EXON 20 and ERBB3 amplification - is Afatinib really an option? - 1264755

gaw1
Posts:18

My brother's lung cancer has progressed after 1st line chemo and Avastin maintenance. So we are considering options: standard 2nd line chemo, pdl1 trial pending results of test for expression, or targeted therapy if he has a marker.

I received a copy of my brother's next generation sequencing report based off a biopsy from a few weeks ago. It lists EGFR D770_N771insG and ERBB3 amplification. Afatinib is listed next to both as an FDA approved therapy. However, when I read the fine print of the report and search the internet, this type of EGFR has EXON 20 insertions which in general are shown to be less sensitive to reversible EGFR inhibitors than the classic EXON 19 and 21. So my questions:

1. Why would Afatinib be listed as an option if it really isn't? It seems really odd. Does it have something to do with the ERBB3 amplification? Or his particular insertion? Is there something special perhaps regarding the insertion number and the ERBB3 amplification in combination? His doctor is of the opinion that Afatinib is really not an option.

2. Does it make sense to talk to an expert in this area such as Dr. Ross Camidge out of Univ of Colorado because he led trials with Afatinib? Perhaps he has seen this particular insertion first hand.

3. I've read nearly all of the posts on here regarding EXON 20. They lead me to believe that we should just consider him EGFR Wild for all intents and purposes. But I don't want to leave anything unturned if we are misunderstanding something. Is it time to move on and pray for the PDL1 lottery to hit?

Thanks!

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Reply # - July 3, 2014, 08:09 AM

catdander
Posts:

gaw1, I'm sorry your brother has progressed on avastin. There are 3 options with clear data and are fda approved for 2nd line treatment, alimta (for non squam only), taxotere, and tarceva. There are other chemo drugs that are used such as gemzar and navelbine but are less well studied. http://cancergrace.org/lung/2010/10/04/lung-cancer-faq-2nd-line-nsclc-o…

It's never a bad idea to get an opinion from a lung cancer expert though unless your brother has easy access to Dr. Camidge most any other nsclc expert will have access to the same info because of their specialty and can be found at teaching and or research facilities. The time to look at clinical trials or any new treatment is during transition times such as your brother is experiencing. Dr. Weiss has written this blog post about second opinions. In it you will find there are several excellent reasons to get one including times of transition/tx changes, looking for possible trial opportunities, and having a second pair of eyes on the case. I think it can help answer a couple of your questions. http://cancergrace.org/cancer-101/2011/11/13/an-insider%E2%80%99s-guide…

I can't answer the questions about why afatinib (perhaps because tarceva is a second line option for wild type?) or the specific mutation sequencing report. I'll ask a faculty to respond.

All best to you and your brother. He's lucky to have you.
Janine

Reply # - July 3, 2014, 05:11 PM

Dr West
Posts: 4735

Unfortunately, the next gen sequencing reports don't necessarily have a high threshold for listing a drug as an option to pursue. In this case, they identify a target, and then if there is a drug that is in their database that is listed as hitting that target, it gets listed.

In this case, afatinib has been shown to NOT be especially effective for rare EGFR mutations (and results of EGFR TKIs in patients with exon 20 mutations have tended to be unimpressive, or at best quite variable), and its value in treating ERBB3 (HER3) is unknown, but we couldn't presume it will be effective. Because afatinib is not approved by the FDA for people with these mutations, it may not be covered by your insurer. Even if it's possible to get it paid for, it very well may be ineffective.

I have generally given an EGFR TKI to most patients, at least as a later treatment option, because sometimes I have been surprised to see an excellent response in someone reported as not having an activating mutation. I think that's a reasonable approach to try here, and afatinib might be a fine one to try based on the ERBB3 (HER3) mutation as well. However, the report's mention of afatinib should be construed more as "hey, you could always try afatinib, I suppose", rather than "afatinib is highly likely to lead to a good response".

Good luck.

-Dr. West

Reply # - July 3, 2014, 08:58 PM

catdander
Posts:

Dr. Suresh Ramalingam had this to say in response via email to your post, “The specific insertion mutation in exon 20 noted in the report is known to be resistant to EGFR inhibitors including afatinib. I do not feel that the presence of ERBB3 amplification necessary changes much with regards to this. Proceeding with chemotherapy or other experimental approaches is very reasonable.”

I hope this is helpful,
Janine

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