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Combinations and Other Options for Acquired Resistance in EGFR Mutation-Positive NSCLC

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GCVL_LU-F14_Combinations_Other_Options_EGFR_Acquired_Resistance

 

Dr. Nathan Pennell, Cleveland Clinic, describes other options for treatment of acquired resistance, including chemotherapy, ablation with SBRT and a combination of Gilotrif and Erbitux.

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On other videos in this series, we talked about next generation inhibitors for molecularly defined subgroups of patients who’ve developed acquired resistance. Now I want to talk about other options — if you don’t have a clinical trial available, or if you’ve already tried a next generation inhibitor and it stopped working.

We know that for patients with EGFR mutation-positive lung cancer, or ALK-positive lung cancer, the targeted therapies with drugs like Tarceva or Xalkori are more effective than chemotherapy and are really the standard of care for these patients. But unfortunately, most patients go on to develop what’s known as acquired resistance, where the cancer eventually begins to grow despite initially being controlled by the targeted therapy. While there are drugs being developed that are better inhibitors in that setting, they’re not always available outside of a clinical trial, or perhaps not ideally suited for a particular patient’s situation. So, what do you do in that setting?

There are a number of different options. The first thing to keep in mind is, not every patient who is developing acquired resistance needs to change what they’re doing. Sometimes, if the cancer is beginning to grow, it can grow in a very slow, asymptomatic way. In other words, it’s not causing symptoms, every time you do a scan it’s a little bit bigger, but the patient feels fine, is not having a lot of side effects from the drugs — you can continue to watch these. This can be anxiety-provoking, but I’ve watched patients for six months, nine months, sometimes longer before we really need to make a change. In the same vein, we know that about 20% of patients who develop acquired resistance don’t develop resistance everywhere in the body. Maybe only one or a couple of the tumors are growing, and if you biopsy those you can see that new mutations and mechanisms of resistance can arise in individual tumors while the rest of the cancer remains under control.

To borrow a phrase from my friend Dr. Ross Camidge at the University of Colorado: don’t overthink it — if one of the tumors is growing and all of the rest of them are the same, we can ablate the tumor that’s growing, essentially eliminate that, and patients can stay on the drug that they’re already on, sometimes, again, for six or nine months, sometimes longer, before resistance emerges elsewhere in the body.

The most commonly used mechanism for this is something called stereotactic body radiotherapy, or SBRT, which is a very effective way of using radiation to target individual tumors that tends to have very few side effects. Most patients, however, will eventually need to change the therapy that they’re on.

So, if you can’t stay on the drug any longer and you need to make a switch, one thing that many patients don’t even consider is going to chemotherapy. We know now that, since patients are being tested for EGFR mutations and ALK gene fusions upfront, many of them never receive chemotherapy and they start on a targeted therapy, but chemotherapy can be very effective for patients with EGFR mutant lung cancer or ALK-positive lung cancer, and in fact, tends to work better on average than in people who don’t have these mutations. I’ve had many patients who’ve had longer periods of disease control on chemotherapy than they had on the targeted therapies that everyone was so excited about. So, don’t despair if your doctor suggests chemotherapy because it may be a good option for you.

There are other clinical trials available, we’ve got the immune therapies that are out there — just the same treatments that are available for other types of lung cancer. There is one other thing I want to mention, for EGFR mutation-positive patients, there is a second generation inhibitor called afatinib, or Gilotrif. Gilotrif by itself is not effective for acquired resistance in EGFR, but when you add it to a second EGFR inhibitor called Erbitux, or cetuximab, in a large phase IB trial, we know that about a third of patients will have a major response to that combination, regardless of why their cancer developed acquired resistance. Sometimes this can last, on average, seven or eight months; I’ve used this and actually seen pretty good responses. It can be a little bit tough — both drugs cause diarrhea and skin rash, which can be worse when given together, but these tend to be manageable for most people.

So, in 2015, if your cancer develops acquired resistance to a targeted therapy and there isn’t a clinical trial available for one of the newer agents, don’t despair. There still are a number of things that can be tried, from remaining on the drug, to ablating the limited number of spots that are progressing, to switching to chemotherapy or participating in another clinical trial.


GRACE Video

SBRT for Oligometastatic Lung Cancer

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GCVL_LU-F10_SBRT_Oligometastatic_Lung_Cancer

 

Dr. Jeffrey Bradley, Radiation Oncologist at Washington University in St. Louis, defines oligometastatic lung cancer and describes the recent trend toward the use of stereotactic body radiation therapy to treat it.

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First, let’s define the term “oligometastatic disease.” Oligometastatic disease typically means patients who have metastatic disease, but have a few metastases that, if they could be eradicated, their life could be prolonged. There are some good examples of the literature where patients have been resected, let’s say for metastatic colorectal cancer, or metastatic renal cancer, let’s say they had a brain metastasis that was resected and given curative therapy for their primary cancer, and there is about a 20-25% overall survival rate in that situation.

That, broadened out with the development of stereotactic body radiation therapy, has brought into play SBRT for patients with oligometastases for a variety of tumors. There is some recent literature in lung cancer, let’s say, that show that if you have patients with a few metastases that are receiving systemic therapy, that you can achieve median survivals approaching 20 months in metastatic lung cancer, and that’s previously unseen. That data was a trial from UT Southwestern and the University of Colorado groups, published this past year in the JCO — one of the most cited papers in the JCO this past year.

I think the oligometastatic patient population is a good patient population for focused radiation therapy. People ask, “what is oligometastasis?” It has classically been defined as patients with three or fewer metastases who have their remainder of the disease or the disease burden is under control with  systemic therapy; some have expanded that to five or six metastases. It typically doesn’t matter where they are. The classic example, of course, is a metastasis to the brain. We’ve applied this to patients in the lung, liver, spine, various places that are able to receive this focused radiation dose, and I think it’s a good tool, if chosen for the right patients, to extend their survival — perhaps we could even cure a few.


GRACE Video

SBRT for Medically Inoperable Stage I Lung Cancer

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GCVL_LU-D08_SBRT_Medically_Inoperable_Stage_I_Lung_Cancer

 

Dr. Jeffrey Bradley, Radiation Oncologist at Washington University in St. Louis, describes the history and current use of stereotactic radiation therapy for inoperable lung lesions.

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The classic example of the use of stereotactic radiation therapy in the body is for lesions of the lung. This technology started in the 1990s in Japan and in Germany where they were giving five or fewer fractions of radiation therapy to a solitary nodule in the lung in a patient who couldn’t have surgery because they had underlying problems like heart disease or lung disease that wouldn’t allow the patient to have surgery. So they were giving, let’s say 15 gray doses, up to 20 gray doses, in three fractions, to eradicate these tumors in the lung.

That spread to the United States in the 2000s, and it’s a very common treatment today for patients who have been evaluated for surgery but can’t have surgery, usually because their pulmonary function is too low. This technique is very effective, the local control of eradicating that lesion is better than 90%, and 95% in some series. It’s stood the test of time, results are available at five years, giving a good indication that it’s probably equivalent to surgery in the population that’s high risk.

A very controversial area today, are patients who are operable candidates for stereotactic body radiation therapy, and that’s the next topic.


GRACE Video

What is Stereotactic Radiosurgery/Radiation Therapy to the Brain or Body?

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GCVL_LU_D07b_Stereotactic_Radiosurgery_Radiation_Therapy_Brain_Body

 

Dr. Jeffrey Bradley, Radiation Oncologist at Washington University in St. Louis, describes the use of stereotactic radiosurgery and stereotactic radiation therapy.

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Stereotactic radiosurgery and stereotactic radiation therapy are techniques used to deliver high doses of radiation therapy with very tight dose distributions to one or a few lesions, let’s say in the brain or in the body. If it’s a single fraction of treatment, it’s called stereotactic radiosurgery. The classic example of that is radiosurgery to a brain metastasis, or something like that.

Stereotactic radiation therapy, or stereotactic body radiation therapy uses five or fewer fractions — so somewhere between two and five fractions, and sites for that can be brain, lung, liver, spine, various places throughout the body where you really want to deliver a high dose that eradicates the tumor, kills the tumor cells, and do it with minimal normal tissue toxicity.


GRACE Video

SBRT as a Potential Alternative for Fit Patients with Early Stage Lung Cancer

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GCVL_LU-D09_SBRT_Alternative_Early_Stage_Lung_Cancer

 

Dr. Jeffrey Bradley, Radiation Oncologist at Washington University in St. Louis, provides evidence for the use of stereotactic body radiation therapy as an alternative to surgery for operable early stage lung cancer.

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There has been a growing interest in stereotactic body radiation therapy in the United States and across the world. As patients have come to learn about this, they have sought alternatives to surgery today. Now, surgical techniques have improved — minimally invasive surgery has proven to be quite effective in eradicating early stage lung cancer, but there is a good alternative in stereotactic body radiation therapy, and the literature is coming out now that SBRT probably offers equivalent cure rates and equivalent outcomes to minimally invasive surgery or lobectomy for early stage lung cancer.

The best example of that is a randomized trial published in The Lancet Oncology this past May. It was a randomized trial from two centers, or two groups, one in the United States — an Accuray trial comparing lobectomy to radiosurgery or stereotactic body radiation therapy. The second trial was in the Netherlands, the ROSEL trial, and it also compared patients with lobectomy to stereotactic radiation therapy. Neither trial was able to meet its accrual goals — both under-accrued and were closed due to lack of accrual. So, taken individually, these trials couldn’t give us the answer about this comparison, but the authors and the groups decided to combine the data and publish the data, and the data indicate that SBRT, in this series, proved superior to surgery in this population.

This has caused quite a controversy today. Needless to say, I think stereotactic radiation therapy does offer a reasonable alternative to surgery. Other trials are needed to prove that this is the case since that trial was underpowered to show a true difference, although it does indicate that SBRT is at least equivalent and should be considered for these patients.


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