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Trial of Tarceva in BAC: New Info on Who Benefits with Tarceva
In a recent issue of the Journal of Clinical Oncology, Dr. Vince Miller and colleagues published the results of an important trial of the EGFR inhibitor tarceva (erlotinib) in the unusual NSCLC subtype bronchioloalveolar carcinoma, or BAC (abstract here). This work was predicated on the observation, also by Dr. Miller and his colleagues at Memorial Sloan Kettering Cancer Center in NYC, that EGFR inhibitors, and specifically gefitinib in the earliest clinical experience, appeared to be most associated with great responses in patients with adenocarcinoma and particularly BAC, and also in never-smokers (abstract here). Over the past several years, much of our greatest interest in drugs like iressa and tarceva has focused on BAC, including a trial with iressa that I led with the Southwest Oncology Group (SWOG) and subsequently published (abstract here), and also the trial with tarceva that Dr. Miller ran with collaborators at Vanderbilt-Ingram Cancer Center in Nashville and MD Anderson Cancer Center in Houston.
Over several years, these investigators enrolled 101 patients, most of whom had adeno/BAC and not the pure form of BAC (see prior post for discussion of this spectrum), which is representative of the eligibility of most or all of our current trials that we say are for “BAC“: the majority, and sometimes the vast majority, are BAC mixed with some invasive adenocarcinoma. In truth, different pathologists, even great ones, differ in their definitions of what is BAC, what is adenocarcinoma with BAC features, and what is BAC with focal invasive adenocarcinoma. Continue reading
Tarceva vs. Standard Chemo Compared for Marginal Performance Status Patients, by Dr Laskin
One of the issues we struggle the most with, as oncologists, patients, and families, is how to choose a therapy that won’t make someone feel worse. There are so many things to factor into these decisions: what is the baseline function of the person, what comorbidities (other chronic illnesses) might interact or interfere, what side effects are acceptable or worth the risk, to what degree is the cancer interfering with their functioning and can this be reversed with chemo, and of course what does any individual patient want and expect from chemo? Not to mention the choices between a few different agents or combinations of agents!
The issue of “performance status” (PS) is fundamentally important in lung cancer, especially in non-small cell lung cancer (NSCLC). There are different scales we use to measure this, which have been posted and discussed previously. Most publications use the Eastern Cooperative Oncology Group (ECOG) scale – partly because it’s rated 0 – 4 which is easy to remember. Zero is normal, and 4 is very debilitated, essentially bed-bound. Perhaps it is somewhat surprising that despite all of the fancy molecular markers and blood tests we have, a person’s functional impairment of PS is one of the most important predictors of how “bad” a cancer is. The other two factors are stage (how much cancer is there?) and degree of weight loss. It is well described, and there are other posts on the site elaborating on this, that if someone is very sick either from the cancer or from other concurrent illnesses, standard chemotherapy will only make things worse. But there’s an “in between” group, with a performance status of 2, who may not be as well served by the more aggressive standard approaches but still may benefit from cancer treatment.
The great hope of the next generation of “targeted” therapy is that oncologists will be able to more accurately predict who will benefit from which drug and that the newer drugs will be less toxic and thus perhaps even better for people who are too sick to tolerate our current forms of chemotherapy. Continue reading
XL647: Novel Agent As An Alternative or Follow-up After Tarceva
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:
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
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:
(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).
These differences were all statistically significant, and I would argue also clinically significant, even if we wish the results were better still. Continue reading
Tarceva Metabolism with Proton Pump Inhibitors
I still need to add a post on the more recent history of managing Pancoast tumors, but I wanted to add an important and potentially relevant bit of information I learned today. I’m attending a small meeting in New York and had the opportunity to talk with some folks from the company that makes Tarceva, OSI Pharmaceuticals, who relayed some potentially relevant news people here should know. In follow-up of concerns voiced by several OncTalk members, I had previously asked people at the company what information they have on metabolism of tarceva in people taking a class of drugs called proton pump inhibitors (PPIs), drugs like protonix, nexium, prevacid, and prilosec that block the stomach’s ability to make gastric acid. These agents are very helpful in treating gastro-esophageal reflux disease (GERD, or just “heartburn”), and they generally have few side effects. I was told by the folks I spoke to that they were looking into it.
As I described in a prior post back in May, there have been some lingering questions about whether these drugs limit the stomach’s ability to absorb oral edpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like iressa and tarceva. Most of the evidence on this potential interaction is with Iressa, which really isn’t commonly used any more in the US, but Iressa and tarceva are similar in so many ways that there would be reason to suspect that the same issue may exist for the commonly used tarceva.
I was just told that they’re providing additional information to the FDA based on pharmacokinetic studies (measuring blood levels of drugs over time) that apparently do show that people on PPIs have lower circulating drug levels of tarceva. The person I spoke to didn’t have any details available about what the research demonstrated or what the FDA would be doing, but I imagine it may add some language in the official package insert document that advises for doctors to consider this potential interaction when starting someone on tarceva. I don’t believe there are data out there to say what would be the “right” dose to use in someone who was continuing on one of these drugs that keeps the stomach from being an acidic environment and thereby limit absorption, but I would be inclined based on this information to advise patients on one of the proton pump inhibitors to stop it if it wasn’t definitely necessary while they were on tarceva. In some other situations when people need an acidic environment to absorb a medication, you can take it with something acidic at the same time, like orange juice, coca cola, or vitamin C (ascorbic acid), but I’d probably prefer to avoid the issue by having someone suspend taking both a PPI and tarceva at the same time.
I’ll let you know more when I have more to tell.
EGFR inhibitors (Tarceva, Iressa) and Stomach Acid
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
Smokers and Tarceva: Is More Better?
As I’ve described in a prior post, one of the most consistent findings in the work with the EGFR inhibitors Iressa (gefitinib) and Tarceva (erlotinib) is that never-smokers are far more likely to demonstrate a response and survival benefit than patients who do smoke or did smoke. Here, for instance, is the set of survival curves separated by smoking status for the large randomized trial of tarceva vs. placebo in previously treated patients with advanced NSCLC (abstract here):
(click to enlarge)
We really haven’t explored why that as, and that’s partly because there is a lot we don’t know. We do know that never-smokers are far more likely to have mutations than current or ex-smokers with lung cancer, but it’s really not all or nothing. The likelihood of having an EGFR mutation is higher in ex-smokers than in current smokers, and it’s also a gradually higher likelihood with a longer period since patients quit smoking, and with less overall tobacco exposure in terms of pack-years, the product of the number of packs smoked per day (PPD) x the number of years smoked, so 2 PPD x 20 years would be a 40 pack-year history. You can see that between never-smokers and major smokers are a population of patients who fall in between in terms of their smoke exposure and likelihood of having an EGFR mutation (abstract here):
But it’s probably not all about EGFR mutations, which are still only seen in a minority of patients with lung cancer, somewhere in the 5-15% range in the US (more in Asia). It’s quite possible that one of the more important issues may be the metabolism and different pharmacokinetics (the way a drug is processed by the body, specifically the changing levels in the blood over time) between smokers and non-smokers, which may mean that what is an optimally effective dose in a smoker may be higher than the optimal dose in a non-smoker. Continue reading
Tarceva Drug and Food Interactions
Before turning back to brain metastases, I wanted to cover a topic that has generated some recent questions, and that is the issue of potential interactions of tarceva with food and other drugs. Just as an introduction, the standard dose of single-agent tarceva in lung cancer is 150 mg by mouth daily, and this is meant to be taken on an empty stomach, at least one-hour before or two hours after eating. Taking tarceva with food can make the absorption of tarceva greater but is overall so variable that it’s very hard to know what kind of blood levels to expect, so the established target is 150 mg taken on an empty stomach. Tarceva is broken down by a collection of liver enzymes known as the CYP (pronounced “sip”) family, and particularly a liver enzyme known as CYP 3A4. These enzymes can also be found in the intestinal lining and can affect absorption of drugs like Tarceva. The CYP enzymes, and particularly CYP 3A4, can have their levels affected by other medicines and foods. Interestingly, tobacco smoking is another factor that can increase clearance of tarceva: in active smokers, tarceva clearance is about 25% faster, so the blood levels are lower. The potential that tarceva may need a different dose level for active (not likely former) smokers is a question that needs to be addressed further, and one I’ll have to cover in a separate post.
The medicines that inhibit CYP 3A4 can dramatically increase levels of tarceva. These are drugs like ketoconazole, an antifungal medicine, and other antifungal and antiviral drugs, including several used to treat HIV/AIDS. Grapefruit juice also inhibits CYP3A4. Any of these agents can decrease tarceva clearance by about 2/3, so reducing the dose of tarceva should be considered, particularly if a patient is experiencing significant tarceva-related side effects.
On the flipside, a bunch of other medicines can significantly increase CYP3A4 activity and reduce tarceva levels by about 2/3. These include an antibiotic called rifampin, multiple anti-epilepsy drugs (including dilantin, tegretol, and phenobarbital), and St. John’s Wort. One recommendation in the tarceva product information is to not take these other drugs if there is a possible alternative, but otherwise, it is recommended that a higher dose than 150 mg daily be considered. In fact, studies of patients with primary brain tumors, who often need to be on anti-convulsant drugs like dilantin, have demontrasted that higher doses of 300 mg or even up to 500 mg daily are safe (abstract here), and that the 500 mg daily dose in someone on a CYP 3A4 inducing-drug like dilantin is associated with tarceva blood levels similar to the 150 mg dose in someone who isn’t on one of these CYP 3A4 inducers (abstract here). While there isn’t an official recommendation to prescribe a higher dose, the FDA acknowledges that this is something that should be considered for patients on drugs that are known to increase tarceva clearance. Continue reading
The Iressa/Tarceva Saga, Part II
Iressa was approved by the US FDA in May of 2003 as a third-line therapy, and for the next 18 months it was the only EGFR inhibitor on the market. At the ASCO conference a year later, Frances Shepherd, from the Princess Margaret Hospital in Toronto and chair of the Lung Cancer Committee for the NCI-Canada, first presented the positive results of the BR.21 trial randomizing patients in a 2:1 fashion to either Tarceva or a placebo as second- or third-line treatment for NSCLC; this was subsequently published in the New England Journal of Medicine (abstract here). I’ve summarized the trial and the demonstrated survival benefit in a prior post. So we came out of that meeting knowing that at least one EGFR inhibitor had a proven significant benefit, and while Iressa was the only EGFR TKI on the market, it continued to be prescribed and generally presumed to have similar benefit, given that the two drugs had the same mechanism of action, very similar side effect profile, and shared characteristics for patient populations who seemed to demonstrate the most impressive responses, such as Asians and patients with adenocarcinomas, especially BAC. I also gave an oral presentation confirming responses, some dramatic and long-lasting, for Iressa in BAC, at that ASCO meeting in 2004 (subsequently published, abstract here).
For a little more than six months, we expected the approval of Tarceva based on the proven benefit, and we saw similar characteristics with Iressa. Most of us in the field considered the two drugs to be like Coke and Pepsi, with some mild distinctions, but more similar than different. We were waiting on a trial of Iressa against placebo, but until November of 2004, Iressa was the only commercially available option, so there wasn’t much of a question of which drug to prescribe. People began to switch with Tarceva’s approval, but the big shocker came in December of 2004, when the first announcement of the ISEL (for Iressa Survival Evalaution in Lung Cancer ) trial was released, indicating that there was no significant survival benefit of Iressa compared to a placebo (abstract here).
(click to enlarge)
Shortly after that, the FDA no longer allows new prescriptions of Iressa, but patients who aren’t progressing can stay on it, and it’s also in other clinical trials. It continues to be widely used outside of the US, especially in Asia, and we’ll talk about why. Continue reading
EGFR Inhibitors Iressa and Tarceva: A Tale of Two TKIs (Part I)
I haven’t really covered the history or issues of directly comparing the two oral inhibitors of the epidermal growth factor receptor, or EGFR, which are Iressa (gefitinib) and Tarceva (erlotinib). This is really because over the last few years, gefitinib has had disappointing results in some important trials and is no longer readily used or available, while the remarkably similar drug Tarceva has been approved by the US FDA and is a standard treatment for patients with advanced NSCLC that has previously been treated with chemotherapy. So you already know where we are in the story in early 2007. While it appears that Iressa for lung cancer is no longer very relevent for clinical management of lung cancer in the US, several trials of Iressa are still emerging that compare it to chemotherapy, so it’s important to review the similarities and differences of Iressa and Tarceva as we consider whether the effects with Iressa can be generalized to the “class” of EGFR inhibitors.
We’ll step back for a moment to say that the molecular target for both drugs is EGFR, which is expressed on some normal body tissues, including skin (it’s an epidermal growth factor), but it’s also expressed on 40-80% of NSCLC tumors and many other kinds of cancers. In fact, in lab studies using test tube as well as animal models, activating the receptor leads to activities in cancer cells that lead to cancer cell growth and division, as well as decreased likelihood of the cancer cell dying and a higher chance of it invading tissues and spreading elsewhere in the body.
(click to enlarge)
In people, several types of cancers that have high degrees of expression of the protein on the tumor cells have been shown to be more aggressive and be associated with more aggressive behavior and worse survival outcomes. On the other hand, drugs that inhibit EGFR, which can be antibodies that block EGFR on the outside of the cell (such as Erbitux (cetuximab) and Vectabix (panitumumab) or tyrosine kinase inhibitors (such as Iressa and Tarceva) that act on the inside of the cell on the back end of the receptor, block the cancer-promoting effects of an activated EGFR molecule. So Iressa and Tarceva act on the same part of the EGFR molecule.
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