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Just another negative trial, or a worrisome trend?
Last week, the preliminary results of interim analysis the ESCAPE (Evaluation of Sorafenib, Carboplatin, And Paclitaxel Efficacy in NSCLC) trial were presented by Dr. Scagliotti at the 1st IASLC (International Association for the Study of Lung Cancer)-ESMO (Eurpean Society for Medical Oncology) Lung Cancer Conference in Geneva, Switzerland. This was a randomized, placebo-controlled, double-blind phase III study for patients who have not yet had chemotherapy for advanced NSCLC. Patients were treated with a standard course of chemotherapy (carboplatin and paclitaxel) and were randomized to receive sorafenib or placebo along with chemo. As you may recall from other posts, sorafenib (also known as nexavar) is an oral multitargeted tyrosine kinase inhibitor which primarily acts to block the VEGF receptors thus inhibiting tumour angiogenesis (blood vessel growth and development). Dr. West previously noted in a prior post that this trial was reportedly negative, but I was able to see the first presentation of the actual results.
In recent years the idea to combine antiangiogenesis agents with chemotherapy has become very popular, and this strategy was further encouraged by the positive results of the E4599 study that demonstrated a two month survival advantage when the monoclonal antibody to circulating VEGF, Avastin (bevacizumab), was combined with carboplatin/paclitaxel. Unfortunately, we have also recently learned that a similar trial with cisplatin/gemcitabine plus Avastin (AVAiL) failed to confirm this survival advantage (prior post here). What the future of this combination looks like is now unknown, at least for the countries who have not funded chemotherapy plus Avastin based on E4599.
In any case, the ESCAPE trial enrolled 926 patients over approximately 18 months (Feb 2006 – May 2007). The demographics of this population were very similar to other studies, about 62% male, medically fit for chemotherapy (ECOG performance status (PS) of 0 or 1), and no brain metastases at the time treatment started. Approximately 25% of patients had squamous cell carcinoma, the majority having adenocarcinoma: this is all very typical for phase III studies in advanced NSCLC. The toxicities were fairly predictable, and the median number of cycles of chemotherapy was 5 for the chemo alone group and 4 for the chemo plus sorafenib group. The response rates were also standard for the chemo alone arm with response rates of 5% complete (no evidence of residual cancer), 23% partial response, and 51% with stable disease. The chemo plus sorafenib arm was very similar with 1% complete, 30% partial response, and 46% with stable disease.
The progression-free survival was 5.1 months in the chemo alone arm and 5.4 months in the chemo plus sorafenib arm. The median survival was similar in both arms: 10.7 and 10.6 months in the control and experimental arms, respectively. Neither of these reached statistical significance. Thus, this trial did not meet its primary endpoint, which was to improve survival by the addition of sorafenib.
One interesting feature that came out of this study was the subgroup of patients (25%) who had squamous cell carcinoma. In this group the median survival for those who received sorafenib was worse than the control arm, 13.6 versus 9.8 months. In the non-squamous carcinoma group, the median survivals were similar at 10.3 and 11. 5months for the control and the sorafenib arm, respectively. The toxicities were not particular different for the patients with squamous cancers, though more patients died of progressive disease on the sorafenib arm (33%) than the chemo alone arm (25%). Overall, the reason this possible worse outcome for squamous patients on sorafenib plus chemo remains unknown — however, the 13.6 month survival for the squamous arm is longer than one would expect from previous studies, so perhaps there was some biological imbalance that was not evened out by the randomization process.
The results of this study, although I stress that these are only the preliminary results, are troubling for a number of reasons. Of course it is disappointing that this strategy did not make a significance difference in survival. But more than this, I am concerned that this might be a trend, and this is particularly worrisome after the early closure of a very similar study (BR-24, run by the NCI-Canada) with carboplatin/paclitaxel with or without AZD2171 (cediranib, with the trade name Recentin), another oral multitargeted tyrosine kinase inhibitor of VEGF receptors. Although no results have been released from this study (it will likely be presented at the ESMO meeting in Sept 2008), it is troubling that it was stopped early after an interim analysis that showed it could not meet its primary endpoint to improve overall survival with the chemo-AZD2171 combination. There are rumours that that there were toxicity issues rather than a lack of efficacy, but still it is something of a disappointment.
The potential failure or problems with tyrosine kinase inhibitors of angiogenesis with chemotherapy reminds me of the earlier failures of the combinations of chemo and the oral EGFR inhibitors (INTACT 1 and 2, TRIBUTE, and TALENT; described in a prior post here). And now with the lack of improvement in survival in the AVAiL trail (cisplatin/gemcitabine with or without Avastin), perhaps lung cancer investigators, myself included, have to at least consider the possibility that this strategy isn’t working. Or it isn’t working for all types of NSCLC. Of course all of these studies have a solid foundation in basic (lab-based) research, with tumour models suggesting this is a successful strategy making the results in people all the more frustrating and disappointing.
To me, this reinforces the need to collect human tumour tissue and work closely with our colleagues in the labs to figure out some of the differences among various lung cancers. Perhaps it stimulates other questions out there.
As always, I’d be interested to hear your thoughts.
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
Clinical Trials with Sutent (Sunitinib) in NSCLC
One of the novel agents being studied in lung cancer is sutent (sunitinib), a multi-targeted oral anti-angiogenic drug that I’ve described in a prior post. While I’ve mentioned a small study I’m leading at my own institution with this agent in advanced NSCLC patients with bronchioloalvelar carcinoma (BAC) or who have never smoked (information here), I wanted to describe a couple of larger studies that are being run by Pfizer, the company that is developing sutent, in lung cancer. Their development program is a series called the SUN trials, for Studies to UNderstand Sunitinib, another acronym that is a bit of a stretch in order to be memorable.
These trials are based on the combination of sutent/tarceva, which has been studied in a limited trial in kidney cancer (abstract here), and another one in NSCLC is being conducted at the University of Wisconsin (information here).
The largest trial is SUN-1087, which is an international phase III randomized trial of the combination of sutent and tarceva (erlotinib) compared to a current standard for previously treated patients with advanced NSCLC of tarceva with a placebo. The SUN-1087 trial is ongoing and will plan to enroll 956 patients in the second or third line setting, and it patients with any kind of NSCLC (adenocarcinoma, squamous, or less common subtypes). It will look at potentially important variables such as whether enrolled patients received prior avastin (bevacizumab), whether they are a never-smoker, ex-smoker, or current smoker, and also their EGFR status (I believe my looking at immunohistochemistry, the levels of EGFR protein on tumor cells. These factors will be monitored and compared between the two arms so that neither arm receives far more never-smokers, prior recipients of avastin, etc. – a balancing act called stratification. The tarceva will be given at the standard starting dose of 150 mg daily, with sutent at 37.5 mg daily, and the trial will treat all patients until they develop either progressing cancer or prohibitive toxicity. The goal of the study will be to see whether the tarceva/sutent provides a significant overall survival (OS) advantage over tarceva alone (with tarceva). Further information on this trial, including participating sites, is available here.
A smaller trial known as SUN-1058 has a very similar design of tarceva/sutent vs. tarceva alone, but it doesn’t have a placebo included. It is enrolling essentially the same population of previously treated patients with advanced NSCLC (second and third line), with any NSCLC subtype, but will only enroll a total of 126 patients and will be looking at progression-free survival (PFS) as the primary endpoint. Further information on this trial, including participating sites, is available here.
You might ask yourself why a company would conduct two trials with such similar designs – it’s not a typical approach, and I’m still not sure why the company would do this. However, I speculate that the reason for running a small trial at the same time as a large trial is a strategy to obtain early feedback from a small trial looking at PFS (a quick endpoint) that could potentially lead to changes or an early termination of the larger trial looking at the longer-term endpoint of OS before having invested far more millions into the larger trial. Continue reading
Second Line Treatment in Elderly Patients
Completing the analysis of the randomized trial that compared alimta (pemetrexed) and taxotere (docetaxel) in second line treatment of NSCLC (abstract here), which showed nearly identical response rates and survival but a more favorable side effect profile with alimta, another retrospective review of results looked at differences between the arms in older vs. younger patients (abstract here).
Typically, the trial enrolled only a minority of patients 70 and older, who accounted for only 86 of the 571 patients on the study (15%), despite the fact that the median age for patients newly diagnosed with lung cancer in the US is now just over 70. Besides age, they didn’t differ significantly in performance status, NSCLC subtype, or other variables from the younger patients. There were also no clear differences between the older patients who were randomized to taxotere vs. alimta.
The trial as a whole showed no differences in efficacy between the two drugs, and that was true for the 85% of patients who were under 70. But in the patients 70 and older, there was a better progression-free survival (PFS) and overall survival (OS) in recipients of alimta:
(Click on images to enlarge)
By the numbers, median PFS in patients 70 and older was 2.9 months with taxotere and 4.6 months with alimta; for OS, the numbers were 7.7 and 9.5 months, respectively. One year survival numbers weren’t different, 23.1% vs. 20.4%. Continue reading
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