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

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-th…
https://www.onclive.com/insights/multimodal-advanced-nsclc/pacific-tria…

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?

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.

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.

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

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…

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.

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?

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

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.

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.

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

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.

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.

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.

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.

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=20…

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}

[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]

[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

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.

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.

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

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

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)

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).

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).

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

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.