Pulsatile Tarceva for Lepto... Afatinib for Lungs? - 1262432

sanjuandaughter
Posts:4

My 76 year old mother was successfully treated with second-line Tarceva for nearly four years before Leptomeningeal metastases were discovered in October of 2013. First line chemos of gemcytabine, carboplatin, cisplatin and alimpta did not work. After being told she would likely be dead in three months her Lepto disease has shrunk or stabilized under 1500 mg Tarceva 1x week.

Her lung cancer is now growing again, with a T790m mutation. She does not want to go back to nonspecific chemo drugs. Pulsatile Tarceva has kept her alive long past when anyone thought she would be, and it has yet to be proven in clinical trial. Afatinib is an approved drug for post-Tarceva progression. Other than the fear of side effects because the two drugs have not been tested together, why would we NOT do Afatinib? My mother's Tarceva side effects would tend to be more clustered around the day when she takes all of her Tarceva; obviously, she wouldn't do Afatinib on the same day.

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Reply # - February 21, 2014, 08:36 PM

JimC
Posts: 2753

Hello,

Welcome to GRACE. There are always concerns when trying two drugs which have not been tested in combination. There is the fear that they may interfere with each other and, as you pointed out, the combined side effects may be unmanageable or dangerous. As Dr. Sequist has said:

"I would say one thing I would not recommend is adding afatinib to erlotinib – there is no safety data on that combination and my guess is that it would not be safe." - http://cancergrace.org/topic/tarceva-with-avastin-or-afatinib#post-1261…

JimC
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Reply # - February 22, 2014, 08:04 AM

sanjuandaughter
Posts: 4

Jim C, with all due respect to the doctor, as he accurately states, it is his guess, and not scientifically proven. I respect that he wishes to do no harm and act conservatively. On the other hand, if he is wrong, my mother basically has no other options. Her cancer is not resectable, traditional chemo doesn't work, and she has already had radiation. In addition, there are no clinical trials near her. So, under an "Afatinib-is-the-only-approved-option" scenario, is denying the patient further treatment for lung cancer the next step?

Reply # - February 22, 2014, 02:04 PM

JimC
Posts: 2753

sanjuandaughter,

I understand your mother's dilemma and your desire to find a treatment option for her. I lost my wife to lung cancer after she developed LMC and her cancer was progressing elsewhere concurrently, so I know the difficulty of trying to choose a treatment to address both areas of progression. I don't claim to have the answer, but I have a few comments and questions:

Dr. Sequist practices at Massachusetts General Hospital, a teaching hospital of the Harvard Medical School, which from the beginning has been at the forefront of research into EGFR inhibitors such as Tarceva and Afatinib. So her "guess" is a very well-educated opinion based on experience with the two drugs. And when she believes it would not be "safe", I think she means just that...not somewhat worse diarrhea or skin issues, but possibly dangerous complications due to combining the drugs, especially in an older patient.

Second, the half-life of Tarceva is 36 hours, so a day and a half after taking 1500 mg, there is still 750 mg in her bloodstream, and 375 mg a day and a half after that. If there is a compounding of side effects or antagonism between the drugs, after 4.5 days there is still more than a full normal dose of Tarceva in her body. Any possible conflict between the drugs can't really be avoided by adjusting the timing of dosages.

Finally, did your mother have a spinal tap which confirmed LMC or have typical symptoms of it, or was the diagnosis based only on radiographic findings? My wife's lepto was seen on an MRI and though a spinal tap was not performed, her symptoms confirmed the suspicion. But LMC can be an overcall on a scan, so that may affect her oncologist's consideration of a treatment choice. In other words, can you be certain that pulsed Tarceva has eradicated or stabilized LMC?

JimC
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Reply # - February 22, 2014, 03:20 PM

sanjuandaughter
Posts: 4

Thanks, Jim. We've had three neuro-oncologists look at multiple MRI's. All are highly confident it is Lepto, without lumbar punctures. First scan in October, second in December, third in January, fourth yesterday (still unseen). From first to second, during which we started with 1200 mg Pulsatile Tarceva, expansion of Lepto; from second to third, after we moved to 1500 mg, shrinkage and stabilization. My mother has some confusion symptoms, which is why the MRI was done "off-schedule." That being said, her predicted imminent death isn't emerging.

It would seem that Afatinib, as an irreversible inhibitor, would bind to the places where Tarceva is now failing to attach. Afatinib might also replace Tarceva in the lung cancer cells where Tarceva is still working, by having a higher affinity for the binding sites that Tarceva uses. Afatinib would not reach the brain because it is not in high enough concentrations (though doctors seem to be looking into a clinical trial of Pulsatile Afatinib), leaving Tarceva free to circulate and work in the brain. However, because both of these drugs target the same EGFR sites on cells (with Afatinib targeting additional sites), I don't see how combining them would cause worse side effects... if the drug is not binding, it should be ineffective. The only way I see this being a problem microbiologically is by putting both drugs in, there are suddenly more sites affected, thereby causing additional side effects. Antihistamines work this way. You can combine them in ways you cannot combine "cold medicines."

Reply # - February 22, 2014, 07:36 PM

Dr West
Posts: 4735

I certainly appreciate the concern about little to lose, but I think you are greatly overestimating the efficacy of afatinib (Gilotrif) in acquired resistance after progression on Iressa (gefitinib) or Tarceva (erlotinib) -- it's VERY minimal in nearly all patients -- while potentially greatly underestimating the potential toxicity of this combination based on a thought process and no hint of evidence. This combination has never been tried because no lung cancer specialist believes the combination would add any benefit, and there is very good reason to be concerned that it could be profoundly, dangerously toxic. I would say that Dr. Sequist represents about the pinnacle of careful reflection on issues related to acquired resistance and made a point that combining afatinib with Tarceva was a singularly bad idea. She doesn't have a vested interest for or against, "doesn't have a horse in this race", and yet made the point in another thread that she would be concerned about this combination.

As physicians, we are charged with a responsibility to not do things that are overwhelmingly more likely to be harmful than beneficial for our patients, even if a desperate patient wants to accept all the risk in the world. There is a point at which we need to recognize that these medications can act as poisons. The absence of compelling alternatives shouldn't lead us to treat wildly outside of what is considered appropriate treatment.

I'm sorry if this counters what you hope to pursue, but I would consider a doctor giving the treatment you are seeking arguably committing malpractice. Again, I have no stake here, except that it would be painful for me to think that someone is getting an ill-advised treatment with a rationale that is based more on desperation than justifiably anticipated benefit.

-Dr. West

Reply # - February 23, 2014, 08:14 AM

sanjuandaughter
Posts: 4

I greatly appreciate your thoughts. I would argue, however, that my question is not about desperation, but rather about the microbiological basis for avoiding the treatment. Many people were likewise as concerned about Pulsatile Tarceva for the same reason... too much of a drug would lead to toxicity. For fear of toxicity, some would still argue against it. And yet, it is proving in Lepto-progressed, NSCLC patients to be a fourth treatment that extends quality of life with fewer side effects beyond that of Whole Brain Radiation Treatment or Intrathecal Chemo or lumbar punctures--all of which are more invasive. And for the same reasons, the first doctors that tried Pulsatile Tarceva might have been accused of malpractice.

Reply # - February 23, 2014, 09:52 AM

JimC
Posts: 2753

Of course no one here can tell a patient what treatment choices to make, we can only offer the general reasoning for or against those possible choices. I think there is a difference between adjusting the dosage schedule of a drug and combining two drugs which have not been tested together. The original pulsed Tarceva treatments consisted of 600 mg every four days, which was the same total dose as the standard 150mg/day. After that proved not to be too toxic for many patients, oncologists began to experiment with higher total doses.

I would also say that pulsed Tarceva only helps a minority of patients with LMC. All we have is anecdotal data, but in a number of GRACE accounts of such treatment, including my wife's (despite her exon 19 mutation), pulsed Tarceva did not slow the progression of LMC at all.

Finally, there are often good arguments for the efficacy of a treatment from the microbiological point of view which prove false in the real world. As an example, it is perfectly reasonable to assume that Tarceva would be effective as adjuvant therapy in EGFR+ patients, but the trial evidence revealed worse results compared to conventional chemotherapy. http://cancergrace.org/lung/2014/02/02/adjuvant-targ-rx/

JimC
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Reply # - February 23, 2014, 10:34 AM

catdander
Posts:

You make being desperate sound like a bad thing. I see it more as a warning to look closely twice three and four times over because it's a very stressful time, you've got a lot to learn and no time to do it. It appears you'll have to let her go soon and it's a horrible balancing act to plan for. You want her to live and die peacefully without pain and stress. Adding dangerous side effects could easily destroy any possibility for a peaceful going.

From your earlier post "...I don’t see how combining them would cause worse side effects…" I don't think you're understanding how side effects work. It's not what affects the mechanisms for cancer growth instead it's the unwanted effects the drugs have on the rest of the body that any doctor would worry about. I'd imagine it would be difficult to find a doctor who'd prescribe both tarceva and afatinib and certainly insurance wouldn't pay.

In a previous thread about transitioning from tarceva to afatinib Dr. West said "It is. And while the idea of minimizing the interval between Tarceva and afatinib makes good sense to reduce the risk of a disease flare, the two drugs are so similar in mechanism I can't imagine combining them. It would be too close to just taking twice as much of one of these agents as is considered safe and recommended." http://cancergrace.org/forums/index.php?topic=10732.0

FWIW, Our faculty of cancer specialists like all oncologists must work with more of a feel for what is appropriate for a person. There's no standard patient profile or flowchart that fits all. Every cancer has it's own biology like every person does. Some doctors are more conservative than others in their practice but all must make difficult calls. The best come to know his and her patients and take into consideration what's best for the individual.

I wish your mother a smooth life,
Janine

Reply # - February 23, 2014, 08:34 PM

Dr West
Posts: 4735

sanjuandaughter,

I can see your point about the first use of pulsed Tarceva for LMC, though in fact it was tested at these kinds of doses in limited studies outside of LMC before being given specifically for that. I appreciate that desperate times call for desperate measures, and that significant risk is acceptable if the alternative is bleak enough, but I don't share your optimism about the biological rationale here and do think it'd essentially be like just giving an extremely high dose of the same EGFR inhibitory drug, with potentially overwhelming toxicity. And while that may seem acceptable in the face of evidence of some progressing cancer, I think it's troubling for a doctor to be the agent writing for a treatment that is the immediate cause of death or overwhelming toxicity compared with the natural, arguably inevitable course of the underlying illness. Medicolegally, it is far less permissible to kill the patient by your active interventions than to fail to reverse the course of a progressing cancer, particularly in the setting of there being no anticipated way to reverse that course.

-Dr. West

Reply # - February 24, 2014, 12:26 PM

commodore64
Posts: 37

I'm very sorry your mother has progressed to LMC. How are her symptoms presenting, now 4 months (?) removed from original Dx? I know you are grasping at straws, and I've been there too, which why I'm asking about her condition now. We got about 6 weeks after LMC Dx.

We didn't pulse Tarceva for my mother because she was too weak to tolerate it, our onco never suggested it, and because, after much agonizing, we accepted that adenocarcinoma related LMC was her end. We did not push for the pulsed Tarceva approach. I could find no reports about a positive trajectory once LMC presents in the way it did with my mom (everywhere in the CNS), paralysis from the waist down, incontinence, and rapidly diminishing mental state.

All of those things helped us transition to hospice care. It really was only then that my mom got some modicum of relief from the suffering. I'm so sorry your mother has LMC.

Reply # - February 25, 2014, 04:34 PM

laya d.
Posts: 714

sanjuandaughter:

I have nothing to add here. . .but just wanted to send your Mom lots and lots of good thoughts. I hope that the the progression of her disease is super slow - - irrespective of whatever treatment plan she opts to pursue from here forward.

Laya

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