EGFR+ Exon21 nvr smoke 54 YO Asian female stage 3 taking Durvalumab? - 1294669

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cubety
EGFR+ Exon21 nvr smoke 54 YO Asian female stage 3 taking Durvalumab? - 1294669

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-...

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!

cubety
PS- this apparently is the

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!

catdander
Hi cubety,

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

catdander
From the conclusions to the

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?

cubety
Thank you so very much

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.

cubety
I should make a correction, 6

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.

cubety
PS- I hope I did my math

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

onthemark
Hi Cubety,

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.

cubety
Thank you very much onthemark

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.

cubety
Here was the specific text

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.

onthemark
Hi Cubety,

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)'

https://www.youtube.com/watch?v=k5lfjoyuZrU

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

cubety
Hi onthemark, you are

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.

cubety
Typo in above post, should

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 :).

cubety
Interesting, this is Dr West

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

catdander
I didn't read the your

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

catdander
I've asked for input on this

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-...

onthemark
Hi Janine,

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.

cubety
Hi Janine thank you so much

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.

catdander
Thanks otm, So I guess my

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?

onthemark
Yes Janine. There's no

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

catdander
There were 43 egfr + patients

There were 43 egfr + patients in the study 39 of which were in the durvalumab group. That's a pretty small number but could suggest one way or other for more followup in that population.

I'm sure Dr. Kelly isn't the only one with that opinion. But she's the one writing for asco who I believe are a little more conservative in interpreting data.

I imagine the different interpretations are due to the immaturity of data and the lack of understanding of the drug and even newer treatment.

The thing I find interesting is that it's believed the checkpoint inhibitors work differently when following chemo/rads.

onthemark
Hi Cubety,

Hi Cubety,

EGFR+ patients are more likely to be never smokers than random, so once again you cannot just multiply these probabilities because the events are not independent.

cubety
catdander and onthemark, an

catdander and onthemark, an important note that should be mentioned:

I believe in the Pacific study one critique was that the placebo group PFS and OS were lower than what would normally been expected from a representative sample of stage 3A/B non-resectable patients.

So the figure 2 bars potentially somewhat over express benefit in all groups due to this IMO. It may be a reason Dr Kelly gave her opinion in the manner she did (bringing into consideration the low bar set by the placebo group which would mean all groups shifted a little to the left than what would have happened had the placebo group performed more normally). I’ll try to find where I was reading the Pacific study’s placebo group underperformed on PFS and OS. Regardless, the overall results are still a major major advancement for a lot of people. Wait, I think this is it:

https://www.targetedonc.com/case-based-peer-perspectives/lung-cancer/wak...

Here is the relevant part to my slight concern:

"The progression-free survival for the patients getting the durvalumab was in excess of 16 months. For those getting the placebo, it was less than 6 months. One of the criticisms of the trial was that the placebo group did seem to underperform historical controls. There are a lot of questions around that—some of which are around the high numbers who had weekly carboplatin/paclitaxel without any consolidation. Carboplatin/paclitaxel—we don’t really know the answers."

Again, thank you for the continuing help as this will be something many people will be pondering with EGFR+ mutations going forward having nonresectable stage 3 disease.

cubety
Having a heavy smoker and

Having a heavy smoker and former smoker representation in the study at 91% might be one reason there was a bit of underperformance in PFS for placebo group but that's just a guess.

cubety
Ah it was Dr Marina C.

Ah it was Dr Marina C. Garassino,a well known person in the field mentioning not using immunotherapy on never smoker EGFR+ people. Here is the exceprt regarding treating EGFR never smokers:

Could immunotherapy be used for patients with driver mutations?

"This is a very interesting story. If we look to the subgroup analysis of all randomized clinical trials, there is no clear benefit in never-smokers or EGFR-mutated patients. Therefore, it is difficult to say whether it is better to treat these patients with immunotherapy or chemotherapy. We have just a few data coming from the ATLANTIC trial with Imfinzi. In the ATLANTIC trial, patients with EGFR and ALK translocation were selectively treated with Imfinzi at the standard dose every two weeks. In ALK-translocated patients there was no benefit, but in EGFR-mutated patients, who were PD-L1-positive — more than 25 percent — there was a good PFS and a very good OS. I am going to present the results of the expanded access in Italy with Opdivo, where there is some benefit in EGFR-mutated patients.

My personal opinion is that immunotherapy is not the best treatment for these kinds of patients because they have a low mutational burden, but we do not know clearly about the further lines."

Here is link to article full discussion:
https://www.curetoday.com/articles/expert-discusses-immunotherapys-expan...

I would add that as I recall the EGFR+ responders in Atlantic (group 1 where I think there were 10 EGFR+ responders) mostly were former/current smokers (like 6) and had ultra high PD-L1 expression (I think 8), so again not representative of most never smokers EGFR+ people (smokers tend to have higher PD-L1 expression as I recall).

So Dr Garassino generally expressed not using immunotherapy on never smoker EGFR+ people.

OK back to work, have a good weekend all.

cubety
Onthemark- sorry I keep

Onthemark- sorry I keep wanting to make everything independent with my lack of interpreting data. So with 43 EGFR+, maybe let's say roughly 25% could be neversmokers EGFR+ (That would be almost 3x the never smoker rate of 9% in whole study participant rates). It seems there may have been maybe roughly 10-11 people under that assumption.

If there were 10 EGFR+ never smoker people, catdander brought up a good point on if any were wild type as they tend to have good response compared to mutant so even one wild could potentially skew EGFR+ response. The high level of smoker population also should skew EGFR+ data favorably vs the never smokers in this study.

When we consider some bias in results potentially on PFS and OS due to the noted underperformance of placebo group (less than 6 months PFS as I recall), it sure seems not difficult to generally assume the EGFR+ mutant neversmokers did not benefit.

Especially knowing both never smokers and EGFR+ people have repeatedly been shown to not respond as well to immunotherapies historically as Dr Garassino noted although this study involves hitting cancer right after chemo/rad.

It is possible (maybe likely) the EGFR+ people in the study's bar graphs that crossed over to worse than placebo were the never smokers. And with placebo underperformance, those results may have looked better than historical expected 'normal'.

Thank you for all the input, hopefully we receive some deeper more informed thought from expert opinion looking at things such as the smoker population over representation and the placebo group underperformance.

Also wondering how it relates to a path forward for those that were not in focus in the study- never smoker EGFR+ people, especially knowing the never smoker population unfortunately continues to grow in number and therefore % representation of this disease moving forward.

Durvalumab is a huge step forward for a lot of stage 3 NSCLC people but maybe not all.

Dr West
This is a legitimately

This is a legitimately controversial question. I would say that a modest majority of experts are of the mindset that the patients with an EGFR mutation were included in the PACIFIC trial, there was a major benefit for the overall trial population, and the subset analysis isn't compelling enough to say it's wrong to treat EGFR mutation-positive patients. On the other hand, the minority, which isn't a tiny minority but probably about 1/3 of thoughtful specialists in lung cancer, who look at the subset analysis that looks like EGFR mutation-positive patients get less or maybe no benefit, and they look at the disappointjng results for immunotherapy in metastatic NSCLC, and then perhaps also factor in the small study from UCLA that I just featured in a video (again, about metastatic disease) and think EGFR mutation-positive patients shouldn't do durvalumab.

It's a legitimately controversial question. There is no clear best answer right now. I think it makes sense to discuss the ambiguity with the patient and consider their preferences. None of us should be too dogmatic when there is so little good evidence to inform us. -- hence the differences in interpretation of how to fill in the gaps.

Good luck.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Medical Oncologist
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

cubety
Thank you very much Dr West

Thank you very much Dr West in clarifying the complicated and split thoughts on decision making for EGFR+ mutation stage 3 nonresectable people when it comes to Durvalumab consolidation therapy.

The Pacific study is certainly an encouraging boost for most nonresectable stage 3 NSCLC people. Hopefully with more time, clarity on the specific subset of EGFR+ (and further for my wife's specific case never smokers) will be more definitive. Also, hopefully the approach of using consolidation immunotherapy right after concurrent chemo and radiation becomes something that shows more and more promise for future treatment of people with further study.

Looks like we will have a difficult decision to make around mid-late July.

Again, thank you very much Dr West for weighing in (and thank you catdander, onthemark for highlighting and presenting helpful information).

onthemark
Thanks Dr. West for

Thanks Dr. West for clarifying expert opinion.

Cubety, it's also relevant to consider that your wife might lose eligibility for future clinical trials of immunotherapies (possibly in combinations) if she was already exposed to an immunotherapy like durvalumab. Immunotherapy in EGFR+ patients is still and under-developed area but there is no reason to believe this will continue to be the case in the future.

Plus there are well established treatment lines if she develops evidence of disease after chemoradiation using TKIs like tagrisso. These treatments are only available for EGFR+ patients.

I'll be happy to write to you privately at inspire about probabilities.

Briefly P(A and B) = P(A)*P(B) if and only if A and B are independent events. Here P is the probability and the symbol * means multiplication.

So event A could be a never smoker with lung cancer and event B could be and EGFR+ person with lung cancer, both drawn from the sample. The probabilities only factor if the events A and B are independent, which they surely are not in most cases and can be proven to be dependent in this particular case.

onthemark
Cubety,

Cubety,

About the supposedly low PFS in the control arm of the PACIFIC study, this is misleading.

It should be clarified that the PFS of 5.6 months is actually similar to other chemoradiotherapy studies which describe a PFS of 11 months; the PFS was calculated from the time of randomization after completion of chemoradiotherapy in the PACIFIC study rather than upon initiation of chemoradiotherapy (3). The benefit was observed regardless of tumor histology or PD-L1 status. The overall survival (OS) data is not yet mature.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906257/

See:

Immunotherapy after chemoradiotherapy in stage III non-small cell lung cancer: a new standard of care?

The authors go on to write about the PACIFIC trial:

The investigators must be commended for their “all-comers” trial design. The main exclusionary criteria were limited to patients unable to complete conventional chemoradiotherapy, which supports extrapolation of the findings to the general population. As such, it allowed patients to participate with epidermal growth factor receptor (EGFR) mutations and non-smokers, both increasing in frequency in the lung cancer population and known to have lower response rate to immunotherapy (14,15). Of note improvement in PFS was observed in never-smokers, but less so in the EGFR subgroup, raising the possibility that their mechanisms of relative resistance may be different.

From the way this is written, my guess is that the final representation of EGFR, women, never smokers etc. was not by study design but by who was referred to the clinical trial and signed up.

cubety
Thank you for your continuing

Thank you for your continuing sharing of relevant information specific to my wife and also in many areas more generally to the EGFR+ NSCLC community and how Durvalumab may enter the picture.

It is good to see the extra information on study design, possibly there was a bit of bias in referral given past history of poor performance of EGFR+ mutant type on immunos but guesswork only.

I did find a study showing never smokers had no benefit to Durvalumab but they were treatment naive with only 59 people:

https://www.sciencedirect.com/science/article/pii/S2468294216301265?via%...

This was the part about never smokers and Durvalumab (again this is small sample size so I am only posting in regards to my wife):

"Most importantly, no clinical response was observed among never-smokers irrespective of PD-L1 expression and histology types, while the ORR in the ever-smokers was 33% for those with high PD-L1 expression and 13% for those with low/negative PD-L1 expression."

Back to work. Take care. And thank you again... All of this is just my opinion, I don't wanmt anyone to make any decisions off a message board and am just trying to gather information for our particular case. Well wishes to everyone out there involved in this community.

cubety
Interesting reading the

Interesting reading the different wording of the part you mentioned (non smoker benefit for PFS on durvalumab) with the part I had (never smokers regardless of PD-L1 status or histology having a zero response although that was with a median 8 week treatment on Durvalumab and was retrospective plus not consolidation).

I'm assuming the mention of Pacific trial using the word 'non smoker' in your link instead of 'never smoker' means they are clinically interchangeable? Not sure but do know never smokers are defined as less than 100 cigarettes in their lifetime (wife has never touched cigarettes and did not grow up in a smoker environment).

On your very interesting highlight of favorable TKI response for EGFR+ mutation and potential future study ineligibility because of previous immuno treatment if we went forward with Durvalumab, I found this from Dr West going back a ways:

"Moreover, it was also known that certain clinical/demographic characteristics, such as being Asian, female, a never-smoker, and having an adenocarcinoma or bronchioloalveolar carcinoma (BAC) tumor histology was associated with a higher probability of a significant response to EGFR TKIs as well . . . "

http://cancergrace.org/lung/2011/07/23/egfr-mutations-in-adenocarcinoma/

My wife does fit all those categories Dr West brought up and I worry just a bit about what Dr West mentioned in the 2018 Youtube link you provided about small UCLA study that was stopped early when an immuno was being investigated as a first line EGFR+ treatment I think.

I wonder if we do nothing but scans, would a micrometastasis recurrence (likely for her) be of similar origin to her current EGFR+ exon 21 substitution? That would make us a bit more likely to say 'no' to durvalumab consolidation. The thought that a likely recurrence could be treatable with a good prognosis of having a TKI treatment on her PFS/OS given history of EGFR+ mutation female Asian never smoker status is a little encouraging.

Take care everyone.

onthemark
Hi Cubety

Hi Cubety

If you look at Table 1 and Figure 2 in the NEJM paper, and look at the columns with the number of patients, you will see that the original authors use non-smokers in figure 2 to be the same patients as never smokers in Table 1. There were 43 patients on durvalumab and 21 patients on placebo. This total of 64 patients is referred to as never smokers in Table 1 and non-smokers in Fig 2.

Although the error bar is large the result seems to exclude statistically the possibility that durvalumab does harm to never smokers as a group. It seems to be a significant benefit looking at Fig 2. In fact the expected result is shifted more to the left than any other subgroup, but again the error bars are large because of the small subgroup size.

The article I quoted was using the naming system according to Fig. 2. I don't think these terms are generally interchangeable though. That's why the numbers help out here.

The EGFR+ subgroup also has large error bars but is shifted more to the right and cannot exclude statistically that as a group durvalumab does more harm than good.

Thank you for digging up Dr. West's quote on the favourability of TKI treatment for your wife's situation.

I am not a doctor but if I were in your shoes I think about leaning to surveillance, and go to TKI if there were still evidence of disease at scans sufficiently past chemoradiation. This can buy a lot of time. Possibly years. Then I would look at progress on developments referred to at the end of this publicly available article

Navigating the “No Man's Land” of TKI-Failed EGFR-Mutated Non–Small Cell Lung Cancer (NSCLC): A Review

publicly available at: https://www.sciencedirect.com/science/article/pii/S1476558617304700
[Neoplasia, Volume 20, Issue 1, January 2018, Pages 92-98. open access]

Edited to ad: From what I have read activating mutations do not go away with treatment. Rather, what happens is that new mutations accumulate.

cubety
onthemark, luckily we still

onthemark, luckily we still have weeks to decide. One semi-small worry I would have is if my wife harbors BIM protein deletion. This deletion is rare in Caucasian populations but is close to 15% in Vietnamese population I believe.

Here is a real quick blurb on BIM. I think BIM deletion potentially interferes with TKI's mechanism to inhibit EGFR mutation cell growth.

http://europepmc.org/articles/PMC4132037

On another note, the Dr West UCLA study video you linked to me mentioned one responder that did quite well on an immunotherapy drug and that it was found out they were wild type. Possibly the Pacific trial had a few wild type and they were the reason for such a large slant to the left in response (I have no idea but have not been able to locate whether any EGFR+ people were wild type in Pacific)?

IF that were the case, it would beg the question in my mind do EGFR wild type people look to have an oversized boost to immunotherapy potentially compared to mutated and maybe even some other NSCLC forms?

Thank you again for your very thorough and thought provoking information!

onthemark
Hi Cubety

Hi Cubety

"Wild type" just means the person doesn't have the mutant form. In the case we are discussing it means that all the people who are not EGFR+ are "EGFR wild type".

Thank you for mentioning BIM. I'll look into it as it is not something I am familiar with.

cubety
Thank you for clarity on EGFR

Thank you for clarity on EGFR wild type, I have a steep learning curve process to go thru :). It does make the far left responders look interesting given the history of EGFR+ mutations and immunotherapy generally.

onthemark
Hi Cubety,

Hi Cubety,

I also found the same range of percentage of Asian people with BIM deletion polymorphism. But it seems to be an open question whether it affects clinical response to TKIs and overall survival for all populations. See the June 2015 publicly available research paper which looked at a relevant cohort for your wife in Korea:

The BIM Deletion Polymorphism and its Clinical Implication in Patients with EGFR-Mutant Non–Small-Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors

https://www.sciencedirect.com/science/article/pii/S1556086415330410

The majority of patients were younger than 65 years (74%), female (68%), never smokers (76%), and had stage IV NSCLC (67%). There were no associations between the BIM deletion polymorphism and clinicopathological features including gender, age, smoking status, histology, stage, and number of metastasis sites. Patients with and without the BIM deletion polymorphism had similar objective response rates (91 vs. 84%, p = 0.585). Progression-free survival and overall survival did not differ significantly between patients with and without the BIM deletion polymorphism (median progression-free survival 12 vs. 11 months, p = 0.160; median overall survival 31 vs. 30 months, p = 0.452). Multivariate analysis identified significantly predictive markers for clinical outcomes of EGFR TKIs including Eastern Cooperative Oncology Group performance status 0–1, adenocarcinoma histology, recurrent disease, and EGFR mutation type. The results were validated in an independent cohort of 69 NSCLC patients.

Conclusions
It remains to be determined whether the BIM deletion polymorphism provides intrinsic resistance or decreased sensitivity to EGFR TKIs in EGFR-mutant NSCLC patients.

It might be worth having a look at the papers that cite this one and are more recent here:
https://scholar.google.com/scholar?cites=12633231255172724802&as_sdt=200...

JimC
Terrific discussion here, to

Terrific discussion here, to which I'll just add a couple points.

As far as Dr. West's older comment about the better response to EGFR TKIs, this goes back to the early days of Iressa and Tarceva therapy, before EGFR mutation testing became widespread. Trials had shown a better response among patients who were non-smokers, asian and/or female. It turns out that is because activating EGFR mutations are more prevalent among those groups of patients. So although Dr. West's comment is still true, it's the presence of an activating EGFR mutation that predicts good response to an EGFR TKI. As Dr. Melissa Johnson stated a few years ago:

The IPASS (Iressa Pan-Asian Study) affirmed the hypothesis that Asians never/light smokers with EGFR mutations had better outcomes than when patients with EGFR mutations are treated with chemotherapy.

I'd only add that there were other older studies dating back to 2004 when Tarceva and Iressa were still in clinical development which focused our attention on this group of patients to begin with...two groups in Boston and one group in NYC took the tumor tissue of the patients on the clinical trials testing Tarceva and Iressa who responded best to these drugs, and found that what these patients had in common was a mutation in EGFR. Then, the investigators described the clinical characteristics that collectively described these patients: more likely to be Asian, more likely to be never-smokers, more likely to adenocarcinoma or BAC histology. I guess you might say, that's where the story really began... - http://cancergrace.org/forums/index.php?topic=10629.msg85730#msg85730

As far as the use of the terms "non-smoker" and "never smoker", it is not helpful to use those terms interchangeably. "Non-smoker" includes those who have quit smoking, and it's more accurate to consider such patients in terms of their total smoking history.

[continued}

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

JimC
[continued]

[continued]

As Dr. West pointed out:

We do know that the lung cancers in never-smokers tend to be more genetically simple than those of long-term smokers, and this makes sense: without the mutagenic (“mutation-inducing”) effect of cigarettes, which tend to lead to cancers caused by a critical mass of multiple genetic insults over time, lung cancer in never-smokers tends to occur more directly by getting a direct hit through a random mutation on a critical signal in cell growth and division, such as EGFR, EML4-ALK, or others yet to be identified. That’s also why the lung cancers in never-smokers in lung cancer may have an “Achilles heel” if you can find and turn off the switch with an EGFR or ALK inhibitor, while our gains against smokers in lung cancer tend to be more “chipping away” than dramatic shrinkage. They have multiple drivers and aren’t amenable to being turned off with a single mechanism. But of course, mutations don’t just pile up at the time you light your 100th cigarette (since “never-smoker” status is defined as having smoked fewer than 100 cigarettes in a lifetime); instead, there are plenty of people who smoked very little a long time ago and just happened to get a lung cancer like that seen in a never-smoker. So there’s likely a spectrum of people with one or a few very important mutations on one end and many, many less significant mutations all added together as the other extreme. So smoking status is more of a continuous variable (can be anywhere in a range, like height) than a discrete variable (like being pregnant or not).

In fact, that’s what the relatively scant evidence shows us. Several years ago, the folks at Memorial Sloan-Kettering Cancer Center (MSKCC) published work from their own more detailed analysis of smoking history, which recorded both “pack-years” (the product of average number of packs per day x number of years smoking) and time since a patient quit, if applicable.

[continued]

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

JimC
[continued]

[continued]

Patients were tested for the EGFR mutation, and the investigators found that never-smokers had the highest rate of having an EGFR mutation (51%) (yes, we knew that), but also that ex-smokers had a higher rate of the EGFR mutation than current smokers (19% vs 4%). All of these numbers are higher than seen in some other North American studies, probably because of some self-selection of patients who head out to MSKCC (patients with EGFR mutations are more likely to seek an opinion there). But also quite importantly, patients who quit smoking many years ago had a higher probability of having an EGFR mutation than people who quit smoking just a few years ago... - http://cancergrace.org/lung/2009/11/23/smoking-as-a-continuous-variable/

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

onthemark
Thank you Jim for all your

Thank you Jim for all your insights and taking the time to educate us with lessons from cancergrace.org and Dr. West in particular.

I add a quick note to this discussion up to now that it may not be wholly appropriate to compare 'mutation simple' like driver driven lung cancers in Stage IV to Stage III post-radiation. My understanding is that radiation makes cancers more mutagenic, just like cigarette smoking does over the long term (as Jim quoted from Dr. West). What that means is that the cancer accumulates more mutations after treatment with (chemo)radiation. So what were once cancers that could 'hide' from immunotherapies become more visible to the immune system and then treatment with immunotherapies can become more effective post radiation or chemoradiation.

I can dig up some references for this too. I mention this because it is something to think about when taking lessons from past clinical trials for your wife's situation.

onthemark
ps. This could also be

ps. This could also be related to the plausible possibility that a treatment order starting with (1) chemoradiation and (2)immunotherapy [possibly concurrent] and then (3)TKI can induce more adverse effects than a different order like (1) chemoradiation (2)TKI and then (3)immunotherapy. This was hinted at in Dr. West youtube video about a recent trial that was discontinued due to early deaths that I linked to earlier in this thread and Dr. West referred to in his reply.

JimC
onthemark,

onthemark,

It's certainly true that radiotherapy can cause additional mutations, but as Dr. Julie Brahmer from Johns Hopkins discussed in this podcast the concept that testing for increased mutational burden will result in improved outcomes with immunotherapy is not quite ready for use in routine clinical practice.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

Dr West
Yes, there is certainly some

Yes, there is certainly some preclinical (lab-based) research and strands of clinical research that support the concept that radiation may induce a greater probability of a good response to immunotherapy, but I agree with Jim and Dr. Brahmer here in saying that this is more a premise than a conclusive finding at this time. To me, it at least provides a reason to not just presume that the situation is exactly the same between the settings of consolidation immunotherapy after chemo/radiation and treatment for metastatic NSCLC.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Medical Oncologist
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

onthemark
Yes I also agree with Dr.

Yes I also agree with Dr. West and Jim and was merely pointing out one shouldn't make the assumption that these two situations are the same for mutation simple cancers, and what some of the consequences might be if they are, in fact, different.

For people who are interested in learning about the immune system and cancer there is a very nice p Nature paper (it's a bit dated from 2006 but highly cited so you can believe what is written by and large)

Cancer despite immunosurveillance: immunoselection and immunosubversion

https://www.nature.com/articles/nri1936
Nature Reviews Immunology volume 6, pages 715–727 (2006)

cubety
Thank you to everyone here

Thank you to everyone here helping me learn. I can already go back and see errors I've made in posts showing how quickly I'm learning thanks to the very helpful exchange of information with you all.

Wish I had more time to learn more in depth ahead of important decisions to be made for our situation but this information should be very helpful to others in a similar situation going forward.

It helps to see the information relating to BIM protein deletion, I will have to look into that more when time is available. Sounded like a blood test could determine that status but based on onthemark's continued great information it might not be something to worry about in terms of having negative effect on TKI action.

Thank you JimC too on the point about updated information clarifying why Asian subgroup in particular were performing well in the past on TKIs with the higher EGFR+ mutation prevalence in the subgroup.

I hope you all have a great day and thank you for thisontinuing insightful help.

onthemark
A Dec 2017 paper:

A Dec 2017 paper:

"Emerging biomarkers for the combination of radiotherapy (RT) and immune
checkpoint blockers (ICB)"

links to Jim's and Dr. West's remarks about biomarkers and summarizes the current state of knowledge.

RT increases the antigenicity of malignant cells by promoting the upregulation of MHC class I molecules on the cell surface [10,11], by favoring the expression of tumor-associated antigens [12], and (at
least potentially) by enhancing genetic instability or reactivating endogenous retroviruses [13,14]. Moreover, RT boosts the adjuvanticity of cancer cells by at least two mechanisms...

"The potential predictive value of the biomarkers discussed above needs to be studied in patients receiving RT plus ICBs. Indeed, some of the biomarkers that are associated with improved clinical responses to RT or ICB-based immunotherapy may have limited predictive value in the context of combinatorial regimens. As an example, while high PDL1 expression levels are robustly associated with the response of melanoma and NSCLC patients to nivolumab or pembrolizumab (see above), a benefit on progression-free survival was observed irrespective of baseline PD-L1 expression in NSCLC patients treated with chemoradiation followed by durvalumab versus placebo [130]. This result is consistent with the hypothesis that RT can induce PD-L1 expression in the tumor microenvironment, as demonstrated in preclinical settings
[131]...
Here, we will focus our discussion on mechanism-based biomarkers that are emerging as candidates
to specifically predict the response to RT plus ICBs (not necessarily to either of these treatments administered alone).

onthemark
A Dec 2017 paper:

A Dec 2017 paper:

"Emerging biomarkers for the combination of radiotherapy (RT) and immune
checkpoint blockers (ICB)"

links to Jim's and Dr. West's remarks about biomarkers and summarizes the current state of the art.

RT increases the antigenicity of malignant cells by promoting the upregulation of MHC class I molecules on the cell surface [10,11], by favoring the expression of tumor-associated antigens [12], and (at
least potentially) by enhancing genetic instability or reactivating endogenous retroviruses [13,14]. Moreover, RT boosts the adjuvanticity of cancer cells by at least two mechanisms...

"The potential predictive value of the biomarkers discussed above needs to be studied in patients receiving RT plus ICBs. Indeed, some of the biomarkers that are associated with improved clinical responses to RT or ICB-based immunotherapy may have limited predictive value in the context of combinatorial regimens. As an example, while high PDL1 expression levels are robustly associated with the response of melanoma and NSCLC patients to nivolumab or pembrolizumab (see above), a benefit on progression-free survival was observed irrespective of baseline PD-L1 expression in NSCLC patients treated with chemoradiation followed by durvalumab versus placebo [130]. This result is consistent with the hypothesis that RT can induce PD-L1 expression in the tumor microenvironment, as demonstrated in preclinical settings
[131]...
Here, we will focus our discussion on mechanism-based biomarkers that are emerging as candidates
to specifically predict the response to RT plus ICBs (not necessarily to either of these treatments administered alone).

cubety
It looks like the hopeful

It looks like the hopeful results of the Pacific study for many might lead to some further developments clarifying this line of thinking with possibly mutational burden increased to radiotherapy cancerous areas that might lead to better immunotherapy response shortly after radiation finishes (hope I have that correct)?

Would that hypothesis imply then the idea that simpler EGFR+ homogeneity is not as responsive to immunotherapy than post radiated EGFR+ which could be more heterogenous? Sounds like all this is hypothetical at this point and maybe the Pacific study is a potential piece of evidence to support the idea. Wish I had more time to digest this but have to get back to work.

I'll have to think when have time over order of treatment with TKI before immuno or the risk of having vice versa based on the real small study stopped early in UCLA. I'm not sure when TKIs would possibly be started post chemorad concurrent treatment (guessing not untila progression is noted?)...

Thank you all again.

JimC
Hi cubety,

Hi cubety,

Sorry if I take you away from work again, but just a couple of points.

First, although eventually we may have sufficient evidence to support the very reasonable hypothesis that radiotherapy can improve the efficacy of subsequent immunotherapy, the history of cancer treatments is replete with examples of concepts that seemed quite logical yet failed in real-world testing, despite initially promising results in preliminary testing.

Second, the full effects of radiotherapy do not become apparent for some time (even a few months) after the course of treatment has ended. That's because the scarring which radiation can cause can make it difficult to judge what is scar tissue and what are cancer cells when looking at a follow-up scan. In addition, unlike the laser beams used as weapons in sci-fi movies, radiotherapy does not instantly dissolve tumors (would that it were so!) Instead, it alters the DNA of those cancer cells in such a way that they die off or fail to multiply and grow, and that process takes some time. That may be a reason to delay subsequent TKI treatment until it's clear what is left in the wake of chemorads.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

onthemark
Hi Cubety

Hi Cubety

Jim has given you good advise. I am not sure what the protocol period to wait after chemoradiation to get a PET scan is, in the absence of new symptoms, but it might be good to hold off on the PET scan until the after effects of radiation have settled down. I am not sure about this but it is something to look into.

There is another piece of indirect evidence to add to your puzzle, and that is the early discontinuation of clinical trials involving combinations of immunotherapy and TKIs, due to adverse side effects. This can be added to the alarming results Dr. West pointed to in his video that I linked to earlier in his thread. That was also enough to call off a small study.

There is no doubt that immunotherapies change the immune system both in beneficial ways and sometimes in harmful ways, depending on what other medications are involved at the time. It is a bit like playing with fire at the moment though with TKIs. That is my view. Then there is also the possibility of losing an entrance into a promising clinical trial down the road for people who progress on TKIs involving immunotherapy if one had previous exposure to it. Finally there is the expert advise you pointed to originally recommending EGFR+ patients not consolidate with durvalumab.

One more point is that your wife has a predilection to auto-immune disorders, from what you wrote before.

On the other side is a promise of great benefit and potentially increased odds of a cure by taking durvalumab as consolidation as a non-smoker. The evidence for that population is significant, unlike the EGFR+ subgroup.

In the end it comes down to a personal choice that one makes with the knowledge one has at the time.

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