GRACE :: Lung Cancer

Third-line therapy and beyond

Who Benefits from Third-line Treatment for Advanced NSCLC?

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The Benefit of Zactima: Damning with Faint Praise

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Member Neil Berch just wrote a nice summary of the four large randomized clinical trials being done with Zactima (vandetanib), an oral targeted therapy that can block both the VEGF (angiogenic) and EGFR pathways. In fact, the name vandetanib comes from blocking V and E. In the single agent studies, one comparing Zactima to Tarceva (erlotinib) and the other to a placebo (in patients with advanced NSCLC previously treated with an EGFR inhibitor like Tarceva), the Zactima dose was 300 mg, which is a dose thought to block both pathways. In the chemotherapy trials, the daily dose of Zactima was 100 mg, which the lab work would suggests is enough to block angiogenic activity but probably not block the EGFR pathway. Why? A prior, preliminary trial of the chemo agent Taxotere (docetaxel) with either placebo or Zactima at 100 mg or 300 mg daily actually demonstrated clearly better results with Zactima at the lower dose, a finding that I suspect may be because blocking the EGFR pathway while also giving chemotherapy could well be detrimental. In any event, we can’t presume that a higher dose would lead to better results with chemo in the current large trials.

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Stable disease is just fine, thank you.

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At the 1st ESMO-IASLC Lung Cancer Conference in Geneva last week I saw a presentation that I thought would interest this general readership. The study, presented by Dr Grossi, from Italy, is a retrospective review of 61 patients with advanced NSCLC of all subtypes treated with either Tarceva (erlotinib) or Iressa (gefitinib) in the 1st or 2nd line setting.

The groups were similar, remember this was not a randomized prospective study; the median age was 65 for those receiving Tarceva and 74 for those on Iressa. About 26% of the whole group were never/former smokers. They all were pretty physically fit (ECOG PS of 0 or 1), and most of them (55-58%) had adenocarcinoma.

There were no complete responses and the rate of partial response was 6% and stable disease of 26% for the people on Tarceva and 13% partial response and 29% stable disease for those on Iressa. These figures, although low, are entirely in keeping with previous study results for both drugs given to unselected patient populations.

What was interesting was that for the people who had a partial response the median survival was 9.7 months, but it was 9.1 months for those who had stable disease, and only 3.7 months for those who progressed on treatment. This was a trend noted in other studies and one I certainly see in my clinic, but it was reassuring to see it reproduced. And hopefully reassuring to anyone who might have “only” stable disease. Dare I say “size isn’t everything”?


Clinical Trials with Sutent (Sunitinib) in NSCLC

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One of the novel agents being studied in lung cancer is sutent (sunitinib), a multi-targeted oral anti-angiogenic drug that I’ve described in a prior post. While I’ve mentioned a small study I’m leading at my own institution with this agent in advanced NSCLC patients with bronchioloalvelar carcinoma (BAC) or who have never smoked (information here), I wanted to describe a couple of larger studies that are being run by Pfizer, the company that is developing sutent, in lung cancer. Their development program is a series called the SUN trials, for Studies to UNderstand Sunitinib, another acronym that is a bit of a stretch in order to be memorable.

These trials are based on the combination of sutent/tarceva, which has been studied in a limited trial in kidney cancer (abstract here), and another one in NSCLC is being conducted at the University of Wisconsin (information here).

The largest trial is SUN-1087, which is an international phase III randomized trial of the combination of sutent and tarceva (erlotinib) compared to a current standard for previously treated patients with advanced NSCLC of tarceva with a placebo. The SUN-1087 trial is ongoing and will plan to enroll 956 patients in the second or third line setting, and it patients with any kind of NSCLC (adenocarcinoma, squamous, or less common subtypes). It will look at potentially important variables such as whether enrolled patients received prior avastin (bevacizumab), whether they are a never-smoker, ex-smoker, or current smoker, and also their EGFR status (I believe my looking at immunohistochemistry, the levels of EGFR protein on tumor cells. These factors will be monitored and compared between the two arms so that neither arm receives far more never-smokers, prior recipients of avastin, etc. – a balancing act called stratification. The tarceva will be given at the standard starting dose of 150 mg daily, with sutent at 37.5 mg daily, and the trial will treat all patients until they develop either progressing cancer or prohibitive toxicity. The goal of the study will be to see whether the tarceva/sutent provides a significant overall survival (OS) advantage over tarceva alone (with tarceva). Further information on this trial, including participating sites, is available here.

A smaller trial known as SUN-1058 has a very similar design of tarceva/sutent vs. tarceva alone, but it doesn’t have a placebo included. It is enrolling essentially the same population of previously treated patients with advanced NSCLC (second and third line), with any NSCLC subtype, but will only enroll a total of 126 patients and will be looking at progression-free survival (PFS) as the primary endpoint. Further information on this trial, including participating sites, is available here.

You might ask yourself why a company would conduct two trials with such similar designs – it’s not a typical approach, and I’m still not sure why the company would do this. However, I speculate that the reason for running a small trial at the same time as a large trial is a strategy to obtain early feedback from a small trial looking at PFS (a quick endpoint) that could potentially lead to changes or an early termination of the larger trial looking at the longer-term endpoint of OS before having invested far more millions into the larger trial. Continue reading


Second Line Treatment for NSCLC: Choosing Among Several Options

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Member Sandra recently asked the question that several other people have asked in one form or another: how do we choose among the treatment options for second line therapy in NSCLC. I’ve covered in several posts and a huge number of responses in the Q&A Forum the leading options we generally consider for second line therapy for NSCLC. I’ve consistently stated that there are three agents that are most commonly used — taxotere, alimta, and tarceva — because they’ve all been pretty well studied, and they’re all approved by the US FDA for this setting based on the evidence available. Moreover, they also have what appears to be very comparable activity: taxotere and alimta have been compared head to head and shown to have remarkably similar efficacy, and while we don’t have data yet for direct comparisons of tarceva vs. one of these chemo options, we do have data from the large INTEREST trial (post here) that showed that iressa, which the preponderance of evidence would say is the slightly weaker EGFR inhibitor vs. tarceva, had the same efficacy as taxotere in a huge worldwide trial.

So we’ve got these three leading options (and it’s also reasonable consider others, even if they aren’t as well studied), and how do we choose among them? My first question is whether I’m inclined to recommend chemo or an EGFR inhibitor as second line therapy. And the two leading factors I’d consider are prior response to chemo in first line, and smoking status. To me, they both count pretty similarly. The main principles are that if someone responded well to chemo in first line, they’re more likely to respond well to second line chemo. On the other hand, someone who progressed after the first two cycles is not someone I’d be especially optimistic about for a better response to second line chemo. So the better the first line outcome with chemo, the more inclined I’d be to recommend more chemo; conversely, the more disappointing the outcome, the more inclined I’d be to recommend EGFR inhibitor therapy with tarceva, although in this case I’m selecting it as the “not more chemo” choice more than because it’s an EGFR inhibitor. I’d consider it more of a wild card, and a wild card is good when you’re expecting a bad outcome with what you’ve already got (for instance, more chemo), but it’s less appealing if you’re expecting a good outcome with what you’re holding.

The second big factor is smoking status. We’ve spoken mostly about never-smokers, and as I’ve mentioned all over the website, never-smokers appear to have a distinct biology (post here) and are consistently more likely to do well with EGFR inhibitors like tarceva (post here). So in my mind, never-smokers should receive tarceva early: many experts consider it to be an appropriate first line treatment (I’d consider myself in that camp), but if not used first line, I’d almost always advocate to use it second line. And I wouldn’t wait for someone to have major progression on first line chemo. If a never-smoker’s scans looked convincingly worse, even if the difference didn’t technically meet criteria for progressive disease, I’d almost certainly move them to tarceva ASAP. But the important point is that while that’s a neat answer for the 10-15% of lung cancer patients who never smoked, what about the other 85-90%? And the point is that it isn’t ALL or NOTHING, ever-smoker or never-smoker. People who smoked relatively little (say, less than an average of a pack per day for 10 or 15 years) and who quit smoking 20 or 30 years before diagnosis often have the molecular and treatment characteristics of the never-smoker population (as described in one of the referenced posts above, on different response to treatment in never-smokers). Some of our current trials on smoking status also include remote, light smokers in addition to never-smokers. We don’t know if they will do as well as never-smokers, but in the real world, the less a person has smoked and the longer they’ve been off of tobacco, the more likely I think it is that they’ll get an impressive benefit from tarceva. However, I don’t want to completely overstate this association. There are never-smokers who don’t benefit, and there are smokers who do well with tarceva as well. Smoking status is just a useful predictive tool, not a guarantee.

So putting this together, I’d definitely advocate chemo for someone who responds well to first line chemo and has a significant smoking history. And I’d strongly favor tarceva second line for someone who either has a minimal/remote smoking history or progressed quickly through chemo. What is someone is a remote and/or light prior smoker AND responded pretty well to chemo? Either choice is very reasonable, so I talk with the patient about whether they’d prefer IV chemo or an oral targeted therapy, discuss the different side effect profiles, and then make a decision or flip a coin (kidding — hasn’t happened yet). And most of the time, whichever we didn’t do second line is going to remain a feasible third line option, so it’s more choosing the order of treatment than which treatment they’ll get. We don’t need to burn bridges, unless a person declines too quickly to tolerate more therapy.

In terms of which chemo, either is very appropriate, but I and many other oncologists have come to clearly favor alimta. If patients haven’t lost their hair, most would prefer not to lose it (which occurs far more commonly on taxotere). Alimta was approved by the US FDA based on its modestly more favorable toxicity profile overall vs. taxotere, and although the differences weren’t striking, my clinical experience, and that of many of my oncology colleagues, is that the toxicity of alimta is appreciably less than taxotere, overall. Of course, there are patients who have a hard time with it, just as with any cancer medication.

In patients who are strong enough for long enough, it’s possible to give first line therapy and then all three of these agents at some point, and sometimes more. But beyond these general principles, I largely individualize my treatment plans with patients, as most oncologists do.

I’d be interested in learning how Dr Laskin approaches second line therapy. She may have a similar approach, or she may have a different perspective, working in a system that, from my vantage point, has more rigid guidelines in place. There’s plenty of lattitude for differing views, but at the present time, this is how I approach my patients after they have completed first line therapy.


XL647: Novel Agent As An Alternative or Follow-up After Tarceva

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In the Q&A forums recently, members Jianming and Neil introduced us to the novel agent XL647, in clinical trials now, but I figured it was worth me collecting more background and providing a more thorough background. XL647 is an oral small molecular that inhibits multiple tyrosine kinases, receptors on cells that trigger cascades of activity in the cells, thereby leading to tumor development and growth. Felt to be most important among these is EGFR (the target of tarceva and Erbitux, for instance), HER-2/neu (which is very important in breast cancer and may have a role in some lung cancers), and VEGF, which mediates blood supply in normal tissues and also cancers. So here is a figure of the key targets for XL647, sitting in a cell membrane:

XL647 Targets image

The tyrosine kinase portion, which is like an ON/OFF switch for a parade of cellular activities like growth and dividing, is on the inside of the cells.

We have drugs that block each of these targets separately, but that entails giving three different medications. We don’t know yet whether hitting all three targets simultaneously with one drug, a multi-kinase inhibitor, is a better approach.

One other key factor that triggered interest in XL647 emerges from lab work with cancer cells that have a mutation that induces resistance to tarceva, called T790M and found in about half of the cancers that transition from responsive to resistant. This research has shown that XL647 has activity in cells that have this mutation, thereby potentially inducing responses in patients who have become resistant to tarceva. But this is still lab work, not people. Continue reading


An Example of Successful Patient-Reported Outcomes (PROs): Tarceva’s Effect on Lung Cancer Symptoms

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One of the successful examples of incorporating patient-reported outcome (PRO) measures into an important clinical trial was in the NCI-Canada study BR.21 (abstract here). This study assigned patients to either tarceva or placebo in a 2:1 randomization to the active drug:

BR.21 Schema

(Click on image to enlarge)

This study showed a 9% response rate and an improvement in median overall survival of two months with tarceva, which led to it’s US FDA approval and subsequent widespread use. While the fact that there were responses (although only 8%) and a survival benefit is very important, and probably the most important factor to many patients and oncologists, it’s important to ask whether this comes at the cost of significant side effects. Do patients need to trade quality of life for improved survival? A separate report on the BR.21 trial described PROs on this trial (abstract here).

In BR.21, patients were required to complete questionnaires that asked about a wide range of symptoms commonly seen in lung cancer, as well as global quality of life (QoL) and ability to function normally. Several questions focused on measured of cough, pain, and shortness of breath. The questionnaire was completed before starting treatment, every four weeks during treatment, four weeks after the end of treatment, and (for patients who came off of the study for reasons other than progression, such as side effects) every 12 weeks after ending the study, until progression. Completion rates were about 93% at the start, dipping down to the 80% range as the trial continued. Such a decline in returned responses is typical for QoL patient response assessments.

The symptom-based portion of the study assessment focused on pain, shortness of breath (SOB, also known as dyspnea), and cough. Importantly, the key measure was the time before progression of these symptoms rather than whether there was improvement in these symptoms. Why time to symptomatic worsening rathe than improvement in symptoms? Because you can’t have improvement if you don’t have the symptom, but everyone is a candidate for worsening of symptoms.

The results clearly demonstrated that the survival improvement with tarceva was also accompanied by a relative improvement in cancer symptoms. Specifically, while patients tended to have eventual worsening of symptoms at some point (as indicated by the downward slope of the curves below), recipients of tarceva had an average of a 1-2 month delay in their development of worsening of cough (4.9 vs. 3.7 months), SOB (2.9 vs. 4.7 months), and pain (2.8 vs. 1.9 months).

BR.21 Symptoms change

These differences were all statistically significant, and I would argue also clinically significant, even if we wish the results were better still. Continue reading


Is There a Better Way to Combine EGFR Inhibitors and Chemo? The Concept of Pharmacodynamic Separation

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Our tendency in oncology is that once we find a new active drug in cancer, we try to add it to our current standard treatment approach and see if we can do better than what our current standard achieves. More is better. And we knew that the epidermal growth factor receptor inhibitors Iressa and Tarceva could lead to significant shrinkage of some lung cancers. So the lung cancer community was relatively optimistic about the clinical trials that compared chemo alone to the same chemo with Iressa or Tarceva. In fact, each EGFR inhibitor was studied in two different first-line trials, one each with carbo/taxol, for a primarily US-based experience, and also cisplatin/gemcitabine, a common standard for much of the rest of the world. Of these four trials, each with over 1000 patients, the overall results showed no benefit with the addition of either EGFR inhibitor:

Intact 1 and 2 OS results Tribute OS (Click to enlarge either)

So how could we add two active anti-cancer approaches and not get any additional benefit? One idea is that perhaps we looked at the wrong group, that we should use targeted therapies in a targeted way. We did see encouraging results in the never-smokers on the TRIBUTE trial, who had a more than doubling of their median survival when tarceva was added to carbo/taxol:

TRIBUTE never-smokers

As I described extensively in my prior post about why I don’t give chemo and EGFR inhibitors concurrently, I think those results are encouraging, but I’m struck by the fact that the tarceva arm really seems to start doing better several months into the trial, right around the time when they’d be finishing the planned 6 cycles of chemo. So to me it seems that the never-smoker tarceva recipients did well despite receiving chemo and tarceva concurrently, because they really come into their own when the chemo is over (arrows added for the approximate time when 6 cycles of chemo would end):

Tribute NS with Arrows Continue reading


Predicting Survival on EGFR Inhibitor Therapy Using Serum Samples

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NOTE: ALL FIGURES CAN BE SEEN BY DOUBLE-CLICKING ON THEM, EVEN THOUGH NOT ALL APPEAR AS THUMBNAIL VIEWS PROPERLY.

We’ve discussed various ways of predicting outcomes with EGFR inhibitors like Tarceva or Iressa using clinical variables like smoking status or BAC subtype, as well as molecular markers like EGFR mutations, or EGFR gene amplification or protein expression. These can all be of value, but we know that the clinical markers are quite inexact, while the molecular markers are still a work in progress. Moreover, the molecular testing that has been the subject of most of the work thus far has come from tumor tissue material, which is often hard to come by and usually requires a biopsy or resection to obtain. But a recent article in the Journal of the National Cancer Institute, by a international collaborative group led by Dr. David Carbone from Vanderbilt University, describes their recent success in predicting survival after administration of EGFR inhibitor therapy using serum samples from patients all around the world (abstract here — full article also available from that page).

Dr. Carbone and his team at Vanderbilt have been leaders in the field of serum proteomics, which is the study of the proteins in the serum, the straw-colored fluid that remains after blood has clotted, so the cells and clotting proteins are absent. Obviously, collecting blood, from which serum samples can be analyzed, is much easier than collecting extra cancer cells in a biopsy to send off for studies. The approach they used at Vanderbilt is called matrix-assisted laser desorption ionization (MALDI) mass spectroscopy (MS), or just “mass spec”, which is very complex (code, perhaps, for me saying I really don’t understand it well? we only had to do a year of college physics to get into medical school, you know), but basically it is a way of analyzing a serum sample to report a set of peaks that represent different proteins in the sample:

MALDI diagram Mass Spec Peaks fig (Click to enlarge) Continue reading


EGFR inhibitors (Tarceva, Iressa) and Stomach Acid

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Several members have raised questions in the last several weeks around the question of whether antacids like garden variety Rolaids or Tums, a class of drugs called histamine H2 blockers like zantac and tagamet, and also proton pump inhibitors (PPIs) like prilosec (the “magic purple pill”), protonix, nexium, etc. that effectively shut down stomach acid may actually be problematic if taken in combination with Iressa or Tarceva (I’m going to focus primarily on Tarceva here, since that’s the drug marketed in the US right now). This issue isn’t one that has been highlighted in the general research and teaching about these oral agents. We do know that absorption is variable, but the reason it is recommended that they be taken on an empty stomach is that it’s more predictable in that setting. Taking these agents with food tends to increase absorption, but unpredictably, so the best way to have a good idea of what’s going into the body is to take the recommended amount (or a dose reduction, as needed) on an empty stomach.

It’s certainly understandable that the absorption from the stomach and gastrointestinal tract be moderated in part by stomach acid or lack thereof, since it’s the job of stomach acid to help digest food (it’s not just to cause heartburn), but there has never been any instruction on having antacids and/or PPIs be considered contra-indicated medicines (advised to not be taken at the same time). In fact, the Iressa package insert does mention that zantac and sodium bocarbonate (antacids), given to keep the pH above 5 (outside of the highly acidic range, which is the low numbers like 1-2), reduce Iressa absorption by 44% in one of the studies by the manufacturer (AstraZeneca). Member NeilB was kind enough to e-mail me this link to a chart in a summary article about the EGFR inhibitors, which notes some of the key drug interactions observed with EGFR tyrosine kinase inhibitors like Iressa and Tarceva. Another official document summarizing extensive pharmacologic information on Tarceva tablets (here) also documents that tarceva absorption appears to be diminished in the absence of an acidic stomach environment and suggests that “caution should be exercised when these medicinal products are prescribed with erlotinib” (Tarceva) (page 19 of this pdf document). Continue reading


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