GRACE :: Lung Cancer


Adjuvant therapy

Denise Brock

ASCO 2017 – Lung Cancer – Improved Progression-Free Survival with Iressa as Adjuvant Therapy for EGFR Patients

H. Jack West, MD
Medical Director
Thoracic Oncology Program Swedish Cancer Institute
President & CEO, GRACE
Matthew Gubens, MD
Thoracic Oncologist
Thoracic Surgery and Oncology Clinic
UCSF Helen Diller Family Comprehensive Cancer Center
Jyoti D. Patel, MD
Director Thoracic Oncology
University of Chicago Medicine


Drs. H. Jack West, Medical Director of the Thoracic Oncology Program at Swedish Cancer Institute in Seattle, Washington and President and CEO of GRACE, Matthew Gubens, Thoracic Oncologist at the Thoracic Surgery and Oncology Clinic of the UCSF Helen Diller Family Comprehensive Center in San Francisco, California, and Jyoti Patel, Director of Thoracic Oncology at University of Chicago Medicine gathered post meeting to discuss new information from ASCO 2017 regarding lung cancer.   In this roundtable video, the doctors discuss  Improved Progression-Free Survival with Iressa as Adjuvant Therapy for EGFR Mutation Positive Patients and Why That Doesn’t Change Anything.



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The Role of Targeted Therapy Post-Resection

GRACE Cancer Video Library - Lung



Dr. Heather Wakelee, Stanford University Medical Center, evaluates the lack of evidence for the use of targeted therapies after surgery, and describes ongoing trials attempting to resolve that issue.


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Since the mid-2000s we’ve known that many patients who have non-small cell lung cancer, particularly the adenocarcinoma type, have particular gene mutations that we can identify and when we find them, treat with specific new drugs. We know this data from patients with metastatic lung cancer — the first to be discovered was EGFR or epidermal growth factor receptor, then ALK or anaplastic lymphoma kinase. Now there’s a very long list of gene mutations that we can identify when we look in patients with advanced stage lung cancer, and when we find them, offer specific targeted therapy that can have a very high likelihood of shrinking the tumor. This has really changed the way we think about and treat advanced stage lung cancer. However we haven’t figured out how to best use those treatments for patients who have earlier stages of lung cancer.

So in the setting of an early stage lung cancer that’s been removed with surgery, patients are theoretically cured at that point. Chemotherapy has been proven to lower the chance of the cancer coming back, but when you find one of these mutations in the tumor, the temptation is to give one of these targeted drugs. That strategy has been looked at in multiple clinical trials and we still don’t have a straightforward answer.

The largest trial to look at this so far was called the RADIANT trial and in that trial, after getting chemotherapy if that was the right thing for them, patients either received the EGFR drug called erlotinib, or a placebo. Now most of those patients in that trial actually did not have a specific mutation in EGFR because the study was designed before we knew about how important those mutations were. In the subset of patients who did have the EGFR mutation, those getting erlotinib seemed to have more time before the cancer came back, but if you looked at their overall survival, it wasn’t any different than the patients who had been on the placebo arm. The theory is that those who were on the placebo arm who had the cancer come back, when it came back they were then able to get erlotinib or a similar drug and have the same benefit. So it’s not clear that starting the erlotinib right at the time of surgery actually helps people live longer, though it might slow down the time to recurrence.

That’s obviously not a complete answer so there are more studies happening now trying to get a better sense of what we should do in that setting. There are a couple of trials in China, actually several trials in China, a study in Japan, and now a big study in the United States, all with the same general idea that a patient who has a tumor resected or removed by surgery, who is shown to have an EGFR mutation in that tumor, is randomized to either get an EGFR drug or to get placebo. Some of the studies have chemotherapy before or after, some compare it to chemotherapy, so there are some differences, but the general idea is whether or not giving the EGFR targeted drug will actually help people be cured or live longer versus waiting, and then for those who do have recurrence, giving it at that time. So those are really important trials that are ongoing and we’ll hope to know the answers in the next few years.

For the patients with the ALK translocation in the United States, the big trial called ALCHEMIST is open not just to EGFR but also to ALK patients. What that trial is about is asking that any patient who has a surgery at a site that’s participating in ALCHEMIST have part of their tissue from the tumor sent in to a central laboratory to be tested for EGFR or ALK. Those patients who have EGFR are then randomized to either get the EGFR drug erlotinib, or to get a placebo pill, and those who have ALK to get the ALK drug crizotinib versus a placebo pill. Over time people will be followed to see — does this change when the cancer comes back, and does it ultimately change overall survival for the patients where the cancer does come back?

So this is a really critical trial and it’s going to help us know what the best way is to use these targeted drugs for patients in this setting. Until we have those trial results back, I do not recommend that patients get the EGFR or ALK targeted drugs after surgery because we just don’t know if that’s going to help them live longer.


Targeted Therapies in a Post-Operative/Adjuvant Setting

GRACE Cancer Video Library - Lung



Dr. Nathan Pennell, Cleveland Clinic, reviews the available trial evidence for the use of targeted therapies in the post-operative/adjuvant setting.

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I’d like to talk to you now about adjuvant treatment with molecularly targeted therapies for non-small call lung cancer. We know that early stage patients, so patients with stage I, II, or III non-small cell lung cancer — many patients are cured with surgery, but unfortunately, many patients go on to recur with metastatic disease. The reason this happens is that some of the cancer cells have escaped from the tumor before surgery and spread elsewhere in the body. This is called microscopic metastatic disease, and for this reason, we offer patients at high risk of occurrence adjuvant therapy. Adjuvant just means that we give four cycles of chemotherapy after surgery, and we know that this provides a modest, but significant improvement in cure rates after surgery alone.

Well, what about for patients who have molecularly defined subgroups of cancer, like EGFR mutation-positive cancer, or ALK-positive cancer? We know that, in the advanced setting, targeted therapies like Tarceva or Gilotrif for EGFR-positive cancer, or crizotinib or Xalkori for ALK-positive lung cancer, are better than chemotherapy in terms of inducing tumor responses, delaying the progression of cancer, and potentially even improving overall survival.

Since they work in the advanced setting, wouldn’t it make sense that they might work better in the adjuvant setting as well? Well, it’s not quite that simple. For one thing, we don’t have any evidence for any type of molecular subgroup, other than EGFR mutation-positive patients, but even in that setting, we really don’t have good evidence that adjuvant therapy improves cure rates after surgery alone. We have a little bit of evidence, so we know that the doctors at Memorial Sloan Kettering Cancer Institute in New York have treated several hundred patients with adjuvant Tarceva after surgery and they’ve reported that the patients have probably a lower than expected recurrence rate compared to what we might expect for that risk of patients, and they’ve suggested that maybe even they’re improving cure rates with adjuvant Tarceva.

Unfortunately, you can’t draw conclusions from a retrospective series and not a prospective trial. There have been at least two prospective trials that have been done, including one phase II trial that treated patients with two years of adjuvant Tarceva after surgery and then a subgroup of patients from a phase III trial called the RADIANT trial — so these were not EGFR mutation-positive patients in the overall trial, but there were 160 mutation-positive patients on the trial who were treated with two years of Tarceva, or two years of a placebo. All of these put together have suggested that adjuvant Tarceva does potentially delay the recurrence of cancers, but once the adjuvant treatment stopped, many patients went on to recur at a later time. None of the trials have suggested that patients lived longer or were cured at a higher rate than patients who were treated with standard treatment, including adjuvant chemotherapy.

What we really need is a randomized prospective phase III trial. Luckily, there is one that’s open and enrolling called the ALCHEMIST trial. Patients with stage IB, II, or III non-small cell lung cancer are tested for EGFR mutations or ALK gene fusions, and if those are found, they’re randomly assigned to two years of Tarceva for EGFR, or Xalkori for ALK-positive lung cancer patients, or two years of a placebo. Hopefully, at the end of this trial we’ll know whether patients are cured at a higher rate when treated with these adjuvant target therapies, versus just delaying the recurrence of the cancer.

For now, in 2015, I would not routinely recommend adjuvant therapy with a targeted drug like Tarceva or Xalkori outside of a clinical trial, but would strongly encourage patients to enroll in the ALCHEMIST trial.

Dr West

Treating Invisible Disease in Lung Cancer


Here is a brief and basic summary of the concept of why we’re concerned not only about the cancer we can see but the potential cancer we can’t.

This is the first presentation I’ve done that uses a format called a “slidedoc”, essentially a more detailed set of images that provides a visual version of complex ideas in a way that can stand alone without someone presenting slides to you. Those who are interested can leard more about the concept here, as explained in a slidedoc by presentation guru Nancy Duarte.

Treating Invisible Disease: How the Probability of Disease We Can’t See Changes Our Treatment Strategy in Lung Cancer from H. Jack West
For those who want to print it, here’s the pdf file: Treating invisible disease GRACE
My hope is that people will be able to find this a very brief, understandable way to explain big ideas about cancer. This format also has the advantage of being easily sharable and can be viewed easily on many platforms, including mobile devices.  If people like the format, I’ll try to present more posts in this way.  I hope you’ll provide feedback.

Dr West

Targeted Therapy as Adjuvant Treatment: Should We Extrapolate from Advanced NSCLC to Earlier Stage?


This past week, I saw a new patient who had just moved from another part of the country and needed long-term management of her high risk lung cancer.  A never-smoking Asian woman, she was found to have a stage IIIA lung cancer with “N2″ mediastinal lymph nodes involving cancer in her mid-chest. As is typically done, she received chemotherapy with a cisplatin/Alimta (pemetrexed), a very strong treatment option for her lung adenocarcinoma, and she then proceeded to surgery.  There, she was found to have a small amount of residual cancer in her mediastinal lymph nodes, which suggests a high risk of recurrence. Her oncologist recommended post-operative radiation to treat this area.

Though radiation to the mid-chest is commonly and I think appropriately favored for patients with residual N2 nodal disease after surgery, especially if they hadn’t received it before surgery, this woman declined the radiation. She was far more receptive to more systemic therapy, especially in the form of targeted therapy once it was discovered that her tumor has a ROS1 rearrangement. This is rare (only about 1-1.5% of lung cancers, disproportionately in younger never-smokers with an adenocarcinoma) and has been found to very often respond well to XALKORI (crizotinib), the same agent used for the 4-5% of patients in the US (more in Asia) who have an ALK rearrangement, for whom XALKORI is approved. XALKORI isn’t technically FDA approved for people with a ROS-1 rearrangement, but it’s often covered by insurers when they are made to understand the profound value of this agent for these rare patients. 

But when we talk about XALKORI for patients with an ALK or ROS1 rearrangement, or an EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatinib) for those with an EGFR mutation, we’re focusing on the overwhelmingly favorable data obtained in patients with metastatic cancer.  It’s an entirely different situation with curable and potentially cured lung cancer. When someone has undergone surgery or chemo/radiation or some other combination for stage I-III NSCLC, we know that some of these people are already going to be cured without adding any other treatment. When we give targeted therapies for lung cancer who may already be cured, we often presume we can only be helping them.  However, that wasn’t true when adding Iressa after chemo/radiation for patients with stage III NSCLC — in fact, Iressa was significantly harmful and shortened survival. We decided, with the benefit of hindsight, that this was because the patients on that trial were not molecularly selected as having an EGFR mutation; they didn’t check for or require EGFR mutations, so we presume that 90% didn’t have an EGFR mutation, and we know such patients typically benefit modestly at best from EGFR TKIs.  However, when we saw the results of a trial of post-operative (adjuvant) Iressa in early stage NSCLC patients, we saw that not only was there a trend toward worse outcomes for the recipients of Iressa in the overall, molecularly unselected population, but the trend of worse outcomes was especially pronounced in patients with an EGFR mutation. If there was ever an observation that was humbling in highlighting how wrong we could be in our presumptions, it was that one.

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