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Questions about Benefit from Avastin in Older Patients
A group of investigators at Dana Farber Cancer Institute in Boston, MA recently published a very newsworthy article in the Journal of the American Medical Association (JAMA) that argues that patients with advanced non-small cell lung cancer (NSCLC) who are over 65 don’t appear to benefit from the addition of Avastin (bevacizumab) to standard chemotherapy with carboplatin/Taxol (paclitaxel). Several years ago, Avastin was demonstrated in the ECOG 4599 trial to lead to a survival benefit when it was added to carbo/Taxol in Avastin-eligible patients, who are a pretty limited subgroup with a good performance status, no brain metastases (a requirement since relaxed with more experience), no significant hemoptysis, and non-squamous NSCLC histology. However, there have always been elements of the story that have cast some doubt as to how much benefit it really offers, particularly in older patients. A subset analysis of the ECOG 4599 trial showed that patients over 70 experience disproportionately greater side effects and complications from Avastin and no survival benefit. Meanwhile, another large randomized phase III trial called AVAiL (AVAstin in Lung cancer) that was conducted in Europe showed a statistically significant but overall very unimpressive improvement in response rate and progression-free survival when Avastin was added to a different standard chemotherapy backbone of cisplatin and gemcitabine, and this study demonstrated no benefit at all in survival.
Since Avastin was approved by the US FDA in October of 2006, it has been considered a standard of care but not clearly the standard of care, and only about 20-25% of patients in real world clinics actually get it. The reason it ends up being given to only a minority of patients is a somewhat open question, but in truth, I think that when you disqualify patients with many of the clearer contraindications and then also factor in some relative contraindications such as a cancer next to major blood vessels or a poorly differentiated cancer that is suspected may be of squamous histology, the actual proportion of patients who are really strong candidates for it is probably below 40%. And then, there is also the question of how much stock clinicians place in the ECOG trial vs. the AVAiL trial that failed to show a benefit…and the fact that the median age of newly diagnosed lung cancer in the US is now around 71 meaning that a very significant fraction of patients with advanced NSCLC are in an age range where the value of Avastin is quite questionable.
Preliminary Results from the AVAPERL Study: The Alimta/Avastin Combo in Maintenance Looks Favorable
I’m at Swedish Hospital, not in Stockholm, Sweden now, where the European Multidisciplinary Cancer Congress is going on. But there, the preliminary results of the AVAPERL phase III randomized trial were just reported, and they certainly look encouraging for the combination of Alimta (pemetrexed) and Avastin (bevacizumab) as a maintenance therapy for patients with Avastin-eligible advanced NSCLC who hadn’t progressed after four cycles of cisplatin/Alimta/Avastin, compared with maintenance Avastin alone.
(click on image to enlarge)
As I mentioned, I don’t have all of the details from the presentation, really just the press release, which at least conveys some highlights. As shown above, a total of 362 patients who hadn’t progressed after first line chemo/Avastin were randomized to either of the two maintenance therapy arms, and the combination arm showed a significantly longer progression-free survival (PFS) counting from the beginning of all treatment, at 10.2 vs. 6.6 months (HR 0.50, p < 0.001), but also a numeric result for PFS that far exceeded the numbers we’ve seen from other first line trials, where PFS has generally been in the 5-7 month range. There were no unexpected safety issues, but otherwise, I don’t have other details.
Quick Update from ASCO
I apologize if it seems that the updates about ASCO have been slow in coming. This is mostly because the lung cancer program this year has most of the higher profile presentations occurring in the second half of the meeting, which we’re just getting into. And, truth be told, this isn’t going to be a blockbuster year for developments in lung cancer. But let’s review what we’ve found out about thus far.
Lung Cancer FAQ: I’m coming to the end of my first line chemo for advanced NSCLC. After 4 (or 6) cycles are done, should I take a break or continue with some form of maintenance therapy?
The historic standard for advanced NSCLC up until a few years ago was for patients to complete 4-6 cycles of platinum-based doublet chemo, and then for patients who were doing well and had responded or demonstrated stable disease to take a break from treatment and be followed until progression. At that point, many patients would re-initiate chemo or targeted therapy with an oral agent like Tarceva (erlotinib).
Part of the premise was that ongoing treatment with challenging chemotherapy generally led to cumulative side effects, and at the same time, the limited work that had been done on fixed duration vs. ongoing chemotherapy until progression failed to show a significant improvement in survival with prolonged chemo, though it was associated with increased side effects.
Lung Cancer FAQ: I’ve just been diagnosed with advanced NSCLC. What treatment should I be starting with??
The initial or “first line” management of advanced NSCLC has evolved quite a bit over the past 10 years, in that time moving from a much more uniform approach of very similar treatment for just about everyone to a revised approach that is far more individualized. First, we assess key issues like the subtype of NSCLC, focusing largely on whether it is squamous cell or non-squamous NSCLC, because treatment tends to diverge very early based on this factor. Second, a patient’s performance status is another important issue, as patients who are frail often need a customized approach, because a more aggressive standard approach may be prohibitively difficult and even harmful. Third, a minority of patients (about 10% in North America and Europe, closer to 1/3 in Asia) will have a particular molecular marker, specifically a mutation in the epidermal growth factor receptor (EGFR), that is associated with a high probability of having a dramatic and long-lasting response to targeted therapy that inhibit the EGFR pathway. This particular activating mutation is most typically seen in never-smokers or people with a minimal, remote prior smoking history who also have an adenocarcinoma subtype of NSCLC.
Recommendations for first line therapy are most typically for a two drug chemotherapy combination, often with the drug Avastin (bevacizumab) — a targeted therapy that blocks the blood supply to the cancer — added for many patients who don’t have squamous NSCLC. However, for patients with an EGFR mutation identified before they have started treatment, several recent studies have demonstrated that the rate of significant tumor shrinkage and the time before the cancer progresses are significantly longer with an oral agent that works as an EGFR inhibitor, such as Iressa (gefitinib) or Tarceva (erlotinib). Consequently, one of these agents is increasingly recognized as a very appealing first line treatment approach.
Elderly patients are often treated the same as younger patients if they have minimal limitations in their activity level. In contrast, frail patients are sometimes recommended to receive single agent chemotherapy rather than a multi-agent combination that may be prohibitively difficult to tolerate. The available evidence suggests that elderly and frail patients who have an EGFR mutation also typically have a very significant response to EGFR inhibitor therapy.
Further information is available through the following links:
Podcast on introduction to first line chemotherapy for advanced NSCLC
Podcast on personalization of first line therapy
Reference library summary on selecting optimal first line treatment for advanced NSCLC
Using molecular markers to guide treatment: The IPASS trial
Alimta (pemetrexed) benefit is histology-specific
Treatment approaches for first line therapy in frail patients with advanced NSCLC
Podcast discussion of managing advanced NSCLC in the frail and/or elderly
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.
Update on ATLAS: Overall survival
We learned several months ago that the ATLAS trial of maintenance Avastin (bevacizumab) with either Tarceva (erlotinib) or placebo did not demonstrate a significant improvement in overall survival (OS) with Tarceva, despite the fact that it was associated with an improvement in progression-free survival (PFS). This is in contrast with the similar trial called SATURN that randomized advanced NSCLC patients after first line chemo to maintenance Tarceva vs. placebo, but without the Avastin during and after first line chemo, as SATURN demonstrated a significant improvement in OS along with a significant improvement in PFS.
In Dr. Mark Socinski’s great overview of the topic of maintenance therapy, he noted these discrepant results, with no obvious explanation. We received additional information about the OS results at ASCO, where it was reported that at the latest time point of analysis, in July of 2009, the median OS was 15.9 months vs. 13.9 months, favoring the addition of Tarceva. This corresponded with a hazard ratio of 0.90, or 10% improvement, over the entire course of treatment, a result that was not statistically significant. The overall survival curves are shown below:
(click on image to enlarge)
Admittedly, it doesn’t look like a major separation, but there is a modest advantage with the combination. You can decide whether that’s a glass half empty or half full.
Q&A Session with Dr. Ramalingam on Personalizing Treatment Recommendations for Advanced NSCLC
The second podcast from Dr. Ramalingam’s excellent webinar on Personalizing Treatment for First Line NSCLC is the question and answer session that followed it, which includes many questions about EGFR-based therapy, antiangiogenic agents, and other relevant issues for individualized treatments for patients.
Here is the audio and video versions of the podcast, along with the figures and transcript for it.
ramalingam-personalizing-first-line-nsclc-therapy-qa-transcript
ramalingam-personalizing-first-line-nsclc-therapy-qa-transcript
ramalingam-personalizing-first-line-nsclc-therapy-qa-figures
Podcast: Play in new window | Download (0.0KB) | Embed
Dr. Suresh Ramalingam on Personalizing First Line Therapy for Advanced NSCLC: Podcast Available
I’m very pleased to offer the excellent podcast produced from the recent webinar by Dr. Suresh Ramalingam, a leader in the lung cancer field who heads the Thoracic Oncology Program at Emory University in Atlanta. He’s also a good friend I’ve known since our fellowship training days, and he was kind and generous enough to refuse the honorarium we offered for his participation, instead requesting that it be donated back and used for other GRACE programs. Instead, he was happy to do this entirely out of a commitment to the lung cancer community. This is part of a small series of programs supported by an educational grant from Eli Lilly, so we are now enabled to do an additional program because of his generosity.
His webinar provides a very brief historical overview of NSCLC in general and then advanced NSCLC in particular, including a historical perspective of the evolving standards of care first with chemotherapy alone, and then with the integration of targeted therapies. He describes how our approach now individualizes our treatment recommendations based on such issues as particular NSCLC histology, molecular factors, performance status, and sometimes age to offer what we hope will deliver the best combination of efficacy and safety for a patient.
Podcast: Play in new window | Download (0.3KB) | Embed
The Predicament of Poorly Differentiated NSCLC/NSCLC NOS
A topic that came up in a recent expert round table case discussion was the issue of how to manage a patient with a lung cancer for which the pathology report says “NSCLC not otherwise specified (NOS)”, or “poorly differentiated NSCLC, NOS”. What does this actually mean, and what does it mean in terms of treatment options?
Tumors of pretty much all types are categorized by their tumor grade, how “differentiated” they are, which basically means, “how much do the cancer cells look like the cells they started out as?”. Different cells of the body start out as stem cells, which means that they’re not specialized to be any special kind of cell, like one that detects light in the back of the retina, lines the esophagus, or is optimized for lung function. Most cells of the body are differentiated, so that the appearance under a microscope shows that it’s a liver cell, part of the kidney filtering mechanism, heart muscle, etc.
Cancer cells, however, have mutations in them that make them grow and divide faster than other cells (that’s why they make a tumor that pushes other tissues aside), and they usually have several. As they grow and divide, they often make sloppy copies of their DNA that leads to more mutations. Cancers therefore are made of cells that may look a lot like the normal cells they originated from (well-differentiated), or they have lots of mutations that make the cells look so chaotic that they don’t look at all like the cells they started out as (poorly differentiated).
Today, oncologists want to know whether a non-small cell lung cancer (NSCLC) is an adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma, etc. But about 20% of the time on various studies, we get an answer back of “NSCLC not otherwise specified”. As explained by Dr. Matt Horton, expert lung cancer pathologist, a lung tumor may be classified as NSCLC NOS because of either of two reasons:
1) there isn’t enough tissue, because the biopsy material was very scant, or
2) the tumor is so poorly differentiated that even with all of the material in the world, a good pathologist couldn’t identify the underlying NSCLC histology
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