Saturday 16 May 2020

Deciding between Chemo and Targeted Therapies for Recurrence

I've been a longtime follower of this community and I'm hoping that others here can help me cut through all the information I'm being given to make some decisions for my husband.

Background
My husband was diagnosed at age 34 in October 2018 after having neck pain for a few weeks and then a sudden onset of extreme disorientation. He had an emergency resection (97.8% debulked). His tumor was originally located in the left parietal lobe. His tumor is unmethylated, IDH wild-type. Initially he followed SOC. Radiation concurrent with TMZ, then Stupp protocol 5/23 with Optune.

In May 2019, he had progression, stopped TMZ and Optune in preparation for surgery. Second resection in June 2019. He got a pre-surgical infusion of Keytruda (Pembrolizumab). Second surgery was MRI assisted at Memorial Sloan Kettering. Resection was successful and he followed with a short course of photon radiation and Keytruda infusions every 3 weeks. Around this time we also stopped doing a strict Keto diet because he had dropped close to 40 pounds. We now follow it in moderation.

We used Store My Tumor to preserve a tissue sample from the second surgery and used that to create an autologous dendritic cell vaccine from whole tumor lysate at Thomas Nesselhut's clinic in Germany. He was primed with an oncolytic virus, also used adjuvants of Inter-leukin 2 and Aldara cream.

Fall 2019 we continued Keytruda infusions and his dendritic cell vaccine with Tetanus adjuvant. In October 2019 he had an adverse event (possible focal seizure or pressure wave). We discontinued Keytruda (had completed 7 rounds). Started on a course of Avastin infusions and 4 mg Dexamethasone to control inflammation. We made the decision to discontinue Optune at this time. It was a quality of life decision. It was really interfering with his enjoyment and activity (we have twin toddlers). I am 100% okay with that decision and won't force him to do something he hates.


In November 2019 he was accepted into the SurVaxM clinical trial via compassionate release. He completed a priming dose (4 rounds) of the peptide vaccine SurVaxM. His most recent dose was in April 2020. In January 2019, it looked like there was further progression in the corpus callosum. We decided to continue with Avastin infusions and dendritic cell treatment and did a course of Proton Beam radiation.
His first MRI post radiation showed a modest reduction in tumor. (March 2020).
His most recent MRI in May 2020 is showing new growth. The area that got proton beam radiation continues to shrink, but there is a new tumor measuring 2.9 X 1.7 cm within the posterior medial left temporal lobe. Thankfully he has remained largely asymptomatic and stable. He has issues with leg weakness from prolonged steroid usage and his right arm and hand have lost dexterity. He has never had a seizure. He has some memory issues and lately some issues with processing.
Now we are faced with a decision about what to do next and we are getting a lot of differing opinions.
His tumor has the following markers:




x





We are deciding between adding a cytotoxic chemotherapy and a targeted therapy. One team of doctors is strongly recommending CCNU. Their other options would be Metronomic TMZ, Carboplatin, or Irinotecan.

Our vaccine team is very wary of cytotoxic chemo and believe it would negate the immunotherapies. They are okay with metronomic TMZ or metronomic Cytoxan.

A third doctor recommended Carboplatin and keeping Keytruda.

We have been offered the possibility of trying a targeted therapy to match his genetic markers. The choices there are Abemaciclib (CDK4/6 inhibitor) or Cabozantinib (MET fusion). I would like to get a PI3K/Mtor inhibitor or an MDMA inhibitor but there are next to none that are commercially available and I don't think we can get into any trials or want to wait that long. Piqray is one potential option in the PI3K/Mtor area. We don't know if we could combine them with chemo. I think we would have to see how he responds to one before adding them together.

Surgery and radiation seem unlikely though we are going to pursue consultations for surgery (we are based in NY) and gamma knife with Dr. Christopher Duma. I don't think these will pan out, but the consultations can't hurt.

I am really struggling with how to make these choices. His quality of life is fairly good. None of these options seem to have strong data behind them, but all have those small percentages of patients where things work and no one knows why.

I want to make a decision quickly. I am leaning towards Metronomic chemo (even though I know he is unmethylated and the chances of it working are small). But we can get it immediately and we know somewhat how he responds on chemo. He always tolerated it well, never had low counts and managed side effects with cannabis and IV fluids and colace. I think we could try chemo for one month and do another scan and see quickly if there is any impact.

We would have to get approval for the targeted therapies and I think perhaps it makes the most sense to hold those while we try something else.

He has been on his vaccine for almost one year and I have no idea if it has done anything, perhaps it's simply held things back.

I know this community has so much knowledge. I welcome any insight. He is 19 months past diagnosis and we have never had a long stretch of stability. We have thrown everything at this disease. Given how aggressive its been, I hope that all that we have done has given him more time than if we had just done SOC. I want to give him time, good time.

His genetic markers are:
TERT
CDKN2A
MDM2
CCND2
PTEN
FOXP1
TET2
YAP1
CCND2
BIRC3
PTPRZ1-Met Fusion


We completed EVA-PCD assay through Nagourney Cancer Institute. Tumor tissue sample allowed for testing of 5 agents. Results were:
  • Dactolisib (PI3K/mTOR)--sensitive
  • Palbociclib (CDK4/6)--sensitive
  • Crizotinib (ALK/MET/ROS)--intermediate
  • Carboplatin & Topotecan--intermediate
  • Olaparib (PARP)--resistant


His medications are as follows:

Immunotherapy
Dendritic Cell Vaccine
SurVaxM vaccine
Keytruda
Tetantus adjuvant
Aldara adjuvant
Lion's Mane

Apoptosis/Autophagy 
Chloroquine 
Mebendazole 
Artemisinin 
Simvastatin 
Escozine 

Anti-Angiogenic
Avastin
EGCG 

Metabolic 
Metformin 

Anti-Inflammatory
Bromelain 
Curcumin 
Boswellia Serrata
Quercetin

Other 
Cymbalta 
Clonazepam
Valproic Acid
Melatonin
Turkey Tail
CBD (sublingual)
Cannabis (whole flower, vaporized as needed)

 


3 comments:

  1. Hi Jane,
    I'm sorry if the following comments come too late to be useful.
    Regarding conventional chemo drugs, if he is still doing vaccine treatments, the metronomic Cytoxan (cyclophosphamide) would be an interesting addition as it can have immunostimulating effects at the proper dose, although I'm not sure if they've shown this in humans.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485826/
    I believe it was for this reason cyclophosphamide was added in the following trials
    https://clinicaltrials.gov/ct2/show/NCT03152318
    https://www.clinicaltrials.gov/ct2/show/NCT01903330 (cycloposphamide dose of 50 mg per day)

    Metronomic cyclophosphamide would probably be my choice in combination with vaccine therapy. As standalone chemo I would probably try a round or two of lomustine (CCNU) or metronomic TMZ. With MGMT unmethylated status these would likely be less effective, although there is some evidence lomustine and Avastin work better together than either agent alone, including in MGMT unmethylated tumors.

    I wouldn't necessarily trust the results of in vitro drug sensitivity testing. These kinds of tests usually completely disregard the existence of the blood-brain barrier (BBB). A drug might be highly effective in vitro, but if it can't reach the tumor cells, that is of no concern. Yes the blood-brain barrier may be disrupted in the center of a GBM tumor (the area that is most likely to be removed surgically), but the invasive edge and periphery of the tumor is protected by a fully intact BBB in most cases.

    I'm haven't seen anything to make me particularly enthusiastic about carboplatin or irinotecan.

    Another idea would be regorafenib, which proved to be more effective than lomustine in a randomized phase 2 trial.
    https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30675-2/fulltext

    After seeing trial after failed trial, I have a pessimistic view of most targeted kinase inhibitors for GBM (this is the other class of drugs you mentioned in your post). Most of these were developed for cancers outside the central nervous system and have sub-optimal crossing of the blood-brain barrier. Also when used as a single agent they are more likely to fail than as a part of a broad-spectrum cocktail. Regorafenib (the drug in the trial mentioned above) is in fact the only kinase inhibitor I've seen with an outcome better than a conventional chemo like lomustine when compared head to head in a randomized trial for GBM.

    If you read the comments for this old blog post,
    http://btcocktails.blogspot.com/2017/11/surgery-avastin-or-study-drug.html
    I discussed the fact that in an early stage trial in GBM, CDKN2/B deletions were not necessarily predictive of response to abemaciclib as expected, and unexpectedly the GBMs that responded to it in this trial all had TP53 mutations.
    Still, abemaciclib could be worth a try if you could get access to it.

    I hope some of these comments can be useful to you.

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    Replies
    1. Hi Stephen,
      I know this is an older post that I am responding to but curious about your comment: "Metronomic cyclophosphamide would probably be my choice in combination with vaccine therapy." Would you have recommended DCVax-L or SurVaxM?
      Thank you!

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    2. Sorry it has taken over 2 weeks to reply to this. As far as DCVax versus SurVaxM I wasn't sure I had the most up-to-date info (seeing the last clinical trial data I had seen was 2018 for both trials). The best I can do would be to compare the still-blinded (all patient) phase 3 DCVax trial data from late 2018 to the 2019 ASCO poster data for SurVax M. Both trials are for newly diagnosed GBM.

      For MGMT methylated subgroup, SurVaxM data has the edge at 2 years, while DCVax has a greater percentage surviving as you get closer to 3 years.

      For the MGMT unmethylated subgroups, SurVaxM has larger percentage surviving at 2 years (44% versus 32.6% for DCVax).

      A huge caveat is that the DCVax trial is still blinded, so the reported data is for ALL patients in the trial (both those who received DCVax and placebo initially). The DCVax trial data is now locked in preparation for final analysis and (presumably) publication.
      https://nwbio.com/northwest-biotherapeutics-announces-data-lock-of-phase-iii-trial/

      I would expect to see the data for DCVax to improve even more when looking at the treatment arm in isolation - those who received DCVax upfront rather than only at recurrence (the placebo arm got the vaccine at the time of recurrence).

      Given all this, I would probably go with DCVax-L, if both options were available. It is personalized and multi-targeted and the data looks good (significant tail of long-term survivors) even when looking at the still-blinded data. SurVaxM is single targeted, and patients may not even express that target significantly. Both are good options, but I think DCVax has the edge.

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