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Biomarkers Predicting Clinical Benefits for BAC Patients Receiving Tarceva
Continuing with the analysis of a publication about tarceva (erlotinib) for patients with advanced BAC that I introduced in the last post, we’ll turn now to the analysis that Dr. Vince Miller and colleagues did on the biomarkers that might predict more or less clinical benefit with an EGFR inhibitor like tarceva (abstract here). The trial looked at three different ways of measuring EGFR:
1) EGFR activating mutations in the gene, which are located in the part of the EGFR molecule where drugs like tarceva and iressa (gefitinib) work, and which have been associated with a high likelihood of response to these agents
2) EGFR “copy number”, which measures overall amplification of the number of copies of the gene in cancer cells, and which at high levels has been shown by some groups to be associated with a higher likelihood of response and prolonged survival than low/normal levels; this was measured here by “chromogenic in situ hybridization, or CISH, similar to the more commonly used test called fluorescence in situ hybridization (FISH)
3) EGFR immunohistochemistry (IHC), which measures the amount of the protein on the surface of the cancer cells, and which has been least clearly associated with better or worse results with EGFR inhibitors, at least the oral tyrosine kinase inhibitors like tarceva and iressa.
In addition, the investigators also looked at K-RAS mutations in the cancer, which have been associated with smoking and rarely seen in never-smokers, and they’ve also been associated with resistance to EGFR inhibitors and likely also many types of chemotherapy. K-RAS mutations appear to be associated with resistance and poor response in general, and some people have suggested that EGFR inhibitors not be tried in patients with K-RAS mutations, because responses have rarely if ever been seen in patients with K-RAS mutation-positive cancers.
Of the 101 patients with advanced BAC and treated with tarceva on the trial, 82 had enough tissue for at least one of these biomarker studies, and 61 had enough tissue collected to perform all four studies. As with several prior studies that have looked at EGFR mutations, the 22% of patients with EGFR activating mutations (higher than expected for a North American population, probably because EGFR mutations are more common in BAC than in lung cancer in general) had a response rate (RR) of 83%, compared with only 7% for patients without EGFR mutations (“wild type”). This highly statistically significant difference was also mirrored by a significantly longer median progression-free survival (PFS) among EGFR mutation-positive patients (13 vs. 2 months), but the difference became attentuated and wasn’t statistically signficant for median overall survival (OS) (23 vs. 17 months). Gene amplification by CISH showed the same pattern, but not as dramatically: those patients with EGFR gene amplification by CISH showed a significantly higher RR (43% vs. 13%) and median PFS (9 vs 2 months), but no significant difference in median OS (25 vs. 16 months). And EGFR IHC really didn’t show any trends at all for any of these efficacy parameters.
Meanwhile, K-RAS mutations showed what they have tended to: a significant difference in RR, with responses never seen in patients with a tumor harboring a K-RAS mutation (0% vs. 32%)), but no significant differences in median PFS (4 vs. 5 months) or median OS (13 vs. 21 months). As you can see from some of the differences in the numbers, however, the small numbers of patients being compared kept some pretty big differences from being what would be considered “statistically significant” (the larger the trial and the number of people available for comparison, the smaller the differences in outcomes need to be in order to be considered overwhelmingly unlikely to be caused by chance alone).
Another interesting way of looking at response is with a “waterfall plot”, in which measured changes in the volume of the cancer with treatment are plotted from largest progression on the left to greatest shrinkage on the right, making what looks like a waterfall. The bars that go downward represent a response (anything from minor to major), and the upward bars are progression:
(Click on image to enlarge)
There are several interesting points here. First, most of the best responses were seen in patients with EGFR mutations, but not all. Second, many of the patients with EGFR mutations also were positive for EGFR by CISH. Third, even though there were no responses among patients with K-RAS mutations, there were patients with these mutations who demonstrated stable disease. Finally, at least half and I would say closer to two thirds of patinets experienced no change or some degree of shrinkage on tarceva, even though the response rate overall was 22%. And we know that survival can be improved in populations with stable disease.
Another interesting issue, though it isn’t addressed here, is that we’ve seen that survival is best for patients with EGFR mutations, apparently no matter what treatment they get. So though we would think that a drug like tarceva or iressa would be the critical driver for improved survival in patients with tumors that have EGFR mutations, they actually seem to just do better overall, so it may be a marker of a generally more responsive and/or slower-growing cancer. The opposite is seen with tumors that have a K-RAS mutation (and we have almost never found a tumor with both an EGFR mutation and a K-RAS mutation): they are not only resistant to EGFR inhibitors, but they also appear to be resistant to conventional chemo as well and just appear to do worse overall.
Although I think the biomarker story is interesting, I would argue that the results here show that you don’t need to have an EGFR mutation to respond, that survival is not significantly better for EGFR mutation patients or any other biomarker, and that patients with tumors that show K-RAS mutations may not respond but may show stable disease on tarceva. Taken together, I think the biomarker story is interesting but wouldn’t really guide my clinical decisions at this point. I wouldn’t only offer tarceva to patients with an EGFR mutation or gene amplification, and I wouldn’t necessarily exclude a patient with a K-RAS mutation from getting tarceva either.
As always, I welcome your thoughts and questions.
Trial of Tarceva in BAC: New Info on Who Benefits with Tarceva
In a recent issue of the Journal of Clinical Oncology, Dr. Vince Miller and colleagues published the results of an important trial of the EGFR inhibitor tarceva (erlotinib) in the unusual NSCLC subtype bronchioloalveolar carcinoma, or BAC (abstract here). This work was predicated on the observation, also by Dr. Miller and his colleagues at Memorial Sloan Kettering Cancer Center in NYC, that EGFR inhibitors, and specifically gefitinib in the earliest clinical experience, appeared to be most associated with great responses in patients with adenocarcinoma and particularly BAC, and also in never-smokers (abstract here). Over the past several years, much of our greatest interest in drugs like iressa and tarceva has focused on BAC, including a trial with iressa that I led with the Southwest Oncology Group (SWOG) and subsequently published (abstract here), and also the trial with tarceva that Dr. Miller ran with collaborators at Vanderbilt-Ingram Cancer Center in Nashville and MD Anderson Cancer Center in Houston.
Over several years, these investigators enrolled 101 patients, most of whom had adeno/BAC and not the pure form of BAC (see prior post for discussion of this spectrum), which is representative of the eligibility of most or all of our current trials that we say are for “BAC“: the majority, and sometimes the vast majority, are BAC mixed with some invasive adenocarcinoma. In truth, different pathologists, even great ones, differ in their definitions of what is BAC, what is adenocarcinoma with BAC features, and what is BAC with focal invasive adenocarcinoma. Continue reading
Cavitation of Lung Tumors on Anti-Angiogenic Agents
Tumor cavitation has been one of the issues we really haven’t discussed but that has been a challenging question as we test more and more anti-angiogenic drugs, which target the tumor blood supply, in the setting of lung cancer. Since we started testing these agents, we’ve noticed that in addition to sometimes increasing the rate of tumor shrinkage, many patients who receive anti-angiogenic drugs develop cavitation, or a response on the inside of the tumor that leaves the rim of the tumor intact, as shown here:
(Click on image to enlarge)
There are a few key points here. First, while we think these cavitating tumors represent a nice response (from the inside of the tumor out), when the outer dimensions of a measurable tumor don’t change, it’s considered stable disease and not a response. Consequently, many of us think that our current way of measuring response underestimates the real anti-tumor activity of drugs that cause tumor cavitation, contributing to our growing sense that tumor shrinkage may not tell enough of the story of the potential benefit of a drug.
A second key issue is the concern that tumor cavitation may be associated with a higher risk of a cancer bleeding. While most clinical trials with anti-angiogenic drugs like avastin (bevacizumab) and sutent (sunitinib) don’t exclude patients with cavitating tumors from enrolling, and they also don’t tend to require patients to come off of trials with such agents if they develop cavitation during treatment on the trial, many of us become a little nervous about patients perhaps having a higher risk of pulmonary hemorrhage if they cavitating lesions, based on a sense that perhaps cavitation is an important predictive factor. One issue is that we generally have felt that squamous tumors are far more likely to cavitate, with or without anti-angiogenic drugs, and squamous histology has been a factor commonly implicated in increased risk of bleeding. But a new publication from investigators at the MD Anderson Cancer Center (MDACC) in Houston (abstract here) helps characterize the frequency and level of risk associated with tumor cavitation among patients who received anti-angiogenic agents, rather than just speculate.
The study was a retrospective review of 124 patients from MDACC who were enrolled in any of 10 different trials there over several years. Some of these excluded patients with squamous tumors, following the approach with avastin, but others included patients with all histologies. One key point was that cavitation isn’t rare, present in 13% of the patients before starting treatment, and then developing in another 14% of patients during treatment in these trials; the median time to developing cavitation was 1.8 months. Although significantly more common in patients with squamous tumors, some patients with adenocarcinomas also had cavitation at baseline or developed it during treatment. But the most important factor was that tumor cavitation was not associated with a worse prognosis, but rather was comparable for both progression-free and overall survival on anti-angiogenic drugs; it also wasn’t associated with a clearly increased risk of life-threatening or fatal pulmonary hemorrhage. Although there were a few bleeding deaths, they also occured rarely in patients who did not develop cavitation, with no clear signal that cavitation escalated the risk.
With results from just one institution, we don’t yet have definitive information about whether it is advisable to stop anti-angiogenic therapy once a patient shows cavitation of their tumor. But I have patients for whom I have been reluctant to direct them to clinical trials with newer anti-angiogenic agents because they have cavitation of lung tumors. This report sheds some light on this issue and suggests that it would be a mistake to be overzealous in directing patients with cavitating tumors away from such trials based on a worry about risk that may not be justified. I hope we learn more about this, but it’s helpful just to get this level of guidance on an issue that many of us have struggled with over the past couple of years.
Can Patients on Blood Thinners Safely Receive Avastin?
Because the anti-angiogenic drug avastin (bevacizumab) has been associated with some degree of increased risk of bleeding since the beginning of its development in lung cancer, the key trials have historically excluded patients who have been on blood thinners, at least at the standard dose (full dose anti-coagulation, or FDAC). In fact, though, patients with colon cancer have historically not been restricted, so the question has really been whether it’s necessary to restrict NSCLC patients who need FDAC from receiving avastin. In the US-based ECOG 4599 trial that compared chemo (carbo/taxol) alone to chemo/avastin and led to avastin’s approval (abstract here), patients who developed a blood clot that required blood thinners were taken off of the study. But is that necessary?
The bit of evidence we have about FDAC and avastin comes from the AVAiL trial done in Europe that compared chemo (in this case, cisplatin/gemcitabine) and placebo to the same chemo with either low dose or high/standard dose avastin. While patients on the AVAiL trial were not eligible if they were already on FDAC before the trial, the study did allow patients who developed a blood clot while on treatment to stay on the trial after initiating blood thinners. This gave an opportunity to compare the rates of bleeding complications among the patients not on FDAC to those who started FDAC and continued with avastin.
Developing blood clots is pretty common among patients with cancer, especially those with adenocarcinomas, who were the clear majority of patients on this trial that also excluded patients with squamous cancers. A total of 86 patients, divided pretty evenly among placebo arm, low dose, and higher dose avastin, were followed on while on FDAC along with their treamtent. They were compared to 900 other patients who remained off FDAC. As presented by Natasha Leighl from Toronto (reference here), there were no serious or fatal pulmonary hemorrhage events (coughing up blood) in patients on FDAC while also on avastin; there was a higher risk of bleeding in all patients on FDAC, including those who received placebo instead of avastin, but the real excess of bleeding events were just the mild grade 1 episodes like slight blood streaking with a cough, or a bloody nose.
Other studies are beginning to look at blood thinners with avastin and other antiangiogenic drugs, and at this point it’s really to early to declare it safe to give them together, but there also isn’t a clear signal of a significantly increased risk of bleeding, at least not beyond the risk of bleeding we see in patients on blood thinners overall. I’ll update with any new information if we see more study results presented at the ASCO meeting in early June.
Survival Benefit in Another Erbitux Trial for Advanced NSCLC Reported
Although it’s only a leak from a “reliable source”, news came yesterday (link here) about a new lung cancer development from a financial source (yet another example of us learning oncology from Wall Streeters). Specifically, we heard that the BMS-099 that I described in a prior post is actually demonstrating a significant benefit in overall survival (OS). To summarize the BMS-099 trial, it’s one that compared standard chemo of carboplatin/taxane (either taxol (paclitaxel) or taxotere (docetaxel) at the physician’s discretion) with or without the EGFR inhibitor Erbitux (cetuximab), which is an IV monoclonal antibody and “targeted therapy” in a population of patients with previously untreated advanced NSCLC. The schema is as shown here.
AVAiL Trial Negative for Overall Survival Benefit
We got some big news in the form of a press release today: avastin (bevacizumab) didn’t produce a survival benefit in the European AVAiL (AVAstin in Lung Cancer) trial of cisplatin/gemcitabine with or without avastin at either a higher dose (15 mg/kg IV every three weeks) or a lower dose (7.5 mg/kg IV every three weeks):
(Click on image to enlarge) Continue reading
Use of Avastin (Bevacizumab) in Patients with Brain Metastases
Since the anti-angiogenic agent avastin (bevacizumab) has been shown to confer a survival benefit in a subset of patients with previously untreated advanced NSCLC (see prior post), we have been struggling with questions of whether the restricted eligibility requirements in the pivotal initial avastin trial were necessary. Specifically, the trial, called ECOG 4599 (abstract here) excluded patients with squamous NSCLC, known brain metastases, on full dose anticoagulation/blood thinners (not low, prophylactic doses that are occasionally used to try to prevent patients from developing blood clots), with a history of clots or bleeding problems, or with a history of coughing up blood. While the trial was positive, these exclusion requirements have left only a minority of real world patients in the real world eligible for avastin — most experts estimating perhaps 30-50% of advanced NSCLC patients. Since then, the question has remained whether these exclusions are really necessary or are actually overly conservative. For example, avastin had already been approved for patients with advanced colon cancer, in whom there is no restriction on blood thinners or presumed need to check for brain metastases in that population. These restrictive factors have been evaluated over the last few years to try to establish whether it may be feasible to treat patients with these potentially “soft” exclusion factors with avastin.
Patients enrolling on trials to receive avastin have historically been excluded if they had a history of brain metastases, even treated with radiation or surgery, based on a single case in a phase I trial early in avastin’s development, in which a patient with liver cancer had an unsuspected brain metastasis and developed a fatal bleeding event in the brain (abstract here). Since then, avastin has been studied with chemo in some small trials of patients with primary brain tumors (cancers that originate in the brain, as opposed to the more commen reason for tumors in the brain, which is from spread to the brain from another source, most commonly lung cancer). In these trials, a few dozen patients with brain cancers have received avastin, and there has been a single reported bleed in the central nervous system (CNS, basically just another way of saying “brain”) thus far (abstracts here and here).
Since avastin was approved, there has been a change in practice for patients with advanced NSCLC. Before avastin was approved, many oncologists did not routinely perform head MRI scans looking for brain metastases if a patient was already known to have advanced NSCLC and did not have any neurologic symptoms. The idea was that there was little reason to look for brain metastases if some patients would never have symptoms from them, and if it didn’t need to change management. In fact, there is some evidence that patients can have shrinkage of brain metastases from chemotherapy that is in the same range as that seen outside of the brain (post here), leaving even less incentive to jump in to treat something that could be treated along with the cancer in the chest and elsewhere. But with avastin approved only for lung cancer patients with no evidence of brain metastases, we now go looking for brain metastases routinely in patients who are otherwise appropriate candidates for avastin. And now that we do head MRIs looking for them, we find them more commonly than we used to suspect; I and other lung cancer experts have estimated that somewhere in the range of 10-20% of patients will now be found to have brain metastases when you look hard for them. So there are many patients who are technically ineligible for avastin based on prior brain metastases. On the other hand, I’ve seen many patients in second opinions who have received avastin despite their having treated brain mets; some very good oncologists just provide a careful discussion of risk and benefit balance with avastin and treat patients with brain metastases despite the potentially increased risk of bleeding, especially since we really don’t know whether we’re just being paranoid. In fact, though, there were three patients on the avastin arm of the ECOG 4599 trial who developed bleeding in the brain, at least one of whom with new development of brain metastases that hadn’t been seen on initial presentation (Sandler, personal communication). Continue reading
Outcomes of Resecting Solitary Adrenal Mets: The “Precocious Metastasis” Revisited
I’ve previously described the concept of the “precocious metastasis”, the situation in which a patient presents with early stage NSCLC, except for a single metastasis, most typically in the brain or adrenal gland (see prior post). Our conventional teaching is that a patient with any metastatic disease almost certainly has additional micrometastatic disease, cancer cells floating in the bloodstream, that will inevitably lead to development of new areas of visible metastatic disease in the future (so having a small amount of metastatic disease would be like being “a little pregnant”). But as with so much of medicine, there are few absolutes, and about 25% of patients with solitary lesions that are surgically removed (or, presumably, alternatively, radiated with an approach like sterotectic radiosurgery, but this hasn’t really been proven) can have long-term survival. And a recent publication in the Journal of Clinical Oncology by several investigators in the lung cancer group at Moffitt Cancer Center in Tampa, FL (abstract here) provides a much needed characterization of outcomes for patients with solitary adrenal metastases who have undergone an adrenalectomy (removing one of the two adrenal glands, above the kidneys).
The study was a retrospective review of published reports, with at least four patients per publication, who had undergone adrenalectomy along with treatment of their early stage NSCLC. Importantly, the study divided patients into those who had synchronous metastases, meaning that the adrenal met was present when they first found and treated the main tumor in the chest, and metachronous lesions, which are mets that were not present initially but became evident an interval of time after a patient’s initial presentation and treatment (actually, a cutoff of six months is the usual definition of synchronous vs. metachronous).
Oncologists and surgeons have often perceived that patients with synchronous cancers are less likely to do well than those who return with a single metastasis a year or two after their treatment. The metachronous lesion that occurs 18 months later, for instance, has already demonstrated that new lesions aren’t going to be popping up rapidly. With a synchronous metastasis, it’s possible that this is just a snapshot in time, and the cancer is just early on its way to spreading to many areas in the body. Continue reading
EGFR Vaccine Early Results Published
The epidermal growth factor receptor (EGFR) is a central component of a cell pathway for growth and cell division that is thought to be affected in many cancers, including NSCLC. EGFR inhibitors have been the focus of clinical trials for several years and are now used for many types of cancer. Nearly all of this work has focused on either oral tyrosine kinase inhibitors that inhibit the back end activity of the receptor inside the cell or monoclonal antibodies that block the extracellular front end of the receptor that binds to the ligand (the matching protein that attaches to the receptor) that is supposed to trigger the receptor. But a new study was just published in the Journal of Clinical Oncology that describes the early experience of studying a new vaccine against EGFR in the treatment of advanced NSCLC (abstract here).
This study came out of Cuba (investigators not known to me) and used a vaccine made of one of the proteins that serves as a ligand for EGFR, attached to a carrier protein. This vaccine is given with an adjuvant, which in this case doesn’t mean post-operative treatment, but rather refers to a treatment that is given with a vaccine to help stimulate the immune system to generate a robust immune response.
A total of 80 patients with advanced NSCLC who had completed first line platinum-based chemo (4-6 cycles) at least 28 days earlier were then randomized (1:1, so evenly divided) between the active vaccine approach and “supportive care”, or general follow-up and treatment of any specific symptoms a patient developed. The patients who received the actual treatment received a low dose of cyclophosphamide, a chemotherapy that in this setting was used as an immunostimulant/adjuvant, 3 days before the vaccine, and then the vaccine injection on days 1, 7, 14, 28, and then monthly after that. Continue reading
Resources
Lung Cancer Support Community: A collection of patient discussion threads with broad participation that helps foster a true sense of community for patients and families of those with lung cancer. Funded by the LUNGevity Foundation, the only organization in the United States dedicated exclusively to funding lung cancer research.
National Lung Cancer Partnership: Formerly Women Against Lung Cancer, this group still focuses significantly on gender differences in risk for and treatment outcomes of lung cancer, but continues to grow and broaden its scope. They support clinical research and education about lung cancer and particularly women with lung cancer, and the site contains information for both patients and clinicians, with links to ongoing trials.
Lung Cancer Online: Developed by lung cancer survivor Karen Parles, this site features a remarkable collection of resources, including extensive links to other sites with valuable information about identifying specialists, work-up of lung cancer, treatment options, and clinical trials for the full range of patients facing lung cancer.
Lung Cancer Alliance: The only national non-profit organization dedicated to support and advocacy for those with lung cancer or at risk for it. Information, support, news, and other resources.
LCA Survivors Community: Among the many offerings of the Lung Cancer Alliance, this network provides discussion boards and blogs as part of an online community for those affected by lung cancer.
Lung Cancer Caring Ambassadors Program: Nonprofit dedicated to patient advocacy as well as education for the lung cancer community. They offer an educational guidebook called With Every Breath that can be ordered exclusively through their site, with content also offered free as pdf files for each chapter.
Lung Cancer Action4Life: After her husband was diagnosed with NSCLC in 2006 and encountered difficulties with obtaining certain drugs like Tarceva because of the limitations of the health care system there, Deanne Jenkyns started a website dedicated to providing information and practical advice aimed at increasing treatment options for lung cancer patients. They offer a combination of support and grassroots political action.
Lung Cancer Information Center: An electronic library of educational materials on cancer for healthcare professionals and patients.
MedLine Plus, Lung Cancer: A very comprehensive collection of manuscripts, links, and news covering the entire range of lung cancer from genetics and underlying causes, screening controversy, and treatment options. Sponsored by the US National Institutes of Health, and the US National Library of Medicine.
Joan’s Legacy: The Joan Scarangello Foundation to Conquer Lung Cancer, founded in memory of a never-smoking woman who developed bronchioloalveolar carcinoma (BAC), supports clinical research and journalism about lung cancer, with a special focus on recognizing never-smokers, BAC, and women with lung cancer.
Never-Smokers with Lung Cancer: A website fostering a network for never-smokers who developed lung cancer, with links to articles about this subtype and emerging research.
Roy Castle Foundation: UK-based charity dedicated to eradicatin lung cancer, supporting research and education particularly about early detection and smoking cessation.
The Mesothelioma Center offers the most comprehensive information on asbestos exposure and treatment options for those who have received a mesothelioma diagnosis.
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