GRACE :: Lung Cancer



Dr West

Lung FAQ: What treatment should I receive now that my NSCLC with an EGFR mutation is progressing after responding for a year?


The response of cancers with a specific driver mutation , such as an EGFR mutation or ALK rearrangement, to a targeted inhibitor of that target, is often dramatic and long-lasting, but it is also almost always limited in duration, typically lasting several months or a few years.  Beyond that point, we tend to see a subset of the cancer cells become resistant progress, perhaps manifested as one or several  new lesions or growth of one area against a background of most of the remainder of the cancer still being well-controlled.  

In other cases, the progression is more multifocal, sometimes very slow, and sometimes more rapid.  What is the best treatment for patients whose cancer is now progression in this setting of “acquired resistance” after an initial good response to an EGFR tyrosine kinase inhibitor (TKI) or ALK inhibitor?

The short answer is that there is no consensus, so the best we can offer is a thoughtful perspective as someone with both experience in treating many such patients and a knowledge of the current data, which are limited.  And in assessing an optimal treatment approach, I would contend that it really depends on the features of the particular case. Is this someone who demonstrated a very long response interval of at least 8-12 months, or a relatively short period before progression was demonstrated?  Is the pattern of progression very limited, such as just one or a few lesions growing, or much more diffuse? Is the progression very indolent, such as just a few millimeters of change between scans done 2-3 months apart, or faster than that? And is the person with progression experiencing symptoms or not?  And how we’ll are they tolerating the targeted therapy?

It’s worth noting that a minority of people with acquired resistance to an EGFR inhibitor (and likely also with an ALK rearrangement, though this hasn’t been reported specifically) will demonstrate faster progression once the EGFR inhibitor is discontinued, leading to a conclusion that “bad brakes are better than no brakes”…even though someone is experiencing progression, they may experience faster progression if someone discontinues that targeted therapy than if they continue on it.  

The key questions, then, are:

1) Should someone make a change at all?

2) If a new treatment is needed, what should it be?

3) If a new treatment is started, should the person discontinue the targeted therapy or continue it?

Tackling the first question, one point is that asymptomatic, slow progression need not necessitate a change in treatment.  Many patients can continue to demonstrate slow progression and a disease burden far less than they started with prior to targeted therapy, so as long as patients are monitored with regular clinic visits and scans (I personally would do scans every 6-12 weeks or so, with clinic visits interspersed in between in some cases to ensure the person is still feeling well), I consider this not only appropriate but arguably optimal.  You are very unlikely to burn bridges and stretch out the subsequent remaining treatment options over a longer period.

If there’s enough progression to warrant an intervention, what should it be? In those with progression in one lesion (e.g., a new lung or bone lesion, or progression in the brain only, with good disease control outside of the brain), some patients can do very well for months or even years with just a local therapy such as radiation or surgery directed to the progressing lesion and ongoing targeted therapy for the rest of the disease (no real change after the local treatment).  This is particularly appealing for those with slow progression who are tolerating the targeted therapy well and progressing after a longer interval.  

For those with more multifocal progression, initiation of a systemic therapy is warranted.  While there are clinical trials directed towards reversing the resistance and focusing on continuing the targeted therapy as the main intervention, the most common approach is to start the best treatment that would be given as if the person didn’t have a driver mutation.  In most cases of advanced NSCLC, that’s going to be a doublet chemotherapy with or without the anti-angiogenic agent Avastin (bevacizumab).  There haven’t been meaningful studies to confirm this, but that is the recommendation that is pretty close to a consensus among experts, especially since most patients with acquired resistance have as good a performance status as they did before they started any treatment, if not better.

This leaves the question of whether to continue the targeted therapy with the new treatment, a question for which there is almost no real evidence.  There are no prospective trials, though these are now being done.  Though years ago I was not a fan of concurrent chemo and concurrent EGFR TKI therapy, that was in a setting of treating a broad range of patients, most of whom don’t have a driver mutation.  In the setting of treating patients with a driver mutation associated with a very good response to that therapy, I believe that integrating a new chemotherapy-based treatment is appropriate and likely advisable for patients with slower progression of their disease, and who are tolerating that therapy well.  It’s also still reasonable to discontinue the targeted therapy and consider “re-treatment” with the targeted therapy after an interval off of it, as this is occasionally (though not frequently) associated with a response due to re-sensitization, or at least several months of non-progresison.

This is an area in which thoughtful oncologists might well have different recommendations, as there are few studies to guide our plans.  Fortunately, this is an area of keen interest, and we can realistically hope to have more information in the next few years to help guide our recommendations.

For additional information: 

Webinar on Acquired Resistance to EGFR TKIs, by Dr. Lecia Sequist, MGH 

Acquired Resistance Case Discussion by Multiple Cancer Specialists

Local Therapy in Acquired Resistance

Ongoing Treatment Beyond Progression with Targeted Therapy

Retreating After Progression with Targeted Therapy

Dr West

FAQ: I started an EGFR inhibitor two weeks ago but haven’t developed a rash. Does this mean it’s not working?


The short answer is no.

Since the introduction of the targeted agents that inhibit the epidermal growth factor receptor (EGFR), both the oral EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) or Tarceva (Erbitux), and the monoclonal antibody therapies against EGFR like Erbitux (cetuximab) have been identified as often having a rash as a leading side effect. Though often annoying and sometimes very difficult to manage, the development of a rash has also been identified as somewhat of a double-edged sword, as several early trials identified development of a rash as being associated with a better result on oral EGFR inhibitors, and even that there may be a correlation with best outcomes in patients who develop a more severe rash. Moreover, this same trend has also been seen in patients who receive Erbitux for lung cancer as well as for colon cancer.

Meanwhile, other corroborating tangents included the finding that smokers on Tarceva had fewer side effects and have also been consistently identified to not do as well with oral EGFR inhibitors as never-smokers or ex-smokers, very possibly related to faster metabolic breakdown of these agents in current smokers. It remains a possibility, though still not well studied and unproven, that a higher dose of EGFR TKI therapy may be more effective in current smokers.

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Dr Pennell

An Overview of Molecular Markers in Lung Cancer


Introduction to Molecular Markers

A molecular marker is an identifiable molecular characteristic (usually DNA, RNA, or protein) in a patient or a tumor that can be used to provide prognostic or predictive information about the cancer or about a particular treatment. A prognostic marker is one which indicates a better or worse outcome irrespective of treatment. For example, a mutation in the KRAS gene has been widely regarded as a poor prognostic molecular marker (see below), but does not necessarily guide us in selecting therapy for a particular patient. In contrast a predictive marker indicates a better or worse chance of an outcome for a specific treatment. Identifying this type of marker is a major goal of translational research and forms the basis of “personalized medicine”, which is simply saying that you may be able to determine ahead of time which treatment will or will not work in a specific patient.

In this chapter, I will try and describe the most common molecular markers being investigated in lung cancer, including some tests that are already being used in practice today. Continue reading

Dr West

Lung Cancer FAQ: My advanced NSCLC has progressed after initial chemo. What are the leading options now?


In the last decade, the treatment of NSCLC has evolved very significantly, and one of the leading ways has been that we’ve gone from having no established role for treatment after initial, first line therapy to having multiple agents with a proven benefit.

It’s worth clarifying that as maintenance therapy is increasingly being considered as an option after first line therapy, a distinction between this and second line therapy. Maintenance therapy is given to prolong the period before someone who has achieved a response or stable disease on first line treatment demonstrates progression for the first time, while second line therapy is the term more commonly reserved for treatment after someone has demonstrated evidence of progression for the first time after first line therapy.

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Dr West

Lung Cancer FAQ: I’m coming to the end of my first line chemo for advanced NSCLC. After 4 (or 6) cycles are done, should I take a break or continue with some form of maintenance therapy?


The historic standard for advanced NSCLC up until a few years ago was for patients to complete 4-6 cycles of platinum-based doublet chemo, and then for patients who were doing well and had responded or demonstrated stable disease to take a break from treatment and be followed until progression. At that point, many patients would re-initiate chemo or targeted therapy with an oral agent like Tarceva (erlotinib).

Part of the premise was that ongoing treatment with challenging chemotherapy generally led to cumulative side effects, and at the same time, the limited work that had been done on fixed duration vs. ongoing chemotherapy until progression failed to show a significant improvement in survival with prolonged chemo, though it was associated with increased side effects.

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