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Why Avastin is a No-No for Patients with Squamous NSCLC: A Brief History
At the time that OncTalk (the predecessor to GRACE) was just getting off the ground in the fall of 2006 (wow, three years have gone quickly!), Avastin (bevacizumab) was just getting FDA approval in the first line treatment of advanced NSCLC. The main focus was on the randomized trial that showed a survival benefit and led to its approval, and in the rush to generate summaries of the treatment highlights for various treatment settings in lung cancer, the story of Avastin skipped over its development in lung cancer. Many people may know that Avastin is given only in patients with non-squamous cancers, but it’s worth backtracking to understand why.
The first significant trial of Avastin in NSCLC was a randomized phase II trial done at Vanderbilt University and that enrolled about 100 patients with advanced NSCLC who received either chemotherapy with carbo/taxol (paclitaxel) alone every three weeks., or the same chemo with Avastin at either 7.5 or 15 mg/kg IV every three weeks. This trial was open to patients with any NSCLC histology. Importantly, patients who were enrolled on the chemo only arm as first line therapy were allowed to cross over to the Avastin alone (at the higher dose) after progression on carbo/taxol.
(Click on image to enlarge)
AstraZeneca Withdraws Zactima from Consideration of FDA Approval for Advanced NSCLC
AstraZeneca (AZ) just issued a press release noting that they are withdrawing their application for the “multi-kinase inhibitor” Zactima (vandetanib) to receive FDA approval to be given along with chemo in advanced NSCLC right now. Zactima is a pill that has the potential to block both the EGFR and VEGF (angiogenic) pathway, and I’ve described some of the larger clinical trials being pursued by AstraZeneca with Zactima in a prior post. I also covered the more complete presentations of the data earlier this year and why I felt that the benefits of Zactima appeared quite underwhelming, while member and GRACE board member Neil Berch made an argument favoring a meaningful benefit with Zactima.
Dr. Ralph Aye, Thoracic Surgeon, on Surgery in Management of NSCLC
As the next installment of the podcast series from the GRACE NSCLC Patient Education Forum, I’m pleased to offer a presentation by the Chief of the Thoracic Oncology Division at Swedish Medical Center in Seattle — my own institution. Dr. Aye has been at the center of the program from the beginning, and whatever success our center has achieved in the field is a reflection on his steady leadership. He was one of the leading reasons I felt I would be happy at Swedish, and nearly seven years later, I can say that he’s been one of my favorite aspects of working there. Not every lung cancer program is as collegial and collaborative in its multi-disciplinary approach.
He’s also a terrific surgeon, and his talk is on the general principles of surgery for early stage NSCLC. Here’s links to the video and audio only versions of his presentation, as well as the transcript and figures.
dr-aye-surgery-for-nsclc-transcript
dr-aye-surgery-for-nsclc-figures
Dr. Aye Surgery for NSCLC Audio Program
Podcast: Play in new window | Download (50.4MB) | Embed
ATLAS Trial Falls Short of Overall Survival Benefit
On October 15th there was a press release that, as far as I can tell, went almost entirely unnoticed. News outlets reported that Roche (owner of Genentech, the maker of Avastin (bevacizumab)) reported to OSI Pharmaceuticals (the maker of Tarceva (erlotinib)) the final overall survival results from the ATLAS trial.
There have been a number of posts on the ATLAS trial in the past, including one by me this summer after the primary results were presented at ASCO. To review, ATLAS was a phase III trial that randomized patients with advanced NSCLC, all of whom had completed 4 cycles of first-line chemotherapy plus Avastin, to either maintenance Avastin alone (the standard arm) or maintenance Avastin plus Tarceva.
ATLAS was one of two maintenance Tarceva trials, the first of which was called SATURN and did not include Avastin. The SATURN trial and ATLAS trials both met their primary endpoints, significantly prolonging progression-free survival (PFS). However, much to the surprise of many people (like me), the SATURN trial was also reported at the 2009 World Conference on Lung Cancer to be positive for an improvement in overall survival (OS).
The ATLAS overall survival data was not yet mature at the WCLC, so we were left to see if there would also be an OS benefit from the combination of maintenance Avastin and Tarceva (or what I like to call “Almost the Most Expensive Regimen Ever”). This week, however, without a hint of fanfare, we apparently got our answer. I can’t even find the original press release, but these results were confirmed to me by a contact at OSI. Continue reading
When Will Patients with Squamous Cell Lung Cancer Get a Break?
When one reviews the excitement that has been generated over the last several years in regards to the advancement of therapy for NSCLC, it becomes painfully apparent that patients with adenocarcinoma have reaped the greatest benefits, and patients with squamous cell lung cancer have been more or less left out in the cold.
The addition of Avastin to doublet chemotherapy prolongs life for patients with non-squamous cell lung cancer, while patients with squamous cell lung cancers have an increased risk of life-threatening bleeding from the lungs. Although Tarceva can prolong survival for patients with advanced NSCLC of all histolologies that has grown after chemotherapy, patients with the greatest chance of benefit in the first-line or salvage setting (those with activating EGFR mutations) almost exclusively have adenocarcinoma. Alimta, a “traditional” chemotherapy drug with a much lower toxicity profile than most chemotherapy agents, was shown to be active in non-squamous cell lung cancers, and to have virtually no activity in squamous NSCLC. This caused Alimta to lose its indication for NSCLC of squamous cell histology.
Recently, a new mutation has been identified for NSCLC, the EML4-ALK translocation. This translocation, much like the EGFR activating mutations, drives cancer cell function in a dependent fashion, and inhibition with a novel c-met and ALK inhibitor is showing promise in early clinical data. Again, this mutation occurs in patients with non-squamous cell lung cancers, more commonly in lifetime never smokers.
So where is the drug for squamous cell lung cancer? Although squamous cell NSCLC is decreasing in frequency as adenocarcinoma of the lung becomes more common, squamous cell tumors are far from rare.
Dr. Gerard Silvestri, Pulmonologist, on Lung Cancer Workup and Staging
This is the first of the presentations by guest speakers at our NSCLC Patient Education Forum back in September. Dr. Gerard Silvestri is a pulmonologist, a lung disease specialist (not only cancer), and he is also one of the most important leaders in lung cancer within the field of pulmonology, as both a writer of some very important work and as a great speaker.
His talk was a general introduction to the process of the workup and approach to staging a lung cancer. Below you’ll find the links to audio and video versions of his presentation, the figures, and the transcript for his talk.
Silvestri Lung Cancer Workup and Staging Audio
silvestri-lung-cancer-workup-and-staging-figures
silvestri-lung-cancer-workup-and-staging-transcript
Podcast: Play in new window | Download (49.5MB) | Embed
And Another One Bites the Dust: Avastin in Small Cell Lung Cancer
Keeping with the weekly theme of small cell lung cancer (SCLC), I thought I would comment on a newly published study by the Eastern Cooperative Oncology Group (ECOG), ECOG 3501.
As Dr. Sanborn so aptly described earlier this week, small cell lung cancer has stymied the oncology establishment for decades. This horrible disease is treated today almost exactly the same way it was treated 20 or even 30 years ago, with only minor advances being made in decreasing toxicity of treatment and with prolonging survival with radiation. The only blessing during this period has been that the incidence of SCLC continues to fall in developed countries, although my guess is that the rise in smoking in developing countries like China and India will keep those of use who treat SCLC in business for a long time.
As Dr. Sanborn pointed out, the lack of advancements is not for lack of trying. Numerous combinations of chemotherapy and novel, targeted agents have been tested in this disease and have uniformly been disappointing. Small cell has destroyed more careers than Jessica Simpson (thank you, folks, I’ll be here all week).
Perhaps one of the reasons “targeted” therapies have not worked well to date is the lack of a good target to aim at. Whether it be p53, hedgehog, matrix metalloproteases, or bcl-2, there is no lack of upregulated genes in SCLC that sound promising on paper. However, I have yet to see a single gene, protein, or pathway that, if inhibited, would have major impact on the disease. If cancer oncogenes were represented as a graphic equalizer on a stereo, then SCLC has turned all the knobs up to 11, making inhibiting one of those pathways unlikely to do much.
So on the surface, testing a drug like Avastin (bevacizumab) in SCLC makes a lot of sense. Avastin is an antibody against vascular endothelial growth factor (VEGF), and is commonly used in combination with platinum chemo in non-small cell lung cancer (as well as in breast, colon, kidney, and brain cancer). In my opinion, much of the activity of Avastin against cancer comes from its ability to “normalize” tumor blood vessels so that chemotherapy can reach more of the cancer and thus can be more effective. Avastin rarely has much activity by itself. Continue reading
Can BCL-2 inhibitors make progress in SCLC?
The development of targeted therapy drugs has improved survival for patients with NSCLC, and the “pipeline” of agents in development awaiting further testing in clinical trials seems to be increasing by the day. The improvements in survival in particular subpopulations of patients with NSCLC inspires both patients and physicians who treat lung cancer to hope that similar gains may be made, perhaps incrementally, for patients in all subpopulations of NSCLC.
In contrast, progress in small cell lung cancer (SCLC) has been disappointingly slow. Although there was hope initially about improved survival with the combination of cisplatin and irinotecan over the “old standard” of cisplatin with etoposide based upon a trial in Japan, two randomized trials in a more heterogeneous North American population, one trial community-based and another conducted by SWOG, failed to show any survival advantage. The greatest gains we have thus seen recently for patients with SCLC come from radiation, with twice daily radiation improving survival for patients with limited-stage disease (for those patients who may be able to tolerate the increased toxicities) and prophylactic cranial irradiation (PCI) improving survival for patients with extensive stage disease.
This frustrating lack of improvement from a chemotherapy front does not come from lack of effort. Much like for NSCLC, a large number of targeted therapy drugs have been tested in SCLC, but with no major breakthroughs.
But lung cancer doctors are by definition optimists, and we are always hopeful that breakthroughs that make real differences in the lives of our patients may be just around the corner. One of the active areas of research involves BCL-2 inhibitors. BCL-2 is a protein involved in cell survival, and is overexpressed in many cancers, including SCLC. Overexpression of BCL-2 helps to protect a cancer cell from dying, and increased levels of BCL-2 expression help make a cancer cell more resistant to chemotherapy.
Podcast on Current Questions, Clinical Trials in Adjuvant Therapy for Resected NSCLC
GRACE is very happy to have the opportunity to present this podcast by Dr. Heather Wakelee, medical oncologist at renowned lung cancer expert at Stanford University Cancer Center. The focus of this particular program, supported by an educational grant from GlaxoSmithKline, is on the most important research questions and clinical trials in the field of post-operative therapy for resected NSCLC.
Podcast: Play in new window | Download (38.8MB) | Embed
EGFR Mutations in African American Patients: What Little We Know
In the last several years we have seen an explosion in the knowledge and understanding of the molecular basis of cancer behavior. The identification of EGFR mutations, and their utilization in predicting response and survival in patients with untreated advanced lung cancer, provides lung cancer oncologists with the optimism that we may truly be able to offer effective “personalized therapy” for patients with lung cancer in the near future.
The majority of knowledge regarding EGFR mutations comes from studies of patients of East Asian ethnicity or of Caucasian backgrounds from either the US or Europe. It is evident and widely discussed from the data from these populations that lung cancer patients of East Asian ethnicity have a higher rate of EGFR mutation than Caucasian patients do.
What about patients however of other backgrounds? Do African American, Latino, or Native American patients have the same rates of EGFR mutations as Caucasians or East Asians, or are they different? How great is the disparity of mutation rate between never-smokers and those patients with a smoking history in these populations?
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