Durvalumab not working, based on Guardant 360 Tumor Response Map...

[yenlilly]

Hello All,

I've been a frequent reader/follower of this discussion forum, albeit never poster (until now), but just want to let everyone know I'm very appreciative of all the technical advice and positive supportive messages that are shared on a daily basis here. I've finally decided to jump in and share my story:

After ~5 months of primary care and pulmonologist appointments/scans/incorrect diagnoses of pneumonia, my never smoker 64 year old mother was diagnosed with Stage 3 Squamous Cell lung cancer in OCT 2021. The tumor biopsy revealed a CDKN2A Deletion mutation, with a high PD-L1 of 90%; and low Tumor Mutation Burden. Once the doc confirmed the best past forward, in DEC 2021, we commenced the chemoradiation sequence of 7 weeks of daily radiation + weekly low dosage chemo treatments of Carbotaxol.

In FEB 2022, 16 days after the last radiation dose was administered, we immediately began her monthly immunotherapy regimen of Durvalumab (Imfinzi). We did a CT scan at that point that revealed a marked improvement from the PET/CT that was conducted in SEP 2021. The onc also ordered a Guardant 360 test contemporaneously, and we received a baseline tumor response map that indicated she still had relatively low levels 4 separate biomarkers present.

These past 5 months have been (fortunately) mainly uneventful, with the only symptoms presenting being coughing and shortness of breath, likely attributed to a mild to moderate case of pneumonitis from either the chemoradiation of Durvalumab treatment. During this period, I was feverishly researching stats on my mothers case; stats on Durva, and became more and more hopeful that she was going to have a very positive response from the treatment, especially due to her high 90% PD-L1 expression.

Last month, the onc ordered the another CT scan, which came back very positive, as interpreted by the onc - he said they did not see any additional growth and there was no mention of any masses present - merely increasing consolidative opacity in the perihilar with air bronchograms and moderate pleural effusion, which we assume can be chalked up to the pneumonitis. But the doc's consensus was that this was something to celebrate, as it appears the treatments are working based on the scans alone. To be sure though, he ordered another Guardant 360 test to confirm that, on a molecular level, the treatment is directionally working as intended (ie. we would expect the percentages of each biomarker present in the last test to be trending downwards as the treatment progresses).

We have not yet had the appointment with the doc to discuss the results of this second Guardant 360 test (will be next week), however, I was able to log on and retrieve the reports on my own and was devastated to see that the biomarker percentages have increased substantially from the FEB 2022 baseline test (see image attached). This directional change would seem to indicate that the Durvalumab treatment is not working for her in the 5 months since she began. My question is, can anyone who has done this test please confirm that that is the accurate interpretation of the results?

I have not yet discussed with my mom as I do not know what to even tell her. She has been very pragmatic through this whole ordeal, and only just after the last doctor's appointment with the positive CT scan, did she begin to have hope and talk about travel plans for next year, and potentially beyond. This is truly even more devastating to me than the initial diagnosis, as I had such high hopes for this treatment - I was sure that she was going to beat it and be one of the lucky survivors that would last beyond the 5 year mark. Next question here is, what are the next steps for a Stage 3 Squamous Cell (she has not been restaged since initial) chemoradiation patient who, currently only based on the Guardant 360 testing as her tumors have not reappeared yet via scans, does not appear to be responding to Durva?

Apologies for the long long post here 😌 Appreciate any feedback that I can solicit, and appreciate you all!

Regards,

Lilly

[Denzie Moderator Volunteer]

This is something the doctor should review and discuss with her. The test itself stated “Variants of Uncertain Clinical Significance.” To me that mean the people and programs that developed the test do not have enough information to call it progression or not progression. They will follow your moms case and add her results to their growing body of knowledge.

If her doctor had seen growth he would have told her that. Telling your mom that she’s experiencing anything at this point may cause her unnecessary anxiety.

Has she signed the HIPAA form giving the Doctor permission to discuss these with you? If yes, reach out to the doctor’s office and ask what he interprets this to mean.

[Dariada]

Your mom is very lucky tj have your support. I don’t know much about the guardiant test but will be researching it since it sounds very interesting. Like you, I research quite a bit and find it helpful to. See stand what’s happening to me (or in your case, your mom). That being said, my doctor is able to take my specific information (tests and scans, etc) and explain what I don’t understand. The important thing I’ve learned is that everyone is different. Even if I had the exact same cancer and exact same treatment as your mom our responses could be very different. I’m hoping you’ll update us after your moms dr appointment. In the meantime I’m sending my prayers

[Denzie Moderator Volunteer]

Have you heard from the oncologist yet?

[yenlilly in reply to Denzie]

Hi Denzie,

Thank you for checking in! Yes, we had the appointment, and he said the results were not very definitive enough to have him make a decision to change course in treatment currently. So plan is to stay on Durva for at least one more session, and then we will retake the Guardant test after next month.

I had brought up the fact that my mother had had her blood drawn for that test immediately after (on same day of appointment) her Durvalumab drip was administered. I've read in a couple studies that the CtDNA levels will typically peak ~4 hours after treatment of chemo is administered, and asked if that may have tainted the test, despite Durvalumab being an immunotherapy versus chemotherapy. He agreed that that may have affected the result. In addition, the 2 other variant alleles that spiked are variants of "Uncertain Clinical Significance", as you had also mentioned, and he believes that these are likely of oncogenic sources, however, it is not fully known yet what the derivations are of these types of variant alleles, so he is just going to keep watch, as clinically, in her CT scans, she appears to be "clear".

So ultimately, just waiting for a couple more months until we can retest with Guardant, and possibly rescan with CT. Will keep you guys posted here. Thank you so much!

Lilly

[yenlilly]

Also, wanted to add that the blood test we are utilizing is the Guardant360 Response test - press release link below that gives a bit more info:

investors.guardanthealth.co....

Believe this is a fairly new technology, but is supposed to give earlier indication at the molecular level as to whether the levels of CtDNA are rising/decreasing (which I understand to be directly correlated to immunotherapy response). The benefit being, doctors would be able to tell much earlier than via RECIST (traditional monitoring via scans), whether the current treatment is working, or whether they need to pivot quickly to another alternative treatment. I'm not 100% on that, but that is what I understand based on the research I've been doing on my own.

Again, thank you all and appreciate all of the positive vibes and prayers.

[Denzie Moderator Volunteer]

Guardant 360 is awesome. I recently had it because of the breast cancer in my family. It’s amazing stuff. Glad you shared the link for the new people who read this.