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Clinical variables in EGFR therapy

Clinical factors predicting significant clinical benefit with EGFR-based therapies

Dr West

Is immunotherapy the wrong choice for some lung cancer patients?

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Amidst all of the glowing reports about immunotherapy for lung and many other cancers, it would be understandable for patients and physicians to be tempted to rush toward prioritizing immunotherapy as the first treatment strategy to pursue. In fact, a highly publicized trial called KEYNOTE-024 was just presented at the ESMO meeting in Copenhagen and demonstrated a significant improvement in progression-free and overall survival over standard chemotherapy doublet treatment as the first line approach for patients with high level expression of the PD-L1 protein on their tumor (about 30% of patients).  But there is also converging evidence that some patients are consistently less likely to benefit from immunotherapy — specifically, those patients with an EGFR mutation and perhaps others with another “driver mutation” such as an ALK or ROS1 rearrangement.  This is an important issue to know, because I and some other lung cancer specialist colleagues see patients with one of these highly targetable lesions sometimes being mistakenly recommended immunotherapy over the optimal targeted therapy for their cancer, or patients deflect a recommendation for an EGFR or ALK inhibitor in favor of immunotherapy based largely or completely on the hype around the latest new idea in cancer treatment.

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GRACE Video

Third Generation EGFR TKIs for Acquired Resistance

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GRACE Cancer Video Library - Lung

GCVL_LU-F12_Third_Generation_EGFR_TKI_Acquired_Resistance

 

Dr. Nathan Pennell, Cleveland Clinic, discusses the concept of acquired resistance and new agents designed to address it, including Rociletinib and Merelitinib.

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So I’d like to talk now about third generation, or mutation-specific inhibitors for epidermal growth factor receptor mutation-positive lung cancer. We know that for EGFR mutation-positive lung cancer, targeted therapy with drugs like Tarceva, Iressa, or Gilotrif are the standard of care based on trials showing they’re better than chemotherapy for improving tumor responses and the time to progression of cancer for many patients, and they can be very effective and sometimes last a long time.

Unfortunately, the majority of patients will eventually go on to develop something called acquired resistance, where the cancer begins to grow despite continued treatment with the drug that worked so well, sometimes for a long time. Something has changed in the cancer that has caused it to be resistant to the drug. When we biopsy these tumors that are progressing, what we find for EGFR mutant patients is that about 50-60% of these tumors have a new mutation, something called T790m, in exon 20. The original mutation is still there, but now it has a new mutation and this has caused the cancer to no longer respond to the Tarceva or the Gilotrif.

The good news is, there’s a whole new class of drugs available that have been specifically designed for this type of cancer, the T790m-positive cancer. These are called mutation-specific inhibitors because they inhibit only the mutant EGFR, and not the normal wild type EGFR that’s spread throughout the rest of your body. So, they tend not to have the same side effects that drugs like Tarceva or Gilotrif would have. They have less of the acne-like rash, less diarrhea; they do have different side effects. For example, one of the best known drugs is called Rociletinib, formerly CO-1686, and while it doesn’t have a rash or much diarrhea, it can raise blood sugar similar to type 2 diabetes which usually can be managed in the same way with oral drugs. The other well known drug is called AZD-9291, and one or both of these drugs is likely to be approved within the next year for T790m-positive EGFR mutant lung cancer.

Both of these have had large trials that have been presented showing that between 50% and 70% of patients with the T790m mutation will have a major response, and the vast majority of patients will have disease control, with a median time, average time, somewhere in the 8-10 month range before progression — some patients significantly longer. These are really nice options for patients who have this specific type of cancer.

Unfortunately, patients will need to have a new biopsy of their cancer at the time of developing acquired resistance, although they are trying to develop blood tests which are hopefully going to eventually replace needing a new procedure to biopsy your cancer. In 2015, for patients who develop acquired resistance, I would recommend a biopsy of the progressing cancer, and if they have T790m, enroll them on one of the clinical trials with either Rociletinib, AZD-9291, or one of the many other third generation EGFR inhibitors that are farther back in development.


GRACE Video

Treatment Options for EGFR T790M Negative Acquired Resistance

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Dr. Jack West suggests that progression in T790M-negative EGFR lung cancer patients may not require a change in therapy. In this video he details what should go into the decision to modify treatment for those patients.

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GRACE Video

Emerging Options for T790M-Positive Acquired Resistance

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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

Individual Treatments for Individual EGFR Mutations

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There are sub-types within the sub-type of EGFR mutation positive lung cancer. In this presentation, Dr. Jack West discusses the different activating mutations within EGFR positive tumors and how they impact treatment.

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