiving an EGFR inhibitor. The company gave me the opportunity to send off a few of these tests at no charge, and after a few weeks of trying it in a handful of patients, I’m finding that it seems to do what it says it does, for better or for worse.
What they specifically say is that, by separating serum samples into the two thirds that will have a “good” survival and the one third that will have a “poor” survival after getting an EGFR inhibitor, clinicians can use this test to determine which patients shouldn’t get an oral EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) for advanced NSCLC. The test may well be great for this, but I haven’t had the opportunity to send this test off in the last few weeks for this purpose.
Instead, what I was hoping we might use this test for is to get a faster answer about whether a patient will do well with an EGFR inhibitor. Even though I and many other lung cancer experts are increasingly becoming converts to the idea that EGFR mutations are quite relevant and override clinical predictors of benefit with EGFR tyrosine kinase inhibitors (TKIs), these mutations aren’t always very accessible. Only a minority have enough tumor tissue from their original biopsy to send off for mutation testing, and the test itself takes 3-4 weeks, which is long enough that many patients will not be inclined to sit around and wait for a month before starting treatment.
New Podcast on the ABCs of BAC
Here’s a video slide presentation that provides a basic introduction to bronchioloalveolar carcinoma (BAC), including the demographics, natural history, imaging appearance, and patterns of response that make it a unique subpopulation within lung cancer. The audio only version is below the video.
[display_podcast]
In addition, we’ve got the final slides in pdf form, so people can follow along with the audio or just study them at your own pace, along with the transcript from the presentation:
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.
(Click to enlarge)
Iressa for Elderly and/or Poor Performance Status Patients with an EGFR Mutation
Several years ago, we learned that EGFR tyrosine kinase inhibitors (TKIs) were not a very helpful strategy for an unselected population of frail patients in the US, clearly inferior to standard chemotherapy (see prior posts here and here). This work was in patients who hadn’t been tested for molecular markers like EGFR mutations, and our interpretation of the previous US-based trial left us with the conclusion that an EGFR TKI like tarceva (erlotinib) or iressa (gefitinib) was an inferior chemotherapy alternative and apparently ineffective treatment for the majority of patients with a marginal performance status, but it could still be an effective option for patients selected to be especially likely to benefit from this class of agents, like patients with an EGFR mutation.
This was the subject of pure speculation until now. A manuscrupt by Inoue and colleagues (abstract here) has just been published that describes the experience of treating patients with an EGFR mutation and who are either elderly or have a poor performance status or both with an EGFR TKI (iressa at the standard 250 mg/day) as first line therapy. Specifically, they enrolled 30 patients who either had a poor performance status (3 or 4 on a scale of 0 to 5 where 0 is asymptomatic and 5 is dead: details here), or were 70 or older with a marginal performance status (2 -4) or 80 or older with any symptoms (1-4). It’s worth noting that there are relatively few studies that include patients with a performance status of 2, and almost none that have included patients with a performance status of 3, who spend more than half of their day in bed and can’t take care of many of their activities of daily living. Continue reading
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