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Lesser Known Lung Cancer Mutations Part 2: BRAF inhibitors as another targeted therapy bullseye?
Recently, I described the rationale for targeting HER2 mutations in non-small cell lung cancer (NSCLC). Most of our experience with HER2 targeted therapy comes from studies in breast cancer. Now, I’d like to introduce you to BRAF, another novel target in NSCLC that is a central component in cell signalling, growth, and division.
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Most of our current information about BRAF comes from promising studies conducted with BRAF inhibitors in melanoma, a cancer that has been notoriously difficult to treat. Overall, BRAF mutations are one of the most common mutations in human cancers, though in lung cancer we estimate the frequency of BRAF mutations at only 1-3%. We’ve known for a while that these mutations occur in NSCLC but interest is really just picking up. Why? First, there are several BRAF inhibitors, some of which are showing promise in BRAF-mutated melanoma. Second, we now have more widespread ability to test for BRAF mutations (thanks to the success in melanoma) and to identify patients for clinical trials of BRAF inhibitors.
Lesser Known Lung Cancer Mutations Part 1: HER2, a promising therapeutic target?
By now, most patients (and hopefully, all oncologists!) are familiar with the significance of EGFR mutations in non-small cell lung cancer (NSCLC). The discovery of ALK mutations and the successful use of crizotinib in this setting has also been big news in the lung cancer world. I’d like to bring everyone up to date on two lesser known abnormalities that can occur in non-small cell lung cancer: HER2 and BRAF mutations. This post will cover HER2 mutations in NSCLC, and I will cover BRAF in a companion post to follow shortly. Dr. West alluded to these mutations in his recent post on the Lung Cancer Mutation Consortium study, and you can see in the figure he previously presented the relatively low frequencies of these mutations compared to more common mutations such as EGFR and KRAS.
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Introduction to Locally Advanced, Unresectable Stage III NSCLC
When I was a medical student, the question about lung cancer that was always asked on “the Boards” had to do with the difference between stage IIIA and stage IIIB non-small cell lung cancer (NSCLC). The reason this question was always asked is because patients with stage IIIA NSCLC might be considered for surgery, whereas patients with stage IIIB NSCLC would not be considered for surgery and instead would be treated with chemotherapy and radiation. The idea is that young doctors should be able to make that distinction and to direct patients to the appropriate specialist/treatment. While I guess it makes a good test question, this distinction is too simplistic and doesn’t really give anyone a good understanding of the complexities of managing stage III lung cancer. And, in reality, all patients with suspected stage III lung cancer should be evaluated by a multidisciplinary team that includes thoracic surgeons, radiation oncologists, pulmonologists and medical oncologists. If the Medical Board would write a test question aimed at getting across this important principle, I’d breathe a big sigh of relief for lung cancer patients.
What I really do: Molecular testing for NSCLC
I’m fortunate to practice at Moffitt, where Dr. Gerold Bepler and Dr. George Simon pioneered a molecularly directed approach to front-line chemotherapy in NSCLC. Data from the phase II clinical trial demonstrated impressive median survival for a platinum-based doublet: 13.3 months. The schema of the MADeIT clinical trial is shown below and I’m happy to say that I am able to put many of my patients on this clinical trial. Dr. West recently posted a podcast featuring Dr. Simon, where he describes the trial in more detail.
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The testing for ERCC1 and RRM1 is performed at Moffitt and turnaround time is typically around a week or less. I consider this a very reasonable interval since patients are unlikely to experience progression or declines in their performance status in a week. A sample from a prior biopsy can be used and fresh tissue is not required. Even when we have to obtain tissue from another institution, we can usually get the patient started in a very reasonable time frame. Right now, we only perform testing as part of the clinical trial. I think this is the right thing to do: although our hypothesis is that molecularly-directed therapy will be superior, we don’t know that for sure yet.
Women, Tamoxifen, and Lung Cancer
One of my areas of interest is studying gender-related differences in lung cancer. Earlier this year, I wrote a post about interesting data that had come out of the Women’s Health Initiative study. This was the landmark study that established that hormone replacement therapy (HRT) for postmenopausal women did more harm than good. When originally presented in 2002, the investigators noted significantly increased risks of breast cancer, cardiovascular disease and stroke. At ASCO 2009, they also reported an increase in lung cancer incidence and lung cancer mortality among postemenopausal women who received HRT compared to those who received placebo.
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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.
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.
Prophylactic Cranial Irradiation for Stage III NSCLC: Some Answers, Some Open Questions
In my last few weeks as a GRACE guest faculty, I have been struck by the number of forum discussions that deal with brain metastases. Brain metastases are a growing problem in non-small cell lung cancer (NSCLC), as well as in multiple other cancers. Why is this? Twenty years ago, patients who developed brain metastases were usually at the end-stage of their cancer, with widely metastatic disease and few systemic treatment options. The prognosis for these patients was very poor, but not really because of the brain metastases. Brain metastases were simply a marker that the cancer was taking over and patients often were on hospice care at that point. Some of the fatalism of those days still holds over to today, but the clinical picture of a patient with brain metastases has changed dramatically.
Now, we have many more effective systemic therapies. Unfortunately, most of those therapies do not penetrate the blood-brain barrier (BBB) very well. The brain thus becomes a “sanctuary site” for cancer cells, where they can hide out and start to grow while the cancer cells in the rest of the body are susceptible to chemotherapy or targeted therapies. I am increasingly seeing brain metastases in stage IV patients with good control of cancer in the rest of their body. I am also seeing more patients with earlier stage lung cancer where the brain is the only place that the cancer has relapsed. This is particularly true of patients with locally advanced (stage III) NSCLC. And this was the motivation behind a rather disappointing trial that was presented at ASCO recently.
Patients with stage III lung cancer have very high rates of brain metastases. Published studies show rates of brain metastases of 30-55%. More importantly, up to 30% of patients have brain metastases as the first site of recurrence. Even though many patients do well with treatment for brain metastases, it would certainly be desirable to prevent this from happening. In small cell lung cancer (SCLC), for instance, prophylactic cranial irradiation (PCI) is now standard practice for both limited-stage and extensive stage patients. Not only does PCI decrease the incidence of brain metastases but it improves survival in SCLC, another disease where the brain is a common site of relapse.
The investigators of tthe trial by the Radiation Therapy Oncology Group (RTOG 0214) hoped that similar results would emerge for patients with locally advanced NSCLC. The trial included patients with stage IIIA and IIIB NSCLC who had undergone treatment and had not progressed with their initial treatment (chemoradiation for most, with 1/3 of patients having undergone surgery). The primary endpoint of the trial was overall survival. Secondary endpoints included disease-free survival, incidence of CNS metastases, neurocognitive function, and quality of life. The trial was designed with a target accrual of 1058. This target accrual for a clinical trial is calculated by statisticians as the number needed to accurately access your hypothesis. Unfortunately, accrual of patients was VERY slow, and though the trial was open for six years, only 356 patients were enrolled. For this reason, the trial closed early.
Get ready to throw out your Premarin (again): Thoughts on hormones and lung cancer
The role of hormones in the development and progression of lung cancer in women has generated much interest. Unfortunately, a lot of the data to date has been observational, which doesn’t establish a “cause and effect” relationship. The Nurses Health Study (more on this below) is a good example: a large cohort of women was observed over time. The women completed questionaires on all sorts of exposures (diet, hormone replacement therapy, tobacco, etc), and they were followed over time. Then, investigators tried to sort out whether there were differences in exposures between women who got a given disease and those who didn’t. These types of studies can be “hypothesis-generating” but rarely yield clear results. It can be very difficult to isolate one exposure amongst many other confounding variables.
At ASCO this year, the Women’s Health Initiative (WHI) Study investigators presented important new findings from this landmark study of hormone replacement therapy (HRT). Most women are familiar with the earlier reported findings of this study because those findings led physicians to STOP recommending HRT for post-menopausal women (previously considered beneficial). Most may not be familiar with the details of the study design so here is a refresher. This study enrolled healthy post-menopausal women with no history of breast cancer. Over 16,000 women were enrolled: half were randomized to HRT with estrogen plus progesterone, the other half received placebo. The investigators were primarily interested in the risk of breast cancer and cardiovascular disease. Other cancers specifically studied included endometrial cancer and colorectal cancer. The study was stopped early, because the investigators found significantly more risks than benefits associated with HRT compared to placebo. Specifically, women who received HRT were 30% more likely to develop cardiovascular disease, 26% more likely to be diagnosed with breast cancer, and had a 40% increased risk of stroke.
Though the study stopped early, the women continued to be followed. In a recent update, the investigators noted an increase risk of malignancy (other than the three previously studied cancers) in women who took HRT. They decided to analyze the risk of lung cancer in the two cohorts of women.
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