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Lung Cancer Update Issue 1, 2008

DR HANNA: For patients with metastatic NSCLC, a PS of 0 or 1 and no contraindications to chemotherapy, I believe a platinum-based, two-drug regimen is standard. For patients who don’t have brain metastases, squamous histology, a history of hemoptysis or uncontrolled hypertension, the addition of bevacizumab is reasonable.

I treat those patients initially with two courses of chemotherapy and repeat their CT scans. If they appear to obtain clinical benefit, I administer four courses of chemotherapy. Because the Sandler study continued patients on bevacizumab, I administer it as maintenance until the time of disease progression.

The only randomized Phase III data combining first-line chemotherapy with bevacizumab are with carboplatin/paclitaxel and cisplatin/gemcitabine. I believe it’s reasonable to use either of those regimens with bevacizumab. Bevacizumab is likely to be safe and effective with other regimens, too.

At ASCO 2007, Dr Patel reported an improved response rate and acceptable toxicities with carboplatin/pemetrexed and bevacizumab. I believe those types of regimens would be perfectly acceptable.

Lung Cancer Update Issue 3, 2008

DR F ANTHONY GRECO: For front-line therapy, I favor either gemcitabine/carboplatin or pemetrexed/carboplatin. Although I use taxanes with carboplatin, I’m using them less often now off study because of the toxicity issues.

Gemcitabine/carboplatin is one of my preferred chemotherapy combinations because it’s as effective as other regimens and it’s well tolerated. Based on the emerging data, I also like pemetrexed/carboplatin for a tumor with nonsquamous histology. I believe that combination is even better tolerated than gemcitabine/carboplatin and the results are equally good, if not better, in that patient population.

Maintenance pemetrexed will probably increase the survival of patients with nonsquamous histologies, so I would also consider that therapy for select patients. However, to me, what we use in the front line is probably more important, and this is evolving. Pemetrexed will likely be one of the major drugs to use with a platinum in front-line therapy for nonsquamous cancer, and it’s likely to occur soon.

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Lung Cancer Update Issue 4, 2008

DR GREGORY J RIELY: One study that has changed the way I practice is reported in a paper by Scagliotti in the Journal of Clinical Oncology. It’s the largest randomized trial in up-front treatment for patients with Stage IV NSCLC ever published. Patients were randomly assigned to either gemcitabine/cisplatin or pemetrexed/cisplatin.

The analysis of the overall patient population revealed no difference in overall survival or progression-free survival by treatment arm. In a pre-specified subset analysis evaluating histology, patients with nonsquamous histology and, particularly, adenocarcinoma, fared better when they received the cisplatin/pemetrexed as compared to cisplatin/gemcitabine.

These data have led me to use cisplatin/pemetrexed as a first-line therapy for patients with adenocarcinomas.

I believe it’s reasonable to treat with a platinum-based doublet combined with bevacizumab.

Depending on the histology, my top three combinations to administer with bevacizumab off protocol are carboplatin/paclitaxel, cisplatin/pemetrexed and I still occasionally use gemcitabine/cisplatin. I have no objection to combining carboplatin with pemetrexed and bevacizumab, either — I just prefer to use cisplatin when possible.

Lung Cancer Update Issue 2, 2008

DR PEREZ-SOLER: The AVAiL study results, reported at ASCO 2007, demonstrated that bevacizumab adds benefit to the cisplatin/gemcitabine chemotherapy regimen in advanced NSCLC. Improvements in response rate and progression-free survival have been observed with the addition of bevacizumab.

The hazard ratios were good but were not as good as what was seen in ECOG-E4599, which evaluated the addition of bevacizumab to carboplatin/paclitaxel.

Initially, the premise was that bevacizumab would work independently of the chemotherapy used. I believe we are starting to learn that may not be true. Some chemotherapy regimens are better than others. For example, cisplatin/gemcitabine — which was used in AVAiL — may not be as good of a backbone as carboplatin/paclitaxel.

Some chemotherapeutic agents, particularly taxanes, are toxic to endothelial cells. They destroy blood vessels, which may help an anti-angiogenic agent and might explain why a taxane, at least in lung cancer, may be better. So it seems that a taxane-based regimen is probably a better option.

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Lung Cancer Update Issue 3, 2008

DR THOMAS J LYNCH: I believe bevacizumab is a beneficial agent and American oncologists have shown a remarkable ability to use it safely. The toxicity reports on the ARIES study, a registry trial of thousands of patients who have been treated with chemotherapy and bevacizumab, are consistently better than those from either the ECOG-E4599 or AVAiL trials. That suggests practicing oncologists are selecting the right patients to treat with bevacizumab.

Lung Cancer Update Issue 3, 2007

DR HEATHER A WAKELEE: In terms of off-protocol options for chemotherapy regimens to combine with bevacizumab in the metastatic setting, carboplatin/paclitaxel with bevacizumab is approved in the United States. Considering the AVAiL data, gemcitabine/cisplatin would certainly be reasonable now.

We’re conducting an ongoing trial with carboplatin/gemcitabine. I wouldn’t say that regimen is “ready for prime time” — not until we have the toxicity data, given the increased thrombocytopenia and neutropenia associated with that regimen. Substituting docetaxel for paclitaxel is reasonable because we don’t have any toxicity differences that would be of concern.

Lung Cancer Update Issue 4, 2008

DR RIELY: When determining treatment and whether to administer bevacizumab for a patient with advanced lung cancer, it’s important to discuss the potential risks, such as thromboembolic events and heart attack, because they can be quite dramatic if they occur. Stroke is a debilitating side effect, and patients need to hear about it.

I also discuss hemoptysis, and fatal hemoptysis, because that is an important cause of death among patients who are treated with bevacizumab: Those numbers are in the order of three to five percent.

As I sort through the risk factors for hemoptysis, certainly squamous histology comes to mind as a major one. Evidence of cavitation of the tumor before treatment is also something that I examine, and it drives me away from using bevacizumab in that setting. Central tumor is one we talk about a lot, but it’s not really well defined. I examine the scan to see if a tumor is abutting crucial large vessels — that’s my simplified take on what a central tumor represents.

Lung Cancer Update Issue 4, 2007

DR EDELMAN: I have worked fairly closely with the ECOG-E4599 eligibility criteria when administering bevacizumab for metastatic NSCLC. Patients are concerned about the risk of hemoptysis, but again, viewing this in the aggregate, patients fared better with bevacizumab. They live longer, so if we have patients who would have been eligible for that, we approach them about the use of bevacizumab.

I have used bevacizumab pretty much as it was used in E4599 with carboplatin/paclitaxel. The only difference is that I tend to use less cytotoxic chemotherapy — I use four cycles, not six, and I base that on my belief that the evidence is fairly compelling that cytotoxics do not aid you after four courses of therapy. I could certainly be criticized, but I believe it’s a reasonable approach and it’s well tolerated.

Lung Cancer Update Issue 1, 2008

DR PAUL A BUNN JR: It is reasonable to use bevacizumab to treat metastatic NSCLC for patients who are similar to those who were eligible for ECOG-E4599, the randomized study of paclitaxel and carboplatin with or without bevacizumab in advanced, metastatic or recurrent nonsquamous cell NSCLC.

Lung Cancer Update Issue 2, 2008

DR PHILIP BONOMI: Although improvements were modest on ECOG-E4599, we are now moving into the adjuvant setting with the ongoing ECOG-E1505 Intergroup study of postoperative chemotherapy with or without bevacizumab, and on that study we have fewer eligibility exclusions.

Lung Cancer Update Issue 3, 2008

DR LILENBAUM: The main difference between AVAiL, which evaluated the addition of bevacizumab to gemcitabine/cisplatin, and ECOG-E4599, in terms of anticoagulation, was that although patients who’d experienced thromboembolic phenomena were not eligible for either trial, if patients on AVAiL developed one of these complications while receiving bevacizumab, they were allowed to continue the bevacizumab with full anticoagulation. These individuals did not have significantly higher rates of pulmonary hemorrhages or bleeding complications.

Lung Cancer Update Issue 3, 2007

DR SOCINSKI: I view patients with Stage IV NSCLC and a good performance status as belonging to one of three major groups: patients who should receive bevacizumab, patients who shouldn’t receive bevacizumab and “never smokers.”

It’s interesting to talk to physicians across the United States about the percent of patients in their practices they consider eligible to receive bevacizumab. A wide spectrum is evident, ranging from approximately 20 percent to about 60 to 70 percent.

As for maintenance therapy with bevacizumab, in ECOG-E4599 patients were supposed to continue bevacizumab until disease progression. One of the philosophical debates we often have is whether the benefit of bevacizumab or anti-angiogenic drugs is maximized in the presence of chemotherapy — do you obtain much benefit after the chemotherapy is stopped?

We’ve had trial designs in which bevacizumab was stopped when the chemotherapy was ended. I don’t believe we have an answer.

I believe that if you conduct a Phase III trial and it’s positive, then when you translate that into practice, you should follow the approach used in the Phase III trial. So I have continued my patients on bevacizumab after I’ve stopped the chemotherapy, which is typically carboplatin/paclitaxel.

Lung Cancer Update Issue 4, 2008

DR ALAN B SANDLER: The AVAiL study was the European counterpart of ECOG-E4599. It used a three-arm design to evaluate cisplatin/gemcitabine with or without bevacizumab at two different doses, 7.5 mg/kg and 15 mg/kg. Response rate and progression-free survival endpoints were met in both the bevacizumab arms. Bevacizumab did not add significant benefit to survival, although overall survival was good in all three arms.

The AVAiL study is compelling. The hazard ratio for progression-free survival was 0.75 in the low dose and approximately 0.8 in the higher dose, but E4599 is the only study to date that shows a survival advantage, which is with the 15-mg/kg dose, so I am still administering that dose.

Lung Cancer Update Issue 1, 2008

DR WOZNIAK: Two trials are studying groups of patients whom we perceive as potentially benefiting more from erlotinib. Those are never smokers, who are involved in one study, and patients with bronchoalveolar carcinoma, or adenocarcinoma with bronchoalveolar carcinoma features, in the other. Patients will receive the combination of erlotinib and bevacizumab, which appeared promising in other clinical trials. These trials started recently, so not many patients have enrolled. We will also evaluate biologic correlates — mutations, EGFR expression and FISH analysis — that will be important in order to determine whether characteristics of the tumor predict response.

Right now, I don’t use erlotinib with bevacizumab off study, but we are participating in a Phase III study evaluating erlotinib with or without bevacizumab as second-line treatment. I would like to see the results of that study before proceeding to use the combination off study.

Lung Cancer Update Issue 3, 2008

DR GRECO: I believe those patients with metastatic NSCLC who are nonsmokers should first receive oral tyrosine kinase drugs — the EGFR inhibitors — and I prefer erlotinib. No cure exists for these patients, and if they have exon 19 or 21 mutations, which most of them have, the median survival is close to two years with this agent.

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One could argue that we should administer chemotherapy first, but I don’t agree. Chemotherapy is more toxic, in general, and I’m not sure we gain anything by using it first. We need studies to determine whether we should use sequential therapies or combinations, but right now I would use erlotinib for these patients as a single drug for primary therapy.

Lung Cancer Update Issue 1, 2008

DR WOZNIAK: The only factor I consider in the treatment algorithm for EGFR-positive metastatic disease is nonsmoking status because that seems to have the strongest support for using an EGFR inhibitor. In the clinical setting, I believe the standard approach up front is still systemic chemotherapy. As first-line therapy, I use carboplatin/paclitaxel or carboplatin/gemcitabine. In terms of what to do with the never smoker — someone who’s smoked fewer than 100 cigarettes in his or her lifetime — I will discuss the option of erlotinib. If any patients were going to respond, they would be in that particular group. The majority of patients who dramatically respond to these drugs generally do so within the first four weeks of treatment. So if someone would like that option, I don’t believe there’s anything wrong with it. For a never smoker, I would consider it as first-line therapy.

Lung Cancer Update Issue 4, 2008

DR RIELY: In my Journal of Clinical Oncology publication with Vince Miller, we reported on a multicenter trial, at Vanderbilt and the MD Anderson Cancer Center, with 100 patients who had pure bronchoalveolar cell carcinoma or adenocarcinoma with bronchoalveolar cell features. Adenocarcinomas with bronchoalveolar cell features are more common. All patients were required to have tissue samples to participate in this trial. We treated all of them with single-agent erlotinib at the conventional dose.

We found a 22 percent response rate in the overall patient population. We also performed molecular analysis using a variety of biomarkers, such as EGFR mutation, EGFR gene copy number and K-ras mutation. Among the 18 patients who had EGFR mutations, we saw a response rate of approximately 80 percent, and of the 18 patients with K-ras mutations, we saw a response rate of zero percent. None of the patients with K-ras mutations responded. Patients with an elevated EGFR copy number showed an improved progression-free survival and response rate.

After performing a multivariate analysis examining all these factors, the only factor shown to be a predictor of response was EGFR mutation. The take-home message from our study is that erlotinib is an effective agent for patients with bronchoalveolar cell carcinoma or adenocarcinoma with bronchoalveolar cell features, and the best predictor of response in this setting is EGFR mutation.

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Lung Cancer Update Issue 2, 2008

DR PEREZ-SOLER: The data on bevacizumab with erlotinib are encouraging so far. In the initial study by Roy Herbst with about 30 patients who failed at least one platinum-based regimen, the overall survival was one year with bevacizumab/erlotinib. In CAN-NCIC-BR21, the overall survival was about eight months for that group when treated with erlotinib alone.

In the study by Fehrenbacher, bevacizumab added benefit to erlotinib. The good news was that this combination of two non-chemotherapeutic agents — bevacizumab and erlotinib — was superior to single-agent chemotherapy (docetaxel or pemetrexed).

Bevacizumab also added benefit to single-agent docetaxel or pemetrexed, so you could also combine pemetrexed or docetaxel with bevacizumab as second-line therapy for a better regimen.

However, the key issue is that patients who receive bevacizumab will receive it as front-line therapy. Once their disease has progressed, who will have the guts to keep pushing bevacizumab without data?

The BeTa trial, comparing erlotinib to erlotinib/bevacizumab, is being conducted only with patients who have never received bevacizumab as front-line therapy. It will probably be positive for the combination, but then the question will be how relevant this study is in practice because none of the patients in the trial received bevacizumab as front-line therapy.

I believe many people will conclude that it doesn’t mean anything. We need to determine whether bevacizumab is a good drug as second-line therapy for patients who have received bevacizumab as front-line therapy.

Lung Cancer Update Issue 1, 2009

DR ROY S HERBST: The idea of using a non-chemotherapy doublet for advanced NSCLC in order to avoid the cytotoxicity, myelosuppression, neuropathy and so forth is attractive. The bevacizumab/erlotinib combination is easy to administer and has minimal toxicity — not much more than observed with single-agent erlotinib — and it has shown good activity in Phase II studies compared to chemotherapy. The Phase III BeTa trial compared second-line bevacizumab/erlotinib to erlotinib alone and did not meet its primary endpoint for an improvement in overall survival. However, it did result in improvements in progression-free survival and response. Currently, one has to question whether we will be able to demonstrate survival advantages in any trials in lung cancer, where 30 to 40 percent of patients go on to receive subsequent therapy. We may not be able to use survival as a primary endpoint in trials with these targeted agents.

Lung Cancer Update Issue 4, 2007

DR WALTER J CURRAN JR: There are molecular and epidemiologic predictors of response to EGFR TKIs in second-hand third-line treatment of NSCLC. Patients who are never smokers, women and of Asian descent have a higher likelihood of responding to a tyrosine kinase inhibitor (TKI) than men who are heavy smokers and non-Asian.

In searching for predictors of response at the molecular level, the focus is on mutations in chromosomes 18 and 22. Work is also being conducted at Harvard, Sloan-Kettering and Colorado showing that EGFR mutational analysis is extremely helpful, in the right hands. The FISH-type analysis by Fred Hirsch and others has also been useful for predicting response.

Recently, we’ve seen interest in whether the presence of a K-ras mutation is a sufficiently adverse predictor of response to warrant not using TKIs. I reviewed data suggesting that, although the overall response rate using RECIST is lower in patients with K-ras mutation-positive disease, waterfall-type trends clearly suggest that the range of responses does not appear different in those patients with K-ras mutations than those with non-K-ras mutations.

Lung Cancer Update Issue 2, 2008

DR BRAHMER: Some investigators believe that EGFR mutations are the major predictors of response, while others believe that EGFR gene expression, as measured by FISH, determines benefit from TKIs. We know that patients treated with EGFR inhibitors will respond better if they have EGFR mutations, but will they live longer? The large Canadian trial CAN-NCIC-BR21, which evaluated erlotinib versus placebo, retrospectively addressed this issue, and patients with EGFR mutations did not live any longer than those without the mutations when treated with erlotinib.

However, patients treated with erlotinib who had increased EGFR gene expression as determined by FISH did live longer. Data from the INTEREST study, evaluating gefitinib versus docetaxel, may reverse those findings.

The first-line trials evaluating erlotinib in patients with EGFR mutations will answer whether we should move erlotinib to the first-line setting for those patients. I don’t believe the mutations will indicate whether a patient will live longer with erlotinib versus another treatment, but those patients with EGFR mutations probably need erlotinib up front rather than chemotherapy.

Lung Cancer Update Think Tank Issue 1, 2008

DR RONALD B NATALE: Although we may be headed in the direction of sending each tumor for biomarker analysis, and it may well be the norm in a few years, I don’t believe we’re there yet. I may be an outlier from my colleagues, but I don’t believe we’re at the point at which we should advise community oncologists to request EGFR mutation, immunohistochemical staining for EGFR or FISH analysis for every patient with lung cancer. I don’t believe any of that helps them make a decision regarding optimal therapy at the bedside.

I don’t believe we’ve proven the case just yet. It’s interesting that in the FLEX trial, less than 15 percent of patients were excluded by negative IHC staining for EGFR. FLEX is an important trial and it has interesting data, but I’m not convinced. A hazard ratio of 0.87 does not entice me to rush out and begin administering cetuximab to every patient receiving chemotherapy.

I’m a little more conservative about the results of FLEX. I believe that it’s important for oncologists to know the data, but I don’t believe it should change standard practices at this point.

Lung Cancer Update Think Tank Issue 1, 2008

DR JABLONS: Should every patient who has a resection for NSCLC routinely receive EGFR mutation analysis? This argument arises in our tumor board all the time. In fact, our pathologists don’t even bother asking me in our discussion, because I always request it.

Currently, we don’t know how to handle the data specifically. I believe, especially in the setting of the resected specimen when you have plenty of tissue, the more you know about it the better. Eventually, that’s how we’ll make decisions regarding emerging biologic and targeted therapies.

To me the hard part is justifying the cost. Perhaps in most community practices, pathologists aren’t prepared to conduct molecular analysis. They may be more apt to perform straightforward immunohistochemistry or even FISH for breast cancer. I predict that ultimately, certainly with resected specimens, as molecular-targeted analysis becomes more straightforward and high throughput and RT-PCR molecular diagnostics come into vogue — which is clearly the way things are headed — it will be a routine and de rigueur approach.

The bigger problem is with patients with advanced-stage disease when you don’t have much tissue at all, only a bronchial wash or fine-needle biopsy. I believe that we shouldn’t hesitate to go back and perform biopsies on our patients, when we can obtain core biopsies on them.

Lung Cancer Update Issue 3, 2008

PROF ROBERT PIRKER: The FLEX trial aimed to demonstrate superior survival for chemotherapy with cetuximab compared to chemotherapy alone in advanced NSCLC.

The eligibility criteria included documented Stage IIIB disease with malignant pleural effusion or Stage IV disease. Patients with all histological subtypes were eligible. We included patients with ECOG PS 0 to 2. The other main inclusion criterion was that we did not screen for brain metastases. In the case of known brain metastases, patients were excluded. So it was a broad patient population.

Cetuximab with chemotherapy demonstrated superior overall survival compared to chemotherapy alone, with a hazard ratio of 0.87 and a 30 percent risk reduction.

The median survival in the cetuximab arm was 11.3 months versus 10.1 months, and the one-year survival in the cetuximab/chemotherapy arm was 47 percent compared to 42 percent in the chemotherapy-alone arm for the overall population.

We did not see a significant difference in progression-free survival, however. We also analyzed time to treatment failure, and we observed a significant difference in favor of the cetuximab arm.

I believe that the clinical implications of FLEX are that it will become one of the standard treatments in the future, if not the standard treatment, at least in Europe. I anticipate this because of the survival advantage reported with cetuximab in such a broad population with all histological subtypes.

It’s also of importance to note that a cisplatin-based protocol was used, and I believe that cisplatin-based protocols are slightly superior to carboplatin-based protocols, particularly with regard to patient survival.

Lung Cancer Update Issue 3, 2008

DR LYNCH: Based on the results from FLEX, I believe cetuximab will be used for NSCLC. Patients and doctors want options that improve outcome. Cetuximab with chemotherapy improves outcome, similar to the way that bevacizumab with chemotherapy improves outcome. I believe we’ll see bevacizumab used for bevacizumab-eligible patients and cetuximab used for patients for whom bevacizumab is not an option. Learning more about which biomarkers identify those who might benefit from therapy may broaden the group of patients who are treated with cetuximab.

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Lung Cancer Update Issue 4, 2008

DR RIELY: It’s reasonable to consider cetuximab for patients with advanced squamous cell NSCLC.

The side effects of cetuximab are real, including the rash and the side effect that is rarely talked about, which is weekly therapy. Patients must come to the doctor’s office once a week for the first six cycles of therapy, which is a burden for a patient with Stage IV disease.

I discuss with patients the reported benefit but also the rash, and they are not interested in having the rash. The improvements in overall survival are relatively modest, and it’s difficult for patients to accept the idea that they will receive something that causes side effects without a marked benefit.

The conversation that I have with patients is to help them understand that we use a number of lines of therapy and that all therapy does not have to occur in the first line — it’s like the multiple chapters of a book. I believe it’s reasonable to use cetuximab with most of our standard platinum-based doublets. The FLEX trial used cisplatin/vinorelbine. Certainly, that’s a widely used therapy in Europe, but it’s not a widely used therapy in the United States by any means. We do have a fair amount of safety data from the Canadian study led by Butts demonstrating that it’s acceptable to use cetuximab with gemcitabine/cisplatin. We also have safety data from a trial led by Tom Lynch showing that carboplatin/paclitaxel is safe to administer with cetuximab. I believe that these are safe combinations.

Lung Cancer Update Issue 3, 2008

DR GRECO: The trial data presented by Ciuleanu at ASCO evaluated pemetrexed in patients whose disease had not progressed after platinum-based induction chemotherapy. The patients were randomly assigned to receive pemetrexed or no maintenance therapy. The trial demonstrated an advantage with pemetrexed maintenance for the patients with nonsquamous cell cancer.

I found the data interesting and important considering the advanced disease trial that was presented at the International Association for the Study of Lung Cancer in Korea in September 2007. That study showed that in advanced disease, first-line pemetrexed/cisplatin was superior to gemcitabine/cisplatin for patients with nonsquamous histologies.

I believe pemetrexed is likely to play a major role in the treatment of nonsquamous cell cancer, as first-line therapy and perhaps as maintenance therapy also. It might be that because we’re using a better drug, we could use it in either setting and still obtain the same overall survival benefit. That’s my bias.

Even though this is only one trial, I believe maintenance pemetrexed will increase the survival of patients with nonsquamous histologies, so I would consider that therapy for select patients.

Lung Cancer Update Issue 4, 2008

DR DAVID S ETTINGER: Dr Ciuleanu presented a study at ASCO evaluating maintenance pemetrexed. The study selected several combination chemotherapeutic regimens and then randomly assigned patients two to one to pemetrexed or placebo. Both groups received vitamin B₁₂/folate and dexamethasone. Ciuleanu’s data demonstrated that patients with adenocarcinomas benefited from maintenance pemetrexed.

A caveat to the study was that it did not evaluate immediate versus delayed maintenance therapy. The year before, Dr Fidias presented a study that evaluated docetaxel in the same population of patients, randomly assigning them to immediate docetaxel or delayed docetaxel at disease progression. The “immediate” arm demonstrated an improved response rate and improved progression-free survival. However, the study did not provide an overall survival rate.

For those of us who have been in the field for many years, whether we treated breast, lung or colon cancer, once a patient developed metastatic disease they were administered chemotherapy until they died. These days we have options for patients who do not want to receive chemotherapy, and many feel good about this. Now we’ve almost come full circle to say, “Do patients have to receive maintenance therapy?”

In my practice, I have not been administering maintenance therapy. What I struggle with is whether to add maintenance pemetrexed to maintenance bevacizumab after concurrent chemotherapy and bevacizumab, based on the ECOG-E4599 study. Potentially, a patient achieves stable disease. Do you add pemetrexed? Other studies are evaluating the combination of pemetrexed with bevacizumab and the combination of bevacizumab with cetuximab.

They might provide valuable data, but we do need the trials to prove it. Another reservation I have pertains to cost. Bevacizumab ranges from $8,000 to $11,000 every three weeks, and pemetrexed is not cheap either.

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Lung Cancer Update Issue 3, 2008

DR LILENBAUM: The pemetrexed maintenance study was perhaps the one study at ASCO that has the most immediate impact in practice. This trial is quite relevant.

The Phase III study of maintenance pemetrexed or placebo was powered for progression-free survival, which in this particular setting may be an appropriate endpoint, as opposed to in a first-line trial, for example.

They found a significant difference in progression-free survival. In fact, it doubled. It was a little less than two months in the placebo arm and a little more than four months in the pemetrexed arm. The curves split from the beginning. Even though the difference in median survival was not statistically significant, it trended strongly in favor of pemetrexed. The absolute difference in median survival was nearly three months, with a p-value of 0.06.

This is a strong signal that this agent may have had an impact on overall survival. It’s important because this trial adds to the Fidias trial from ASCO 2007, which addressed a similar issue. Another trial from Japan evaluated gefitinib after three cycles of chemotherapy. Although it examined different issues, it resurrects the whole maintenance question, which has been a dogma for 20 years in the treatment of this disease.

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Also, a meta-analysis of 13 randomized trials was presented at ASCO that indicated, again, a positive effect of maintenance on progression-free survival that was statistically significant. No significant difference was recorded in overall survival.

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