First of, thank you so much for this wonderful forum, giving hope and professional advice to cancer patients and caregivers around the world. This is invaluable and unmatched.
April 2013: mom, 62, white, never smoker, diagnosed with NSCLC/adenocarcinoma with mets in other lung, lymph nodes, and bones. Initial symptoms: swollen neck lymph node. "Allergic" cough.
August 2013: mom finished cisplatin+pemetrexed as first line, and the result was considered 'stable'.
November 2013: missed progression.
January 2014: cut out neck lymph node, sent to Foundation One. They found 10 mutations and suggested two clinical trials (below). Mom's general condition much worse.
February 2014: mom started Tarceva 150mg after clear evidence of progression (and incredible hassle with acquiring Tarceva in Poland). Head CT clear.
April 2014: scans after two packs of Tarceva are showing progression, if I'm reading them properly. New mets in bones and spleen.
The mutations found in mom’s cancer are:
EGFR: E709_T710>D [exon 18] (initially reported by Foundation One as T710del) and amplification
ARID1A: H710Y
ARID2: T491S
BRCA2: I505T
FGFR2: Q412H
JAK2: E846D
LRP1B: D2371N
MED12: Q2120_Q2121>HQQQQQ
MLL2: P4963L
TNFAIP3: I679T
KRAS, ALK and 200 other tested genes are not mutated and not rearranged.
Clinical trials suggested by Foundation One are:
CO-1686, Phase 1/2, targeting EGFR, NCT01526928
AUY922, Phase 2, targeting HSP90, NCT01646125
They did not suggest any trials for FGFR or JAK2, while there exist some, and also there are more other trials related to EGFR... so I'm not 100% sure they did good job.
Due to (understandable) forum rules, I'll try to limit the questions that I pose...
What is the USA standard of care in our mom's situation - third line, after cisplatin+pemetrexed and tarceva, with rare EGFR?
Is it good time now to pursue clinical trials? Knowing all these mutations, are EGFR-related trials, other targeted therapy trials, or immunotherapy trials the best shot?
Reply # - April 7, 2014, 05:16 PM
Reply To: Standard of care after tarceva second line, NSCLC
Hi bolu,
I don't think you can really say there is a "standard of care" at this point in your mother's treatment. In the U.S. there are three drugs which are FDA-approved for second (and later) line treatment - pemetrexed (Alimta), erlotinib (Tarceva) and docetaxel (Taxotere). That leaves Taxotere as the option which has been thoroughly studied and proven effective. Other drugs which are approved in first-line treatment and are also used in later lines of therapy include gemcitabene and navelbine.
So one option is to try another of these traditional chemo drugs. As you've noted, the other choice is a clinical trial. For a patient such as your mother, who attained stability from first-line chemo which was not long-lasting, Dr. West has summed up his thinking as follows:
"So the better the first line outcome with chemo, the more inclined I’d be to recommend more chemo; conversely, the more disappointing the outcome, the more inclined I’d be to recommend EGFR inhibitor therapy with tarceva, although in this case I’m selecting it as the “not more chemo” choice more than because it’s an EGFR inhibitor. I’d consider it more of a wild card, and a wild card is good when you’re expecting a bad outcome with what you’ve already got (for instance, more chemo), but it’s less appealing if you’re expecting a good outcome with what you’re holding."
In your mother's case, she did not respond to Tarceva, and her response to chemo was good but not great, it's possible to try another chemo agent but it may be better to try a novel agent.
As far as the list of mutations found in your mother's cancer, the problem is that for most of them there are no drugs which have been proven effective yet; they are in the very early stages of development and testing. So it is difficult to say that one trial or drug is better than another - we just don't know yet.
[continued in the next post]
Reply # - April 7, 2014, 05:40 PM
Reply To: Standard of care after tarceva second line, NSCLC
[continued from previous post]
Dr. Weiss has stated his thinking regarding the subject as follows:
"One thought, particularly if your cancer is adenocarcinoma (which I assume that it is based on alimta use) and if your smoking history is limited, is to pursue ROS1 testing. This would only really make sense if you’d be able to travel to one of the trial sites if found to be ROS1 positive (if you search ROS1 on GRACE, there’s lots to explain what I’m talking about).
Otherwise, you could really be seen at any major medical center that has trials. Typically, for fourth line, I often look to phase I trials for my patients. These trials tend to have the newest and most exciting new targets, although the skeptic could also argue (very reasonably) that they are the least proven therapies as well. My favorite kind of phase I trial for my patients would combine an agent with known efficacy against cancer with a novel targeted agent that I have some excitement about really helping." - http://cancergrace.org/lung/topic/clinical-trial-search/#post-11911
It really helps to have input from your own doctors, so you might want to consider a second opinion, preferably at the teaching hospital for an academic institution; their doctors tend to be well-informed as to the most promising trials available.
Good luck with the next line of treatment.
JimC
Forum moderator
Reply # - April 8, 2014, 07:41 AM
Reply To: Standard of care after tarceva second line, NSCLC
Dear JimC, thank you so much for this reply.
Yes, mom's tumor was tested for ROS1 (as part of the Foundation One assay), and it is negative.
You also wrote:
You have listed Taxotere first. Does that mean that, in general, Taxotere can be considered as an option with better potential efficacy than Gemzar and Navelbine, and that oncologists would tend to use Taxotere in our situation, not Gemzar or Navelbine?
Which of the chemos that we have talked about here (Taxotere, Gemzar, Navelbine, cisplatin+Alimta) can be the harshest on the patient, in terms of side effects? I'm particularly frightened of the so-called "chemo brain", which can happen after chemo, but I have no idea after which one(s).
Reply # - April 8, 2014, 08:29 AM
Reply To: Standard of care after tarceva second line, NSCLC
First, I'd say that Jim is exactly right in his explanation of a complex issue. Taxotere (docetaxel) is the only agent remaining that has a proven survival benefit in previously treated patients with advanced NSCLC. While it would be reasonable to consider Navelbine (vinorelbine) or Gemzar (gemcitabine), Taxotere was found to be significantly superior to Navelbine when compared head to head, and Gemzar has been tested in 2nd line as well but has never demonstrated a significant survival benefit.
Cisplatin/Alimta (pemetrexed) is likely the most challenging of all of these options but is also a doublet and not a standard 2nd line treatment. Taxotere would likely be pretty universally ranked more challenging than Navelbine or Gemcitabine, but as the only agent with a survival benefit, I think it's important to clarify your goals. If you want to minimize side effects over using a more effective treatment, that's fine, but it's a bit like the drunk who lost his keys in the dark alley but is looking for them in the well-lit street because the light is better there. It's hard to serve two masters, especially as treatment options become more limited with ongoing therapy and a patient becomes weaker. It's perfectly fine to prioritize quality of life, but at some point if you are avoiding a more effective drug to give a less effective one that is easier, it's time to question why you are giving potentially toxic treatments with little probability of benefit and not focusing overwhelmingly on the patient's symptom management.
As for "chemo-brain", it is not well studied enough to say that any one agent or combination is a worse culprit than another. At this point, it is little more than a general observation by some patients that they feel a mental fog on chemo that they didn't notice before it. It hasn't really begun to be carefully studied yet, especially in lung cancer.
Good luck.
-Dr. West
Reply # - April 8, 2014, 09:23 AM
Reply To: Standard of care after tarceva second line, NSCLC
Thank you so much Dr West and JimC.
Dear Dr West, do you have any suggestions regarding clinical trials, given the treatment history, and the mutations that Foundation One has found, which I posted above? According to your personal intuition, what could be best in mom's situation: an EGFR-related trial, another 'targeted' trial (like, say, taxotere+nintedanib (nintedanib targets FGFR and mom has FGFR2 Q412H)), an immunotherapy trial, or something else? I understand that this question is impossible to answer in 2014 (maybe in 2034 it will), but I'm still interested in your gut feeling.
Reply # - April 8, 2014, 05:05 PM
Reply To: Standard of care after tarceva second line, NSCLC
Like Jim noted, I'm impressed that she seemed to do better with chemo than with an EGFR inhibitor, and the rare EGFR mutations often seem to do no better than people with no EGFR mutation when receiving EGFR-based treatments. I think the most appealing concept is some Taxotere-based chemo +/- novel agent trial, but there's no particular one that bubbles up as the clear top choice. Immunotherapy is always a provocative curve ball, but the limited evidence actually suggests that never-smokers tend to be less likely to be major beneficiaries of the immune checkpoint inhibitors (anti-PD1, anti-PD-L1) than current or former smokers.
Good luck.
-Dr. West
Reply # - April 9, 2014, 12:56 PM
Reply To: Standard of care after tarceva second line, NSCLC
I agree with Dr West, except about the never-smokers. I have two never-smokers in clinic (one an EGFR mutant) this week who've had durable remissions on a immunotherapy PD1 trial. I think the never-smokers may have other reasons for doing less well on these type of trials, but there is no reason to think they won't work. I understand there are very limited data presented for one trial by Dr Spigel that suggested smokers were more likely to be PDL1 positive, but that hasn't been established yet. The proof is the pudding, and I have personally seen it work.
Reply # - April 9, 2014, 08:59 PM
Reply To: Standard of care after tarceva second line, NSCLC
I certainly agree that the work on an association of activity of these agents with smoking status is very tenous, quite early at this point, so I wouldn't want to overstate it.
-Dr. West
Reply # - April 12, 2014, 02:56 PM
Reply To: Standard of care after tarceva second line, NSCLC
Thank you Dr Creelan and Dr West for all the insight.
Mom was offered paclitaxel (Taxol) chemo when she gets better after washing out Tarceva. (Currently her performance is too low to even consider treatment with anything.)
What are the differences between paclitaxel (Taxol) and docetaxel (Taxotere) in mom's situation - after a so-so response to cisplatin+Alimta 1st line and erlotinib (Tarceva) 2nd line failure?
Reply # - April 12, 2014, 06:26 PM
Reply To: Standard of care after tarceva second line, NSCLC
The data are more established for Taxotere (docetaxel), but it's also a notoriously challenging treatment to deliver in patients with a marginal perfformance status. I find it exceptionally believeable and probably very wise to NOT pursue it in someone who is pretty frail, and in whom the risk of prohibitive toxicity and very possibly harm could easily exceed benefit.
In contrast, Taxol is less established but is a treatment that may be far more feasible to deliver safely. It is true that there isn't a proof of benefit, but that proof of benefit with Taxotere was in patients who were far more fit than your mother. And absence of proof isn't proof of absence, so the Taxol or some other agent could potentially be effective.
It's an appropriate place for such a judgment call, in my estimation.
Good luck.
-Dr. West