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SAIL Study Reviews Safety of Avastin in Lung Cancer Among >2000 Patients: Few Surprises (Fortunately)
This morning, Joe provided a link to a story about the Safety of Avastin in Lung cancer (SAiL) study, which is just being published in Lancet Oncology. This is not really a new, original study, but rather a post-approval commitment from Roche to generate a registry of real-life experience using the anti-angiogenic agent Avastin (bevacizumab) in lung cancer patients and document safety: the primary goal is to determine whether new, concerning safety signals occur in a broader clinical practice than the initial, well-controlled studies.
Hypertrophic Pulmonary Osteoarthropathy (HPOA): An Unusual But Distinctive Complication of Lung Cancer
Although it’s uncommon, hypertrophic osteoarthropahy, or HPOA, is an odd and therefore memorable syndrome that can be a side effect of lung cancer. It features an abnormal proliferation of skin and bone tissue, primarily in the hands and feet. Patients can develop clubbing, which is most commonly associated with NSCLC (up to 1/3 of patients) more than SCLC (only about 5%), and adenocarcinoma in particular. Here’s what it looks like:
Other features include a buildup of bone in the ends of long bones, and sometimes an effusion (fluid collection) in the joints, particularly large joints.
Patients will often feel painful joints (arthritis/arthopathy), which can look a lot like typical arthritis, particularly when the pain precedes clubbing. But in some cases, that joint pain is an early symptom of lung cancer. What’s interesting is that if patients with an early stage NSCLC and HPOA undergo surgery, their joint pain can resolve pretty much as soon as they come out of surgery (imagine coming out of lung surgery with less pain than you started with!).
Angiogenesis in First Line Advanced NSCLC: Focus on Avastin (Bevacizumab)
Video presentation describing the concept behind angiogenesis and the evidence on the anti-angiogenic agent avastin (bevacizumab) in NSCLC.
[display_podcast]
Or access via web link here.
Slide/figure images from the video presentation are available as a pdf here: Angiogenesis FL Adv NSCLC Vodcast images
Transcript is here: Angiogenesis FL Adv NSCLC Vodcast Transcript
Podcast: Play in new window | Download (33.0MB) | Embed
Potentially Life-Threatening Hypersensitivity Reaction with Erbitux: A Region-Specific Side Effect
Erbitux (cetuximab) is a monoclonal antibody to EGFR, and it’s actually made from a protein that is part mouse and part human (called a chimeric protein, named for the mythologic creature chimera that was composed of multiple parts from different animals). It’s uncommon but not rare for patients to have an allergic reaction to this protein, and in most large national and international studies show rates of hypersensitivity reactions (HSRs) in the 1-3% range. In severe cases, these reactions can be very serious, causing low blood pressure, fainting, wheezing, and shortness of breath; they can even be fatal. While that is a small but real risk, wht is fascinating and especially scary is that there is an area in the southwest US — including Tennessee, the Carolinas, northern Georgia, and perhaps other areas — in which about 20-25% of patients develop these reactions.
Oncologists in these areas had noted over the past few years that they seemed to have a higher than expected rate of these complications, but the problem was highlighted in real terms in a 2007 article in the Journal of Clinical Oncology (abstract here) that retrospectively reviewed the experience of 88 patients on clinical trials and 55 patients off of clinical trials who received erbitux at one of three institutions in the region: Sarah Cannon Cancer Center and Vanderbilt-Ingram Cancer Center in Nashville, TN, and the University of North Carolina at Chapel Hill. They found a 22% rate of moderate to severe HSRs, ten times what we see in the rest of the country or world. These reactions occurred at the time of the first infusion but rarely afterward if someone did well the first time. They were more commonly seen in patients with a history of allergies, and it was interesting to see that reactions were more commonly seen in patients with NSCLC than other tumor types. The association of this type of reaction with lung cancer more than colon cancer is puzzling and suggests that there may be some correlation with a tobacco-related antigen, but we still need to learn more about this.
Can Development of a Rash on Erbitux Predict Who Will Benefit?
The improvement in median survival of 1.2 months with the monoclonal antibody to EGFR erbitux (cetuximab) in the FLEX trial that I’ve previously described was statistically significant, but there’s plenty of room to debate whether it’s really clinically significant (see prior post). What If we could add some way to refine our predictions of who will benefit from the addition of erbitux?
At the Chicago Lung Cancer meeting in November 2008, Dr. Ulrich Gatzemeier presented results of a planned subset analysis of the FLEX trial, in which the results compared the outcomes of patients randomized to receive cetuximab by whether they developed an acne-like rash within three weeks of starting this treatment. This was based on a growing and rather consistent experience that patients who receive EGFR inhibitors, whether oral tyrosine kinase inhibitors or IV antibodies, generally show a a strong trend or significantly better survival than patients who develop no rash (see prior post). The investigators found that there was a very significant difference in efficacy with cetuximab among the patients who developed a rash (of any severity) after two weeks (56%) compared with those who didn’t (44%). The difference in median survival was a near doubling: 15.0 months for the patients with any rash, compared with 8.8 months for those who didn’t:
Tales from the Clinic: Mucinous BAC
In my last post I outlined the typical clinical scenario for pneumonic bronchioloalveolar carcinoma (BAC), which is typically the mucinous subtype of this unusual disease. In fact, we are still actively learning a great deal about BAC, enough for the lung cancer experts to begin to develop a more sophisticated view that the mucinous and non-mucinous subtypes have different behaviors and respond differently to treatments. Here is a case that illustrates a situation that I would consider to be typical for the mucinous, pneumonic form of BAC.
Ella A. was 74 year-old woman with a very long smoking history of about 50 years, who quit last month in the face of worsening pulmonary and other symptoms. Specifically, she experienced an initial dry cough that became productive of sputum over a six-month period, during which time she also developed increasing shortness of breath and a 20-pound weight loss for a woman who was pretty slender beforehand. This led her to her primary care physician, which showed extensive “consolidation”, shadows in both lungs and particularly extensive on the left. These findings were confirmed on a CT.
(Click to enlarge)
As you might suspect, this led to a referral to a pulmonologist for a brochoscopic biopsy. The pulmonolgist needed to start her on oxygen before he could do a thorough bronchoscopy. The biopsy revealed well differentiated BAC, but the pathologist (an expert in lung pathology) didn’t have enough material to specify whether it was mucinous or non-mucinous.
Frankly, at the time when I first met her, in December of 2006, there were only the early inklings that this could be relevant. We don’t have much more information since then, except for the anecdotal experiences of myself and a few others who treatment many patients with BAC, which have corroborated the early impression that the well described effectiveness of oral EGFR inhibitors like iressa (gefitinib) and tarceva (erlotinib) in BAC appeared to be limited to the non-mucinous subtype.
Is it Time for EGFR Mutation Testing? Confessions of a Newly Convinced, Former Clinical Selector
Those who have followed my writings over time will know that I haven’t been inclined to adopt a reflexive strategy of ordering molecular testing without good evidence that having this information will improve outcomes. Testing tumors for EGFR mutations is advocated by a vocal minority of lung cancer experts in Boston and New York City, but this hasn’t been advocated by the broader lung cancer community yet, or adopted as routine clinical practice. Although I’ve felt that we’ll have enough evidence to support broad use of molecular variables to individualize treatment for lung cancer patients in the next few years, I haven’t felt that they have a role yet, but I’ve now seen some results that I believe are enough for me to change that conclusion.
What I Really Do: EGFR Inhibitor Rashes
Though EGFR inhibitors like tarceva can produce some terrific and long-lasting results in many patients, they aren’t toxicity-free. The “targeted therapies” we use just have a very different side effect profile from standard chemo, and the EGFR inhibitors are well known to have skin-related side effects as the leading problem, with loose stools/diarrhea as a less nearly ubiquitous second place issue. In fact, it’s become increasingly well accepted that it’s desirable for patients receiving drugs like tarceva (erlotinib), iressa (gefitinib), or erbitux (cetuximab) to have some degree of a rash: in the studies that have looked at this issue, patients who have no rash don’t have as good a survival and almost never show a significant response, with a frequently seen association of a “severity of rash-dependent” association in which patients with more problematic rashes tending to do the best (see prior post).
This might lead some people to presume that it’s helpful to increase the dose beyond the standard amount, but there’s no evidence that this is the case. A previous trial that escalated dose beyond the standard for patients who didn’t have a rash actually showed disappointing results (see prior post), and my interpretation is that someone’s ability to benefit from EGFR inhibitors is “more nature than nurture”. By this I mean that the people who are going to get a major rash are just very sensitive to the effects, good and bad, of these agents, and the people who don’t generate a skin response can’t be forced into a rash any more than you could transform that male ex-smoker with squamous cancer into a female never-smoking Asian patient with an adenocarcinoma. It’s just not going to happen.
The other implication of this work is that you don’t need to suffer from a terrible rash to be the beneficiary of an EGFR inhibitor: you just need to be a person who could have a terrible rash. Since many of the patients who are most sensitive to rash and other side effects of these drugs could be so bothered by these problems that they stop them and are disinclined to ever try them again, but may be the biggest beneficiaries, I think it’s far more important to get people on a dose that they can tolerate long term. The biggest breakthrough with this class of drugs is that there are some people who can take them and show no progression for a year or even many years, but you can’t do that if every day is endless misery because of the side effects.
Longterm Survival with Iressa in BAC
One of my earliest posts when I started OncTalk was on the use of oral inhibitors of the epidermal growth factor receptor (EGFR), one of the growth signals that is often over-active in cancer cells, against advanced bronchioloalveolar carcinoma (BAC), a unique subtype of lung cancer that tends to grow within the lungs, sometimes slowly, and not progress elsewhere. These EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) have certainly been well studied in NSCLC in general, but both of these drugs have been a focus of particular attention as a treatment for BAC. In fact, the largest trial that has yet been conducted in advanced BAC is one that I led, called SWOG 0126, that gave iressa at 500 mg by mouth daily (actually twice the dose that was eventually settled on, but possibly a more effective dose) to 135 eligible patients with advanced BAC. My colleagues and I published the results of this trial a couple of years ago (abstract here), but this year at ASCO I presented the results with longer-term follow up (abstract here), which yielded some interesting findings.
Obviously, the response rates and side effects didn’t change with a couple of years of longer-term follow up. Nor did the median progression-free and overall survival numbers, since those reflect the point at which half of the patients will have demonstrated progression or have died:
It’s worth noting that while this study enrolled both patients who had never been previously treated and some other patients who had received prior chemotherapy, both the chemo-naive and previously treated patients had the same progression-free and overall survival results, as shown in the superimposed curves shown above.
Refining the Treatment Populations for Erbitux in Lung Cancer: Can We Make the Juice Worth the Squeeze?
There was some evidence that patients with adenocarcinomas received a little more benefit with erbitux than the patients with squamous cancers, as shown in the table below (which also highlights the race-based difference)
(click on image to enlarge) Continue reading
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