Priority Review Granted to Afatinib for EGFR+ Advanced NSCLC

Portal Forums Cancer Basics Clinical Trials and Drug Development Priority Review Granted to Afatinib for EGFR+ Advanced NSCLC

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January 15, 2013 at 7:40 pm  #1252652    

ssflxl

Hello Everyone

I found this online article about Afatanib

http://www.onclive.com/web-exclusives/Priority-Review-Granted-to-Afatinib-for-EGFR-Advanced-NSCLC

ssflxl


Non smoker Asian F, St 4 NSCLC – 11/2010, 6 cm LUL mass, met to paraspinal muscle, +EGFR at Exon 21 L858R. Tarceva in 11/2010, rad to lung mass and met. 5/2012 – PET showed inc SUV in primary cancer, new 1.6 cm lesion in left thoracic inlet causing Horner’s syndrome. Cyberknife to lesion – 5/2012. Restarted Tarceva 75mg/day -5/12, reduced to 50mg. 8/12 – PET- thoracic inlet lesion gone. 11/12 PET – inc SUV in primary tumor, ant mammary node, some SUV uptake in a fibrotic area in apex. Biopsy of this showed fibrosis and scant atypical cell. Cyberknife to mammary node, continue Tarceva. PET-10/13 – incr SUV to 14 in left primary tumor and new 1cm nodule in LUL, no new symptom. 12/13 – biopsy of LUL- same Exon 21, L858R – ?no T790M. on Tarceva 75/50. 1/14 PET – not much change. 2/14 – arm pain, cough, sob. CT – inc tumor to 5.5×5.9 with LUL collapse. 2/14 – Carbo/Pem x6. 4/14 PET – dec SUV but new bony lesions. PET in 6/14 – stable. start Pem every 3 wks in 7/14, Pamidronate every 6 wk.

January 15, 2013 at 8:03 pm  #1252654    
Dr West
Dr West

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

January 15, 2013 at 8:25 pm  #1252656    

ssflxl

Dr. West,

I guess once it’s approved, then Afatinib can be used for those who developed resistance to Tarceva. Has there been any study comparing Afatinib with Tarceva. I know it has more side effects. I wonder what the cost will be too.

thanks

ssflxl


Non smoker Asian F, St 4 NSCLC – 11/2010, 6 cm LUL mass, met to paraspinal muscle, +EGFR at Exon 21 L858R. Tarceva in 11/2010, rad to lung mass and met. 5/2012 – PET showed inc SUV in primary cancer, new 1.6 cm lesion in left thoracic inlet causing Horner’s syndrome. Cyberknife to lesion – 5/2012. Restarted Tarceva 75mg/day -5/12, reduced to 50mg. 8/12 – PET- thoracic inlet lesion gone. 11/12 PET – inc SUV in primary tumor, ant mammary node, some SUV uptake in a fibrotic area in apex. Biopsy of this showed fibrosis and scant atypical cell. Cyberknife to mammary node, continue Tarceva. PET-10/13 – incr SUV to 14 in left primary tumor and new 1cm nodule in LUL, no new symptom. 12/13 – biopsy of LUL- same Exon 21, L858R – ?no T790M. on Tarceva 75/50. 1/14 PET – not much change. 2/14 – arm pain, cough, sob. CT – inc tumor to 5.5×5.9 with LUL collapse. 2/14 – Carbo/Pem x6. 4/14 PET – dec SUV but new bony lesions. PET in 6/14 – stable. start Pem every 3 wks in 7/14, Pamidronate every 6 wk.

January 15, 2013 at 9:26 pm  #1252665    
Dr West
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

January 15, 2013 at 9:34 pm  #1252666    

ssflxl

Dr. West,

Thanks for your comments – it’s very useful to us to have this information.

ssflxl


Non smoker Asian F, St 4 NSCLC – 11/2010, 6 cm LUL mass, met to paraspinal muscle, +EGFR at Exon 21 L858R. Tarceva in 11/2010, rad to lung mass and met. 5/2012 – PET showed inc SUV in primary cancer, new 1.6 cm lesion in left thoracic inlet causing Horner’s syndrome. Cyberknife to lesion – 5/2012. Restarted Tarceva 75mg/day -5/12, reduced to 50mg. 8/12 – PET- thoracic inlet lesion gone. 11/12 PET – inc SUV in primary tumor, ant mammary node, some SUV uptake in a fibrotic area in apex. Biopsy of this showed fibrosis and scant atypical cell. Cyberknife to mammary node, continue Tarceva. PET-10/13 – incr SUV to 14 in left primary tumor and new 1cm nodule in LUL, no new symptom. 12/13 – biopsy of LUL- same Exon 21, L858R – ?no T790M. on Tarceva 75/50. 1/14 PET – not much change. 2/14 – arm pain, cough, sob. CT – inc tumor to 5.5×5.9 with LUL collapse. 2/14 – Carbo/Pem x6. 4/14 PET – dec SUV but new bony lesions. PET in 6/14 – stable. start Pem every 3 wks in 7/14, Pamidronate every 6 wk.

January 16, 2013 at 12:54 am  #1252667    

certain spring

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.


49-year-old non-smoker, dx stage IV NSCLC May 2010 (squamous tumour of the left lung with multiple brain metastases). Radiotherapy to chest and brain; progressed through two cycles carbo/gemcitabine. Repeated lung collapses; pneumonia in collapsed lung, Nov 2010; bronchial stent placed, Dec 2010. Declined second-line Taxotere. Mutation testing Feb 2011, surprise EGFR exon deletion 19. Started Tarceva (150mg), Feb 2011. Progression in liver and elsewhere, May 2013.

January 16, 2013 at 6:21 am  #1252671    
catdander forum moderator
catdander forum moderator

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

January 16, 2013 at 5:15 pm  #1252692    

Jazz

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


Non-smoker, Dx 6/06 Stage IV Adeno. EGFR+ (exon 19 del), T790m+. Trial: 2cyc Carbo/Doce/Avastin + 2 w/Gem 8 – 12/06; Avastin maint. 1 – 4/07. Alimta + Tarceva 5/07 – 2/09. NED to 8/09. Tarceva 150 9/09-5/11, SBRT/XRS to lung & spine met 2/11. Trial MK2206 (AKT inhibitor) + Tarceva 5 – 12/11. Afatinib+cetuximab trial 2/12 -2/13. LL collapsed. 1/13 PET – new bone & adrenal mets. 4 cyc Carbo-Gem-Tarceva 5/13. Brain MRI 10/13 – clear. Lost Dad to LC 5/13.Anti-PDL1@Angeles Clinic?

January 16, 2013 at 7:02 pm  #1252698    
Dr West
Dr West

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

January 17, 2013 at 10:16 am  #1252715    

certain spring

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!


49-year-old non-smoker, dx stage IV NSCLC May 2010 (squamous tumour of the left lung with multiple brain metastases). Radiotherapy to chest and brain; progressed through two cycles carbo/gemcitabine. Repeated lung collapses; pneumonia in collapsed lung, Nov 2010; bronchial stent placed, Dec 2010. Declined second-line Taxotere. Mutation testing Feb 2011, surprise EGFR exon deletion 19. Started Tarceva (150mg), Feb 2011. Progression in liver and elsewhere, May 2013.

January 17, 2013 at 1:46 pm  #1252719    

Jazz

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…


Non-smoker, Dx 6/06 Stage IV Adeno. EGFR+ (exon 19 del), T790m+. Trial: 2cyc Carbo/Doce/Avastin + 2 w/Gem 8 – 12/06; Avastin maint. 1 – 4/07. Alimta + Tarceva 5/07 – 2/09. NED to 8/09. Tarceva 150 9/09-5/11, SBRT/XRS to lung & spine met 2/11. Trial MK2206 (AKT inhibitor) + Tarceva 5 – 12/11. Afatinib+cetuximab trial 2/12 -2/13. LL collapsed. 1/13 PET – new bone & adrenal mets. 4 cyc Carbo-Gem-Tarceva 5/13. Brain MRI 10/13 – clear. Lost Dad to LC 5/13.Anti-PDL1@Angeles Clinic?

January 17, 2013 at 4:33 pm  #1252723    
Dr West
Dr West

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

January 18, 2013 at 6:17 am  #1252737    

panas

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?

January 18, 2013 at 6:33 am  #1252739    
Dr West
Dr West

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

January 18, 2013 at 2:41 pm  #1252761    

certain spring

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.


49-year-old non-smoker, dx stage IV NSCLC May 2010 (squamous tumour of the left lung with multiple brain metastases). Radiotherapy to chest and brain; progressed through two cycles carbo/gemcitabine. Repeated lung collapses; pneumonia in collapsed lung, Nov 2010; bronchial stent placed, Dec 2010. Declined second-line Taxotere. Mutation testing Feb 2011, surprise EGFR exon deletion 19. Started Tarceva (150mg), Feb 2011. Progression in liver and elsewhere, May 2013.

January 20, 2013 at 6:25 am  #1252800    

Dr. Ben Creelan

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.

January 20, 2013 at 6:41 am  #1252802    

certain spring

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?


49-year-old non-smoker, dx stage IV NSCLC May 2010 (squamous tumour of the left lung with multiple brain metastases). Radiotherapy to chest and brain; progressed through two cycles carbo/gemcitabine. Repeated lung collapses; pneumonia in collapsed lung, Nov 2010; bronchial stent placed, Dec 2010. Declined second-line Taxotere. Mutation testing Feb 2011, surprise EGFR exon deletion 19. Started Tarceva (150mg), Feb 2011. Progression in liver and elsewhere, May 2013.

January 20, 2013 at 10:48 am  #1252814    
Dr West
Dr West

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

January 20, 2013 at 8:49 pm  #1252840    

Yan

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.

January 21, 2013 at 12:33 am  #1252843    

certain spring

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


49-year-old non-smoker, dx stage IV NSCLC May 2010 (squamous tumour of the left lung with multiple brain metastases). Radiotherapy to chest and brain; progressed through two cycles carbo/gemcitabine. Repeated lung collapses; pneumonia in collapsed lung, Nov 2010; bronchial stent placed, Dec 2010. Declined second-line Taxotere. Mutation testing Feb 2011, surprise EGFR exon deletion 19. Started Tarceva (150mg), Feb 2011. Progression in liver and elsewhere, May 2013.

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