KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

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DK37
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KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

Postby DK37 » Sun May 17, 2015 8:38 am

Promising new trial results were just published for these patients:
- KRAS-wt
-Patients who initially responded to an EGFR inhibitor (e.g. cetuximab) but became resistant

"Sym004" is a next generation anti-EGFR monoclonal antibody. It is binds differently to EGFR than cetuximab. For patients who initially responded to cetuximab (i.e. patients whose tumors are intrinsically responsive to anti-EGFR therapy) went onto this trial after they became resistant to cetuximab. When dosed with sym004, 67% responded to the new drug (44% experienced tumor shrinkage and another 23% had stable disease). Side effects were similar to Cetuximab (e.g. on-target skin rash) The duration of response was modest (months) but my personal feeling is that I would gladly accept extra months from a tolerable drug that not only allowed more quality time with my kids but also allow more months of immunotherapy research to proceed...

This was a small trial (39 patients were dosed during dose expansion following dose escalation) - but the results were consistent with what you would expect scientifically so I think probably the same data will roughly be seen in the current confirmatory Phase 2 trial.

Phase Clinical Trial results (this is the current link for pre-print, if it stops working, let me know & I'll update to the finalized link):
http://cancerdiscovery.aacrjournals.org ... 2.abstract

Phase 2 confirmatory trial in progress in many locations (randomized versus chemo):
https://clinicaltrials.gov/ct2/show/NCT ... 004&rank=1

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
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lilacbreastedroller
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Re: KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

Postby lilacbreastedroller » Sun May 17, 2015 9:28 am

Lucky for them!! cetuximab did aboslutely nothing for me, and with its partner in crime, irinotecan, made me really sick.

Why doesn't it work for some people? (I was KRAS wild - they only test once,though)

thanks
Karin
dx 6/1/12@45yo
RT, 4 liv, 5 lung
7/12 FOLFOX
2/13 Xeloda 4k mg/d
7/13 DC VAX,1k mg/d metro Xel
11/13 Erbi, Irino
6/14 clinical trial lirilumab, nivolumab
9/14 Stivarga
1/15 clinical trial immunotherapy (young TILs)
RT, mets to liv, lung, adrenal, lns

KWT
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Joined: Thu Jul 11, 2013 7:22 pm

Re: KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

Postby KWT » Sun May 17, 2015 10:18 am

Karin,
That's the great thing about chemo, you get to try it for a few months before you know if it's working :roll: with no rebate available.

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DK37
Posts: 510
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Location: San Diego

Re: KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

Postby DK37 » Sun May 17, 2015 10:24 am

Sorry to hear it didn't work for you Karin... :(

Statistically it works for most (but not all) KRAS-wt patients. Whys doesn't it work in a subset of patients? I think this comes down to cancer being an incredibly complex & personalized disease which the current simplistic KRAS tests can not model accurately. It is clear that if you come back KRAS-mut, you have essentially zero chance of having benefit from cetuximab - in contrast KRAS-wt means that you are "likely" to achieve benefit but since it is a simplistic test - there are false positives in terms of recommending anti-EGFR treatment - which sounds like it happened in you case. Hopefully there will be more accurate screening methods in the near future.

There was a recent paper describing mutations which make a patient resistant to cetuximab. https://clincancerres.aacrjournals.org/ ... 7.abstract Although they are talking about acquired resistance, there is no reason to assume that at least some of these mutations (which would not be uncovered by the currently simple KRAS test) couldn't be pre-existing in some patients. Still other patients significantly upregulate EGF as a non-genetic strategy to be resistant to cetuximab.

Statistically, since they are dosing Sym004 only to the majority of KRAS-wt patients who did respond to cetuximab, as a follow up therapy, it is likely to work in most of that patient population.

Once again I am sorry it was not a successful strategy for you...
-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

jillbugs4110
Posts: 266
Joined: Thu Jul 31, 2014 3:36 pm

Re: KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

Postby jillbugs4110 » Sun May 17, 2015 1:19 pm

Hi

To.confirm because sometimes I'm not the smartest tool.on the shed. Do you have to be KRAS for this to work or will it work on all CRC? Sorry prob a dumb ??
Live One Day At A Time
I Abandon myself to God
46 6 yo.....9yo...
stage 1V liver mets :-(
my one prayer to got to sustain me to raise my two babies this is my only wish then take me out if needed.

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DK37
Posts: 510
Joined: Tue Sep 17, 2013 8:31 am
Location: San Diego

Re: KRAS-wt: Clinical Trial Results for Sym004 (after cetuximab resistance)

Postby DK37 » Sun May 17, 2015 2:15 pm

jillbugs4110 wrote:Hi

Do you have to be KRAS for this to work or will it work on all CRC? Sorry prob a dumb ??


Hi Jillbugs,

Yes - as of right now, it is assumed that you need to be KRAS-wild type, for there to be a chance of this drug working. The phase 2 trial currently enrolling is only offered to KRAS-wild type patients.

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List


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