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The EML4-ALK Mutation Enters the Lung Cancer Clinic
Dr. Pinder previously summarized the early story of the newly identified EML4-ALK mutation in NSCLC, which traces back only a couple of years. Amazingly, in that short time, treatments targeting this mutation have already been identified and administered to patients who are benefiting from these novel agents at this very moment. Still, one of the leading issues with this story of progress is that the EML4-ALK mutation appears to be present in less that 5 percent of the overall NSCLC population, so people may ask how valuable this discovery really is.
That really depends on a couple of factors. First, screening for an EML4-ALK mutation will be much more appealing and feasible if we have some hints of which pateints are more or less likely to have one of these mutations. Second, we need to have a treatment that helps the people we screen who have the ALK mutation.
Broad Screening for EGFR Mutations: The Spanish Lung Cancer Group Experience
In the same issue of the New England Journal of Medicine that contained the IPASS trial results, Dr. Rosell and colleagues reported results of their effort to institute large-scale EGFR mutation testing in lung cancer patients in Spain, who then received erlotinib (Tarceva).
Patients with non-small lung cancer were recruited from selected public hospitals in Spain. Although 100 sites were chosen (at random), the program was so popular that an additional 29 centers requested and were granted inclusion in the study. Patients who were determined to have EGFR mutations in their tumors were offered Tarceva. The summary of the trial is as shown below:
Out of the 2105 patients enrolled, 17% had EGFR mutations. Consistent with previous observations, patients with EGFR mutations were more likely to be female, never-smokers with adenocarcinomas. About 10% of the patients with EGFR mutations had large cell carcinoma, a histology not usually associated with EGFR mutations. In fact, a similar study previously found no EGFR mutations in a series of patients with large cell carcinoma. I’m intrigued by this but also would interpret it with caution. Although the EGFR testing was done centrally, it is not clear to me that the histology of the specimens was also reviewed by the study pathologists. I wonder if some of these tumors may have been more poorly differentiated and perhaps misclassified as large cell carcinomas. I’d like to see this finding replicated in another study before I start sending off EGFR testing on my patients with a large cell NSCLC histology. While the majority of patients with mutations were never-smokers, EGFR mutations did occur in 13 current smokers and in 56 ex-smokers.
Of the patients who received Tarceva, about half got it as first-line therapy and the other half as second- or third-line therapy. The majority of patients who received Tarceva benefited with only 10% of patients with EGFR mutations experiencing progressive disease while on the drug. Median progression-free survival was 14 months and median overall survival was 27 months! These results are impressive, given that the trial allowed patients with a performance status of 2 and patients who had had received 2 lines of prior therapy. There was no difference in outcome whether patients received Tarceva as first-line or second-line therapy.
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There was a substantial difference in outcome according to patient sex. For women, median PFS was 16 months, compared to 9 months for men. Similarly, overall survival was 29 months in women and 18 months in men. These differences were statistically significant. When the authors analyzed the variables that affected prognosis, male gender, the L858R mutation (compared to deletion 19), BAC histology, performance status (PS) of 1 (compared to 0, which is the best, completely unlimited) and the presence of brain metastases emerged as variables associated with inferior survival on Tarceva. It is important to remember that this does NOT mean that these patients did not benefit from Tarceva — just that they did not appear to do as well as other groups. I’d take these results with a big dash of salt, though, as some of the numbers involved here were quite small (only 34 patients with BAC histology) and thus less statistically robust. This is evident in the fact that the analysis suggested that PS 1 patients did worse than PS 2 patients, which doesn’t make a lot of sense. While it has been a consistent finding that women with lung cancer have a better prognosis, it is disheartening that even in patients who all had EGFR mutations and access to Tarceva, men appeared to do substantially worse. It’s frustrating to me that the sex differences we observe in lung cancer are still sort of a black box.
Based on their results, the authors conclude that women, those who have never smoked, and those with non-squamous cancers should be screened for EGFR mutations. They also conclude that large-scale screening is feasible. Although I agree that it makes sense to screen certain populations for EGFR mutations and to make treatment decisions based on these results, I think that doing this in the US may present certain challenges. In Spain, the health care system is a public one: all of the hospitals in the study were part of the same health care system. When patients have more fragmented care, this whole process takes time and in some cases, delaying the patient’s treatment for these results could be harmful. As a practitioner in the US at a tertiary referral center, most patients come to me with biopsies done at a private hospital in their community. Just obtaining the tissue can range from a nuisance to a herculean task. We have had hospitals refuse to release slides and in a few cases, they have called the patients and demanded payment in order to release the patient’s own tissue. Luckily, as this study confirms, it does not seem to impact survival whether a patient with an EGFR mutation receives Tarceva in the first- or second-line setting. I’d feel comfortable starting a patient on front-line chemotherapy even if I thought they had an EGFR mutation but based on the IPASS data, I would not feel comfortable starting a patient on front-line Tarceva without knowing their EGFR mutation status, even if she fit the clinical profile.
Moving to Molecular Defined Lung Cancer Treatment: The IPASS Trial
This week’s New England Journal of Medicine includes not one but two seminal publications on EGFR mutation status, response to EGFR tyrosine kinase inhibitors (TKIs) and sequencing of therapy in advanced NSCLC.
First, Dr. Tony Mok and colleagues reported detailed results of the IPASS trial, which have been outlined previously by Dr. West. The investigators selected for inclusion patients from clinical subgroups associated with high rates of EGFR mutations and response to EGFR TKIs: women, Asians (the study was conducted entirely in Asia), patients with adenocarcinomas and light- or never-smokers. However, the presence of an EGFR mutation was NOT part of the study entry criteria. The trial randomly assigned over 1200 patients with these clinical characteristics to either front-line chemotherapy with a maximum of 6 cycles of carbo/Taxol or to Iressa. The investigators were able to determine the EGFR mutation status for 36% of patients.
The primary endpoint of the trial was progression-free survival (PFS). Patients in both the Iressa and the chemotherapy groups had a median age of 57, were overwhelmingly female (80%) and most were never-smokers (94%). For the population as a whole, the primary endpoint of PFS was met, with the group on Iressa showing a statistically significant 26% decrease in the risk of progression (also known as a hazard ratio of 0.74), as shown in panel A. In the first six months, the survival curve favors chemotherapy but thereafter the curves cross and PFS is more favorable with Iressa. Why? Patients with EGFR-mutant tumors had high response rates with chemotherapy (47.3%) also so both EGFR-mutation-positive and EGFR-mutation-negative patients could have responded to chemotherapy, which lasted a maximum of six cycles, thus favoring chemotherapy early-on. After six months, the high response rates and prolonged PFS in EGFR-mutation-positive patients would have driven the superiority of Iressa.
Summary of Post-Operative Therapy: Part 2 of Lecture from Cancer Lifeline
This slide presentation is the second part of a lecture I gave at the Seattle-based non-profit Cancer Lifeline a few months ago. This covers the evidence supporting post-operative (adjuvant) chemotherapy for patients with early stage NSCLC, the need to recognize that this does not apply to all patients who have undergone surgery, and the emerging clinical research and ongoing trials that may lead to improvements in our cure rate for early stage NSCLC patients in the future.
Here is the presentation in video format, the audio version, transcript, and a pdf file of the figures. I hope it’s helpful.
Cancer Lifeline Part 2 Adjuvant Therapy Early Stage NSCLC Audio Podcast
cancer-lifeline-part-2-adjuvant-therapy-early-stage-nsclc-transcript
cancer-lifeline-part-2-adjuvant-therapy-early-stage-nsclc-figures
Podcast: Play in new window | Download (57.8MB) | Embed
Beyond the SWOG 0023 Trial: Are Iressa and/or Tarceva Harmful after Definitive Concurrent Chemoradiation (CRT)?
In 2008 the SWOG 0023 trial was published, which looked at the question of maintenance Iressa (gefitinib) after definitive chemoradiation in patients with locally advanced (Stage III) NSCLC. The trial randomized patients who had not progressed after completing CRT with concurrent cisplatin and etoposide chemotherapy followed by consolidation Taxotere (docetaxel) to either Iressa or placebo. Patients were then followed until progression or death. In a result which still confounds lung cancer oncologists, it appeared that the arm which received Iressa had a significantly WORSE survival than those who received placebo, with a median survival that was 12 months shorter (23 months in the Iressa arm vs. 35 months with placebo).
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No one has put forth an adequate explanation of why Iressa, a drug used widely now in NSCLC patients for almost a decade, would be harmful (instead of merely ineffective) in these patients. It did not appear that more patients on Iressa died of toxic side effects from the drug, which would have been a convenient explanation. Instead it appeared that the patients receiving Iressa had faster progression of their lung cancer than those on placebo. Some have hypothesized that EGFR inhibition actually stimulates the cancer to progress in this specific population. As a result, this study has been held up as a cautionary tale about how we need to understand that our treatments have the potential to harm patients, not just help or do nothing. I have no bones with this concept in general, but…
SATURN Survival Results: What Can We Say About “Maintenance” Tarceva?
Shortly after ASCO 2009, Dr. Pennell provided the highlights of the early report of the SATURN trial, conducted primarily in Europe, that randomized patients to maintenance tarceva (erlotinib) or placebo after four cycles of first line chemotherapy. The early report described a modest but statistically significant improvement in progression-free survival (PFS), but overall survival (OS) wasn’t reported at ASCO. Frankly, the modestly favorable results in terms of PFS were overshadowed at ASCO by the maintenance therapy trial with alimta (pemetrexed), which showed a significant improvement in both PFS and OS.
One of the more interesting presentations with new data at the World Conference on Lung Cancer in San Francisco a few weeks ago was an update of the SATURN trial results that included OS results. It revealed a significant improvement in OS, with a difference in median OS of one month (11 vs. 12 months, measured from the time of randomization, so patients had generally received about three months of treatment before then). The survival curves are shown below:
More is better than nothing: another look at duration of therapy in NSCLC
Patients often ask me, “Why are we only doing four cycles of chemotherapy for my lung cancer?” This is a great question and one for which the answer is a moving target, based on recent data incorporating maintenance therapies. A recently published meta-analysis took another look at this question in NSCLC. The study authors searched the literature and clinical trial registries to identify randomized, controlled trials of front-line chemotherapy regimens in patients with wet IIIB or stage IV. Trials included compared A) fixed number of cycles of chemo versus continuing chemo until progression, B) shorter versus longer number of cycles (but with a predefined limit rather than continuing until progression) or B) initial chemo versus same initial chemo followed by additional cycles of a different chemo. A total of 13 trials were included, with over 3,000 patients total. None of the included trials incorporated targeted therapies approved for use in NSCLC (Avastin, Tarceva, Iressa or Erbitux).
The investigators found that extending chemo was associated with a statistically significant 8% reduction in death compared with standard duration of chemotherapy. Individually, none of the trials comparing shorter versus longer duration of platinum-based doublets was positive for an overall survival benefit.
Should Patients with KRAS Mutations Be Treated with Epidermal Growth Factor Receptor Inhibitors (i.e. Iressa or Tarceva)?
Hi again! You can think of this as a companion piece to my last post, examining some recent (but admittedly preliminary) evidence suggesting that Iressa (gefitinib) and Tarceva (erlotinib) may not be equivalent for patients with differing types of EGFR mutations. This is a slightly different topic, but one that has been quite contentious for several years: do KRAS mutations, found in 20% or more of patients with NSCLC, identify a group of patients who are resistant to EGFR inhibitors?
KRAS is an oncogene that is mutated in a large percentage of pancreatic, colorectal, and non-small cell lung cancers. The significance of this gene has been known for a while, and anecdotal evidence has suggested that patients with tumors harboring KRAS mutations have a poor prognosis and tend not to respond to treatment (chemo or EGFR inhibitors) as well as KRAS non-mutated (wild type) tumors. Retrospective studies looking at KRAS mutant patients who are treated with EGFR inhibitors like Iressa and Tarceva have very consistently shown that the chance of significant tumor response (shrinkage) of tumors in this group is almost zero. However, we now know that there are 2 clear groups of patients who benefit from EGFR inhibitors: those who get a tumor “response”, and those who get tumor “stabilization”, in which the tumors simply do not grow for some period of time. Even disease stabilization can be associated with a prolongation of survival, and this phenomenon is commonly seen in patients with EGFR wild type tumors.
EGFR wild type tumors also have a negligible rate of tumor shrinkage with EGFR inhibitors, much like the KRAS mutant tumors, but still seem to derive benefit. What has never been convincingly shown by the proponents of the “KRAS is bad” hypothesis is that patients with KRAS mutations (which are mutually exclusive of EGFR mutation) do not get the same level of disease stabilization and survival benefit from EGFR inhibitors as do all other EGFR wild type patients. Well, at the 2009 World Conference on Lung Cancer meeting we did get some indications that KRAS might not be so very bad after all.
In the first example, let us return to the Jackman database that I described in my last post. Not all of the patients in the database had EGFR mutations, and many had KRAS mutations. Dr. Jackman showed that the time to progression and overall survival of patients with KRAS mutations, treated with EGFR inhibitors, had the exact some outcome as patients without KRAS mutations but also without EGFR mutations. Both groups did fairly poorly, but there was certainly no indication that KRAS mutation conferred a worse outcome that anyone else who did not have an EGFR mutation. Continue reading
Looking for Genetic Differences in Never-Smokers who Develop Lung Cancer
Last year I highlighted a research program out of Memorial Sloan-Kettering Cancer Center in NYC that has been trying to identify molecular genetic factors in never-smokers who develop lung cancer that can help provide explanations and even perhaps a better sense of why anyone, including smokers, may be at higher risk for developing lung cancer than others. The study involves just a questionnaire about tobacco and other exposures, and also collecting a couple of vials of blood that can be drawn at your local doctors office and then sent, postage paid, to a lab for genetic analysis.
I saw the investigator leading this effort, Dr. William Pao, at the World Conference on Lung Cancer this past week. He has since been recruited from Memorial Sloan Kettering to Vanderbilt University Medical Center in Nashville, TN, where he’s leadinga growing lab-based effort to better understand the genetic underpinnings of lung cancer. The blood collection and genetic analysis is bearing fruit, and he and his colleagues are in the process of writing some of their early findings from this project. They’ve enrolled many people who found out about this work here, and I’ve also told my never-smokers about it and encouraged them to consider participating. Who wouldn’t want to help understand why some people are at a higher risk for developing lung cancer.
You can find out more information at the website www.vicc.org/neversmokers or by e-mailing neversmokerswithlungcancer@vanderbilt.edu.
One new development is that the survey is now available online, making it even easier.
BAC No More?
The most expert lung cancer pathologists in the world are planning a revision of the classification of lung adenocarcinomas that is expected to be approved and implemented next year, and it’s going to make some big changes. Specifically, it’s planning to eliminate the diagnosis of bronchioloalveolar carcinoma (BAC), reflecting our evolving understanding of this disease.
BAC with lesions less than 2 cm is now being designated as a pre-cancerous adenocarcinoma in situ (AIS), which essentially means it’s a pre-invasive condition with a favorable prognosis. In fact, the available literature, largely from Japan but also including evidence from other parts of the world, shows a 100% 5-year survival for a <2 cm AIS, which is far more commonly the non-mucinous BAC sybtype. The size limit is significant, however, because larger lesions are felt far more likely to have at least some area of invasive disease.
The invasive portion of what is now in the spectrum of BAC with focal invasion to adenocarcinoma with BAC features has a major impact on prognosis. In fact, the size of that invasive component is what drives prognosis, not the invasive part:
The Invasive Component in AdenoBAC Drives Prognosis
So a largely pre-invasive (adenocarcinoma in situ) lesion with a small area of invasiveness will now be designated as minimally invasive adenocarcinoma, and it also has a 100% cancer-specific survival at 5 years.
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