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

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cubety
Thank you onthemark and JimC

Thank you onthemark and JimC for gathering up the cat herd of our info into a more succinct thought.

I noticed there is beginning to be focus on some that respond negatively to immunotherapies generally with this from 2017:

https://www.targetedonc.com/conference/esmo-2017/study-identifies-subset...

Only 2% were EGFR+ Mutation though. But it highlights potential adverse reaction like in UCLA study. The end part also mentioned possibly studying other treatments to see if they may also have a subset of people experiencing HPD.

Given the FLAURA phase III results regarding osimertinib/Tagrisso as first line treatment for EGFR+ 19 and 21 exon mutations, there is at least potentially a good window of time if my wife's exon21 mutation doesn't get wiped out with concurrent rad/chemo therapy underway. With her never smoker status the cancer is possibly more homogenous in nature and lower mutational burden allowing for potential longer good response on inhibitor.

The Pacific study is interesting with the EGFR+ were the worst median responders yet neversmokers had some of the best response so a bit counterintuitive without thinking too deeply on it. You did note the broad ranges in both groups and the smallish sample as possibly being reason for the wide ranges.

Since my wife is EGFR+, that would carry more weight in my mind first before neversmoker status. But since neversmokers tend to have higher EGFR+ mutation it makes me wonder about the breakdown of neversmokers in terms of cancer type.

I'm currently feeling like leaning onthemark's way with thought there is a good line of TKI treatment if there are micrometasteses that survive current treatment to give us time and avoid possible small but significant risk with EGFR+ immuno treatment reactions if going on Durvalumab and taking into account EGFR+ benefitted but not by a lot with Durval.

cubety
I have a question after

I have a question after looking at the supplemental data (Asian population for whatever reason fared better I saw, think in S2 supplement chart).

Do people that discontinue treatment still get included in results? Just wondering how things work if results are only based on those that went the whole 12 months or if there is some statistical weighting or something.

Also starting Durvalumab in first two weeks post radiation gave a meaningful boost that looks interesting for followup investigation.

Wishing you thoughts of wellness onthemark with upcoming scans.

onthemark
Hi Cubety,

Hi Cubety,

To answer your question, the NEJM paper defines their sample of patients as:

"Between May 2014 and April 2016, a total of 709 of 713 patients who underwent randomization (99.4%) received at least 1 dose of study drug as consolidation therapy (473 patients received durvalumab and 236 received placebo)"

From this it's clear they are including all patients who received at least one dose of consolidation therapy (either durvalumab or placebo) in the data they analyze.

And yes, error bars are larger in Figure 2 and similar figures when the subgroup size is smaller and when the spread of results within each subgroup is larger too. The actual true value of benefit has 95% (confidence interval) chance to fall somewhere within the range covered by the error bars. It actually has very small chance to be very close to the central point unless the error bars are very small...

https://www.nejm.org/doi/full/10.1056/NEJMoa1709937

I saw some other reports in the metastatic setting where people who went longer on immunotherapy had higher chance of surviving than people who were treated for less time. See for instance

"In CheckMate-153, among the patients still on nivolumab at 1 year of the study, those who were treated continuously had significantly improved PFS compared with those who stopped nivolumab (hazard ratio [HR], 0.43; 95% CI, 0.25-0.76)"

https://www.onclive.com/conference-coverage/esmo-2017/nivolumab-past-one...

Thanks for pointing out the results on hyperprogression by immunotherapy. I was unaware of that complication and it is also important to take into account.

Yes, I've got my scan tomorrow (fingers crossed) and then have to wait two weeks to see my oncologist to get the result. This wait is unfortunately the norm where I live. So far I have done really well with no recurrence since being diagnosed in October 2015, so I am approaching 3 years now if my luck holds out.

cubety
Oof, 2 weeks that must be fun

Oof, 2 weeks that must be fun. Glad you have history on your side and am hopeful you will keep your winning clear streak going.

Something regarding my wife, they never definitively ruled out the right side cervical node so there is some chance she is not correctly staged. We were told it was a small sample but had lymph tissue so our onc said she felt it was negative and we quickly (thankfully at that point given the 4 1/2 month journey to there) went to chemo and radiation. We later saw the report listed it as indeterminant due to small sample size. At least it wasn't positive but it isn't ruled out either.

So I guess it is potentially important to have the PET scan results to see if it is something we need to rule out right away before doing durvalumab if we went that way.
If it still shows metabolic activity beyond other areas I would want a dissection if possible but don't know if it is possible due to chemo/rad treatments only ending about a week before.. The SUV was 2.6 on cervical node compared to R2 that was 2.7 but I believe the R2 measured slightly larger (basically equal in size) at 0.9 cm if I recall. The primary was 1.8 cm x 1.3 cm I think (going off memory) and 4.1 SUV.

Thank you for your continued help and we are keeping positive thoughts sent your way to sail thru the next 2 weeks without too much dwelling.

JimC
onthemark,

onthemark,

Good luck with tomorrow's scan, and I'm sorry you have to wait so long to hear your doctor's interpretation of it. We'll be keeping you in our thoughts.

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. I just had

Thank you, Jim. I just had the scan (pelvis, abdomen and chest) with and without contrast. If this is unchanged then I'll hopefully go to low dose yearly ct scans just of the chest as the most likely area of recurrence for my type of lung cancer are the lungs and I am concerned about all the radiation I am being exposed to.

Cubety, I found this article about using PET scans as surveillance following radiation therapy. It might be of interest to you.

"FDG PET-CT scan 3 months after treatment of NSCLC with SBRT was a specific but insensitive test for the detection of recurrence or treatment failure. Serial CT scans should be used for early surveillance following SBRT, whereas FDG PET-CT scans should be reserved to define suspected metastatic disease or to evaluate new abnormalities on CT scan, or for possible reassessment later in the follow-up period after radiation-related inflammation subsides."

Assessing the Usefulness of 18F-fluorodeoxyglucose PET-CT Scan After Stereotactic Body Radiotherapy for Early-Stage Non-small Cell Lung Cancer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137590/

cubety
Hi JimC I was reading over

Hi JimC I was reading over the information you posted on page 2 in discussion here a few days ago. I was trying to get a rough idea how to interpret The figure 2 results in Pacific trial since never smokers had the best overall median numbers I think and EGFR+ had some of the worst which was counterintuitive to me.

From a simple logic point of view it goes against traditional thinking (never smokers having higher EGFR+ mutations yet never smokers having some if best results while EGFR+ had some of worst- although HR for EGFR+ was still roughly 0.75 so a benefit overall).

The real struggles I have are for instance how many AE were from EGFR+ group? And with a little history of TKI and immuno (although at same time) toxicity from previous older studies, how might these EGFR+ responders fare going forward if they need to take a TKI from progression down the road?

Here is a blurb summary from looks like a Korean study:
"Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Nivolumab combined with erlotinib was associated with 19% of grade 3 toxicities. The combination of osimertinib plus durvalumab in pretreated or chemo naïve NSCLC patients showed encouraging clinical activity, however, this combination was associated with high incidence of interstitial lung disease (38%), leading to termination of further enrollment. The combination of gefitinib plus durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40–70%). The treatment related Grade 3–4 adverse events were observed in 39% of patients when treated with atezolizumab plus erlotinib."

So in combination TKIs and immuno had high AE. Begs lots of questions for me.

cubety
One concern is if wife takes

One concern is if wife takes Durvalumab, a later recurrence would potentially have her taking a TKI with well substantiated general benefits to PFS and OS (for instance FLAURA trial and osimertinib). Yes she could potentially get part of that approximate 0.75 median HR benefit with Durvalumab now hopefully but I can't find how many EGFR+ made it Thus far thru study and whether they had higher AE incidence. I have several questions about the Pacific study to feel comfortable in logically explaining results to make sense to me personally (like the median difference between never smoker and EGFR+ for example).

Another example, the unknown group performed relatively poorly to others surprisingly to me but maybe they were 'unknown' because of unwillingness to biopsy for health risk reasons or age? I'm not sure but older age also underperformed so maybe it's a possibility.

Also the study was heavily weighted with former smokers and under weighted with never smokers. Could that have had an impact on placebo PFS and OS compared to a more representative weighting of NSCLC people (approx 25% neversmoker)? Then again never smokers responded quite well from median standpoint. I have a bunch of questions probably like a lot of people trying to make tough decisions and just not having a lot of information to go on or time unfortunately.

I do worry a bit for instance if say she needed osimertinib later because of EGFR+ brain mets and might have unforeseen risks if having taken Durvalumab for a year but it is all hypothetical guesswork. That's one reason it would help follow the subgroups as they move forward in areas such as AE. They probably do have that info somewhere but I was unable to find that kind of granularity.

Thank you very much to you and your wife for all the help you provide people. You both are really good people. Take care.

cubety
Interesting, this doctor from

Interesting, this doctor from Spain apparently involved in the study mentioned median time to relapse is around 9 months:

http://www.ascopost.com/issues/september-25-2017/pd-l1-inhibitor-consoli...

So if placebo was 5.6 months plus we add the chemo/rad treatment time, wouldn't that equate to an extra 6 weeks and then up to 45 days after to start? Let's give a median 30 day start although they were pushing for 14 days and that subset performed well. So 5.6 months plus 1.5 months for chemo/rad plus about 1 month for median time period to start following concurrent chemo/radiation gets us to 8.1 months. About 10% below expected PFS for what doctor mentioned so not a big difference but still about a month.

I wonder how much effect one month would have on the Hazard ratio (if placebo group instead of 8.1 months went to 9 months or what would be equivalent of 6.5 months vs the 5.6 reported).

Given the % difference between 5.6 and 6.5 months, that would be more impactful potentially of HR numbers I would think? Not sure.

I guess another small point would be that one premise of the good response is due to the boost Durvalumab may have in the radiated area from damaged cancer cells as had been briefly mentioned here but it is not a well-supported idea with evidence yet as also mentioned in discussion. Given wife's potential fairly extensive nodal involvement, it is pretty likely there may be micrometasteses elsewhere outside the radiated field where the EGFR+ mutation cells don't get hit with radiation so what effect might Durvalumab have on those areas of concern would be another unanswered concern/question. Lots of questions and concerns.

cubety
Another question I wonder

Another question I wonder about is if lower SUV score (EGFR+ mutation) cancers have any correlation to length of time that TKIs might work. The thought being a slower metabolic cancer may not divide as fast and therefore inhibitors may work longer generally before resistance happens because division in cancer cells happens at slower rate.

catdander
Unfortunately in cancer there

Unfortunately in cancer there are more unknowns and unanswered questions than not and that isn't going to change any time soon. The good news is that researchers are making tremendous strides in closing the gap. That often leaves oncologists and their patients to make decisions based on limited data and individuals' needs. This type of oncology is sometimes referred to as the 'art' or 'craft' of oncology because oncologists learn to read patients' individual circumstances both emotional and physical to create a treatment plan that best fits the individual.

The bottom line is we still don't know where egfr+ patients fit here, however it does appear from the immature data suggests egfr+ patients may very well receive benefit from consolidation therapy with pdl1 inhibitor after chemo/rads. In figure 2 from the report suggests the small subgroup of 40 or 50 (don't remember just now) egfr+ subjects did statistically better with the drug but it's still a pretty small number and probably needs further studying.

I'm not sure but it seems you are worried that taking pdl1 inhibitor now will effect the way a tki may work later. I don't think anyone would expect a tki to be less effective because someone took a pdl1 prior to recurrence.

I imagine the reason behind the pacific trial having so few non egfr + patients is because there has been little encouragement from the data of other pdl1 and pd1 trials of stage IV single agent and combos but not so much cherry picking for better results.

I wish there were a way to tease out an answer to whether this is the best thing for your wife but there just isn't. I know how that feels and i'm very sorry. What I do know is that the decision she makes will be the right one and once it's made and put into action (or not) a mountain of stress will be released. (this last bit is from 9 years experience on grace forums)

All best,
Janine

JimC
One important factor to keep

One important factor to keep in mind is that in this study Durvalumab was compared with placebo, rather than an established lung cancer therapy. So although the limited results tend to show that patients may receive a benefit from this consolidation therapy compared to no anti-cancer therapy, the trial was not looking at the question of whether Durvalumab is a better consolidation therapy than, for example, continuing one of the chemotherapy agents. That would be a question for another trial.

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>

cubety
Jim that is a good point you

Jim that is a good point you bring up for further research in regards to other maintenance consolidation like Alimta or something.

Thank you both Jim and Janine for your continued helpful insights as we grapple with decision making near term.

catdander
Jim,

Jim,
It seems to me the trial is comparing to an established treatment of chemo/rad as a curative treatment so comparing to nothing more is comparing to the standard. No?

JimC
Janine,

Janine,

In that sense you're absolutely correct. The trial presents limited evidence that Durvalumab may be an effective option for consolidation therapy after chemorads, but the opposing argument is that any anti-cancer consolidation treatment would be expected to improve PFS somewhat. But how does it compare to other agents?

It's similar to the question of whether maintenance therapy just improves PFS because you're doing something to treat the cancer. The open question any time you measure success by PFS is whether you get improved OS.

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 Jim, Janine, and Cubety

Hi Jim, Janine, and Cubety

One thing to note is that Astrazeneca recently announced "Imfinzi significantly improves overall survival in the Phase III PACIFIC trial for unresectable Stage III non-small cell lung cancer" but the specific numbers are not out yet. They will be announced at a medical conference, hopefully in the near future.

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2...

Also based on the earlier published NEJM study finding a huge improvement in PFS, Durvalumab is approved in the NCCN guidelines as consolidation therapy for Stage III lung cancer, unlike any other medication.

There's a long history of trying other consolidation therapies (chemotherapies and TKIs) but none have had the kind of success that would get them approved by the NCCN, so that is why the standard of care comparison arm in the PACIFIC trial was placebo following definitive chemoradiation.

There's an exhaustive recent (May 2018) summary of this issue:

Consolidation systemic treatment after radiochemotherapy for unresectable stage III non-small cell lung cancer

https://www.sciencedirect.com/science/article/pii/S0305737218300343

I have access through a library account but otherwise it is behind a pay wall, unfortunately.

catdander
Lot's to be impressed by, not

Lot's to be impressed by, not the least of which is onthemark's knowledge. The fact that the trial has already shown an improvement in os is even more impressive especially since this is preliminary data and the numbers can only get better. The os has been proven to be better than any other method of treatment and non treatment for the population. Am I understanding that right? If so wouldn't this treatment be better than the current standard of care for stage IV as well?
Edit to say I've thought about this for minute...For those with stage IV with oligomets might benefit but not so for stage IV who have several mets.

cubety
Interesting point catdander

Interesting point catdander on stage IV.

I still feel like placebo in the Pacific study was underperforming after hunting around trying to find more data on typical time to progression in Stage3.

Jim, on maintenance/consolidation it looks like alimta and tarceva are the 2 main ones approved in US. Here was study on Tarceva from awhile back:

https://www.ncbi.nlm.nih.gov/pubmed/?term=Erlotinib+as+maintenance+treat...

And on pemetrexed/Alimta

https://www.ncbi.nlm.nih.gov/pubmed/19767093

Not a big benefit but wonder if wife as locally advanced could potentially have a maintenance therapy. Onc today said they'd probably just do scans every 3 months without consolidation therapy (edit- IF we did not do Durvalumab). I couldn't get them into any granular discussion unfortunately with Pacific study, they have lots of patients with different things going on.

cubety
Interesting small note to

Interesting small note to Pacific study-

I think the complete response rate was higher in the placebo group than the Durvlaumab group- about 3% of placebo (7 people) compared to about 2% Durvalumab (9 people).

So in terms of % of people, Durvalumab underperformed placebo by 5 people given 2:1 ratio Durvalumab to placebo patients treated. i.e. one would expect twice as many in Durval group comnpared to placebo since there were twice as many patients.

Not sure if maturing study would continue to add to that Durvalumab number?

JimC
I don't think you can draw

I don't think you can draw any conclusions from that data. When you carve up trial results into such small sub-populations (patients with a complete response), you end up with too small a sample to make the data meaningful.

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>

cubety
Yes Jim I completely agree

Yes Jim I completely agree single digit numbers in a 700+ study population are not highly relevant.

It does give a little idea of how lucky few there are to see complete response in fairly short order at that level unfortunately but it does give some hope at least.

I'm still a bit concerned on potential toxicity issues. Given the EGFR+ group as a whole benefited but notgreatly and given PFS for placebo was 5.6 months, this means it could be possible/probable the EGFR+ mutation subpopulation could progress during the 1 year treatment cycle (more than double the time of placebo group to see progression).

This in turn makes me worry my wife could end up[ on Durvalumab only to see at some point during the year progression that would probaby mean a need for a TKI in short order (so switching from Durvalumab to a TKI is quite possible if those things were to happen, e real possibility it seems).

If a TKI was given immediately after a months long exposure to Durvalumab, I wonder if it would have no effect or possibly some of the toxic events shown when both immunos and TKIs were used concurrently.

I'm trying to come up with potential weaknesses to the Durvalumab argument so as to understand potential problems and feel more secure if we go that way by understanding weaknesses as well as strengths since the Dr at SCCA had planned moving ahead with Durvalumab last time we communicated. Currently I feel a little bit uncomfortable to go that route (immuno) and there is a slight chance my wife might be a surgical candidate still.

cubety
Does anyone have experience

Does anyone have experience or information on TKIs administered sequentially with immuno (immuno first)? Just wondering if we have recurrence during a 1 year Durvalumab treatment if it would then be something normal to stop the immuno and quickly start a TKI considering both imm No/TKI together have tended to have fairly high toxicity events for whatever reasons. This is meant as a general question for EGFR+ people looking to start Durvalumab but also may specifically help inform us.

This sure is a struggle for decision.

cubety
This is older but involves

This is older but involves Durvalumab after TKIs had been used, not the other way around but on EGFR+ patients.

http://www.pmlive.com/pharma_news/az_halts_durvalumab_combination_trials...

I wonder if there is a granular breakdown of the PACIFIC trial showing which groups had AE events and at what level. With the small amount of EGFR+ Durvalumab takers it may not be wholly representative but might be helpful for general idea.

catdander
The pacific trial isn't

The pacific trial isn't complete yet but as and I didn't see a breakdown of av into subgroups but I do recall reading or hearing in one of the previous links in this thread that suggests the egfr group didn't appear to have more or significantly more av than the other subgroups.

From the ASCO post last Sept., "Treatment-related adverse events occurred in 68% of patients in the durvalumab group compared to 53% in the placebo group. The rate of immune-mediated adverse events was 24% with durvalumab and 8% with placebo. Severe pneumonitis (grade 3/4) occurred in 3.4% and 2.6% of patients on durvalumab and placebo, respectively. Treatment had to be discontinued due to pneumonitis in 6.3% of patients on durvalumab and 4.3% on placebo.

“Overall, there was a slight increase in toxicity in the durvalumab arm, but severe toxicity was similar between groups,” said Dr. Paz-Ares.

He concluded, “Durvalumab is a reasonably well-tolerated treatment with a manageable safety profile that improved progression-free survival by 11 months. PD-L1 inhibition after chemoradiation appears to be a new option for patients with locally advanced, unresectable stage III lung cancer. It will be important to see the impact on overall survival after a longer follow-up.” " http://www.ascopost.com/News/58042

cubety
Thank you catdander for the

Thank you catdander for the added focus with the "similar between groups" information. I'm hoping to hear back from oncologist to see if we go durvalumab route that we can start fairly soon.
At infusion, time for snack :). Take care.

onthemark
I wish you and your wife all

I wish you and your wife all the best on getting your PET scan results tomorrow, cubety.

Jim and Janine, I had good results today with my own scans. No changes since the last time, and I've graduated to one year till the next one.

onthemark
I just ran across a very

I just ran across a very thorough and understandable article by Dr. West on his takeaways from the PACIFIC clinical trial.

Dr. West discusses durvalumab in EGFR+ and the extent to which patients benefit by starting treatment sooner after chemoradiation (within 2 weeks) rather than later (within 6 weeks), as well as numerous other issues in the context of stage III treatment.

You can read "Data From the PACIFIC Trial have Changed the Management of Stage III NSCLC, Observes West'
Published Online:1:46 PM, Fri August 24, 2018

https://www.targetedonc.com/news/data-from-the-pacific-trial-have-change...

JimC
Hi onthemark,

Hi onthemark,

That's terrific news! Thanks for sharing your great scan results...we always love to hear about them!

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. I get to go a

Thank you Jim. I get to go a year now for the next scan!

Hopefully Cubety saw the article I posted by Dr. West. i think it goes a long way to answering his many questions about the study and what the clinical impact of it is. There are also new results, including overall survival for PACIFIC which are going to be announced in September in Toronto at #WCLC18.

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