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Is Targeted Therapy Feasible As Consolidation in Locally Advanced NSCLC?

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GRACE Cancer Video Library - Lung

GCVL_LU-EA01_Targeted_Therapy_Consolidation_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, reviews efforts to utilize targeted therapies as consolidation after chemoradiation in locally advanced NSCLC.

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Because those strategies testing additional systemic therapy utilized chemotherapy and those strategies did not improve outcomes compared to concurrent chemoradiation alone, we looked to try to give other forms of systemic therapy that were not chemotherapy to see if perhaps that would improve outcomes. Beginning in the 2000s there were a number of new drugs that appeared to be active in people with lung cancer and these are what we call molecularly targeted therapies. The first of these molecularly targeted therapies targeted a certain growth receptor on the surface of cancer cells, and this is called the epidermal growth factor receptor (EGFR) and we had a drug at the time which would target cancer cells that expressed this epidermal growth factor receptor. Well we understood in the 2000s that the vast majority of people with lung cancer have tumors that overexpress these growth receptors on the surface.

So clinical trials were designed to incorporate these new molecularly targeted therapies into the backbone of therapy that we had already established. Probably the best known of these trials was conducted by one of the United States cooperative groups in which all patients with stage III unresectable non-small cell lung cancer received the standard concurrent chemotherapy and radiation therapy backbone. Now in this trial patients were allowed to receive additional chemotherapy after that but the bottom line with this trial and the importance of this trial is then at that point patients were then randomized to receive either this molecularly targeted therapy or to receive a placebo.

At the time, again, this was the most effective molecularly targeted therapy we had in lung cancer and this was our greatest hope for further advancement over just giving concurrent chemoradiation alone. This drug was called gefitinib, it is approved by the FDA today and it is commercially available for people who have metastatic disease. What this trial demonstrated was giving that drug after chemotherapy and radiation therapy did not improve outcomes. In fact more people who received placebo had long term survival compared to those who received the gefitinib. So that hypothesis was utterly rejected and clearly is not the way forward.

Since that trial was designed we’ve come to better understand which patients actually benefit from these drugs that target the epidermal growth factor receptor. In fact we have new targets including a gene called anaplastic lymphoma kinase or the ALK gene and we have molecularly targeted therapy against tumors that have that gene abnormality.

So the current state of the art clinical trials testing molecularly targeted therapy are not just indiscriminately giving everybody the drugs, but they’re testing the idea that perhaps there are subsets of patients who would preferentially benefit from these targeted therapies. So one of the United States cooperative groups right now is conducting a clinical trial for patients with stage III unresectable disease. Everyone is getting concurrent chemoradiation, but those patients who have either an abnormality in the epidermal growth factor receptor gene, or in the anaplastic lymphoma kinase gene are also being randomized to receive the molecularly targeted therapy or not.

So this is a very different idea, this is not just empirically giving everybody these molecularly targeted therapies, but it’s targeting patients for these drugs based on the molecular biology of their disease. Now these trials are ongoing right now and I think we’re optimistic and we’re hopeful because we’ve seen the activity of these targeted drugs in patients who have metastatic disease. Perhaps we’ll see some improvements in outcomes in these targeted populations — that question is probably not really going to have an answer for about two or three years. That’s the current state of the art treatment that’s being tested regarding molecularly targeted therapy in stage III cancer.


GRACE Video

Elderly Patients: Selecting Appropriate Systemic Treatment Agents

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GRACE Cancer Video Library - Lung

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents

 

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, evaluates a variety of particular systemic treatment agents for possible use in elderly patients.

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It is my privilege to speak to you today about elderly patients; consideration of which chemotherapeutic agents might be best. So we’ve seen a lot on CancerGRACE about the advent of targeted therapy and this theme that when you combine a target with a targeted therapy, like a lock and key model, you as a theme get a treatment that has less side effects, is more convenient because they’re often oral, and tend to work better.

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This of course has made lots of work for our medical students as we subdivide by histology, by driver mutations, and an even more complex systems view that probably starts to approach reality. But in the simplest way when thinking about targeted therapies such as erlotinib or gefitinib for EGFR mutants, or crizotinib for ALK or ROS1, and other emerging targeted therapies — as a theme these drugs are very effective and less toxic, and so to my mind, even though we don’t normally speak about them as geriatric drugs, to me they’re the epitome of geriatric drugs because of these themes.

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In terms of traditional chemotherapy, there’s really only one agent that I would consider to have any data for superior efficacy in the elderly. You’re looking here at the design of a randomized phase III trial that randomized patients to carboplatin and regular cremophor solvent-dissolved paclitaxel, versus carboplatin and a newer nano albumin-bound formulation called Abraxane.

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Patients were randomized one to one, you can see the basic results by age at the bottom of this slide. Why I’m showing this to you is that the only subgroup that had a major survival difference was the elderly. In patients of at least 70 years of age, there was a rather important improvement in survival, 19.9 versus 10.4 months — that is statistically significant. I would call that clinically meaningful but it is a retrospective subgroup analysis and so it requires confirmation in prospective studies. Two important studies are ongoing to look at this. One is looking at older patients with this regimen for their first treatment, and the other looking at such patients for their second treatment.

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This was a randomized trial that compared for first treatment cisplatin and pemetrexed, versus cisplatin and gemcitabine. We’ve covered this trial a number of times on GRACE before in terms of looking at histology-specific differences in drugs and we’ve seen on GRACE before that pemetrexed is a particularly effective drug for patients with non-squamous histology, which mostly means adenocarcinoma, where it’s less effective in patients with squamous histology. We’ve also seen that it tends to be one of our better tolerated chemotherapy drugs, and these results held in this definitive trial both for younger patients and for older patients. While I don’t tend to use cisplatin in older patients (we’ll get to that) I do think that pemetrexed is a particularly geriatric-friendly drug for patients with non-squamous histology.

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ECOG 4599, another trial we’ve covered multiple times over the years looked at the standard platinum doublet carboplatin and paclitaxel, with or without the addition of the VEGF inhibitor bevacizumab, otherwise known as Avastin.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_07

We know that trial showed a small but real survival advantage in unselected patients, but why I show it to you today is that treatment advantage really seems to slim down when we look at older patients. So in my practice I don’t tend to use bevacizumab except for my really, really most fit older patients.

All the rage these days, of course, in thoracic oncology are the immunotherapeutic agents. These drugs as a theme are more effective in the second line than chemotherapy and less toxic — these make them good geriatric drugs so bear with me a moment.

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Here’s the data on nivolumab in squamous cell carcinoma, second line of therapy, compared to my second least favorite geriatric drug docetaxel. We can see here a dramatic improvement in survival, and perhaps equally important, a better tail to the curve — more patients living a very long time on the nivolumab.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_09 

A similar effect shown here in non-squamous histology, and as far as to why this is making its way to a talk about geriatric oncology, here’s the toxicity.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_10 

It’s very rare in looking at thoracic oncology trials to ever have this favorable of a rate of grade 3-4 or high-grade toxicity, even for placebo. So these drugs are more effective and less toxic — these are very geriatric-friendly drugs.

Bringing it back to chemotherapy, which is what unfortunately still the majority of patients get — I think it’s worth taking a minute to talk about which of these drugs are particularly geriatric-friendly and which perhaps should be avoided for most older patients.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_11 

So cisplatin is my least favorite drug for older patients. Why? It’s our most nausea- and vomiting-inducing drug, perhaps of any we use in oncology. It has a high rate of harming hearing and there is already age-related hearing decline, it’s one of our worst drugs on the kidneys and kidney function does tend to naturally decline with age. There are plenty of other reasons to hate cisplatin as well, making it my least favorite geriatric drug.

In contrast, its little brother carboplatin I regard as a much more geriatric-friendly drug. It has much, much less for side effects, particularly on the kidneys and for patients who already have a little bit of age-related kidney decline, the dosing formula for carboplatin, it’s called the AUC formula, inherently accounts for this, so you just don’t have to worry about it — you get the right exposure to the drug sort of automatically even if there is some preexisting decline in kidney function.

Paclitaxel I would call a middle-of-the-road geriatric drug, particularly I would call it more favorable when used on a weekly schedule. Docetaxel, as I mentioned, is my second least favorite geriatric drug — there’s a lot of count suppression, a lot of fatigue. When I do use it for older patients, I tend to reduce the dose some from the standard dose. We’ve discussed nab-paclitaxel, otherwise known as Abraxane, because of the subgroup survival data suggesting it may be more effective in older patients. Pending the confirmatory ongoing studies, I think that this is a very geriatric-friendly drug. Gemcitabine I would call on the better side of geriatric drugs, it’s mostly excreted by the kidneys so you need to pay attention if there is kidney decline, but it’s a pretty geriatric-friendly drug — an effective drug with lower side effects. Pemetrexed or Alimta we’ve already talked about as a particularly geriatric-friendly drug, I would comment though that this drug is excreted mostly by the kidneys, and so if kidney function is not ideal, it’s a drug that needs to be used with extreme caution or perhaps not at all.

I thank you for your kind attention.


Dr West

Direct Comparison of 2 EGFR Inhibitors Shows There Are Clinically Significant Differences

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At ASCO 2014, I provided the commentary after a key presentation demonstrated that the second generation EGFR tyrosine kinase inhibitor (TKI) Gilotrif (or Giotrif in some parts of the world) (afatinib) as first line therapy compared to standard chemotherapy in EGFR mutation-positive patients gave a significant benefit in overall survival (OS) that hadn’t been seen when other first generation EGFR TKIs, namely Iressa (gefitinib) or Tarceva (erlotinib) were compared to chemotherapy in EGFR mutation-positive patients. The question was whether this difference meant that Gilotrif is a significantly better EGFR TKI than Iressa or Tarceva. I noted that while these results were provocative, trials with Iressa and Tarceva were far smaller and in most cases were stopped early due to early results showing that the EGFR TKI was clearly superior in short term measures like progression-free survival (PFS) and response rate.  Accordingly, we couldn’t say anything definitive about the efficacy of one EGFR TKI vs. another by making inferences of each compared with an increasingly irrelevant comparator. If trial after trial showed that the EGFR TKI was clearly better than chemotherapy, we can’t draw meaningful conclusions of one being better based on how much stronger one looked than another against an inferior option. Instead,  the only reliable way to compare two EGFR TKIs would be to directly compare two EGFR TKIs in a randomized trial with the same eligible population.  In fact, such a trial, called LUX-Lung-7, had already been not only conceived but enrolled, randomizing EGFR mutation positive patients in Asia, Europe, Canada, and Australia to either Iressa or Gilotrif. We just needed to see how it turned out. Continue reading


GRACE Video

Emerging Options for T790M-Positive Acquired Resistance

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AR_2015_Riely_T790M_Positive_Acquired_Resistance_Options

 

Acquired resistance in EGFR patients is often driven by the T790M mutation. T790M-positive tumors respond differently to treatments than T790M-negative tumors. Dr. Greg Riely details how each status can predict patients’ responses to current treatments.

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GRACE Video

Does the Specific EGFR Mutation (Including “Rare” Mutations) Matter When Choosing an Oral EGFR Inhibitor?

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WCLC_2015_12_Specific_EGFR_Rare_Mutations_Matter_Oral_EGFR_Inhibitor

 

Drs. Leora Horn, Ben Solomon, & Jack West discuss the open question of whether there are clinically significant differences among leading EGFR tyrosine kinases based on the specific EGFR mutation to be treated.

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Dr. West:  What about rare mutations? They’ve really been excluded from a lot of things, but we got a little bit of information at this meeting, the World Conference on Lung Cancer, and there was a publication by James Yang in Lancet Oncology that looked at aggregate results from three different studies with afatinib (Gilotrif), that suggested that at least some of these rare mutations could have a good response to afatinib. What are your thoughts — do you really view all of these rare mutations as one basket, or do you hone it further and treat accordingly, and if you do feel that there are patients who benefit from EGFR inhibitors, is it preferentially afatinib because of these results, or any of them? Leora, what do you think?

Dr. Horn:  So, I thought that James Yang paper was very nice, but I think my bias is that, probably, those rare mutations, would have responded to the first generation inhibitors, as well. We have our database that we’re collecting this data — the DIRECT database, and we’ve got about 3,000 individual mutation patient information in there, so that’s my go-to place when I get information that I’m not sure what to make of a mutation, and I think we’re going to see more and more rare mutations as next generation sequencing is adopted in more places around the world, and we may not always know what to do with that information, and sometimes it may be trial and error.

Dr. Solomon:  Yeah, so I actually have to say your mycancergenome.org is my go-to place, as well, to find out about rare mutations, and I think for patients, and even doctors, who get an EGFR mutation result with a rare mutation, it’s hard to keep track of all these mutations, and at this meeting, for instance, we learned that the group of mutations we call G719X, which includes three different mutations — two of those mutations seem to respond, and one of those, the G719C, doesn’t seem to respond, and so I would encourage people who are uncertain about the significance of mutations to go to mycancergenome.org and make query of the DIRECT database.

Dr. West:  To me, that was one of the themes, both from the Yang paper, and from several of the still relatively small data presentations on rare mutations, is that, de novo T790m mutations, that is, the ones that appear from the time of diagnosis, are associated with a poor outcome, but some of the others, Exon 18, and some Exon 20 insertions, could respond well to these therapies, and it would be a mistake to: A., lump all of these together, because they’re not, we’re missing things, and B., to completely discount the possibility that an EFGR inhibitor could help them.


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