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Anti-angiogenic agents

Current and emerging approaches to anti-angiogenesis in lung cancer

GRACE Video

Maintenance Therapy for Advanced NSCLC

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GRACEcast-522_Lung_West_Maintenance_Therapy_Advanced_NSCLC

 

Dr. Jack West, Swedish Cancer Institute, defines maintenance therapy in advanced NSCLC and discusses maintenance treatment strategies.

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For patients with advanced non-small cell lung cancer, our typical approach, if we have someone who does not have a driver mutation that we typically treat with a pill-based targeted therapy, is to give chemotherapy. That chemotherapy is typically given in a cycle of three weeks or sometimes a four week period of time where the blood counts go down and then recover. That treatment is typically given once every three weeks, sometimes once or twice on a weekly basis in that three week interval, but we typically give that therapy for about four to six cycles of therapy — that’s about three to five months of treatment. By that time, by four to six cycles in, the two drug combination that includes a drug called platinum is usually creating some cumulative side effects: fatigue, low blood counts, and other complicating issues that make it increasingly challenging to administer more of the same potentially intensive therapy, and by four to six cycles you really tend to reach a point of diminishing returns.

At that point we often favor a maintenance therapy approach. That is, dropping the carboplatin or stopping all of the agents that have been given previously and either continuing one or more of the agents from the first line setting, or using what’s called switch maintenance to give a completely different treatment. These maintenance therapies are designed to do what their name suggests — to maintain a response after we’ve seen the most shrinkage that we’re likely to get from the more intensive first line therapy.

When we do a continuous maintenance approach, it’s typically taking a drug like cisplatin or carboplatin in combination with one or two partner drugs, usually a second chemotherapy agent and sometimes Avastin which blocks a tumor’s blood supply, and then after four to six cycles we drop the platinum and we will typically continue a drug like Alimta if that’s been given in the first line setting, and if a drug like Avastin has also been given we might continue that and give Alimta and Avastin together until the cancer progresses.

If a combination like carboplatin and Taxol were given with Avastin, the maintenance therapy is often just the Avastin because Taxol tends to have some cumulative neuropathy issues — numbness and tingling that can lead to a real limitation in how much of that therapy you can give. We might also consider a switch maintenance approach — instead of continuing some of the agents, come in with Alimta as a single agent if a patient has non-squamous histology. Another agent that is approved as a switch maintenance therapy is Tarceva (erlotinib) — this doesn’t tend to be as favored as a switch maintenance because the efficacy of Tarceva in patients who don’t have an EGFR mutation tends to be on the lower side.

What do these maintenance therapies have in common? Well they’re all agents that can be given on a longitudinal basis without a lot of cumulative side effects and they tend to be the agents that have good activity in patients who have already been on prior therapy. So any of these is a reasonable choice, the most common being a continuation maintenance of dropping the platinum and continuing one or two partner drugs that were given with it, or sometimes switching to an agent like Alimta (pemetrexed) or Tarceva (erlotinib). It’s also reasonable to not pursue maintenance therapy if a patient has cumulative side effects and really needs a break from therapy. That is certainly something to discuss with the patient; it’s not as if maintenance therapy is a mandate for all patients, but it is something that is a strong consideration if a patient is motivated and can continue to tolerate ongoing therapy after four to six cycles.


GRACE Video

What is the Role of Bevacizumab in Stage IV NSCLC?

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GCVL_LU-F09_Bevacizumab_Role_Stage_IV_NSCLC

 

Dr. Jack West, Swedish Cancer Institute, discusses the anti-angiogenic agent bevacizumab (Avastin) and the trial evidence of its efficacy for non-squamous NSCLC.

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In addition to standard chemotherapy, usually a two drug combination, we sometimes add a third drug called Avastin, also known as bevacizumab. Now this is not a standard chemotherapy agent — instead Avastin acts as an anti-angiogenic therapy, that is, it blocks the tumor’s blood supply, and it is sometimes included in the treatment regimen really only for the patients who have a non-squamous cancer.

Why is that? Well, years ago when Avastin was first being studied in many different kinds of patients with lung cancer — non-small cell lung cancer, either squamous or non-squamous, we found that a significant minority of patients had problems with bleeding complications, specifically coughing up blood that reached a potentially life-threatening or fatal level. That was found to be almost always limited to the patients with squamous histology. So obviously we decided that was not the way to go, and studies after that really limited treatment with Avastin to patients with non-squamous lung cancer. After that we found that even though you could have bleeding complications in a small minority of patients, it was much less of a concern when Avastin is limited to patients with non-squamous lung cancer.

Now, it is FDA approved in combination with two-drug chemotherapy, specifically the combination of carboplatin and Taxol, also known as paclitaxel. That’s because a key trial known as ECOG 4599, which was done across many different centers in North America, compared standard chemotherapy with carboplatin and paclitaxel or Taxol, to the same chemotherapy with Avastin added to it. The study found that patients tended to live longer by an average of about two months. Because of that, and the tolerable side effect profile, it became standard of care to at least consider adding Avastin to the two-drug chemotherapy combination for patients with non-squamous histology.

Now importantly, a couple of other studies have been done since that time, also using Avastin, that didn’t clearly show a survival benefit, and because of that, Avastin is really considered an option but not an absolute mandate, and many oncologists do not routinely use it for most or all of their patients. It’s something to discuss with a patient perhaps, but for patients who have a history of brain metastases or any potential bleeding complications, it may not be advisable because the safety may be enough of a concern to minimize that, and it has not consistently shown a survival benefit after that ECOG trial that I mentioned. But, for some patients it is reasonable to do a two-drug combination of chemotherapy, whether that is carboplatin and Taxol, or perhaps a different one such as carboplatin and Alimta, also known as pemetrexed, while adding Avastin to that.


GRACE Video

Can Patients Benefit from Broad vs. Focal Genetic Testing?

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WCLC_2015_10_Patients_Benefit_Broad_vs_Focal_Genetic_Testing

 

Drs. Ben Solomon, Leora Horn, & Jack West evaluate the merits of broad genetic testing with a “next generation sequencing” platform compared to selective, limited testing for the most proven driver mutations in patients with advanced NSCLC.

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Dr. West:  One of the bigger questions in the whole management of lung cancer is now whether and how often to do broad genomic testing, or really focal testing for a few clearly actionable mutations like EGFR, ALK rearrangement, ROS1, perhaps others that may emerge. What’s your approach — where do you think that your rank and file community oncologist should be, in terms of using broad genomic testing to find, not only the more common ones, but the rarer ones? Do we have enough rare mutations now to widen the scope of our looking, or are there barriers, whether it’s the turnaround time, or others interpreting the results of various rare rabbit holes to go down, that it make it not ready for prime time? Leora, what do you think?

Dr. Horn:  A lot of academic sites are doing it because we have clinical trials. If we’re talking about practical, you know, what day-to-day, I think that it’s important, at minimum, to do EGFR, ALK, ROS, RET, and even BRAF, because there’s been some promising data. If you can get that all done, and maybe it’s through multiplex testing, or next generation sequencing — the problem is, sometimes these test results come back and you get mutations, you don’t know what to do with them, or there’s nothing available for those patients. So, for a day-to-day, practical, we should do those minimal, actionable mutations. I think it’s always nice to know the additional information, but I don’t think it’s essential in making treatment decisions.

Dr. West:  Ben, what do you think?

Dr. Solomon:  So, I agree — I think what’s essential is that a patient gets the best available treatment. Now, the best available treatment will vary from place to place, and country to country, but currently, in most places around the world, EGFR inhibitors and ALK inhibitors are available, and guidelines from professional societies, such as the College of Pathologists, and ASCO, and IASLC, recommend at a minimum testing for EGFR and ALK, and I think that’s a minimum. Now, I think there’s a good case for adding things like ROS1, because of availability of crizotinib, and with the availability of trials at different molecular targets, I think there is a good reason, in most academic centers at least, to expand the panel to include a larger number of actionable mutations, and I think the eventual place that we’ll get to is where all of these tests get done in one test, and we get a report analogous to a Foundation Medicine report that sums up the actionable mutation.

Dr. West:  Yeah, I think once get beyond three of four, it starts to tip the scale toward just get everything at once. I mean, if we’re moving to a time when HER2 mutations, and MET over amplification, as well as, as you said, BRAF, and others, I mean, there’s RET — the list is getting long enough, and it seems that we’re adding maybe one or two every year or so, that hopefully it will be worth doing a broad panel approach for the majority of patients. But, as you say, it depends on where you are and what your access is.


GRACE Video

ECOG 1505 Study: No Benefit of Post-Operative Avastin in Early Stage Lung Cancer Patients

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WCLC_2015_No_Benefit_Post_Op_Avastin_Early_NSCLC

 

Drs. Ben Solomon, Leora Horn, & Jack West review trial result and implications of ECOG 1505 trial that showed no benefit to addition of Avastin (bevacizumab) to adjuvant chemotherapy for early stage NSCLC.

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Dr. West:  So, we just finished the presidential symposium at the World Conference on Lung Cancer, here in Denver. There were a few high-profile presentations there, including one that was anxiously anticipated, that was presented by Heather Wakelee, a colleague of ours, who presented the ECOG 1505 trial of chemotherapy with or without Avastin (bevacizumab), the anti-angiogenic agent, as post-operative therapy for patients with a resected lung cancer. Unfortunately, a totally negative trial, I’d say. Do you think there was anything to be gleaned from that, or do you think it even might have some negative effects on its use outside of that setting, like metastatic disease, Leora?

Dr. Horn:  So, I don’t think I was surprised by the results, I think I was disappointed, but I don’t think it’s going to really change how Avastin is used outside of — in metastatic disease, outside of the adjuvant setting. I think there’ll be some interesting subset analysis to come out — so things like, is there a difference between the different chemotherapy regimens that were used? Because, I know, in places like the U.S., we extrapolate the metastatic data to the adjuvant setting, and some of the biomarker data.

Dr. West:  Ben, what did you think?

Dr. Solomon:  Yeah, I’d agree completely with Leora, I mean, it was a big study, 1,500 patients enrolled, and I think it gives us a definitive answer about bevacizumab in the adjuvant setting — there was no difference in outcomes whether you had bevacizumab or not. But it is a different situation to the metastatic setting, these patients had no residual disease, and even pre-clinically, we know that the efficacy of bevacizumab may be different in primaries versus metastases. So, I think, in this situation, we maybe need to take a little bit of care from extrapolating from the adjuvant to the metastatic setting.

Dr. West:  What’s the pattern in Australia, in terms of how widely used bevacizumab, or Avastin, is in metastatic disease? I would say it’s certainly used as a standard of care in the U.S., and I think in various parts of the world, but it’s not something that is, certainly, uniformly used in every possibly eligible patient.

Dr. Solomon:  Yes — so, in Australia, I think our sort of usage pattern is a bit closer to the European usage — so, bevacizumab is very rarely used, and partly this reflects the fact that it’s not reimbursed. And I think we’re influenced by the AVAiL data, which didn’t show an improvement in survival, in contrast to the ECOG study which did. So, bevacizumab can only be used in the setting where patients pay for it, and as a consequence, isn’t really a part of common practice.


GRACE Video

Optimal Systemic Therapy for Bronchioloalveolar Carcinoma (BAC)

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GCVL_LU-F08_Optimal_Systemic_BAC_Therapy

 

Bronchioloalveolar carcinoma (BAC) is an unusual subtype of lung cancer; medical oncologist Dr. Jack West reviews the evidence on the best systemic therapy to treat advanced, multifocal BAC.

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One of the unusual subtypes of lung cancer is known as bronchioloalveolar carcinoma, or BAC. That is a subgroup of adenocarcinoma, and many clinicians treat is as a special case. Because of that, it’s fair to ask the question of, “what is the best whole body, or systemic, therapy for that setting?” There are some clinicians who will tell patients that standard chemotherapy does not work and shouldn’t be tried at all. There are some people who feel that oral EGFR inhibitors, drugs like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), might be the treatment of choice. But those are all oversimplifications based on prior information, and we now know better. In fact, as is often the case, we need to individualize for the particular patient, and their cancer.

The first main question to ask is whether it’s necessary to treat at all. Some patients will have an advanced or metastatic, cancer, but it is not growing at a pace that is really a threat, and for patients who don’t have symptoms, and who might have very slow-growing cancer, there shouldn’t be any rush to start treatment right away, just because they have what is technically called stage 4 cancer. There are patients who can go very long periods of times with no symptoms and feel well for months, or even years.

But, if patients demonstrate clinically significant progression of their disease, and especially if they have symptoms, it’s appropriate to think about what the best whole body, systemic therapy is. 

GCVL_LU-F08_Optimal_Systemic_BAC_Therapy.001

The trial that really changed our prospective on how to approach these patients was called IPASS. This was an Asian study of over 1,200 patients, from Asia, who had a never-smoking history, and an adenocarcinoma. And this group of Asian never-smokers with an adenocarcinoma are the kinds of patients who we have long recognized as being especially likely to respond well to oral EGFR inhibitors. Because of that, this trial directly tested Iressa to standard chemotherapy in a large number of patients who were enriched to likely respond well. However, it did not require that patients have an EGFR mutation, because the story about EGFR mutations was still being developed, and we didn’t know how important that really was — really not until this trial.

The study looked for a significant difference in progression-free survival — the time before the cancers began growing again, after an initial response or stable disease. When we look at the results for progression-free survival in the bottom left part of this slide, you can see that it’s an unusual pattern — it crisscrosses – it’s kind of like a figure eight, and when we see that, it suggests that there’s actually two different populations within the broad group here. The study was designed to look for EGFR mutations in patients where there was tissue available, and they looked at over 400 patients who did have tissue available, and found that 60% of the patients did have an EGFR mutation, which of course means that 40% did not, even though they were Asian never-smokers with an adenocarcinoma, and a group that we might reflexively want to give these oral therapies to. 

But, as you can see from the curves shown in the middle and the right side of the bottom portion of the slide, you got completely different results if patients did have an EGFR mutation, versus if they did not. If you did have an EGFR mutation, you did remarkably better getting the oral EGFR inhibitor. On the other hand, if you do not have an EGFR mutation, you did far, far better by getting standard chemotherapy, and we also see this when we look at the response rates. 

GCVL_LU-F08_Optimal_Systemic_BAC_Therapy.002

In fact, when you look at the patients with an EGFR mutation, Iressa was associated with a response rate of 71%; if you didn’t have that mutation, your response rate to Iressa was 1%. You were far better served by getting chemotherapy if you don’t have an EGFR mutation — you had a response rate of about 23-24%, which is, of course, much better than that 1% with Iressa.

So, this really changed our thinking about the field — we used to, perhaps, think that we could clinically separate patients and say, if you’re Asian, never-smoker, if you have an adenocarcinoma, we can just start by giving you an EGFR inhibitor, and expect that we were serving you well. In fact, this showed that if you guessed wrong, you could really do a disservice to the patient. That the patients who don’t have an EGFR mutation should get standard chemotherapy as their first-line treatment, and the same applies to advanced BAC — in patients who don’t have an EGFR mutation, they should go on to get standard chemotherapy, unless they have another driver mutation that we would standardly look for, such as an ALK rearrangement, or possibly a ROS1 rearrangement.

So this is how we now treat advanced BAC — it is individualized based on the molecular characteristics of their cancer. You look for a driver mutation, and if you find one for which we have an oral therapy that tends to work very well, that is your first-line treatment of choice. If you don’t find one of those driver mutations, your first-line treatment of choice is standard chemotherapy based, potentially adding the drug Avastin or bevacizumab, which is an anti-angiogenic agent.


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