Saturday 18 November 2017

SNO summary, episode 1: CeTeG trial (CCNU + TMZ versus TMZ alone)

Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT-methylated glioblastoma patients: the CeTeG/NOA-09 trial presented by Ulrich Herrlinger for the Neurooncology Working Group (NOA) of the German Cancer Society.

The summary below written by SW, who was in attendance at the presentation by Ulrich Herrlinger and took photos of the slides presented.

The CeTeG trial (also known as NOA-09) is a randomized phase 3 trial for newly diagnosed glioblastoma with methylated MGMT promoter, testing CCNU (lomustine) combined with temozolomide (TMZ) versus TMZ alone. This trial was conducted at 17 centers in Germany and was a follow-up to a non-randomized phase 2 trial which had results published in 2006 and 2009. The CeTeG trial was relatively small for a phase 3 trial, with a sample size calculation of 128 patients total, and this sample size was based on expectations of a significant increase in survival rate at 2 years as seen in the phase 2 trial compared to historical controls. 

Patients in this trial had relatively good prognosis, with high rates of complete resection and high average KPS.  Overall the arms were well balanced, with the only significant imbalance between the two arms being gender, which was not prognostically relevant.

In the combination arm receiving CCNU + TMZ, cycles were 6 weeks in length, with 100 mg/m2 oral CCNU given on day 1 of each cycle and TMZ on days 2-6 of each cycle, with a starting TMZ dose of 100 mg/m2 and possible escalation up to 200 mg/m2 in later cycles. Cycle 1 starts at the same time as radiation.

In the control arm of TMZ alone, cycles were 4 weeks in length, and used the standard TMZ schedule (daily at a dose of 75 mg/m2 during radiation, and 150 mg/m2 on days 1-5 of the first adjuvant cycle and possible escalation up to 200 mg/m2 in later cycles.

Importantly, this trial achieved its primary endpoint of increased overall survival. Survival in the CCNU + TMZ arm was statistically superior to TMZ alone, with a p value of 0.049.  Hazard ratio for death from any cause was 0.6 in the CCNU + TMZ arm.

Median reported survival was 46.9 months for CCNU + TMZ versus 30.4 months for TMZ alone, a difference of 16.5 months.  As seen in the Kaplan-Meier survival estimates, the curves did not separate until after the 2 year mark.  1, 2, 3, 4, and 5 year survival rate was 88.8, 71.4, 57.4, 48.8 and 34% in the CCNU + TMZ arm versus 84.4, 65.4, 42.3, 31.4 and 27.7% in the TMZ arm.  Differences in the survival rate between the two arms were greatest at the 3 and 4 year mark, with 15% more patients surviving to 3 years and 17.4% more patients surviving to 4 years in the combination arm versus the TMZ alone arm.



Given the significant overall survival differences, it's surprising to note that progression-free survival was not significantly different between the two arms (p=0.41), although the progression-free survival curves separated somewhat at about 2 years (a phenomenon also seen in the overall survival curves), after which time CCNU + TMZ shows a slight superiority over TMZ alone. Some potential explanations given by the authors for the lack of a strong PFS signal included: "problems with PFS assessment according to RANO?" including potential undetected pseudoprogressions; and "long-term effects of CCNU?", noting that in studies of low grade gliomas treated with CCNU, responses were sometimes seen months or years after the end of therapy.


  
The percentage of patients receiving further lines of therapy after progression was similar in both arms (59.1% in the CCNU + TMZ arm, 63.5% in the TMZ arm).  More patients underwent re-resection in the CCNU + TMZ arm (31.8% versus 22.2%), and more patients received re-irradiation in the TMZ alone arm (23.8% versus 18.2%). More patients in the TMZ alone arm received further chemo or targeted agent therapy (60.3% versus 48.5%).  The percentage of patients receiving bevacizumab after progression was similar in both arms (27% in the TMZ alone arm, 30.3 % in the TMZ + CCNU arm).  The authors concluded that differences in treatment after progression are not an explanation for the superior survival in the TMZ + CCNU arm.



Combination therapy with TMZ + CCNU approximately doubled the rate of low-grade (but not high-grade) hematoxicity (including neutropenia and thrombocytopenia) and nausea.  However no deaths due to treatment toxicity were observed, and no severe infections, liver failure, or lung fibrosis. More brain edema was observed in the combination arm, and more low-grade alopecia (patchy hair loss).

The authors concluded by noting that acute toxicity of the combination treatment was rare, and importantly, "the primary aim of CeTeG/NOA-09 was achieved: the OS superiority of CCNU/TMZ for MGMT promoter methylated newly diagnosed GBM could be demonstrated".

This may well be the most significant trial outcome reported at the 2017 SNO conference. Since TMZ was approved for newly diagnosed glioblastoma in 2005, it has been exceedingly rare for a phase 3 trial in the newly diagnosed GBM setting to achieve statistically significant prolongation of survival with a novel regimen.  More work needs to be done to explain why progression-free survival benefit was more modest than overall survival benefit in this trial. A potential hypothesis for the improved survival results for the combination therapy is a possible synergistic interaction between TMZ and CCNU, whereby cells escaping sensitivity to TMZ through mismatch repair defects are thereby rendered more sensitive to the CCNU treatment (Stritzelberger et al. 2017). Now that the results of CeTeG have been reported to the international neuro-oncology community, the mechanisms behind the improved outcomes with the combination chemotherapy will likely become the subject of more intense investigation.

24 comments:

  1. Thanks for the summary SW :) was there anything also said for this combo for LGG?

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    1. Nothing was said about that. Anything that is said at this point would be speculation, because the combo hasn't been tried in lower grades, at least not in a formal clinical trial.

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  2. The presentation was indeed nice, and the study is certainly becoming a milestone. The 5-year OS for both arms is high. One should also look to the potential difference in rescue treatments between both arms, resulting in similar PFS but different OS.

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    1. I'll insert the slide showing the different treatments at progression into this post, so everyone can see the data.

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    2. The only salvage therapy that might have favored the CCNU/TMZ versus TMZ arm was a higher rate of re-operation in the CCNU/TMZ arm (31.8 versus 22.2%). The TMZ only arm had a slightly higher rate of re-irradiation and a higher rate of chemo/targeted therapy (60.3 versus 48.5%).

      7 more patients had repeat surgery in the CCNU/TMZ versus the TMZ only arm. The authors felt these fairly minor differences in salvage treatment were not enough to explain the survival differences at 3 and 4 years.

      MGMT-methylated GBM is associated with higher rate of pseudoprogression following TMZ-based chemoradiation, and pseudoprogression may be even more of an issue with combined CCNU/TMZ treatment, so we should also be asking how much pseudoprogression played a role in equalizing the PFS curves.

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  3. I've uploaded all the slides from this presentation to the shared Brain Tumor Library.

    Pathway: Conference Abstracts -> 2017 SNO slides -> ACTR-58 (CeTeG trial)

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  4. I've now uploaded nearly all my photos of slides from the conference to the Library:

    Conference Abstracts (2015-2017) -> 2017 SNO slides

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  5. Thanks for sharing this Stephen! how does one enroll for this study/trial? I've been trying hard to reach out to the folks at University of Bonn, but no reply. My doctors don't agree to a CCNU + TMZ combination either.

    My mother is a GBM patient(Methylated), who completed her radio/chemo 10 days back, and starts her 5/23 cycles of temodar 2 weeks from today.

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    1. Recruitment into this trial was during the 2009-2014 and has long been closed to recruitment. Fortunately CCNU (lomustine) has been used for brain tumors since the 1970s and is widely available.

      Did your mother's oncologist give a reason for not agreeing to the protocol? There may be a good reason, for example if her healthy blood counts are too low at baseline, they may feel the combination therapy would cause too much myelosuppression. Or was the reason just because it's not the standard protocol and "we don't do that here"... (not the best reason).

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    2. I'm a newly diagnosed GBM who recently started standard radio/chemo treatment in Germany following Stupp protocol. Here in Germany, the combined (CeTeG) CCNU / Temodal treatment seems to be rapidly becoming mainstream for Methylated MGMT - both neuro oncologists I saw before starting my treatment mentioned they would use this combination in case my MGMT status turned out positive (which, unfortunately, it didn't). I would be surprised if this treatment did not rapidly become a standard everywhere now, given the strong results.

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    3. Stephen, they didn't really agree to the protocol while my mom was on the radiotherapy since it is not a global standard of care yet. So yeah, the reason was "We don't do it here".

      However, my mom starts her 5/23 monthly temodar cycles. Is it possible to make use of the learnings of this study in the coming 6 months of 5/23 temodar cycles? Does using CCNU on one of the days still be effective?

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    4. Yes, in the clinical trial protocol CCNU was given on day 1 of each chemo cycle and TMZ was given on days 2-6. The cycles are 6 weeks rather than 4 weeks.

      I suspect that the way CCNU and TMZ work well together is by thwarting one of the main resistance mechanisms to TMZ in MGMT-methylated glioma, which is the acquiring of mismatch repair defects. If a cell undergoes mismatch repair defects as a form of resistance to TMZ, then it may be even more sensitive to CCNU.

      These ideas come from a preclinical study published recently.
      https://www.ncbi.nlm.nih.gov/pubmed/28825189

      So yes, CCNU + TMZ could still be effective independently of radiation.

      There are still some unanswered questions about the findings of the trial: why was there no improvement in progression-free survival? Was that due to increased rates of pseudoprogression in the CCNU + TMZ arm?

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    5. John,

      Can you please help me with a good oncologist/hospital in Germany which can help me with the TMZ+Lomustine chemotherapy protocol for my mom, and more importantly help me monitor my mom's blood counts when on this protocol? It shall be of a lot of help to me.

      My mother's GBM is methylated, which is why I'd like to follow this protocol.

      I've tried reaching out to Dr Urlich multiple times, but sadly haven't heard back from him.

      Regards

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    6. Hi Sahil,

      I'm not sure I understand exactly what you are looking for. My understanding was you are based in India - shouldn't you therefore be working with a local oncologist for the relevant prescriptions & blood counts? Surely there must be a local doctor willing to prescribe this protocol?

      That being said, another feasible option might also be through the clinic your mom will do the vaccination at. Have you looked into this? I know that IOZK in cologne certainly are able to provide prescriptions as necessary, so maybe the clinic you chose can as well?

      Otherwise, if you really do want to get in touch with the more formal oncology community in Germany, then the following are some of the centers (non-exhaustive) which I think are fairly recognized:

      - University clinic Essen: https://www.uk-essen.de/en/neurosurgery/research/ag-neurooncology/ (e.g. Professor Glas)
      - University clinic Mannheim: http://w2.umm.de/2334/ (e.g. Professor Platten)
      - University Clinic Bochum: https://www.neurologie-kkh.de/ (e.g. Schlegel)

      ... but there are many others.

      Hope this helps. Best,
      John

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  6. Should in theory this combo minimize hypermutation risk (in comparison with TMZ only) ?

    And do you think is there any contraindication in using TMZ+CCNU and PARP inhibitor (also in theory :)) ?

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    1. Very good question. Based on the preclinical data showing cells with mismatch repair defects having increased sensitivity to CCNU, in theory CCNU should limit the outgrowth of mismatch repair deficient/ hypermutated clones.

      On the other hand I believe there have been a few documented cases of MSH6-mutant and hypermutated GBM recurrences following PCV and/or CCNU treatment. In the PCV treated cases, procarbazine could have played a role.
      https://www.ncbi.nlm.nih.gov/pubmed/19584161

      Much more study would be needed, either on older archival tumor tissues obtained before the approval of TMZ, or in preclinical work, to determine the role of CCNU in inducing or preventing hypermutation. Given the differences in mechanisms of action between TMZ and the nitrosoureas, it's likely that the main culprit in inducing mismatch repair defective, hypermutated recurrences is TMZ rather than the nitrosoureas.

      Another piece of evidence to add to the puzzle:
      https://www.ncbi.nlm.nih.gov/pubmed/8968088
      Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea

      (AGT in this study is the older name for MGMT)

      What this and other studies are saying is that mismatch repair deficiency (through mutations in mismatch repair genes such as MSH6), which causes the hypermutation genotype, is a form of resistance to TMZ, but not to nitrosoureas such as CCNU and BCNU.

      The major limiting factor in adding PARP inhibitors to chemotherapy is likely the added toxicity to bone marrow and healthy blood (myelosuppression). This is also the limiting factor in combos such as TMZ + CCNU, and adding PARP inhibitor on top of that would likely lead to even more myelosuppression, and might require limiting the doses of chemo even further.

      "Although the initial phase 1 study
      suggested that full-dose temozolomide could
      be administered with low-dose rucaparib, a
      further phase 2 evaluation of this combina-
      tion in patients suffering from metastatic
      melanoma revealed that myelosuppression
      was a major challenge to the administration
      of this combination"

      http://stm.sciencemag.org/content/8/362/362ps17

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    2. Thanks for this thorough answer! A lot of questions to be answered by trials, at least something is moving forward :)

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  7. Has this study been published? I can only find the abstract online.

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  8. Full publication of the CeTeG (NOA-09) trial results in Lancet:

    http://sci-hub.tw/https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31791-4/fulltext

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  9. Sorry, here I am again with my nonsense question. I wanted to know if this protocol is applicable or worth to be examined on my father? (Just to remind you, He is having his 16th session of first line 120 TMZ + Radiotherapy, no surgery, and no extra information about the tumor.)
    We stop the Phenytoin quit suddenly and after three days I dare to claim he is doing better than before (well, we also start taking one longvida, two Boswellia(wokvel) three days ago and unfortunately 4mg dexa has been added today). Thanks a lot.
    Our oncologist is quite open to experiment and I just need some help from you to push him in this direction :)

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    1. This would only make sense if the tumor had methylation of the MGMT gene. The majority of GBMs (60-70%) are unmethylated, so I probably wouldn't try this protocol without verified methylation of MGMT. Otherwise it could be more harmful than helpful.

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  10. Hi, Stephen. Any insights for treatment cocktails for my son? Hi is in a trial since Dec'18/Jan '19 for Keytruda (pembrolizumab) combined with whole head radiation (10X) . Age 48 Just found out his MGMT promoter is UNMETHYLATED, and tests Negative for IDH1/IDH2 mutations. Originally in 9/17 the called it Anaplastic Aristocytoma Grade III to IV. Now calling it IDH-Wildtype, WHO grade IV.
    His blood sugar has ranged from 139 to 171 & his Calcium is trending up..now at 10.1 Mg/dl

    He takes Bactrim 3x/wk, KEPPRA 750 MG 2x/day , Zyloprim for uric acid 3x/day , Synthroid 100 mcg/day , & 2mg Dexamethasone/day

    As you might expect, the RO's are telling him just eat a balanced diet & no supplements - especially antioxidants.

    With the MGMT & IDH above not good indicators of extended survival, I'm looking for ideas that may have merit other than putting all hopes on the Keytruda.
    Dave

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