One of the longstanding ideas in lung cancer management is that you exhaust the benefit of first line combination chemotherapy after 4-6 cycles of treatment.  This is based on a few trials that showed no survival benefit for treating beyond that point, as summarized in this early post I wrote all the way back in my first few months of doing this (OncTalk days, pre-GRACE).  This standard of care is based in part on the premise that the incremental adverse effects may escalate faster than any incremental benefit for a platinum-based doublet.  With cisplatin, cumulative nausea, fatigue, risk of significant kidney damage, neurotoxicity, and overall “platinum blues” tend to make treatment beyond 6 cycles infeasible and disproportionate to any potential added benefits of ongoing therapy.  With carboplatin, cumulative cytopenias (low blood cell counts) and a rapidly escalating risk of a severe and potentially dangerous hypersensitivity reaction (which can also occur with ongoing cisplatin but is notorious and almost inevitable with carboplatin) make indefinite carboplatin too challenging and inadvisable.

In the last few years, the concept of maintenance therapy for patients who haven’t experienced progression or prohibitive side effects after 4-6 cycles of first line combination chemotherapy has taken hold.  Initially, this default strategy was baked into the development of Avastin (bevacizumab): the trial that led to approval of Avastin gave six cycles of carbo/Taxol (paclitaxel)/Avastin, followed by maintenance Avastin.  It showed a survival benefit for the whole program, but it was not possible to say whether the benefit was from the addition of Avastin with chemo, from the maintenance Avastin, or both components.

Meanwhile, many trials over the last few years have shown a clear improvement in progression-free survival (PFS) and a suggestion of improvement in overall survival (OS) with addition of switch maintenance therapy, where a new treatment is initiated after 4-6 cycles of first line combination chemotherapy is completed in non-progressing patients.   This work is discussed in more detail elsewhere and led to a general standard of at least considering maintenance therapy in this setting for appropriate patients, even if the data supporting a survival benefit are flawed enough to leave most experts considering maintenance therapy far from a mandate.

Read the rest of this entry »

I met DC in April.  He was 62 years old and was principal of a Montessori school.  He had smoked a half pack a day for three years in college (which makes him a former/light smoker in my book) and was in fairly good health until the December before when he developed a cough.  His cough didn’t get better and thanks to all the talk about lung cancer screening, he requested a chest x-ray.  The x-ray revealed a mass, which led to CT scanning.  The CT scan shows a large right upper lobe mass, which was hot on PET as were lymph nodes.  MRI of his brain revealed metastatic disease and leptomeningeal carcinomatosis.  Biopsy was obtained via EBUS, which showed NSCLC, adenocarcinoma subtype.

What is leptomeningeal carcinomatosis?  Well, inside the brain, there is a lake called the fourth ventricle; it’s filled with fluid called “CSF” or cerebrospinal fluid.  This lake lets out into a river at the base of the brain, which leads down the spinal cord.  Leptomeningeal carcinomatosis means that cancer cells have gotten into this fluid-filled space.  This state bears a very bad prognosis in lung cancer.  Patients typically experience neurologic problems such as visual difficulties or unsteady gait and decline is typically rapid. 

  (Click on image to enlarge)

When I met DC, he quickly impressed me as a thinker.  I remember being impressed that despite being weak from his cancer (PS 2) and having brain mets plus leptomeningeal disease, that he asked sharp, insightful questions.  His gait (walking) was a little unsteady, but his speech, strength, coordination, and intelligence showed that his brain was pretty much working.  He was accompanied by his wife, who was very supporting at that time and has been a regular ally in DC’s care, keeping me updated about how he’s been doing.

 DC had already met a radiation oncologist and there were plans in place to start whole brain radiation.  I agreed with this, and also ordered lumbar puncture.  My fellow numbed DC’s back, and then inserted a very thin needle into the CSF space to withdraw some fluid.  The pathologist then looked at the fluid under the microscope and the presence of cancer cells confirmed leptomeningeal disease.  I don’t give chemotherapy at the same time as brain radiation, so I had no conflict between waiting for EGFR test results to come back vs. treating right away with chemo.  I ordered EGFR mutation testing and asked DC to come back after completion of his whole brain radiation.  His EGFR mutation testing came back positive.

At the time I met DC, I was well aware that Dr. Mark Socinski had treated a similar patient with pulse tarceva and that it had worked-Dr. Socinski’s office was next door to mine and he was mentoring me.  I had also read Dr. West’s report (which I blatantly stole the above picture from) of a similar patient right here on cancergrace and had heard scattered stories from other doctors.  And so I approached DC with more optimism than I had ever approached a patient with leptomeningeal disease before.

 What is “pulse-dose” tarceva?  Well, the standard dose of tarceva is 150mg per day.  Actually, patients with EGFR mutations can do well on much lower doses, perhaps as low as 50mg per day.  At standard doses, the drug doesn’t get into the brain very well, but research has shown that at higher doses, it does get in.  So, pulse dose tarceva gives many pills all at once, instead of spread out as a daily dose.  Based on the good results of Dr. Socinski’s patient and Dr. West’s patient at 600mg every four days, I chose this regimen.

DC initially tolerated therapy well, although he got briefly admitted to the hospital for fevers of unclear source.  We never found infection and they got better with Tylenol.  His tumors all showed good response to therapy.  By June, his energy had improved sufficiently that I graded his PS at 1.  Today, his scans again look good.  He reports living an essentially normal life and just had a great time on a vacation to Canada.  In summary, he’s been living a high quality life for 7 months (so far!) with stage IV lung cancer including mets to both brain and the leptomeningeal space.  Neither he nor I have any plans of that stopping anytime soon!

I’m writing about DC’s case, with his permission, to get the word out about this treatment option that now has many reported cases.  Since Dr. Socinski’s case report and Dr. West’s cancergrace.org post, there have been many published case reports and case series of similar patients.

I find one particularly striking.  Memorial Sloan Kettering Cancer Center in NY looked back on 9 of their patients, all with EGFR mutation, who all developed leptomeningeal disease while on standard-dosed tarceva or other similar drugs.  This group is a bit different from my patient, Dr. Socinski’s and Dr. West’s-these patients had already seen tarceva (or a similar drug) and the cancer managed to spread to the leptomeningeal space despite it.  These patients were given a regimen of 1500mg weekly and the results were very good.  6/9 patients had a radiographic partial response in the brain.  1 patient had stable disease, and the other 2 had progressive disease.  Of the five patients whose disease in the rest of the body was evaluable, 3/5 had stable disease and 2/5 had progressive disease.  The median time to progression in the brain was 2.7 months and median overall survival was 12 months.

There are other reports from all over the world with various pulse-dose regimens for leptomeningeal disease and they all give promise to this therapy.  In my opinion, this regimen has become a very strong option for the patient with EGFR mutation and leptomeningeal disease.

DC has been sending me journals of his progress on therapy.  I’ve enjoyed them as a window on the life of a patient and they gave me the thought that he might want to comment on this post.  I invited him to do so, and here’s what he had to say:

          Time to step back from the trees and look at the forest.  Cancer is a trip: you develop the habit of watching your body like a hawk, and it is sometimes hard to know what is a regular headache and what is the cancer.  Nonetheless, you watch yourself constantly.  I’m one of the lucky ones - gradually but pretty inexorably we saw progress:  early on certain days after taking Tarceva were characteristically better or worse, but the pattern changed and by this time it is pretty hard to predict.  But by now usually 3 days out of 4 are good days - sometimes 4/4.  Spiking a fever and going to the ER and hearing the liver enzymes were “elevated” was scary, but the next week it looked like my body was learning to handle that, like everything else.  You learn to live each day more-or-less thinking you’ll be able to do what you plan to do (If you don’t overdo it) but never quite sure.  But I’ve been able to work almost full time for weeks now, go out to dinner when we planned to - as long as I take it easy in between.  Each day is just unpredictable in terms of just how good it will be. 
            It is also true that by this time I’ve learned more about cancer.  Both Dr. Wong and Dr. Weiss have explained things.  Kathy has feelings about each doctor’s styles, but I’ve learned from both, and I believe both care about me.  I’m probably easier than some to care for because I listen and I’m doing well.   But they have explained from the start that they could “treat me, but not cure me.”  And as they both have explained, each in their way, the cancer will, eventually, find a way around the Tarceva and gradually return.   That is how I see the beginning of the end, even though vague references have been made to “other chemos” we could try.  Thankfully, I can enjoy the present - a time when cancer is on the wane - a time when your friends can jauntily email you with boxing metaphors as if I am bloodying my enemy with every Tarceva punch.  Perhaps I am.
            There are worse ways to be very sick.  I can have a great time and I’m surrounded by friends and family.  I am more glad I’ve been the teacher and parent I’ve been because my children, my wife, relatives, family friends, former students, current colleagues and students - I feel the love and am happy to feel it.  A good guy doesn’t always finish first, but always finish surrounded by friends.  I can reflect on my life and be really really proud.  I have no regrets.  I can reflect on all this and yet know I’ve got lots of time left to enjoy what comes next.  The decision to retire next year is immensely “freeing”, and I thank Kathy for suggesting it. (written June 9, 2011)

     Since writing those words in June, the family and I have taken our usual two plus weeks in our cabin in the woods of Maine, and we both have returned to full time administrative jobs at our respective schools.  Since medications are down to practically nothing, Tarceva every 4^th day and some other vitamins and minerals I’ve picked up over the years (to satisfy my desire to improve my health without substantially changing my lifestyle), the days go by without much thought about cancer.  Except the week I go for scans and consultation with the good Dr. Weiss.  Then I’m hungry for the data.  Can’t help it - I can watch the ups and downs of the stock market and not lose any sleep if my portfolio loses 2% in a day (over time it’s held its own) - but I want to see shrinkage in a tumor because the day cancer starts “progressing” (an odd term for getting worse again) feels like the beginning of the end, and I haven’t had to go there yet because it’s been shrinking.  I’ll adjust - I’m an optimist and a happy person (it will be harder on Kathy).  But like everything else about having cancer, it’s a series of ups and downs that you just have to live with.  It is what it is.

I apologize if it seems that the updates about ASCO have been slow in coming.  This is mostly because the lung cancer program this year has most of the higher profile presentations occurring in the second half of the meeting, which we’re just getting into.  And, truth be told, this isn’t going to be a blockbuster year for developments in lung cancer.  But let’s review what we’ve found out about thus far.

Read the rest of this entry »

Continued from part 1

Dr. West: You have a huge portion of your patients who have an EGFR mutation and we know that over time patients develop acquired resistance. So how do you approach the patients who have a great response initially, have a known EGFR mutation, and then you see that slipping away at slow progression? Do you continue the EGFR inhibitor?  Do you add something to it?  Do you change the dose? How do you approach that?

Dr. Mok: I think this is one area where we still have a lot to learn.  First of all, let’s define resistance, or progression. If you use the Jackman criteria (Jackman, J Clin Oncol 2010), that still incorporates the RECIST criteria, which mean if the lesion that has increased by about 30%, then it’s progression. But then one factor we didn’t look into was in the rate of progression within this definition. The second concern is about the occurrence of a new lesion that’s also progression. Now, whether this is directly applicable to a targeted like Tarceva or another EGFR TKI or not, I have some doubts, because simply from your experience and my experience, some of these patients get a new nodule, but they can take a long time to grow and the patient lives a normal life. And we also know the fact that if we take them off the TKI, the disease can progress rapidly. So some of these are slow progressors, then we just keep them on a TKI. Read the rest of this entry »

A few weeks ago I had the chance to speak with Dr. Tony Mok, who is a professor in the Department of Clinical Oncology at the Prince of Wales Hospital in Hong Kong and the Chairman of the Hong Kong Cancer Therapy Society.

He is also the principal investigator and lead author for the pivotal Iressa Pan ASian Study (IPASS), which was published in the New England Journal of Medicine in the fall of 2009.  I started by telling him that I consider that study to be arguably the most influential over the last 5-10 years in the field of lung cancer, because it highlighted that molecular predictive factors trump clinical markers in determining who is likely to do best with a targeted therapy, specifically an EGFR tyrosine kinase inhibitor like Iressa (gefitinib) or Tarceva (erlotinib).  Here’s the first part of our conversation about what we’ve learned about how best to use these EGFR inhibitors and the potential differences in practice between Asia and the US.

Read the rest of this entry »

A few weeks ago, Dr. Lecia Sequist, Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital (MGH), joined us for a live webinar we did in partnership with LUNGevity Foundation.  Dr. Sequist and her colleagues at MGH have been at the forefront of research in EGFR mutations: her group was among the first to identify activating mutations and observe the correlation with response to EGFR tyrosine kinase inhibitors (TKIs), and they continue to do much of the leading clinical research on acquired resistance — the development of progression after an initial good response — and potential mechanisms for reversing this.

In the presentation below, provided in video and audio podcast forms (along with the associated transcript and figures), she provides an outline of the issue and some of the identified mechanisms for resistance.  In addition, she discusses several attempts to manage this and current and emerging clinical trial options for this setting.

sequist-acquired-resistance-to-egfr-tkis-audio-podcast

sequist-acquired-resistance-to-egfr-tkis-transcript

sequist-acquired-resistance-to-egfr-tkis-figures

Read the rest of this entry »

Podcast: Play in new window | Download

Over the past several years, probably the biggest development in the field of NSCLC has been the recognition of the importance of molecularly-defined subgroups that help define the clinical patterns of how patients are likely to do with various treatments.  We’ve seen this clearly illustrated with EGFR mutations vs. EGFR wild type (no mutation), and more recently with the very uncommon but clinically important ALK rearrangements.

One newly defined clinical setting that has emerged has been the group of patients who experience a very good response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib) or Iressa (gefitinib), generally but not necessarily those with an activating EGFR mutation (most typically on exon 19 or 21, as described in this great summary by Dr. Nate Pennell) who respond for a period of months or years and then develop resistance.  Why does it happen, and what are the leading options for managing this situation?

Early work on this problem of acquired resistance (as opposed to primary resistance, which is the situation in which a person starts out by not being very responsive to an EGFR TKI), largely out of the Harvard hospitals in Boston and Memorial Sloan-Kettering Cancer Center in New York City, have shown that about half or slightly more develop a resistance mutation called T790M on exon 20 (and a minority of people with an activating EGFR mutation also have this from the beginning, likely helping to explain why the response rate with one is not 100% but more like 70-75%).  Another 10-20% or so are found to have over-expression of c-MET (targeted by agents like ARQ-197), reflecting a pathway that can bypass the EGFR signaling cascade as a mechanism for resistance.

Read the rest of this entry »

The IPASS trial that randomized never-smoking Asian patients with a previously untreated advanced lung adenocarcinoma to either standard chemo with carboplatin/Taxol (paclitaxel) or the oral EGFR inhibitor Iressa (gefitinib) was a pivotal study that changed how many of us thought about NSCLC.  Clinical factors such as patient race, smoking status, tumor histology, and potentially patient sex have historically been useful in predicting which patients are most likely to benefit from an oral EGFR inhibitor (with Asian, never-smoking status, adenocarcinoma and especially bronchiooloalveolar carcinoma (BAC), and women being prevalent features of major responders).  However, the IPASS study showed that the molecular marker of EGFR mutation is clearly more important than these clinical factors: in those patients who have an EGFR mutation, Iressa was associated with a far better response rate (RR) and progression-free survival (PFS), as well as a trend toward a more favorable overall survival (OS).  On the other hand, in those who don’t have an EGFR mutation, even among Asian never-smoking women with an adenocarcinoma, chemotherapy was a clearly superior option.  It is worth noting that this is specifically for the question of first line therapy, for which chemotherapy is the default standard therapy — the results comparing chemo to EGFR inhibitor therapy as second line treatment have been very comparable in broad populations.

Eligibility on the IPASS trial was based on clinical selection for patients more likely to benefit from EGFR inhibitor therapy, and it was only in a planned retrospective analysis that the importance of the very different results by EGFR mutation status became apparent.  A slightly different question emerges if you know that a patient has an EGFR mutation before you start treatment.  The IPASS trial strongly suggests that patients with an EGFR mutation will be better served by receiving first line EGFR tyrosine kinase inhibitor (TKI) therapy, and this has now been confirmed in three independent prospective randomized trials.

One pivotal study of this concept was done by the North-East Japan Study Group, performing a remarkably similar trial to that done by IPASS: carbo/Taxol or Iressa as first line therapy in patients with a prospectively identified EGFR mutation, using PFS as the primary endpoint.  Though it was designed to enroll 320 patients, it closed early, when an interim analysis showed such a remarkably superior improvement in PFS that the Data Safety Monitoring Board considered that continuing to randomize patients on the trial would be unethical:

(click on image to enlarge)

Read the rest of this entry »

   One of the trials presented at the Chicago Multidisciplinary Symposium in Thoracic Oncology last month was the TITAN trial, one of a pair of studies conducted in Europe to test the oral EGFR inhibitor Tarceva (erlotinib) in patients with chemotherapy pre-treated advanced NSCLC.  The other trial, SATURN, was designed to test Tarceva as a maintenance therapy vs. placebo in patients who had shown a response or stable disease after four cycles of first line chemotherapy (without the VEGF inhibitor Avastin (bevacizumab)) has been summarized previously and ultimately led to the approval of Tarceva as a maintenance therapy in this patient population.  But what happened to the significant fraction of patients who progressed by the time of the repeat imaging after four cycles of first line platinum-based doublet chemotherapy?  They were directed to the TITAN trial, which was a head to head comparison of Tarceva vs. either Taxotere (docetaxel) or Alimta (pemetrexed), both well studied and commonly used second line agents for advanced NSCLC.  The trial looked for an improvement in overall survival with Tarceva.

 (click on image to enlarge)

    The trial closed earlier than planned, due to slow enrollment, with just 424 patients, which leaves it quite underpowered to detect a difference even if there really is one between the two treatment approach.  Still, there may be some conclusions that can be drawn from what they saw, even if limited by smaller numbers than needed to say anything definitive.

   Read the rest of this entry »

    Just prior to ASCO, I mentioned the early results of the Cancer and Leurkemia Group B (CALGB – Group A long-since defunct) 30406 trial.  This study enrolled 181 people with advanced lung adenocarcinoma who had either never-smoked or had a rather minimal smoking history of 10 “pack-years” or fewer, and who were randomized to receive the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) alone or in combination with standard chemo of carboplatin and Taxol (paclitaxel) as first line treatment.  The idea of this trial was that the selection of patients by the clinical factor of smoking status was meant to enrich for a higher probability of such patients having an EGFR mutation, and it had also been recognized that never-smokers (less than 100 cigarettes in their lifetime) or “oligo-smokers” (oligo meaning few, so the term means those ex-smokers who had a light smoking history but didn’t qualify as never-smokers) in many clinical trials of EGFR inhibitors appeared to be the greatest beneficiaries of an EGFR inihibitor like Tarceva or Iressa (gefitinib).  At the same time, there was reason to question whether combining chemo with an EGFR inhibitor might provide additional benefit, have no effect, or might even be detrimental. 

    (click on image to enlarge)

Read the rest of this entry »