EGFR+ Exon21 nvr smoke 54 YO Asian female stage 3 taking Durvalumab?

Portal Forums Cancer Treatments / Symptom Management Immune-based Therapy / Vaccines EGFR+ Exon21 nvr smoke 54 YO Asian female stage 3 taking Durvalumab?

This topic contains 75 replies, has 5 voices, and was last updated by  onthemark 2 days, 5 hours ago.

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June 27, 2018 at 12:16 pm  #1294669    

cubety

Durvalumab has been a breakthrough for stage 3 NSCLC given DFS and OS in Pacific study and recent FDA approval for nonresectable stage 3. But there were statistically 0 Asian female never smokers in the Pacific study (possibly/probably by design).

One concern is, with I think Atlantic study and IMpower 150 studies showing EGFR+ Stage IV never smokers not statistically benefitting from Durvalumab, why would my wife still go ahead with Durvalumab for a year when there is not evidence supporting her to benefit from the treatment and go thru side effect risks, etc…

Durvalumab treatment looks to be contraindicated being given to EGFR+ Stage 3 nonresectable by Dr Kelly here:

http://www.ascopost.com/issues/january-25-2018/durvalumab-takes-a-giant-leap-into-stage-iii-nsclc/

I can tell this is going to be a difficult decision for my wife to make after chemo/rad finishes soon (couple weeks).

What I am hoping for is if anyone can point me toward evidence or studies relating to Durvalumab monotherapy helping EGFR+ Adeno never smokers, including Asian ethnicity and female would be a big bonus.

I’ve found a little to support possible Erlotinib post concurrent treatment but nothing on using Durvalumab for EGFR+ never smoker female Asian.

Statistically, the Pacific trial had 6% EGFR+, 9% never smoker (already making it about 0.5% of group). Then throw in female at 30% of group and I think 27% Asian… think that equates to less than 0.05% of study group as Asian female never smoker EGFR+.

Since there were less than 1,000 people in the study, it shows there was not even one Asian female EGFR+ never smoker in the study. This really makes me scratch my head why a chemo oncologist would push forward with the idea of one year on Durvalumab given lack of evidence to support it. What am I missing?
REALLY appreciate all the help, especially moderators. Wish I could bend Dr West’s ear for direction :).

Take care, thank you so much for any help with info/studies!

June 27, 2018 at 12:32 pm  #1294670    

cubety

PS- this apparently is the recommended plan from chemo onc for my wife even after finding she is EGFR+ with exon21 mutation (L858R), hence asking for any supporting scientific evidence to treat EGFR+ never smoker female Asian with Durvalumab from the deep knowledge base found here.

My guess is the chemo onc is excited by the terrific results in the Pacific study and that they think it is warranted to try even if my wife’s defining characteristics were not represented. I would much rather have some science and a little less unknown to start down a one year treatment path. Almost seems scanning might be a better option possibly unless there is info out there to support giving Durvalumab to EGFR+ never smokers with female gender and Asian ethnicity being two other potentially important factors.

My wife is generally in good health and trying her best to walk daily during chemo/full dose radiation, eat well and of course stay hydrated.

Again, thank you so much for everything you do in this community- mostly aimed at moderators but also any and all contributors!

June 27, 2018 at 3:13 pm  #1294671    
catdander forum moderator
catdander forum moderator

Hi cubety,

Great questions which led me looking for answers. I found the oncologists’ videos on onclive very informative and answers the question why may someone unlikely to normally benefit from immune checkpoint inhibitors benefit as much as someone with high likelyhood. The idea is that chemo/rads prepare the remaining cancer for immunothapy no matter what the pdl1 expression. Other than entering a trial chemo/rads are otherwise the definitive treatment for unresectable stage III nsclc.

The links below may need you to subscribe, but is free/well you don’t have to pay in money but you do have to give up your email.

https://www.onclive.com/onclive-tv/dr-spigel-on-the-rationale-behind-the-pacific-trial

https://www.onclive.com/insights/multimodal-advanced-nsclc/pacific-trial-in-la-nsclc

June 27, 2018 at 3:39 pm  #1294672    
catdander forum moderator
catdander forum moderator

From the conclusions to the study, “Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).”

https://www.ncbi.nlm.nih.gov/pubmed/28885881?dopt=Abstract

It sounds like a reasonable option if you can add another treatment after chemo/rads. Do you know that insurance has signed off on it?

June 27, 2018 at 5:12 pm  #1294673    

cubety

Thank you so very much catdander for the reply.

Unfortunately, if you look at the very small EGFR+ and nonsmoker groups in the Pacific study (people with both those identities would be about 0.5% of study and as mentioned it is statistically provable there were 0 EGFR+ asian female never smokers in the 700+ people within the group), the benefit was not statistically realized for the EGFR+. In fact, they were the one group that did not benefit as Dr Kelly pointed out in her review (see my above link to her article in ASCO).

There was some benefit to people with PD-1/PDL-1 expression if I recall but again don’t think it was statistically significant for never smoker EGFRs. I’d have to pull up the NEJM full article on the study and design to get the specifics but am at work.

If I had to guess, it seems not hard to fathom that the leads in the study did not want heavy representation from EGFR+ (only 6%) never smokers (only 9%) because I’m guessing they had reason to believe the benefit may not have been as visible or large (and that proved out in the study).

The Pacific study is a truly wonderful breakthrough for local late-stage people having to deal with squamous, adeno w/o EGFR mutation, etc… but with my wife’s EGFR+ status and being female Asian never smoker, it seems a large leap of faith to me to experiment to see if she might benefit or not with no science to go on for her specific subgroup.

Ugh, back to work no time :). Thank you again, take care.

June 28, 2018 at 1:25 am  #1294674    

cubety

I should make a correction, 6% of participants in Pacific study were known EGFR+. However, 27% were not known. Given the high number of current and former smokers (91%), it would be a stretch to assume half the 27% unknowns were EGFR+ considering there were only 25% and 30% Asian and female represented but for sake of erring to caution in a calculation, let’s say half the 27% were EGFR+.

This would mean EGFR+ could have been almost 20% under this assumption. Now to look at the study, 709 people were involved I believe.

Let’s look at the data through my wife’s defined independent 4 characteristics of never smoker, female, EGFR+ Asian ethnicity.
Never smokers represented 9%,
females represented 29.8%,
EGFR+ let’s generously say 6% known plus 14% from unknowns (representing just over half the unknown mutation population) so a total of 20% EGFR+ under this probable high number assumption,
and 25.2% were Asian.

So we multiply the percentages (convert to decimal form) to get a number of what percent in the study were all 4 characteristics.
9%=.09 numerically, 29.8%=.298, 20%=.20 and 25.2%=.252
.09 x .298 x .20 x .252 = .00135

If we convert that into percent, .135% of the 709 people were all 4 characteristics if we assume the unknowns mutation group was overrepresented by EGFR+ (highly unlikely but this is just number crunching).

Interestingly, 1 person out of 709 people represents .141% so you can see it is impossible for there to have been 1 person with all 4 characteristics because at a minimum the 1 person % representation would be .141% and it was less than that.

So my conclusion is the Pacific study had zero Asian female never smoker EGFR+ people in it. Sorry if this is too much drawn out math :), I probably gave someone a headache and also sorry if I come across headstrong, I consider myself on the way to curmudgeonhood.

Thank you so much for all the information you and husband provide the public (like myself) in helping us get thru all that is going on.

June 28, 2018 at 1:39 am  #1294675    

cubety

PS- I hope I did my math correctly. I have no stats background but think that would be the way to calculate the numbers….

June 28, 2018 at 9:20 am  #1294676    

onthemark

Hi Cubety,
To answer your question directly, multiplying odds is only correct when the events are independent, which they definitely are not in the sample in question. Because women with cancer are more likely to be non-smokers compared to men and because Asians are more likely to have EGFR than Caucasians…

So one cannot just multiply.

It could be that order of magnitude somewhere between 1 and 10% were Asian females. I would not be comfortable pinning any number more specific than an order of magnitude based on what you wrote.

But also there is no treatment plan that is specific to Asians vs. Caucasians as far as I know in lung cancer. (Please correct me if I am wrong here).

Treatment plans are only based on properties of genes and now potentially also proteins. So it doesn’t make sense at the moment to define female and Asian as the same class of object as EGFR+. I hope this makes sense.

I also hope your wife doesn’t suffer long term consequences of her treatment now, which is always a risk and something to keep your eyes out for, esp. lung symptoms. Some of these conditions can be quite debilitating long term too.

I would be cautious about using immunotherapies in someone who has tendencies to auto immune diseases, especially if it were in a case where there was no measurable disease. Then I would wonder about the tradeoff esp in view of the expert recommendation to not consolidate EGFR+ Stage 3 patients with durvamulab, that you pointed out.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 28, 2018 at 11:07 am  #1294678    

cubety

Thank you very much onthemark for excellent thought-provoking information. Yes Asian and female certainly would not define treatment of EGFR+ patient and the mutation status could help clarify a path forward.

I’ll try to find out if they received information on other molecular data such as PD-1 and PDL-1 expression.

A main concern I have is having an associate director of a major cancer center (Dr Kelly) publish an overview of the Pacific study where she noted EGFR+ people should not take Durvalumab due to the lack of response that other groups saw and the history of that subset not responding well in other studies but she did not give in depth thinking into why that conclusion was reached.

It is going to be a tough call for us it looks like in a couple weeks.

Thank you all for the help.

June 28, 2018 at 11:16 am  #1294679    

cubety

Here was the specific text from the ASCO post Dr Kelly submitted:

“Question of Routine Molecular Testing

All subgroups benefited from durvalumab except the small group of patients with an epidermal growth factor receptor (EGFR)-mutated tumor. This is not surprising, given that immune therapies have consistently shown no benefit in such patients with stage IV disease. These patients should not receive durvalumab, and the finding raises the question of routine molecular testing in patients with stage III disease, especially those with adenocarcinoma histology.”

Also it seemed the Pacific study was designed to tilt toward smoker and former smokers with those groups comprising 91% of the total group also making it less relevant to my wife’s specifics. I believe never smokers typically make up something close to 25% (and growing) of NSCLC Lung cancer cases.

So the design was excellent in getting great results for many important groups that haven’t always had clear treatment options but also was not representative of EGFR+ never smokers in my opinion.

I very much appreciate the great input here and elsewhere from people, it really is valuable to us.

June 28, 2018 at 7:23 pm  #1294681    

onthemark

Hi Cubety,

Dr. West has a short video on youtube: ‘Small Trial Shows Big Risks of First Line Pembro to EGFR Mutation-Positive Patients (BMIC-042)’

He also goes over a number of other studies related to EGFR+ patients and immunotherapy.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 29, 2018 at 1:11 am  #1294682    

cubety

Hi onthemark, you are excellent at finding truffles. The discussion is a bit different than wife’s situation- potential 2nd line treatment or adjuvant treatment using Durvalumab after the chemo/rad softens up cancer-infected tumor and lymph nodes vs first line treatment mentioned by Dr West in his example. But the main point seems quite relevant so thanks for sharing. I wonder if his opinion has changed much since the video. He comes across a very nice guy in the videos I’ve seen. The stud sample size was obviously very small but a bit alarming with the unexpected deaths (thought he mentioned 2). No idea what the patient physical abilities and ages were, wonder if it can be dug up. His point was specific to first line treatment but it doesn’t take me much brain power to be concerned having my wife try an immuno knowing she’s EGFR+ exon21 substitution L858R even with some limited data from the Pacific study not showing outsized major side effects. only 0.54% of participants were known never smoker EGFR+ people in the Pacific study though so I still don’t feel great relying on that as a basis to treat my wife..

He does give very logical reasoning to possibly ruminate on the idea of doctors to “first do no harm” especially when curative treatment is being tried as first line in wife’s case and knowing she has a common EGFR driver mutation that has generally not reacted well to immuno in other studies. Granted, my wife with the major mediastinal lymph node involvements will be at elevated risk of recurrence but it still feels uncomfortable to me presently to go for Durvalumab.

I’ll try emailing nurse to forward to SCCA Onc to see if there might be any ongoing info or other material/experience that may be helping shape her opinion or if she is going on the faith of the Pacific results.

Thank you so much! This will be a big issue/tough choice for others I’m guessing in the near term unless some major new info helps clarify things. You are a great help.

June 29, 2018 at 1:18 am  #1294683    

cubety

Typo in above post, should have been *the sample size (not the stud sample size). Getting a bit late for my brain and think the iPad autocorrected or something :).

June 29, 2018 at 1:51 am  #1294684    

cubety

Interesting, this is Dr West on the Pacific study specifically. He does mention wanting to give Durvalumab to all his patients (stage 3 nonresectable I assume) but he might have been meaning all non-driver mutation patients, as they now have an impressive new development in helping fight back against NSCLC. Hope this link works:

https://m.youtube.com/watch?v=4EjbBUkjfvM

June 29, 2018 at 11:20 am  #1294685    
catdander forum moderator
catdander forum moderator

I didn’t read the your initial link carefully enough yesterday and just saw this. I’ve not found any specific breakdown of mutation positive v wildtype in the any other description of the trial. “All subgroups benefited from durvalumab except the small group of patients with an epidermal growth factor receptor (EGFR)-mutated tumor. This is not surprising, given that immune therapies have consistently shown no benefit in such patients with stage IV disease. These patients should not receive durvalumab, and the finding raises the question of routine molecular testing in patients with stage III disease, especially those with adenocarcinoma histology.” This from link in your first post seems to wrap up the answer of whether this is a good option for your wife. Why is her onc contemplating putting her on an outrageously expensive treatment that didn’t show any promise for egfr positive patients and very possibly more harmful than good?

Knowing that many or even most people do what their doctors say without question I understand your wife may very well feel she must submit without question believing the onc to be all knowing. We know better but how to go about making sure your wife gets the best care after all it’s her decision. Make copies of relevant material to share with her onc could help show your point. I’m curious where to find the breakdown of mutants in that trial that Dr. Kelly referenced.

Janine

June 29, 2018 at 12:49 pm  #1294687    
catdander forum moderator
catdander forum moderator

I’ve asked for input on this one.

The questions come from differing views and the fact that the data aren’t mature.

A Pacific trial article in nejm states all subgroups are benefiting with durvalumab (figure 2 list subgroups and prognostic factors 43 total egfr+) http://bit.ly/2IDXyJJ .

While Dr. Kelly in an ASCO article states, ” All subgroups benefited from durvalumab except the small group of patients with an epidermal growth factor receptor (EGFR)-mutated tumor.” obviously she is reading the data differently. http://www.ascopost.com/issues/january-25-2018/durvalumab-takes-a-giant-leap-into-stage-iii-nsclc/

June 29, 2018 at 1:14 pm  #1294688    

onthemark

Hi Janine,

Thank you for pointing to the relevant information in the original NEJM article and getting expert opinion on this one. I don’t see a contradiction, though. If you look at Fig 2, technically all subgroups benefited but the error bars on the EGFR+ subgroup (as shown in Fig. 2) don’t exclude that durvamulab actually did harm rather than offer benefit.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 29, 2018 at 1:46 pm  #1294689    

cubety

Hi Janine thank you so much for looking for clarity.

I don’t think Dr Kelly is the only one sharing the opinion not to necessarily treat nonresectable stage 3 NSCLC EGFR+ patients with Durvalumab consolidation. I found another published research Dr in Europe but can not locate article, the gist I got was that they personally felt it would not be the best treatment for these EGFR+ Never smoker patients partly due to low mutational burden.

I have not found much at all (anything so far) published where doctors openly note prescribing Durvalumab consolidation for stage 3 EGFR+ never smokers. If anyone can find any doctors noting prescribing this treatment specifically for EGFR+ never smokers, I would be very interested in the material to help us in decision making.

Something I continue to think about is that only a little over 0.5% of Pacific study patients were known to be both EGFR+ (6%) and never smokers (9%). That equates to about 4 people in the study (total 709 participants).

It is a tremendous breakthrough in general (Pacific study using Durvalumab consolidation post concurrent chemoradiation treatment) but given the study participant design and very small sample size of EGFR+ never smokers, it seems not very relevant to them at this point. Especially in light of many previous studies of immunotherapy generally and Durvalumab specifically showing little objective benefit to that group although those studies were under different conditions of course.

Thank you so much for the tremendous information you are sharing in helping us make some very important decisions soon.

June 29, 2018 at 1:48 pm  #1294690    
catdander forum moderator
catdander forum moderator

Thanks otm, So I guess my question is why did Dr. Kelly in her asco article (linked to in op) say the egfr group didn’t benefit?

June 29, 2018 at 1:56 pm  #1294691    

onthemark

Yes Janine. There’s no statistically significant benefit for EGFR+ patients because the error bars go over 1 in Fig. 2.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

  • This reply was modified 2 weeks, 6 days ago by  onthemark.
  • This reply was modified 2 weeks, 6 days ago by  onthemark.
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