Tag Archives: ALK inhibitors

The downstream effect of two miracles of science

My friend Dr. Tom Marsilje wears a number of hats–devoted parent, dedicated scientist, cancer patient and absolutely amazing advocate/activist.

Tom holds a special place in my heart and personal history but sometimes I have to stop and remind him; we both suffer from chemo brain, a subject he recently covered in his column for the The Philadelphia Inquirer.

He was in town briefly last week so we met for lunch and a photo op in front of Miracle of Science in Cambridge. I mean, how could we not.

Linnea and Tom: two miracles of science

Linnea and Tom: two miracles of science

After snapping our selfie we headed down Mass Ave to Flour, one of my favorite little cafes. Lunch banter was about any number of things including Tom’s relatively new role as a writer, and he noted that it makes him feel good to be really making a difference. I just looked at him incredulously before exclaiming “Dude!”

At this point I should remind you that Tom codeveloped LDK-378, the second ALK inhibitor I was on trial for. Also known as ceritinib and now marketed as Zykadia.

I then used my finger to draw an imaginary line on the table. “This” I said, “is my lifeline. And this is where I started taking ceritinib. No ceritinib and my lifeline stops right there.” And then, for further emphasis: “I am alive because of you and don’t think I ever forget that, even for a moment.”

By this point I was getting a little weepy. I went on to say that if Tom were a war hero rather than a scientist who developed a lifesaving drug for a pharmaceutical company, than his role would not be so seemingly anonymous and that he would be celebrated. But that the lack of accolades in no way diminished what he had already accomplished, which was to extend the lives of so very many ALK positive cancer patients. Including yours truly. And that I was grateful to the moon and back.

Such a tight connection between the individuals who come up with these drugs and those of us who take them. A lot of cause and effect going on there and to think that Tom and I would have the opportunity to also develop a human connection is just way, way cool. This guy had my back long before he ever met me (but must of known of my existence as an ALK+ individual). Gotta say I’ve got his back now but sometimes that just feels like hanging onto contrails as he’s jetting around with astounding energy and putting his fine intellect and experience to work as an advocate/activist for patients with advanced cancers. I feel both honored and blessed (and damn fortunate) to have him in my life.

Which leads me to this closing thought: maybe we should nave a national hug a medical researcher day. Followed by a bunch of bang up fundraising.


Just doing it

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I had my six week scan review yesterday—twenty months of stability and counting. At these appointments Dr. Shaw always gives my lungs a listen and this time she kept her stethoscope pressed to my back a little longer than usual and I wondered what it was that she heard. Nothing, as it turns out. I’ve had a little wheeze in the bottom of my upper left lobe all along, but for the first time, she couldn’t find it. ‘Maybe I’m cured’ I said. ‘Maybe you are’ she replied. Or maybe that’s just what I imagined.

What she did say was that she was relieved as she’d been feeling a little anxiety as to what might transpire after my being off drug for a week. Me too. It might be coincidence but my progression on crizotinib followed a break from therapy when I had surgery on a shattered left ankle. And resistance to zykadia came in the wake of my second bout of liver toxicity and subsequent pause in drug.

My labs three weeks ago indicated elevated amylase. My liver enzymes have been only mildly elevated on PF-06463922 so I have continued to enjoy a glass of wine most evenings. Now alcohol was no longer an option.

And why the break in drug? Two weeks ago I began to feel really crummy. A virus, probably strep throat, and then several days later a sinus infection as well. I was also really constipated, an unfortunate side effect of treatment. But then I started to get really uncomfortable with a burning pain in my abdomen and super nauseous–combined with my elevated amylase these symptoms were highly suggestive of pancreatitis. I was in touch with Dr. Shaw, who had prescribed an antibiotic for the ear infection. She felt it would be wise to test my amylase again and as I had an appointment with my ear nose throat doctor on Wednesday we agreed to do it then. In the meantime I would fast and drink only clear liquids so as to give my pancreas a rest. By late Tuesday I was feeling so very bad that I texted Alice and asked her if I should consider going to the emergency room.

Alice called me back and when I told her I felt this represented pancreatitis her response was ‘Linnea, I really hope you don’t have pancreatitis because if you do, it would be grounds for exclusion from almost all further clinical trials.’ This was news to me. Just the day before I had spoken to a friend who’d been excluded from a trial for pancreatitis but I was under the impression that hers was a singular experience pertinent only to that particular trial.

So I told Alice I was not going to get my amylase tested again–that I hadn’t come this far only to learn that I had no more treatment options because of an elevated lab result. She said we’d see how I felt the next day. The following morning I received a text from her  asking me how I felt. My guarded and completely disingenuous response was ‘Hi. Better.’ She then gently but firmly urged me to come in for labs. And I responded with this message:

Alice, I guess I haven’t been paying attention but until I spoke to Margaret I did not know it was grounds for exclusion and it was only after speaking to you that I understood that exclusion meant virtually all trials. I have a very strong commitment to surviving and treatment options are part of my hope for the future. Under any other circumstances I would get that lab work done but as it stands, it is absolutely not in my best interest in the long run. I’m sorry. I would like you to advise me as to how long I can safely hold food for though. Thanks.’

Alice Shaw is a fabulous doctor and I consider her a friend as well. I admire her in so many ways and one of them is how she can just roll with the punches. She heard what I had to say and yet stood her ground. She advised me that if I were feeling better and merely had an elevated lab result it would not be considered pancreatitis. I needed greater reassurance–‘Would that protect my future options?’ She repeated what she had already said, that a lab test alone should have no impact.

So I assented. I got the lab work done and it came back completely normal. Only then did I acknowledge that I still felt absolutely awful. A quick reassessment of symptoms and Alice surmised that this was likely gastritis and possibly a peptic ulcer, which I could address with laxatives and anti-reflux medication.

We also talked a little bit more about what could have happened if I’d actually had pancreatitis. I told her that I felt these sorts of exclusions were patently unfair, and she said that the rationale behind the exclusions was that certain individuals were more likely to experience serious side effects.

I don’t buy it. When I entered my first clinical trial in 2008, I was taking on enormous risk–the only other person in the trial had died almost immediately, in large part because of the toxicity of the experimental therapy. Knowing this did not in any way deter me because I understood that if I chose not to enroll in the trial (my only hope and a thin sliver at that), I would be dead within a couple of months anyway. It was a no brainer.

My explanation to Alice was this: If I experienced life threatening side effects I might be fucked but at least I’d be fucked with options. But that having no treatment options meant that I was totally fucked as I would experience the most devastating adverse event of them all—I would be dead. And that it is my viewpoint that patient safety might be a secondary concern to getting drugs to market faster and without hitches (like adverse events).

I trust Alice implicitly and know that she is highly invested in my personal outcome. However, I hold no illusions about what it means to move from patient to participant in a clinical trial–the loss of autonomy can be really, really frustrating.

In the end, nobody loves this life of mine as much as I do and self advocacy is key to survival. Woody Allen once said that 80% of success is showing up and when it comes to tomorrow, I will not be a no show.

As it turns out, not quite enough (of me)

The word from the lab looking for the PD-1 protein in my biopsy is that there weren’t enough cells (cancerous or otherwise) for a thorough analysis. If it is determined that enough tissue was ‘banked’ after the biopsy, a sample will be resubmitted. Dr. Shaw is not particularly optimistic.

So, the plan for the moment is to watch and wait. We will rescan in November and as long as I don’t become significantly more symptomatic, my situation will be reassessed at that time. In lieu of a PD-1 antibody, I could potentially return to one of the ALK inhibitors which I previously benefitted from:  LDK378 or Crizotinib—although as the LDK is still in trial, I’m not sure how that would work. Chemo remains an option but given the slew of side effects, I would say it is the least attractive choice. What I’m really hoping is that I can hold out until the next ALK inhibitor comes to trial (rumored to be end of this year or beginning of next)—the timing could be just right for me.

In the meantime, my plate is plenty full. I’m looking for a place to live as well as a means of support. I realize that statement implies much and answers little; I’ve got a lot to process and when the time seems right, I will discuss this new chapter in my life.

The numbers look good

I have a newly developed and profound sense of respect for my liver. The AST/SGOT is down to 53 (normal range is 7-30) and my ALT(SGOT) is 43 (normal range is 9-32). This constitutes a mild but entirely acceptable level of inflammation/irritation; the insult and injury has been forgiven. I savored my final grapefruit on Thursday of last week, and last night I started back on LDK 378 at 400 mg.

I experienced a small amount of cramping post dose and felt enough fatigue that I took a nap after breakfast this morning, but all in all, it is an uneventful rechallenge thus far. On Thursday I will have my liver enzymes checked at the local lab; to do so is not mandated by trial protocol, but both Dr. Shaw and I will feel better not waiting until next Monday for my weekly blood draw.

Better yet, Alice (Dr. Shaw) called with some additional news this morning. My tumor response from the last chest CT scan had again been reevaluated, and it has jumped from 45% to 62.4%, which is approaching the phenomenal c 70% I experienced on crizotinib. Now that’s what I call a sweet vote of confidence, or as Mary Poppins might say, ‘just a spoonful of sugar helps the medicine go down.”

Cancer, your little vacation is over. We’re back on track.


Playing the numbers

Slow, but steady. The results are in from my recent CT scan and 40% resolution has eased on up to 45%. A significant five percent, as the negative side effects (gastrointestinal issues) from LDK378 have increased in intensity as well.  Dr. Shaw and I had spoken about possibly moving my dose back down to 400 mg if there had been no incremental improvement in tumor burden.

The Radiology Report is less cheering, although certainly is not what I would characterize as a bad report. It reads:

IMPRESSION:  Persistent groundglass opacities in the anterior and inferior left lung and along the right minor fissure. The opacities in the left lung are slightly more prominent. There are no definite new lesions.

It’s all a curious algorithm; this response/non-response thing. “Tumor size has traditionally been estimated from bidimensional measurements (the product of the longest diameter and its longest perpendicular diameter for each tumor)” (quoted from an article in the Japanese Journal of Clinical Oncology) Basically, a linear measurement, which is quite dependent upon the outside diameter of a lesion, is used to estimate volume. Baseline measurements are taken at the onset of a particular treatment, and response (and/or stability or progression) is assessed by comparing successive scans to the initial chest CT. Evidently my earlier 40% (https://lifeandbreath.wordpress.com/2011/12/14/big-four-oh/) was not the cutoff for partial response but rather exceeded it. I should have done my homework. From Wikipedia:

Evaluation of target lesions

  • Complete Response (CR): Disappearance of all target lesions
  • Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD
  • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
  • Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesion

Odd as well is the 5% increase in response coupled with the possible area of greater consolidation noted on the radiology report. Which to me illustrates the limitations of any sort of quantitative measurements; it is all seems a bit hypothetical/ best guess sort of stuff. Data collection. Bottom line, my lungs feel and sound pretty darn good.

The numbers on my labs are closer to normal as well; the oral iron supplement I began taking several weeks ago is helping.

The one concern of the moment is my liver enzymes, transaminases-SGOT and SGPT.

So what is a transaminase? From MedicineNet.com: The transaminases are enzymes that catalyze chemical reactions in the body in which an amino group is transferred from a donor molecule to a recipient molecule. (!)

SGOT is an acronym for serum glutamic oxaloacetic transaminase and SGPT for serum glutamic pyruvic transaminase. Just in case you wanted to know. What is really relevant is that they are enzymes in the liver and elevated values of either can be an indicator of liver inflammation.

My SGOT/SGPT values were ever so slightly elevated the entire time I was on crizotinib. When I went off treatment they fell to normal levels, but soon after my first dose of LDK378, the levels again became slightly elevated. After my dose went up to 500 mg, the values began to rise again.  My SGOT level peaked at 84 a week ago and is now down to 67. The normal reference range for SGOT is 9-32 U/L  (units per liter of serum–the liquid part of blood). My SGPT was at 79 last week and this week  topped out at 102. Normal reference ranges for SGPT are 7-30 U/L.

Hopefully the SGPT has peaked and will start to go down. In the meantime, a glass of wine in the evening is not an option. Sadly, we’ve been invited to a wine tasting party this very weekend (for the oenophiles out there, all with a rating of 93 or above). When I asked Alice (Dr Shaw) if I’d be able to participate, she said, “Wine tasting is just sips of wine, right?” “Well…” I replied, “it can be done that way”.  So I’ve been given clearance to slosh a bit around in my mouth. Just like the real sommeliers. I don’t believe I’ll be able to bring myself to spit it out though; that just wouldn’t be right.

Big four oh!

I had my second chest CT scan since starting on LDK378 a little over a week ago. The report from the radiologist was basically ‘stable’, But at a scan review with Dr. Shaw, there was clearly visual evidence of further improvement (lessening density of the ground glass opacities). The trial review board at Novartis must think so as well, because several days later Alice emailed to say I was now at the 40% mark, which is the cut off for a partial response. It’s not as clean in there as it was after I started crizotinib (Xalkori), at least not yet. But we’re working on it.

September of 2008/pre-crizotinib

November 2008/post-crizotinib

For comparison, here are the before and after images of my lungs in 2008. The left lung is actually on the right of each individual image. It is smaller than the right lung, because the entire lower lobe was removed in 2005, at the time of my diagnosis. Before I started the PF-03241066 trial (crizotinib, Xalkori), the remaining upper lobe of my left lung was getting pretty filled up with cancer, and you can see some activity starting in the right lung as well; particularly near the top.

August 2011/pre-LDK378

The image above is from a photograph I took of my chest CT scan as displayed on a computer monitor, so it’s not as clear as it could be. I’ve not included the two scans I’ve had since I started the trial, as I’m not certain if I am allowed to do that yet (as a subject now, not a patient, the rules are not the same). I’ve included this image simply to give you an idea of how much cancer had come back. Not as diffuse as in 2008, but well on the way and really rather dense in the bottom of the remaining upper left lobe.

So, what I can’t show you, but can tell you, is that the most recent scan is significantly clearer (and if you are considering percentages, 40% certainly sounds twice as good as the initial 19% resolution). I’m no longer coughing and my lungs feel fine.

This trial is in the dose escalation phase, and I entered at 250 mg. Per protocol, once the subjects at the next higher dose had gone without adverse events for two cycles (a cycle is three weeks long), I would be allowed to go up to that dose, or 500 mg. Last monday was my first day at the stronger dose. I’m hoping stronger=more effective yet.

So all in all I’m feeling well. Occasional bouts of diarrhea would seem to be a side effect, and I’ve become mildly anemic, which leaves me a bit rundown and intolerant to cold (not quite as rosy as I once was either). It would seem to be a mixed etiology of nutritional anemia and anemia of chronic disease, according to my labs (and my oncologist!). My hematocrit is 31.2 (normal reference range 36-46), my hemoglobin is 9.6 (normal reference range 12-16) and my MCV (mean cell volume) is 72 (normal reference range 80-100). My iron level is 18 (normal range 30-160) and ferritin is 6 (normal range 10-200).

In a subsequent post I will  go into greater detail about anemia (I’ve been reading up on it, and it’s rather fascinating).

So that’s the medical update. I’m off to eat some spinach.

A scan and a plan; but first, a tribute

I had a message from Beryl, Guillermo’s wife, this morning. Guillermo Berazadi passed away on Wednesday morning July 13th. His wife and two daughters were by his side.

Although I have known for several weeks that this was an inevitable conclusion, I am beside myself.

Guillermo’s first contact with me was ‘I like your blog and I like you’. It was mutual, as I fell in love with this man of insatiable curiosity, humor, and zest for life. Guillermo’s comments were little novellas, and as he shared his own remarkable story, Gil built a devoted following. When he was silent for too long, I would receive personal emails inquiring as to his well being. I would then harass him (he like playing hard to get sometimes) until he burst forth with some fresh brilliance.

I am glad Guillermo is no longer in pain, but I shall miss him so. My life has been made richer by his friendship. I take comfort from the wise words of Stephanie (a member of the Guillermo fan club):

“G – as always, believe there is solid ground beneath us or that we learn to fly as we take that next step.”

Rest in peace, my friend.

And now, my own update.
Slight further progression compared to my scan of two months ago, however, rather significant progression in general. In other words, slow but steady.

As Alice (Dr.Shaw) said; she would have preferred stability, (oh hell, let’s just go for remission), but at least it’s not galloping. And, we now have a menu of options.

As my performance level is still very good, Alice would like to keep me on crizotinib until we know that it will receive FDA approval (for which it is currently being fast-tracked) that way, should other treatments fail, I have the option of returning to crizotinib (as it would seem to yet confer a partial response).

Once approval is certain, I would get in queue for a trial of Novartis’ LDK 378, the first second generation ALK inhibitor. LDK 378 is administered in tablet form, is a very selective inhibitor and exhibits five times the potency of crizotinib. In addition, a model of my mutation in the lab (from the cell line started with material from my last biopsy) was sensitive to this particular ALK inhibitor. So, it is very promising.

Another experimental drug from Novartis, AUY922, an HSP-90 inhibitor, remains an option as well, but would involve weekly infusions and possibly broader side effects. Although not specific to ALK mutations, my  secondary mutation model again showed sensitivity to this particular HSP-90 inhibitor in the lab.

So, on the one hand I am sad to be going down this path again, but I am also mindful of the fact that this time I have a compass, a map and Dr. Shaw by my side.

I will close today’s blog with some photos from an excursion I undertook last weekend with my friend Julia, to Strawberry Banke in Portsmouth NH. We had a wonderful time and I was much taken with one of the displays; an old home preserved in a marvelous state of decay. Just a reminder that there is beauty everywhere, every day, no matter what.