Priority Review Granted to Afatinib for EGFR+ Advanced NSCLC - 1252652

I don't think there's much question it'll get approved by the FDA in the next few months. I think the key question is what impact this will really have for patients. The approval will only be for people with an EGFR mutation, and it's not clear that this agentis more active than Tarceva (erlotinib) or Iressa (gefitinib) for people who have an EGFR mutation. Afatinib also has a little worse side effects than either Tarceva or Iressa: generally the same kind of side effects, but more frequent and more severe.

I'm not sure I'd be inclined to give it to my patients who have an EGFR mutation if they can just take Tarceva instead. I'm not convinced it adds anything but more side effects.

-Dr. West

Afatinib has been used after Tarceva, and it shows a little activity. It's not clear that it's more activity than you'd get just from re-trying Tarceva after being off of it for a while. In the trial that just compared patients getting afatinib to placebo in patients who had already received Tarceva or Iressa, the progression-free survival was 3 months, vs. 1 month with placebo, but there was no improvement at all in the overall survival of the patients who received afatinib. In fact, the trends was toward a worse survival in the patients who received afatinib.

Nothing about that work has convinced me that afatinib is clearly better than Tarceva, and my sense is that the company has gone out of its way to avoid a timely comparison of the two agents head to head in the light of day.

-Dr. West

Yes, thank you. I think there is still a perception in some quarters that afatinib is a good treatment for cases of acquired resistance to Tarceva.

I wonder if there will be a head to head trial between the 2 to test for initial efficacy or acquired resistance.

it's true that Afatinib may not stand up as well to Tarceva in a head to head trial, but in the context of acquired resistance, Afatinib in combination with cetuximab is worthy of approval. Tarceva with cetuximab couldn't overcome resistance in the same way, so perhaps the thought is to start folks on Afatinib from the get go, then add cetuximab way down the line, when resistance sets in (assuming cetuximab gains approval for that use). The only other thing that would make afatinib more palatable would be cost. If it was priced below Tarceva, it may actually gain a foothold. But with Tarceva and Iressa already entrenched, I wonder where the market is for afatinib in context of first or second-line treatment.

Jazz

Jazz,

Those results were in a rather small trial at a few centers, associated with very challenging side effects (particularly skin-related), and often the results of a small trial don't hold up when tested more carefully. I don't think the FDA or even the folks at Boehringer-Ingelheim, who make afatinib, think that the evidence they have, scant as it is, is in the ballpark of being definitive enough to warrant approval.

-Dr. West

Sorry Dr West, you mean approval for the trial combination of cetuximab/afatinib?
What is disappointing is that we've never found out (or have we?) whether afatinib works better in some resistance settings (clinical characteristics/particular mutations) than in others. I agree that it seems a bit pointless to have a drug that does the same thing as Tarceva/Iressa, only with worse side-effects,
As long as it works for 11-cycle Jazz though, that is a good thing!

13 cycles, natch!

It's the market niche that would be baffling, as the one BI was aiming for suddenly isn't there. Cetuximab already has a market but expansion of share is always good.

This trial seems to be stuck in Phase 1b/II so perhaps the FDA will demand a Phase III, and as Dr. West says, it may not hold up. I must admit I can't wait for an end to these side effects. I just can't figure out why I sometimes break out into a horrible rash all over my face, as I unfortunately did over Christmas, when my husband's family decided to have a family portrait taken. Ugh! It's taken about 3 weeks to clear, but my scalp is a lost cause. I never thought I'd have such a large collection of hats...

I would say that I and many others in the lung cancer community are hopeful about the afatinib/Erbitux (cetuximab) combination, and it's frustrating that it hasn't moved forward faster. But I have heard from both patients and oncologists that the side effects can be a major challenge. Moreover, many of the people who participated in this phase I/II trial were especially motivated, so very likely a broader population of patients would be less tolerant of very difficult skin side effects.

And no, we haven't found that the afatinib/cetuximab combination is more effective with one molecular profile vs. another. Preclinical, lab-based work suggested that patients with a T790M mutation, associated with acquired resistance in about 50-60% of patients who experience acquired resistance to an EGFR mutation, but the trial results showed that the patients with vs. without a T790M mutation showed extremely similar patterns of activity.

-Dr. West

So, from what I see Afatinib alone or combined with Erbitux is not a very promising option for people with acquired resistance to Tarceva. Are there any other drugs under clinical trials that may provide some hope to this subgroup of patients?

There are several being looked at. You'll need to use the search term "acquired resistance" to find the discussions of the topic here and elsewhere online. No agent has emerged as the clear horse to bet on here.

-Dr. West

Thanks Dr West, that has resolved a long-standing perplexity of mine about the trial. I must say that I am pretty downcast about afatinib.
Poor Jazz, what a time you have had with it. Your portrait story is so entirely credible!
panas, best of luck to your mother. Hopefully the Tarceva will work well for her and you will not have to worry about the "what next?" question for a long time to come.

I agree with everything said, I just wanted to offer two small points in favor of afatinib.

1) It is the only EGFR TKI to my knowledge that has reported a survival benefit compared to alimta+cisplatin.

2) It is the only of these trials, to my knowledge, to enroll mainly from Canada, USA, Australia, etc.

I suspect that the dramatic % of side effects reported could be *partially* related to more stringent adverse event reporting, and the population tested. I emphasize partially - there is little doubt this drug is likely more side effects than gefinitib.

Thanks Dr Creelan. I have to say that, for me at least, the testimony of a number of GRACE members tends to reinforce the reporting of adverse side effects. And these are usually fit, motivated patients who are amazingly stoical (see Jazz, above). I am not stoical so this has made me wary of afatinib as a post-Tarceva possibility.
I should like to ask what happens now in terms of research efforts. Are attempts still being made to find a "super" TKI inhibitor, or have researchers turned their attention to other combinations of drugs, MET inhibitors, immunotherapies etc?

Dr. Creelan,

I'm not aware of there being a reported improvement in overall survival for afatinib vs. chemo in the LUX Lung-3 trial. A leading criticism of the presentation was that no survival data were presented. Were they reported at ESMO or another meeting since ASCO? If so, I'm surprised that a positive result wasn't more news-worthy.

I haven't used afatinib, though I'll be offering it on a compassionate use basis now and will gain some experience with it. My sense is that the side effect profile is very similar to what has been seen with dacomitinib, both in frequency of adverse effects and in severity, and I have used dacomitinib and found it to be noticeably more challenging, albeit in small numbers of patients thus far.

The not yet reported LUX Lung-7 trial is comparing afatinib to Iressa, so we'll see the head to head comparison -- though I would value a head to head comparison with Tarceva as the more important test, since the latter has been established as improving survival in a broad population compared with placebo, and it appears to be at least comparable to gefitinib in EGFR mutation-positive patients.

-Dr. West

My husband took both Tarceva and Afatinib. I could say my 2 cents from his experience: he took Tarceva for 3 months and then failed ( as first line treatment). Afatinib is his 4th line chemo, and did show significant shrinkage in most of the nodules. Now he is on Afatinib more than 3 months, the side effects of taking 50mg Afatinib is severe, but the side effects of 40mg Afatinib is manageable.

Hope my husband's experience of these two drugs helps.

Thanks Yan - that is helpful to know. I hope your husband continues to do well on afatinib at the 40mg level.

I agree that's helpful. One of my questions is whether we might see people who don't respond to one but do respond to another. I don't know if he's representative of a broader group, but it's very interesting (and very good for him!) that afatinib did provide real incremental value. Knowing that there are a few more people like your husband could make a real believer out of me.

-Dr. West

The trouble is, how many such people are there? I imagine most oncologists whose patients don't have a good response to Tarceva are going to be looking for other treatments altogether, not other TKIs - though obviously it is great that Yan's doctor thought of trying afatinib.
Dr West, can I ask - are attempts still being made to find a “super” TKI to combat Tarceva resistance, or have researchers turned their attention to drugs in combination, MET inhibitors, immunotherapies etc? In other words, has the afatinib experience inhibited enthusiasm for further research into TKIs, or is it just that it was the not-quite-right drug in an evolving category of drugs?

I don't think people have given up on either concept. They aren't mutually exclusive concepts to test, so different trials will test later generation EGFR inhibitors, or "pan-HER inhibitors", while others will look at combinations to inhibit several targets at once.

-Dr. West

Certain Spring, it is really lucky that we got Afatinib as a compassionate drug. Our doctor initially didn't want to apply for the drug, same argument saying it is no better than a placebo. But without applying for this drug, we have no candidate drug available in Canada unless to seek for clinical phase I trials. She was also very surprised to see the CT results showing significant shrinkage.

I don't know whether she is now very optimistic or any other reason, that she hasn't booked any CT scan for my husband since then ( which will be 4 months without CT scan). Now, she asks us to do X-ray every 2 months before the doctor appointment, which makes me feel a bit nervous.

I am Asian 71 yr old woman with EGFR exon 21 was on two cycle low dose cisplatin gemcitabine then switch to Tarceva 150 ml. For eight months. Had little progression my tumor grew from 1.7 cm to 2.4 cm and was very fatigued all the time. Stopped tarceva and got four cycle carbo, alimta and avastin then maintenance avastin and alimta only for another eight cycles. My tumor decreased to 1.7 cm again and progressed again to 2.4 cm so am now on Afatinib with Erbitux every other week. Now finished three months and my Sob increased not withstanding more side effects on skin, scAlp and nails. Can still tolerate but am afraid of my worsening SOB. What should be my next step? Before I was given Afatinib and Erbitux, my onc wanted me to go back to carbo alimta and avastin which I refused because of bad headache and fatigue.Do you have any suggestion DR. WEST? Please help me!

Hello sunflowerphil, Welcome to Grace. We aren't the type of place you want to need but we can provide good information that will help you make the best decisions for treatment.
I'm sorry but our faculty aren't able to say what you should do, each person's cancer is so individual those decisions need to be made by the doctors directly involve in your case.

This is a link that describes the best course of action for 2nd of later lines of treatment. At the end of the discussion is a list of links under, :for more information
http://cancergrace.org/lung/2010/10/04/lung-cancer-faq-2nd-line-nsclc-o…

Dr. West said this about using platinum after 4 or 6 cycles, "Yes. First, it is very customary to stop the platinum-based combination after 4-6 cycles, and there is no established benefit to continuing a two drug chemo combination beyond that point for advanced NSCLC. As the nurses said, such a reaction to carboplatin is common, particularly after more and more treatments, so continuing it beyond that point is problematic, and there are other treatment options to pursue." from, http://cancergrace.org/lung/topic/carboplatin-hypersensitivity-reaction/

and our most recent addition to the library, Here’s the list of videos done at the International Association for the Study of Lung Cancer (IASLC) 13th Annual Targeted Therapies in Lung Cancer meeting. http://cancergrace.org/general/2013/02/20/iaslc-vids/

I hope this is helpful,
Janine

I note that it seems you didn't progress on either Alimta (pemetrexed) or Gemzar (gemcitabine), but rather discontinued them for other reasons, so I consider both of these options to still consider for the future. In addition, Taxotere (docetaxel) is an agent that has an established value in previously treated with advanced NSCLC. I would consider your headache to likely be caused by the Avastin (bevacizumab), the value of which is not clear at all, so perhaps returning to Alimta or gemcitabine, or else trying Taxotere for the first time, would be a strong consideration. And if there happens to be a trial of another option specifically for patients with an EGFR mutation and acquired resistance, that would certainly be attractive as well, though these trials aren't readily available in most places.

Beyond that, it's not appropriate for me to make an individual recommendation, so I think that it would be best to discuss these options with your oncologist.

Good luck.

-Dr. West

Dr. West,
First thanks so much for helping others through the confusion of cancer/treatment. A question and comment. I thought afatanib results showed that if/when tarceva stopped working afatanib would work ? That is upside I see. Question. Asian wife, 50yo, non smoker, egfr positive with 790 and 858 mutations stage four, pleural effusion but no mets beyond single lung. diagnosed June2013. tried tarceva for 2 months no impact, carbo avastin alimta Oct to Feb 2014. Then avast/alimt maintenance. shrunk and stable CT today shows minor growth to three 4mm nodules (2mm to 5mm, 5mm to 11mm, etc.) but large tumors unchanged 3 X 4 cm. Love our oncologist but wondering. He suggests going to afatanib. I am wondering why not go to immunotherapy trial locally for Bristol Nivolumab because what I read ...more you damage your immune system/health prior to immuntherpy then greater the chances immunotherapy may not work.

I should add that I know with limited data it is hard for you to reply possible, but any thoughts would be appreciated. Also, CD 47 Stanford and OTS964 U of Chicago news.......hoping you saw these. I know you don't know tonights lottery numbers but your guess as to when these get to phase II trials? Any hope for my wife. Should we limit sugar/carb intake and move to alkaline diet....or at this point your not convince it helps?

I don't want to speculate about very early clinical trials -- I put no faith in the hype from preclinical work; most of it translates to nothing, but it's very easy to call everything a breakthrough because it works in preclinical studies.

As for afatinib, some people favor it, but I cannot understand why other than that it'exists. It is not because of any evidence. It is not an effective single agent therapy for patients with acquired resistance on erlotinib. The response rate is about 8%, which is about what you'd expect to see from just retreating with Tarceva after being off of it for a while. There is no evidence that as a single agent it is a meaningfully effective agent for acquired resistance.

-Dr. West

So may I ask what would be your suggested next option? If we have tried tarceva no luck, did six cycles of carbo alimta avastin which bought us a year......if your not strong on afatanib then what would be next best option? Thanks, and again I know you are answering with a lack of a lot of information but one more opinion is helpful.

Hi,

There isn't necessarily one best option. As far as traditional chemo, the three agents which are approved for second-line (and later) use are Alimta, Tarceva and Taxotere (docetaxel). Since you've used the first two, Taxotere would receive strong consideration as a next step. Other chemo drugs which are approved for first-line use and are often used in later lines include Taxol, Gemcitabene and Navelbine. Though the evidence is not as strong for their use after first-line, some patients do receive a benefit from them.

Aside from those choices, there are also clinical trials of novel agents, including immunotherapies. Since your wife did not respond well to Tarceva, there might not be much reason to try the acquired resistance trials, unless a specific resistant mutation is found in her cancer cells.

JimC
Forum moderator

We're legally restricted from suggesting a treatment approach for someone who isn't our patient. If you have a specific question about a treatment, we can address it as best we can, but we can't answer open "what should I do?/What would you recommend?" questions, since that's the specific province of your doctor +/- any second opinion consultations you might pursue.

Good luck.

-Dr. West

Dr.West,
As always...thank you so much for writing and replying. If I can ever do anything for you, please ask. Question. I was reading your NSCLC Mutation explanation thread. Excellent but left me confused in one area. My wife, stage iv nsclc, egfr positive. She is mutated in exon 20(790) and exon21(858). I understand 790 can result in resistance to TKI therapies. But does the 790 and 858 tend to be more or less responsive to TKI therapy? Again, I know 790 is a resistance to TKI therapy but not sure if your explanation of mutations is saying that if you have both 790 and 858 then you are better off, or worse off. Is this mutation combination better or worse then just having 790 alone or 858 alone.

Thank you.

Dr. West discussed the situation of a patient having both an activating and resistant EGFR mutation here. He sums up the discussion by stating:

"Specifically, those who had an activating EGFR mutation and no resistance mutation had the longest progression-free survival (PFS), followed by those who had both an activating EGFR mutation but also a T790M resistance mutation, and then patients with no activating or resistance mutation having the least impressive PFS:"

JimC
Forum moderator

If the cancer has developed resistance to an EGFR inhibitor, having a T790M mutation is associated with slower progression in some studies compared with acquired resistance in someone who doesn't have a T790M mutation (and therefore has a different mechanism for acquired resistance). It's also clearly more beneficial to have a T790M mutation in the setting of acquired resistance now that we have agents like AZD9291 and rociletinib (CO-1686), in large clinical trials, at least, for patients with a T790M mutation, since they are associated with a high response rate of about 60%.

In patients who don't yet have evidence of acquired resistance, it's better to just have an activating EGFR mutation and no T790M mutation.

-Dr. West